The idea of finding a means to extend and improve the quality of existing life has captured the human consciousness for as long as humans have had societal stability. Early attempts focused on the short-term like surviving the elements, wildlife or even each other whereas modern times have given rise to tackling biological and biochemical obstacles. The process of aging is evident in almost all living organisms and is characterized by an increased probability of disease acquisition, decline in fertility, loss of physiological integrity, increased physical impairment and obviously increased probability of death.
Aging is not principally viewed as a genetically programmed process, but instead an entropic process; it is also typically categorized into either primary or secondary categories where primary aging is the reduced ability to maintain tissue homeostasis without external assistance and secondary aging involves the symptoms derived from this reduction in homeostasis that have an increased probability of occurrence as an individual ages.1 The term “senescence” is frequently used to refer to primary aging. Primary aging is the focus of most research on life extension because it entails the potential ceiling/maximum lifespan for a given organism. The principle challenge of this research is differentiating between causes of cellular aging and the associated effects of that aging.
Numerous elements have been characterized as keys to aging and critical to developing therapies to reduce or even halt aging: telomere length, reactive oxidative species (ROS), mitochondrial dysfunction, macromolecule accumulation, stem cell depletion, inflammatory cascades, calorie restriction, etc.2,3 Unfortunately it is unlikely that focusing only on one of these elements will result in a treatment that will arrest aging in humans; therefore, an important question is how are these different systems interconnected and how do they contribute to aging in a way that can be addressed through pharmaceutical and/or dietary changes with few detrimental side effects?
One of the most discussed issues in aging is the role of ROS damage. The general idea behind the influence of ROS damage in aging, commonly regarded as the free radical theory of aging (FRTA), is that during the course of metabolism and general function cells accumulate free radical damage from oxidative species like superoxides (O2--), hydrogen peroxide (H2O2-) and hydroxyl radicals (OH-), which lead to accelerated breakdown in cellular communication and mitochondrial dysfunction.4-7 Simply stated FRTA suggests that under normal physiological conditions the majority of the time there is a slight imbalance between prooxidants (elements like free radicals) and antioxidants (elements that can be oxidized without biological detriment) that leads to the accumulation of oxidative damage in various cells and pathway essential molecules that increase the rate of function loss seen in aging.
Free radicals create damage by stripping an electron off another nearby molecule in order to pair its lone electron; however, this process has a high probability of creating a substitute free radical in the molecule that lost the electron. This catalytic-like behavior increases the probability that an important molecule loses an electron changing its characteristics and eliminating its functionality. If enough of these molecules are damaged then the biological pathway they are associated with is also damaged. In addition free radical damage can also lead to cross-linking DNA inducing inaccurate replication producing another avenue for cellular damage.8
Some evidence suggests that the central nervous system is most acutely vulnerable to oxidative stress due to increases in lipfuscin and bcl-2 concentrations, reductions in redox active iron and glutamine synthetase expression and increases in oxidized glutathione to total glutathione ratios.9-13 In addition increased oxidative stress is thought to increase glial fibrillary acidic protein expression as an individual ages along with increased probability for the initiation of the inflammatory response without an initial stimulus trigger.14-16
The origins of FRTA stem from Max Rubner’s work on how oxygen consumption within metabolism correlated with longevity in eutherian mammals.17,18 However, overall interest in the validity of the theory was limited due to the belief that even if oxygen free radicals were produced their existence was transient enough that they could not react with other elements. Later though it was discovered that oxygen free radicals were formed endogenously through standard metabolic processes and their resultant activity induced cellular damage and disrupted various pathways.17,19 Denham Harman modified FRTA later to include a central role for the mitochondria due to their production of the vast majority of ROS in cells, especially because as mentioned above ROS damage can induce mutations to create a positive feedback effect that can fosters even greater concentrations of ROS from the mitochondria.20
Further modifications have been made to include other ROS like aldehydes or peroxides despite not being free radicals because they can damage cells through oxidative reactions.21 In fact some now bifurcate FRTA into “strong” and “weak” versions where the strong version associates oxidative damage to lifespan and the weak version associated oxidative damage to age-related diseases, similar to the categorical split in aging itself.6 Very few individuals dispute the “weak” version of FRTA because numerous studies exist showing a correlation between oxidative damage and age-related disease.17,22
Among various model organisms strong FRTA is supported by work with Podospora anserine (P. anserine), Drosophila melanogaster and various transgenic mice, is questionable in Caenorhabditis elegans (C. elegans) and does not appear important in Saccharomyces cerevisiae (yeast).17,23-27 Other research has demonstrated increased aging and age-related symptoms when superoxides are overproduced in humans.28,29
It has been demonstrated in yeast that blocking mitochondrial free radical production at Complex III, overexpression of methionine oxidation repair enzyme (MsrB) and retaining CuZnSOD or MnSOD versus knocking either one out all increase life span.27-30 However, the biggest problem with accepting strong FRTA in yeast is that research has also demonstrated that growing it under complete anaerobic conditions (which would heavily limit oxygen availability and thus reduce the concentration of available ROS) results in a decreased clonal life span.28 The reasoning behind this apparent contradiction may be due to the role of glycolysis. Most yeast require a significant level of glycolysis for energy to drive growth, especially in anaerobic environments, which produce reactive aldehydes and protein carbonyls.31 These metabolic elements may be the chief cause of lifespan shortening in yeast versus oxygen derived ROS agents, especially because the accumulation of protein carbonyls is a strong indicator of age.17,32
C. elegans are probably the most perplexing organisms when trying to draw support for FRTA. One of the more controversial pieces of support for FRTA in C. elegans is a study by Lithgow demonstrating that superoxide dismutase/catalase mimetics increased life spans, but this result has been difficult to replicate instead sometimes demonstrating toxicity depending on the level of expression.33-35 However, even if the Lithgow work is excluded oxygen tension still modulates life span36 and RNAi screens demonstrate that knocking out most of the proteins in the electron transfer chain increase lifespan by approximately 30%,37,38 and decreased mitochondrial superoxide production also increases lifespan.39
Despite the results of the above studies most opponents of FRTA also find evidence for their opposition in C. elegans studies.40,41 However, there are two important separate issues to consider when studying FRTA in C. elegans. First, there is a significant difference between C. elegans and mammals regarding energy metabolism and oxidative stress mechanisms. Obviously mammals rely largely on aerobic mechanisms to produce energy (most notably through the mitochondrial electron transport chain) for any study of glycolysis reveals the paltry amount of ATP it produces. For C. elegans glycolysis and the glyoxylate cycle are more efficient producing more ATP allowing for multiple day survival in anaerobic conditions.42 More than likely this difference stems from evolution as most C. elegans reside in topsoil, which can have low-oxygen content over certain periods of time. Second, the living environment is important for C. elegans for lifespan is directly associated with ambient temperature, thus living temperature must be controlled across comparative studies. Both of these issue can influence the amount of ROS created over a given time period and create replication problems with the results.17
The chief enzymatic defense utilized by the body against free radicals, especially superoxides, is super oxide dismutase (SOD) augmented by catalase, glutathione peroxidase, peroxiredoxins, glutathione (GSH), thioredoxin, ascorbate, uric acid and alpha-tocopherol.43 There are three major family classifications for SOD characterized by the associated metal cofactor: Cu/Zn (binds copper and zinc), Fe/Mn (iron or manganese) and Ni (nickel). Humans possess three different versions of SOD: SOD1 that contains copper and zinc (family 1), SOD2 that resides in the mitochondria and uses manganese and SOD3 that also contains copper and zinc.
The role of SOD in aging has been somewhat controversial because some studies have demonstrated that increasing SOD activity increases longevity while other studies have demonstrated that increasing SOD activity does not increase longevity. There are two explanations for this apparent contradiction. First, there are numerous types of SOD in both model organisms and humans and these different types interact with ROS in different ways. Also because most ROS cannot freely cross cellular membranes they create three distinct extracellular, cytosolic and mitochondrial pools of free radicals and SOD activity is also typically relegated to these pools.44
Therefore, not only do studies need to factor in the type of SOD they need to focus on the compartmentalization of that particular SOD or the other oxidant/antioxidant being studied as well as the concentrations of other ROS. For example two different studies involving the over-expression of catalase produced contradictory results until it was determined that one study over-expressed catalase in the mitochondria showing lifespan extension in transgenic mice versus the other study that over-expressed catalase in peroxisomes showing no lifespan extension.45,46
Second, there may be an element of avoided detriment due to lifespan restrictions. In some organisms free radical damage may have a greater effect on the maximum lifespan than the average lifespan, but in most experiments the studied organisms die before reaching their maximum lifespan. Therefore, if a model organism never lives long enough to reach the point where the damage significantly increases the probability of death then neutralizing free radicals is irrelevant. It would be similar to developing a cure for Alzheimer’s and then giving it to a population that does not live past the age of 40. Realistically to determine whether or not free radical damage significantly influences aging in humans, studies must be performed on humans or other long-lived primates rather than model organisms like C. elegans and mice.
Another one of the issues with testing the role of free radicals in aging is that there is no standard measure for assessing oxidative damage. For example some measure protein oxidation from ROS by observing carbonyl groups in serum47 while others measure the amount of lipid peroxidation or the number of isoprostanes in plasma and urine.48,49 Clearly the best method would be to directly measure ROS, but many molecules within the ROS “family” are unstable, thus difficult to accurately measure directly. Without a standardized measurement to determine ROS induced damage, experimental replication will have an inherent issue for concern.
Another common evidentiary citation by opponents of FRTA focuses on studies that conclude antioxidant therapies have no significant positive effect in reducing mortality or reducing most detrimental outcomes (symptoms) that are derived from aging and in some cases can even increase rates of mortality.50-53 These studies can lead to the seemingly understandable conclusion that if increasing antioxidant concentrations does not significantly retard aging or the symptoms of aging ROS must not have a significant influence on aging.
One explanation for this outcome that could salvage FRTA is the belief that due to basic biological operations and signaling humans will have a certain level of oxidative stress from metabolism and other triggers and produce a certain amount of antioxidants to manage that stress.54 However, based on these concentrations, generated through expression and signaling, cells may not have sufficient receptors to interact with large concentrations of external antioxidants from either diet or supplements. Therefore, it is not that free radicals fail to significantly impact aging or that antioxidants fail to neutralize those free radicals, but due to certain levels of receptor expression cells are not able to internalize these additional concentrations of antioxidants to retard aging, which is why anti-aging therapies using large concentrations of antioxidants do not appear to be effective. Basically compartmentalization is reducing the effectiveness of the treatment.
Another key element to the utilization of antioxidants in the body may be the involvement of iron and other chelators.43,55 Some believe that transitional metal ions like iron and copper aid in the formation of O2-- and H2O2-. Furthermore these metal ions can also produce OH- through additional reactions with O2-- and H2O2 increasing damage probability.56 The most notable reaction born from this possibility is the Haber-Weiss reaction coupled to Fenton chemistry.56
Some compounds contribute to antioxidant defense by chelating these transition metals and preventing them from catalyzing the production of free radicals in the cell. Metal chelating antioxidants such as transferrin, albumin, and ceruloplasmin avoid radical production by inhibiting the Fenton reaction.56,57
The natural low biological iron concentration is supported by a functional metal redox cycling mechanism where antioxidants can actually become detrimental. For example O2-- or various specific antioxidants (like ascorbate) act as the reducing agent in the Haber-Weiss reaction converting Fe(III) to Fe(II), which can then reenter the Fenton reaction, and convert free O2 to OH-.58 Therefore, increases in O2--, H2O2-, redox active metal ions or certain antioxidants can create a positive feedback environment that can create more OH- leading to further cellular damage. Unfortunately the cellular pools of low-molecular weight iron are not characterized well leaving questions to the prominence of this effect.59
It has also been reported that the iron content of cells increases as the cells age normally, which can enhance the above effect.60 Some excessive iron can be removed from the body by regular blood transfusions like in the case of haemochromatosis.58 Additionally, certain polyphenols inhibit the absorption of iron with flavonoids acting as antioxidant agents through free radical scavenging and metal chelation.61 Therefore, if FRTA is a valid driver of aging one promising treatment strategy could be increasing the concentration of metal chelating elements with smaller increases in antioxidants like vitamin C and E.
One of the most important molecules affecting the aging process appears to be NF-kB (quick reminder NF-kB = nuclear factor kappa beta). In a recent meta-analysis comparing age-related genetic expression profiles of mice, rats and humans the most common signature involved the over-expression of inflammation and immune response genes and those tied to lysosomal system function.62 NF-kB is an essential element in the inflammation and immune response; therefore it stands to reason that even without additional evidence supporting its role in aging, NF-kB would be viewed as an important element in the aging process.
Five different molecules make up the NF-kB transcription factor family: NF-kB1 (p105/p50), NF-kB2 (p100/p52), Rel A (p65), c-Rel, and Rel B.63,64 These different molecules commonly associate with one another to form various heterodimeric and homodimeric elements. The formation of these hetero and homodimeric elements is normally required to induce receptor activation as the NF-kb molecules typically remain inactive in the cytoplasm before compound formation through additional interaction of ankyrin-containing inhibitor-kBs (I-kB).63 The I-kB inhibition complex for NF-kB members is typically made up of three different inhibitor elements (IKKa, IKKb, and IKKg).64 Also note that only the Rel members of the family (Rel A, Rel B and c-Rel) have transactivation domains which can activate transcription.64,65
The most common compound element among the NF-kB family is NF-kB1/REL A or (p50/p65), which is commonly regarded as the “classic pathway” and is activated by tumor necrosis factor alpha (TNFa).65,66 This classic pathway has also been identified in having a role in the promotion and pathogenesis of cancer where activation is largely induced by cytotoxic agents and maintained by oncogenic activation of various tyrosine kinases. An alternative to the classic pathway is induced by binding of other TNF family members and processes p100/RelB to p52/RelB.65,66 The alternative pathway components, which includes IKKa/IKKa homodimers, largely regulate survival of premature B lymphocytes and development of peripheral lymphoid tissues.64,67 Both pathways are complex with various cofactors such as CK2 or Akt influencing whether NF-kB compounds will have a gene inducing or gene suppressing effect including multiple overlaps.64 This complexity makes a straight application of “agent that inhibits element x in the NF-kB pathway” as a therapy difficult because in some pathways it will promote survival and in others it will promote death.
Of the five members of the NF-kB family, fully processed NF-kB1 (p50) seems to be the most important. Not only can it form a heterodimer with p65 which can then activate the classic pathway it appears that its formation of a homodimer (p50/p50) can actually inhibit classic pathway activation.68 While the formation of homodimer (p50/p50) can still bind at the kB binding sites, only those Rel family members have the necessary transactivation domains to begin gene transcription. Therefore, homodimer (p50/p50) binding instead of heterodimer (p65/p50) prevents gene transcription and the activation of the classic pathway.68,69
The influence of NF-kB on aging has been studied most often in skin cells where it is cell autonomous because visible signs of aging in various skin cell cultures can be neutralized or even reversed after exposure to NF-kB inhibitors like 4-OHT.70 NF-kB binding activity increases with age in mice in various tissues including the skin, heart, kidney, liver, spleen and possibly even stem cells.70-72 This increased binding is thought to regulate senescence, but only replicative and oncogene induced senescence have been observed.73,74 In addition SIRT1 and FOXO, which are widely regarded as strong longevity signals, seem to inhibit NF-kB.75 Interestingly because of the increased binding, the effect of NF-kB on aging acts as an age-dependent positive feedback effect.70
Although aging is not perceived as genetic the closest thing to an “aging trigger” at the moment could be NF-kB. It has been hypothesized that aging is not actually the natural state of cells instead the aging phenotype is achieved through the continuous presence of sufficient concentrations of NF-kB and expansion of its influence through its positive feedback effect.70 The elimination of NF-kB through inhibitors removed markers of cell senescence like cell-cycle inhibitor protein p16 and enhanced proliferation of progenitor cells in skin. Overall, at least relative to skin, NF-kB activity appears to be continuously required to facilitate aging.
One of the most telling issues regarding NF-kB and general aging is that p52 and p65 expression increases significantly in older organisms versus young ones, yet p50 expression along with IkB inhibitors IKKa and IKKb remain at similar levels regardless of age.76,77 Also while p52 and p65 expression increase, their mRNA expression levels demonstrate no significant increases.77 The most probable explanation for this result is that NF-kB protein retention in the nuclei increases with age. This additional NF-kB also increases DNA-binding activity, especially in major lymphoid tissue including constitutive activation of NF-kB within T and B-lymphocytes and macrophages.78
There also appears to be a relationship between ROS and NF-kB in that ROS can induce NF-kB signaling after their production by pro-inflammatory cytokines like IL-1beta and TNFa and lipopolysaccharide stimulation.79 However, not surprisingly this interaction is complicated by timing where early ROS production can act as important messengers for NF-kB activation ROS produced after TNFR1 engagement only facilitates cross-talk between NF-kB and JNK with respects to inducing pro or anti-apoptotic pathway activation.80 Of course because JNK acts as a pro-apoptotic trigger, depending on the situation it can be a pro-aging or an anti-aging trigger meaning the relationship of ROS and NF-kB is even more complicated. This complication could be why there is some evidence that demonstrates dietary therapies with antioxidants down-regulating the age-related increase DNA-binding activity of NF-kB in addition to neutralizing the increased IL-6 and IL-12 expression.78
As alluded to above NF-kB also plays a role with various important aging-related genetic elements including SIRT (mammalian homolog family for silent information regulator (SIR)) and FOXO.81 SIRT1 physically interacts with p65/RelA protein complex to deacetylate lysine-310 on p65 inducing an inhibitor effect on NF-kB transcription.81 It appears that SIRT6 can also inhibit NF-kB activity by modifying the chromatin structure of promoters that interact with various NF-kB genes, which appears to reduce speed of aging.82,83 This SIRT interaction with NF-kB is one of the explanations to why calorie restricted diets could reduce aging and the expression of pro-inflammatory elements or reducing calories appear to increase expression of SIRT1 and NAD+, which is required to activate SIRT1.84,85
Forkhead transcription factors (FOXO) are the mammalian homolog to the famous DAF-16 protein in C. elegans. FOXO3a seems to induce inhibition of NF-kB by limiting the length of activation for unnecessary inflammation, which reduces cellular damage thereby decelerating aging.86 Whether or not this inhibitory effect is driven by direct inhibition of the NF-kB complex or indirect inhibition of elements that activate the NF-kB complex like TNFa or even both is not completely clear.86,87
One of the unclear issues regarding NF-kB inhibition is whether or not it actually affects the overall lifespan of a cell. Intuitively it would stand to reason that if inhibiting NF-kB causes cells to revert to a younger biochemistry and behavior then their lifespan would increase as well; however, this may not be the case. There could be other age-related signals that correspond to senescence that NF-kB has no effect on, thus NF-kB inhibition may not change cell lifespan, but simply create younger cell activity over the course of that lifespan. It would be akin to individual A living 80 years and aging normally versus individual B living 80 years, but remaining as a 30 year-old biologically for the last 50 years, but still dying at a chronological age of 80.
Another question is how would inhibiting NF-kB affect the immune system because NF-kB has an important role in influencing immune response, especially c-Rel and its initiation of IL-12 production. Among other things kappa light chains are critical components to immunoglobulins.70 One interesting experiment would be to vaccinate a mouse then apply a NF-kB inhibitor and then determine whether or not the vaccination is still effective against the target infection.
In the last five years rapamycin and the mTOR pathway [mechanistic (formally mammalian) target of rapamycin] has become a promising candidate for life extension and recapturing youth. Rapamycin is an anti-fungal agent utilized by various soil bacteria that was used as a possible tumor suppressor and immunosuppressor. The TOR pathway (note that in invertebrates it is normally referred to as TOR not mTOR) plays a large role in nutrient sensing and growth through lipid biosynthesis and storage and is highly conserved among various different species. TOR is activated by glucose, insulin, free radicals and growth factors.88 TOR first gained significant recognition as a potential factor in aging when it was reported that inhibition of TOR complex 1 (TORC1) in invertebrates increased lifespans in yeast, C. elegans and Drasophila.88 Overall mTOR interacts with numerous proteins to form mTOR complex 1 and 2, which have different upstream and downstream activation pathways. Note that rapamycin only legitimately inhibits mTORC1 and not mTORC2, although it can disrupt the structure of mTORC2 after long-term high concentration treatments.88
The two major pathways that TORC1 interacts with that influence aging are first global up-regulation of mRNA translation, including ribosome synthesis by direct phosphorylation of S6 kinase and eukaryotic initiation factor 4E binding proteins.89 Second the down-regulation of autophagy, although this regulation is complicated by compartmental segregation between elements of the TOR pathway and autophagy initiating factors like ULK-1.89-91 Also there is some belief that TORC1 interacts with other dietary/nutrition pathways like insulin signaling pathway, hypoxic response transcription factor Gcn4 in yeast and Sirtuins (SIRT family).92,93 Note that autophagy involves the degradation of proteins and organelles via the lysosomal pathway and has been shown to decline during aging, which may lead to the increase of misfolded proteins and ROS in older cells. These effects have also been tied to the anti-aging results seen from calorie restriction.94,95
Due to an initial belief that rapamycin might have a therapeutic effect against some forms of cancer the National Institute on Aging Interventions Testing Program (NIAITP) conducted studies in cancer susceptible genetically modified mice. The result of these studies identified that the addition of rapamycin treatment in 600-day (approximately 20 months) old mice significantly increased the lifespan of both male and female mice, noting that the increase in females was significantly larger than the increase in males.96 Another unassociated study also produced similar findings of 16% and 13% maximum lifespan extensions in 9-month old male and female mice respectively.97
Another important initial study with rapamycin observed its influence on S6K1 (mice equivalent of S6) knockout mice and concluded that these knockout mice had significantly increased lifespans.98 This study indirectly increased the viability of mTOR as a pathway for aging because it demonstrated a longevity increase in a second genetically distinct mouse class versus the NIAITP study. The supposed pathway of operation was not identified, but the activation of adenosine monophosphate (AMP) activated protein kinase (AMPK) was thought to be an important element. While the importance of its activation is still unclear some believe that AMPK negatively regulates TORC1 through phosphorylation of Tsc2, a TORC1 inhibitor.99
However, it must be noted that the increase in lifespan was only commonly significant in female mice not males similar to the NIAITP study and in contrast to the Miller study.98 Also the knockout mice were significantly smaller in body mass than the non-knockouts, which is understandable due to the growth elements controlled by S6K1. Finally the activation of AMPK may not be a requirement for life extension as rapamycin application to wild type flies resulted in life extension without AMPK activation,100 thus raising questions about the role of AMPK.
One possibility is that the activation of AMPK may simply be a secondary effect of rapamycin with the primary lifespan expanding effect being its interaction with stem cells in aged animals as it enhanced the in vivo replicatory capacity of hematopoietic stem cells in aged animals.101,102 In addition there is some question to whether or not rapamycin is immuno-active or immunosuppressive. If it has a positive effect on the immune system then this interaction may be how rapamycin affects longevity. For example TORC1 inhibition prevents the secretion of “pro-aging” cytokines IL-6 and IL-8 by Ras-transduced cells.94 Another possibility could be that the enhanced autophagy allows the body to eliminate damaged cells before they can secrete negative feedback molecules that would create a damage cascade negatively affecting other healthy cells in the local area including inducing aggregating proteins that could result in misfolded proteins.
Overall it appears that TOR dependent changes with regards to aging at a cellular or tissue level are hypertrophic in contrast to the atrophic degeneration that is thought to occur through ROS driven damage. These changes also support the idea that rapamycin is able to increase lifespan beyond its apparent tumor suppression effect because aging is the result of multiple pathways activating under certain boundary conditions and cannot be significantly prevented by only stopping a single disease or pathology. It must be noted though that rapamycin influence on stem cells is not entirely positive as it can impair pluripotency through a reduction of proliferation and promotion of differentiation of human, and to a lesser extent mouse, embryonic stem cells.103,104
As mentioned above while rapamycin has demonstrated an empirically valid potential as an anti-aging element due to its interaction with mTOR, the biggest concern surrounding its application is its influence on the immune system. Originally rapamycin was viewed as an immunosuppressive element and used thusly,105,106 at times in attempted treatment of cancer, generating the conclusion that giving it to aged individuals, especially in the era of antibiotic resistant pathogens, would be inappropriate because it would increase the probability of infection and the probability of death from infection. However, rapamycin supporters have attempted to counter this claim stating that rapamycin may bolster immune system activity.101,107,108 So which side is correct on this important issue?
Unfortunately the role of mTOR and rapamycin in immune system functionality is quite complicated and time dependent. mTOR is a part of the phosphoinositide 3-hydroxy kinase (PI3K) related kinase family and the PI3K-Akt-mTORC1 complex can be co-stimulated, which leads to activation by molecules like the Cluster of Differentiation 28 (CD28) in addition to various interleukins (IL-x).109-111 One of the initial results from mTOR activation is an increased activation time for CD8+ cells and developmental enhancement of T-helper 17 (Th17) cells.112-114 Therefore, one would expect that inhibiting mTOR via an agent like rapamycin will reduce these effects.
Recall that there are two distinct types of immune responses: innate and adaptive. The innate immune system is the older of the two, much less specific in its assault and activates upon the entry of almost any foreign pathogen. Elements of the innate system include epithelial and mucosal membrane obstructions that aid phagocytosis and lysis, various phagocytes, natural killer cells along with other leukocytes, dendritic cells to begin recruitment of more specialized cells and the eventual release of cytokines, and the beginning of the inflammation response.108,115 If it is determined, through signaling, that the innate response will not be sufficient to neutralize the pathogenic threat dendritic cells can act as antigen presenting cells (APC) to activate naïve T cells to initiate an adaptive immune response.
The role of these dendritic cells in relation to the adaptive immune response is critical to the influence of mTOR on the immune system as a whole. mTOR appears to measure the standing of the immune environment and influences antigen recognition similar to its nutrient-sensing ability.110,111 This influence affects how the dendritic cells act as APC, thus determining their interaction with naïve T cells.116,117 However, this influence is affected by the types of dendritic cells activated and the length of time that mTOR is activated (i.e. the amount of rapamycin utilized).118,119 Short-term treatment of rapamycin increases the concentration of cytokines IL-12 and IL-1beta and reduces Toll-like receptor induction of IFN alpha and beta, which act as one of the first defenses against viral infections.118
Long-term treatment decreases the innate immunity of monocyte-derived dendritic cells both via the conventional method and the plasmacyoidal method utilizing cytokine Flt3 as well as reducing the up-regulation of dendritic co-stimulatory molecules, thus suppressing mature dendritic function.120-125 Also knocking out the raptor component of mTORC1, which generally mimics inhibition, leads to a change in the ability to initiate anti-inflammation through the production of additional phenotypes of splenic CD8+ and intestinal CD11+ cells.126 Finally long-term rapamycin treatment reduced allogeneic T-cell response while increasing regulatory T-antigen specific Foxp3+ response.127
The adaptive immune response is highly specific and is dependent on the type of pathogen present and its characteristics. The principle agents involved in the adaptive response are B cells, which govern the humoral (antibodies) response and T lymphocytes, which govern the cell (white blood) response. The adaptive response is so named because it changes, normally increasing effectiveness, each time a pathogen triggers it. The best example of the adaptive response is the specific antibiotic response to a specific pathogen, primed through vaccination.
In vitro it has been demonstrated that rapamycin reduces B lymphocyte proliferation and plasma cell differentiation, which would also reduce antibody production reducing adaptive immune response efficiency.128-130 Also a hypomorphic mouse model with a disrupted mTOR transcript demonstrated reduced B-cell development, reduced cell proliferation and reduce B-cell and T-cell antibody formation.131 mTOR also appears to be required for B-cell differentiation to plasma cells as well as LPS-induced B-cell proliferation and differentiation.131,132 However, interestingly enough only one part of the mTOR pathway, mTORC2, may be principally responsible for B-cell development due to the activation of AKT through phosphorylation and progressive inhibition of FOXO1.133 Therefore, it could be that mTORC1 governs dendritic cell maturation and development and mTORC2 governs B-cell maturation and development, thus short-term rapamycin treatment only disrupts dendritic cells, but long-term treatment could disrupt both dendritic and B-cells.
With regards to T-cells mTOR plays a critical role in the differentiation of certain T-helper cells, most notably 1 and 17.134,135 Also mTORC2 activates PKC theta which helps promote T-helper 2 differentiation, although it does not appear necessary.136 Also mTORC1 regulates hypoxia inducible factor 1 (HIF1) and is required for glycolysis, related enzyme activity and glucose homeostasis in activated CD8+ cytolytic cells.137,138
While some evidence exists that rapamycin treatment can induce immunostimulation of CD8+ T-cells,139-141 the effect may be derived from enhanced cytokine production by macrophages and may not be induced directly by mTOR inhibition.142 Also in most studies rapamycin treatments have been low dose and short-term, thus there is no evidence that any “enhancement” effect will persist over the long-term.140-141 Additionally most rapamycin experiments are conducted in environments that do not tend to have pathogens, thus eliminating real-world examination of how the immune system may be augmented or compromised. Finally there is some evidence that increased used of rapamycin fosters various inflammatory events like lymphocytic alveolitis, glomerulonephritis and interstitial pneumonitis.143-145 Surprisingly the best feature associated rapamycin may be its CD8+ anti-tumor training ability versus its potential anti-aging effects or other immunosuppressive effects.146-148 However, that anti-tumor effect may come from the reduction in IL-10 concentration born from mTOR inhibition for the IL-10 cytokine is thought to have an immuno-masking effect.
Currently existing results support the position that short-term rapamycin treatment has an overall negative effect on the innate immune system with some positive attributes and more than likely a negative effect on the adaptive immune system; long-term rapamycin treatment has negative effects on both the innate and adaptive immune system. Most rapamycin proponents seem to focus on the niche enhancement of the innate system from short-term treatments; however, clearly short-term treatments will do very little to ward off the negative outcomes of aging, thus as it stands the use of rapamycin as an anti-aging tool comes with an immunosuppressive trade-off.
One of the more interesting factors of the mTOR pathway is its dependency on other signaling factors, which appear to make it a general feedback catalyst. For example mTOR increases the secretion of aging elements from damaged and/or senescent cells, but also increases the secretion of anti-aging elements from younger undamaged/unstressed cells. This feature is most notable in muscle tissue where mTOR promotes secretion of trophic factors like IGF-1 from young cells and cytokines like IL-6 from old cells.149 Also rapamycin may have a negative effect on wound healing as it interferes with the ability of p38alpha to activate mTOR to balance the synthesis of IL-12 and IL-10 to properly regulate CD4+ Th1 response to wounds and tissue damage.150 Specifically inhibition of mTOR promotes IL-12 production and reduces IL-10 more than likely through its cross interaction with PI3K, which is a IL-10 enhancing signal.145
mTOR is not the only major element that can both influence aging and the immune system. As mentioned above NF-kB also plays a significant role in activating immune system elements to initiate an appropriate response.151,152 The major signaling pathway that is utilized to connect NF-kB to the immune system is the toll-like receptors (TLRs) along with IKKb kinase and various cytokines, which influences inflammatory signaling.151-153 As most know inflammation can be a useful element in combating infection and other anomalies, but chronic inflammation can increase the damage probability for various cells through increasing oxidative stress and lipid peroxidation, increasing unnecessary cytokines and inducing matrix degradation through the production of metalloproteases.154,155 Cytokinese play an important role in creating a balanced and appropriate immune and inflammatory response. IL-10 and IL-12 have been previously discussed due to their association with mTOR; however, other cytokines appear to influence aging outside of the mTOR pathway including IL-2, IL-4 and most importantly IL-6 all of which are influenced by NF-kB. The most important of the three is IL-6, which is a pro-inflammatory cytokine that has enhanced expression as an organism ages and is thought to contribute to numerous pathophysiologic conditions.156,157
One of the major reasons suspected for the success of rapamycin in reducing aging and its effects is increased autophagy potential positively affecting cellular senescence. NF-kB influences cellular senescence through changes in apoptotic resistance and autophagy augmentation. The chief role of NF-kB signaling relative to apoptosis is to increase the expression of apoptosis inhibitors like Bcl-xL, and the IAPs along with repressing expression of apoptosis activators like JNK and elements in the Fas pathway.158,159 NF-kB elements IKKa and IKKb activate the mTOR complex to inhibit autophagy.160 So NF-kB and rapamycin actually compete in their influence of mTOR and its associated elements like cellular autophagy. With respects to NF-kB mTOR interaction appears to have negative feedback structure where continued activation decreases NF-kB concentrations and increases STAT3 concentrations to reduce the rate of inflammation and increase autophagy at least in younger individuals.
With the principal causes of aging born from environmental and genetic factors there is great interest in producing various biomarkers to detect and track aging in response to treatments. Officially biomarkers are defined by the National Institute of Health as “features objectively measured and evaluated as an indicator of normal biologic, pathogenic or pharmacologic responses to a therapeutic intervention.”161 The chief problem with developing biomarkers for aging is that the deterioration associated with aging occurs over multiple systems with unknown levels of interdependency. This problem is magnified when considering biomarkers that can be compared across different species. Despite these problems researchers have attempted to define biomarkers among elements associated with oxidative stress, inflammatory markers, telomere shortening and hormones, but these markers have not been supported by longitudinal studies.161,162
In addition none of these biomarkers can be viewed as genuine biomarkers to describe aging, but instead are related to disease where age is the biggest risk factor for their appearance. Also interesting is that these biomarkers tend to be expressed in primary elderly populations (65-80 years old), but not secondary elderly populations (80+ years old).163.164 Basically when individuals exceed 80 years old standard age-related “biomarkers” like blood pressure and various metabolic syndromes do not associated significantly with mortality, which of course is unexpected.163-165 The only “biomarker” that seems to retain its predictability at some level is telomere length.166
This important aging element was discovered in the 1930s when both Barbara McClintock and Hermann Muller identified specialized repeating structures at the end of chromosomes.167,168 These structures were later labeled telomeres and were implicated as critically important for cell division preventing chromosome fusion and an incomplete chromosomal copy. Telomeres are important because of how DNA polymerase operates during DNA replication due to the opposing leading and lagging strands of replication. The lagging strand requires a RNA primer to attach a short distance ahead of the initiation site. However, the genetic material behind that new starting point is not replicated; this is fine if the fragment consists of the telomere, but can damage the cell if there critical information is left behind.
A possible role for telomeres in aging was not identified until the 1960s when Leonard Hayflict famously observed that human cells could only undergo a limited number of cell divisions before death, a behavior now referred to as replicative senescence.169,170 Soon after the identification of replicative senescence Alexei Olovnikov proposed that telomeres acted as a buffer of sorts that “sacrificed” itself during replication so the whole chromosome could remain intact.171 This process was also viewed as irreversible because of the one-directional nature of DNA replication. In the late 70s Elizabeth Blackburn and Joseph Gall formally identified telomeres confirming both McClintock/Muller’s and Olovnikov’s theories.
It was eventually determined that somatic cells were unable to maintain telomere length after a specific number of cell divisions leading to cell death. While somatic cells are unable to maintain telomere length, stem cells are able to replicate at various levels of frequency due to the expression of telomerase, an enzyme derived from the telomerase reverse transcriptase (hTERT) gene172,173 that is responsible for “rebuilding” telomeres so the telomere is never completely lost eliminating any inherent ceiling to cellular lifespan through replicative senescence.
Telomerase expression is high during embryonic development, but is down-regulated almost entirely soon after birth in almost all differentiated adult tissues with the exception of specialized stem cell compartments and down-regulated significantly, but not entirely in cell types that have rapid division frequencies like lymphocytes or skin keratinocytes.174
It is somewhat difficult to draw conclusions from telomere research in vivo because of the differences in fidelity of DNA repair and replication pathways between humans and various model organisms. In most model organisms like mice, yeast and C. elegans the elimination of telomerase is irrelevant for several generations of cellular replication whereas in humans after cutting telomerase concentration in half numerous negative symptoms arise like aplastic anemia, immune system deficiencies and pulmonary fibrosis after a few generations.175-177 Also genetic linkage analysis is rather muddled due to difficult to identify relationships between clinical phenotypes and telomere-related genes.
The belief that telomeres are important in aging is supported by short telomere association with numerous premature aging syndromes such as Werner syndrome, Ataxia telangiectasia, Bloom syndrome, Nijmegen breakage syndrome, Fanconi anemia, bone marrow failure, dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, etc, due to cross-sectional and longitudinal cohort studies.178-181 There was some question regarding the role of telomeres and aging in that some research supports an inverse relationship between telomere length and lifespan,182 but this relationship did not seem to exclude tumor/cancer related deaths and most of the differentiation between telomere length and lifespan occurs between life forms with > 1 kg mass and < 1 kg mass. Also clearly aging is a more complicated process than simply looking at telomeres especially when considering average lifespan, not maximum lifespan the element that telomere influence, in normal functioning creatures is studied more in laboratory tests.
Also in vitro studies have tied telomere length to oxidative stress and damage, which has some compelling anecdotal evidence in that the estimated telomere loss per cell division is 50-100 base pairs, but lagging end-replication only seems to account for a loss of 20 base pairs.183 Therefore, it is reasonable to suggest that the additional loss is derived from oxidative damage.183 If this association between telomere length and oxidative stress is accurate then one may be able to better manage telomere length through anti-oxidative stress strategies. However, as mentioned above these strategies must be more specific and rational than consuming a large quantity of Vitamin C and E.
Previously some argued that the role telomeres play in aging could be neutralized by simply activating telomerase in somatic cells. However, this strategy is complicated because the deactivation of telomerase in somatic cells acts as a form of tumor suppression limiting clonal proliferation and dominance. This reality is demonstrated in actual cancer cells where one general aspect of their enhanced ability to replicate is dictated by the reactivation of dedicated telomerase gene expression. Also there is some question to whether the activation of telomerase can create a dysfunctional telomere, which can lead to a malfunction in the DNA damage response for a cell creating a pseudo-tumor cell.175
Telomerase deactivation is not necessarily a bad thing as restrictions in the proliferation of somatic cells pose a barrier for the growth of aspiring tumor cells. Unfortunately, the telomere mechanism that limits the growth of pre-malignant cells also provides strong selection for cells that no longer respond to the DNA damage signals originating from short telomeres. Such cells are genetically unstable and have greatly increased ability to acquire genetic rearrangements that provide further growth advantages. The intricate involvement of telomeres in both aging and cancer ensures that pathways involving telomeres and telomerase will remain subject to intensive studies for many years to come.
Interestingly it appears that after reaching adulthood telomere length changes very little between different cells with different frequencies of replication (leukocytes, muscle, skin and fat) due solely to the influence of time passage.184 The difference in telomere length between these cells seems to occur during the first two decades of life creating an intra-individual synchrony among telomere length and cell types.185-188 For leukocytes it is thought that this two tiered telomere length behavior is born from the expansion of hematopoietic stem and hematopoietic progenitor cell pools.189
While it can be difficult to extrapolate it stands to reason that early symmetric stem cell divisions from the progenitor pool versus asymmetric divisions also define telomere length for the other cell types. Therefore, it seems that stem cell division among somatic tissues for maintenance purposes proceeds at similar rates in adults despite their inherent proliferation status. This information could prove useful because if there is a similar reduction of telomere length in various cell types for adults any treatment that increases telomerase concentrations and thereby increase telomeres will not have an imbalanced influence among various cell types. Basically there should not be a higher probability of developing cancer born from a specific cell type over another cell type.
In the age of genomic research a holy grail of sorts for aging would be to identify a single gene that has significant control over the aging process. In the pursuit of this goal along with a better understanding of aging in general numerous potential candidates have been researched among various model organisms and humans. As previously mentioned the Sir2 family of NAD+-dependent lysine deacetylases are viewed as a high quality genetic candidate for regulating aging due to its influence in extending the lifespan of numerous model organisms including C. elegans, yeast and Drosophila. In humans there are seven different Sir2 homologues (Sirtuins) most of which appear to also have influential roles in governing aging with SIRT1, SIRT2 and SIRT6 playing the most prominent roles. The reason for this prominence is that SIRT1 plays a role in metabolism and inflammation, SIRT2 plays a role in cell cycle and tumor development and SIRT6 plays a role in DNA repair, metabolism and TNFa secretion.190-192
SIRT1 is somewhat unique because it tends to become mobile in response to stress relocating to sites of DNA damage where it helps initiate DNA repair.193 However, this movement may increase the probability of gene expression that are enhanced during aging; basically increased stress can indirectly trigger changes in chromatin state due to SIRT1 influence.193 SIRT6 is an important positive element in promoting replicative capacity through maintaining telomeric chromatin.194 It also interacts with NF-kB subunit RelA as a form of negative feedback through the deacetylation of H3K9Ac to reduce NF-kB signaling.195-197 SIRT6 influence on aging may also involve reducing levels of insulin-like growth factor 1 (IGF-1).195 Finally note that because Sirtuins are dependent on NAD+, insufficient concentrations will result in reduced influence and increase aging potential.
Another popular area of aging study focuses on the relationship between aging and insulin interaction. Numerous studies in model organisms have demonstrated that increasing insulin sensitivity results in a significant increase in longevity.198-201 Not surprisingly though while the insulin receptor substrate (IRS)/PI3 kinase pathway influences aging in C. elegans and Drosophila in a rather straightforward manner, insulin pathways are more complicated in mammals with many more receptors thus elimination of insulin-like growth factor (IGF) and its respective receptors (IGFR) can result in perinatal lethality, diabetes, hyperlipidemia, obesity and liver dysfunction.198,201 Also the insulin/IGF-1 signaling (IIS) pathway in mammals has a strong interaction with growth hormones (GH), an element not utilized in non-mammalian model organisms, further complicating conclusions. Despite this increased complexity there is strong evidence that the IIS pathway does play a role in aging in mammals in that significant increases in average and maximal lifespan occur in mice with reduced plasma levels of IGF-1 and insulin.199-202
A study using Fat Insulin Receptor Knockout (FIRKO) mice further supported the idea that insulin signaling was important for longevity where despite having a normal appearance, appetite and fertility the knockouts had higher insulin sensitivity and less fat and outlived controls by 18%.203 This type of research also produced greater understanding behind a potential influencing mechanisms within the insulin pathway demonstrating that increased mitochondrial oxidative metabolism and white adipose tissue (WAT) metabolism play a role in FIRKO increased longevity.204 Unfortunately there is no specific understanding to how this increased metabolism influences inflammatory adipolines beyond the suspicion that there is a positive (increased anti-inflammatory) effect. Some point to adiponectin as a highly influential insulin sensitivity element that is derived from adiopocytes, but there is no definite evidence for the appropriate mechanism.205,206
The influence of IIS in aging is further supported by the detrimental effects of increased insulin resistance on lifespan and the positive effects of increased insulin sensitivity on lifespan. One of the more interesting real-world studies identified lower insulin resistance and more preserved beta cell function in centenarians versus other individuals who were only seventy to ninety years old.207 Some also link the increased life expectancy seen in calorie restricted diets to reduced plasma insulin levels and increased insulin sensitivity.208
While the influence of IIS in aging appears well supported,209,210 the currently understood involvement of GH is more controversial. Mice deficient in growth hormone like Ames dwarf, which do not secrete GH, prolactin or TSH, outlive controls by 35-70% dependant on other environmental factors.202,211 In addition GH receptor (GHR) knockout mice also demonstrated increased longevity.212,213 However, when GH antagonists are used to reduce GH signaling without a corresponding change in insulin levels there is no significant change in lifespan.213
Such a contradiction seems strange in that if GH signaling is eliminated through lack of substrate or lack of receptor then life is significantly extended, but if receptor activation is eliminated through antagonist binding life is not significantly extended. It stands to reason that despite the antagonist some GH does bind to the appropriate receptor initiating the GH pathway. This result seems to imply a very high initial sensitivity to GH binding that reaches activation saturation rather quickly. Think a Michaelis-Menten graph with a sharp initial slope. If this is true then it is difficult to conclude that increased longevity can be acquired through interaction with GH due to some of the negative effects associated with GH knockouts in humans.
The body types produced by GH or GHR knockout mice are somewhat interesting because they appear to have a lean body type whereas humans who suffer from Laron syndrome (the lack of GHRs) develop an obese body type due to increased fat and significant losses in bone density and muscle mass. While some studies have reported a loss of bone density in GHR knockouts this result does not explain the difference in fat content.214,215 From an evolutionary standpoint GH may be required to differentiate pre-adipocytes into adipocytes, a majority of which form white adipose tissue.216,217 Therefore, the loss of the GH pathway eliminates a principle formation pathway for white adipose tissue. However, GH has also been reported to be an important element in suppressing fat accumulation and increase muscle mass, a seemingly contradictory behavior.213
The explanation for this dual behavior is that during development GH is important in initiating the fat storage pathway and after maturity is used to regulate this pathway in a negative manner.213 This behavior is similar to the neurotransmitter GABA, which is excitatory during development and later becomes inhibitory in mature brains. Thus without white adipose tissue, more than likely the lean body type in Ames and GHR knockout mice is born from the development of brown fat and the increased use of lipids as a source of energy over carbohydrates reducing glucose production leading to suppression of gluconeogenesis and increasing insulin sensitivity.218-220 The reason that GH concentrations appear negative to aging is that aging is not advantageous from an evolutionary standpoint in that reproductive success is favored over longevity so rapid growth, early sexual maturation and strong levels of fertility, characteristics directly related to GH pathway activation, would be supported by evolution.
Another element that may support a role for insulin is that the development of hyperglycemia from high levels of insulin resistance appear to increase the synthesis rate of advanced glycation end products (AGEs) and glycation of proteins.198 AGEs typically form when reducing sugars react with carbohydrates and free amino groups and accumulate in structural proteins like elastin and collagen.221 However, there is no clear evidence that increased insulin resistance leads to increased synthesis of AGEs.
For those who have accepted the cause of aging to involve nutrient sensitive signaling elements like IGF-1 and mTOR the effect of these signaling mechanism induce aging through the facilitation of excessive macromolecule build-up within cells. The chief cause of this build-up is largely regarded as the decline in effectiveness and frequency of cellular autophagy removing damaged and unnecessary molecules and the continued expression of these nutrient sensitivity systems after their usefulness has ended.
Not surprisingly one analogy used to encapsulate this aging methodology, largely because it is used for numerous other things as well like global warming, is that of a bathtub with a running faucet. Think of IGF-1 and mTOR as the agents that control the faucet, autophagy as the drain and the amount of water in the tub being the biological age where too much water leads to flooding (i.e. death). If IGF-1 and mTOR expression exceed autophagy then an individual will experience biological aging as water fills the tub. Therefore, to accelerate aging one must either reduce autophagy or increase IGF-1 and/or mTOR expression; to decelerate aging one must increase autophagy or decrease IGF and/or mTOR expression. Proponents of this mindset believe that while ROS may induce genetic damage, cells die from an unbalanced growth/damage correction mechanism long before the genetic damage is sufficient to induce death.
If one is to believe this series of events then between the two treatment avenues enhancing or maintaining autophagy appears to be the superior one due to the negative side effects and quality of life elements associated with inhibiting mTOR or IGF-1/insulin interactions. Therefore, it may be a better strategy for individuals seeking an anti-aging therapy to focus on autophagy enhancement rather than further evaluating rapamycin or similar agents.
Finally one of the most robust and reproducible methods for positively altering lifespan is calorie restriction (CR) that excludes malnutrition or nutrient deprivation. CR is usually studied with non-control animals receiving a diet that is about 10-40% (normally 30% is standard) less caloric intake than control animals. CR-derived life expansion has been demonstrated in a variety of species including C. elegans, Drosophila and mice.222-225 Numerous rationalities have been hypothesized for why calorie restriction is able to achieve such success.
Supporters of ROS argue that reduced calorie consumption results in reduced metabolism and a reduced probability of synthesizing greater concentrations of ROS thereby extending life and youth due to less DNA damage, especially 8-OHdG damage.226-228 Supporters of insulin dependent aging argue that reduced calorie consumption results in a reduced concentration of circulating insulin and a reduced activation of the IIS pathway through IGF-1 binding thereby extending life and youth, although a reduction of protein is also required to achieve this particular effect.225,228-230 Supporters of NF-kB aging argue that CR down-regulates PI3K and AKT transcription which reduces NF-kB activation removing consistent activation of the “aging” phenotype.231 Others still think that CR influences mitochondrial biogenesis and recycling methods like autophagy to increase longevity.222,232 One of the chief benefits of CR is that there appears to be no age floor in which the methodology must start. Basically a 60-year old individual can begin a CR diet and still develop similar positive biological outcomes similar to that of a 40-year old on a CR diet for decades.
While there is significant evidence to suggest that CR plays an important role in influencing aging in various life forms there are some outstanding issues. First, CR has never definitely demonstrated lifespan extension in humans or non-human primates. In fact the one major concluded study that focused on non-human primates, the 1987 National Institute on Aging (NIA) study using rhesus monkeys reported improved health benefits and possible lower mortality rates, but no ceiling life extension.233 A University of Wisconsin study that started in 1989 that is also utilizing rhesus monkeys is still ongoing and has not released final conclusions, but has released studies in 2009 that concluded 13% of the CR group died from age-related causes versus 37% from the control group, which is in contrast to the NIA study.234 However, there are concerns that the diet fed to the controls in the Wisconsin study is too unhealthy (28.5% sucrose versus 3.9% for the NIA study) creating an inappropriate environment for comparison because the monkeys in the Wisconsin study were healthier simply from not eating the unhealthy diet not from the calorie restriction.235
Second, there are some significant drawbacks associated with CR in humans including reduced sex hormone production, reduced immune response, reduced muscle mass and lower bone mineral density.236-238 Whether or not the decrease in bone mineral density will increase the probability of fractures is unknown because bone quality appears retained despite this reduced mineral density.239 Note that all of these results are short-term, thus these issues could exacerbate with time or self-correct at a new type of homeostasis.
Third, the extension of ceiling lifespan in yeast utilizing a CR protocol relies on enhanced respiratory rates.240,241 This result may help support mitochondrial hormesis as an important element in the life extension effects of CR.242,243 However, hormesis is a somewhat controversial concept in biology, thus there is significant skepticism regarding its validity. This methodology could also tie into the reduction of ROS damage, but not on a reduced production level, but increased neutralization efficiency. This hormesis “priming” has some level of support in that induction of endogenous ROS production can extend life in some organisms.243-245 The change in methodology is unknown, but it may have some influence in increasing antioxidant efficiency.
Fourth, there are no good studies where CR is compared against a healthy Mediterranean type diet. Thus, the benefits from CR may be derived not from excluding calories, but from excluding “bad” calories. For example when one consumes additional calories those calories, to a point obviously, would not be negative if the appropriate vitamins and minerals are contained within maintaining a “nutrient/calorie” ratio relative to exercise level versus smaller calorie consumption strategies. This mindset also coincides with the idea that controls isolated solely to a laboratory are not effective wild-type mimics, thus the lifespan increases seen in CR organisms cannot be genuinely regarded as an increase versus wild-type organisms. Overall there is a lot of promise that CR restriction can be utilized as a means to reduce most of the negative age-related conditions, but whether or not CR is an effective means to extend ceiling lifespan is currently unknown because of these concerns.
With respects to anti-aging treatment, despite the positive results seen from treatments with rapamycin, the biggest problem with focusing on rapamycin as an anti-aging therapeutic is there are numerous side effects not simply those associated with immune system disruption. Not surprisingly rapamycin also induces metabolic alterations like hyperlipidemia, decreased insulin sensitivity (which should increase the probability for developing diabetes and may conflict with IGF-1 anti-aging) and glucose intolerance.246,247. Also there are questions regarding how it influences the gastrointestinal tract due to frequent diarrhea events in patients.248 While individuals suffering from illnesses like cancer and transplant recovery could look past these side effects, would it be responsible to expose healthy individuals to them?
Also most of the rapalogs (chemical agents that are derivatives of rapamycin) that have been developed to avoid or limit rapamycin side effects and/or increase pharmacokinetics for treatment like ridaforolimus, 32-deoxo-rapamycin, temsirolimus, etc. have significantly underpreformed relative to expectations both as anti-cancer agents and anti-aging agents.248 Some believe that these rapalogs focus too much on interacting with mTOR and have a lack of interaction with either PI3K or AKT, which facilitates the failure to properly mimic the biological effects of rapamycin.248
Of the numerous studies performed to investigate the causes of aging, a large amount of support has been developed for numerous different pathways. One of the key elements to developing a therapy is to define what is plausible and what is not. For example the expectation should not be to repair all damage incurred through aging because there will always be elements like epigenomic drift. While major players have been identified developing strategies to take advantage of this knowledge must be taken with caution, as shown above with rapalogs, because of the complexity and interactivity of the pathways involved and the natural aging aspect of organized life, which generates a progression towards random patterns of gene expression that may supercede pharmacological intervention.
Some of the key questions with establishing a lifespan extending methodology are as followed:
1) As discussed above there are numerous elements that are responsible for advancing biological age and it stands to reason that none of these elements as a standalone therapy will produce significant results. One might object to this statement citing significant life extension in various model organisms, but it is important to acknowledge that these gains are exclusive to these respective model organisms and as organisms increase in biological complexity the influence of these life extending changes wane as seen in studies of humans and non-human primates. For example genetic dampening of IIS in C. elegans increase average lifespan by 100%, in Drosophila by 25-30%, in mice by 20% and in non-human primates and humans <5%.249-252
2) There is significant overlap and relationship between cancer and various aging mechanisms where most of the mechanisms that appear to retard cancer formation induce aging; how will anti-aging therapies be reconciled with the possibility of higher rates of cancer?
3) There is a difference between extending ceiling/maximum lifespan and extending average lifespan. It can be rationalized that almost all life extension achieved by society throughout human history, the development of antibiotics, surgical procedures, better and balanced diets, etc., has been of the latter category; does human plasticity even allow for the extension of maximum lifespan and how could such a possibility be tested?
4) If maximum lifespan extension is achieved how will society manage the increased population, especially when most of the members of this population will consume more resources than they produce? Or will lifespan extension simply be a commercial industry that only the rich are able to utilize?
5) Clearly there are complexity issues that must be addressed for just because increasing the concentration of Compound A increases lifespan in C. elegans does not mean that increasing it in all situations will induce the same result. For example for the IIS pathway invertebrates have a single receptor that binds molecules that biologically represent insulin or IGF-1 and reducing binding efficiency leads to life extension. However, mammals have distinct specific receptor for binding both insulin and IGF-1 with different and overlapping function (IGF-1 controls growth and insulin controls metabolism). In addition mouse average lifespan is only increased when IIS is influenced in the right tissue with the right signaling elements because of coinciding requirements for an increase in insulin sensitivity. Similar complexity increases are seen in important longevity genes – FOXO and SIR(SIRT) where mammals have multiple genes per family that have a variety of influences.
Overall there are some key molecules that have an important role in aging. Of these molecules mTOR and NF-kB seem to govern youthfulness more than maximum lifespan while telomeres and ROS seem to have a greater influence on maximum lifespan. Therefore, society must develop a strategy to address both of these influencing categories otherwise life extension will either not be plausible or will be a rather torturous experience of extended old age. Also the balance between these categories must be considered in their interaction and consequence. For example with the rise of antibiotic resistant pathogens the loss of immune system functionality to increase youthful lifespan of cells does not appear to be a beneficial tradeoff for individuals or society, thus both mTOR and NF-kB strategies must be carefully studied and applied. However, between the two a pursuit of a NF-kB neutralizing treatment appears to be the better strategy.
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Thursday, January 23, 2014
Tuesday, December 17, 2013
Discussing the Nature and Future of Antibiotics - Part 1
Antibiotics are chemical substances that either inhibit the growth of or terminate bacteria. Typically antibiotics are restricted to bacteria and have no significant effect against viruses or other pathogenic agents due to their points of action. The verbal origins of the word antibiotic come from the Greek anti (against) and bios (life). Despite the existence of the immune system, before the development of antibiotic treatment protocols and their widespread use many illnesses like pneumonia, tuberculosis and typhoid carried very high fatality rates. Now when discounting for bacterial resistance fatality rates from all manner of infection are much lower.
Most of the early work concerning antibiotics occurred between the years 1928 and 1942 with the initial work of Sir Alexander Fleming in 1928 who accidentally empirically discovered the anti-bacterial properties of the mold, Penicillium and Gerhard Domagk who discovered the first class of antibacterial agent, sulfonamides, in 1935. In 1939 Rene Dubos discovered the first naturally derived antibiotic, tyrothricin, but after testing was deemed too toxic for human administration. The substance utilized by the mold to achieve such properties was isolated and unsurprisingly named penicillin by Ernst Chain and Howard Florey in 1942. By the early 1940s both sulfonamides and penicillin began clinical use in treatment of diseases. Later penicillin was first chemically synthesized in 1957 by John C. Sheehan, which generated the basic information required to begin synthesis of synthetic penicillin derived antibiotics to combat resistance.
Antibiotics have two modes of function: prevention of bacterial growth (bacteriostatic) and bacterial death (bactericidal). In normal immune systems typically either function is sufficient for recovery as the patient’s immune system should be able to neutralize the bacteria after antibiotic application. However, in those individuals who have weaker immune systems, elderly, very young children or other immunocompromised, bacteriostatic antibiotics may not be enough to fully treat the illness. The bactericidal behavior of penicillin is largely why it was the favored antibiotic over sulfonamides before bacterial resistance started to emerge.
Antibiotics have a wide range of functional pathways to influence bacterial growth: 1) destroy cell wall either through the production of pores or negation of synthesis elements; 2) neutralize aspects of protein synthesis including blocking ribosome production or their binding to appropriate targets; 3) neutralize DNA synthesis and other nucleic acid metabolism functions.1-4 When identifying a new antibiotic agent testing is important to determine the functionality of the antibiotic, how long it works and how large of a dose is required to receive an effective treatment response. Dosage is important because a large enough dose of antibiotic administered against a non-resistant target will kill it, but will also generate significantly detrimental side effects as well.
One of the major targets for antibiotics currently utilized in treatment is the bacterial ribosome largely because of its significant structural differences relative to its mammalian cousin. Bacterial ribosomes are 70S with a 30S and 50S subunit that are comprised from three types of rRNA (5S, 16S and 23S) versus the 80S mammalian ribosome.2,5 This difference makes antibiotics that target ribosomes attractive candidates as the probability of antibiotic interaction against mammalian (friendly) ribosomes leading to unpleasant side effects is low. Antibiotics that target DNA synthesis can also be attractive candidates because of the ability to target molecules that are not utilized in mammalian cells like bacterial DNA girase (topoisomerase II),6 which packs and unpacks supercoiled bacterial DNA, or bacterial DNA-dependent RNA polymerase.7 Other antibiotics neutralize bacteria through indirect means like targeting unique secondary products that are required for DNA like the metabolism of tetrahydrofolic acid. Tetrahydrofolic acid is essential for the synthesis of purines, pyrimidines and some amino acids. Anti-metabolites interfere with tetrahydrofolic acid synthesis and, therefore, inhibit DNA synthesis.
There are two classifications for antibiotics: narrow-spectrum that only work on a small number of specific bacteria and broad-spectrum that work against a large number of bacteria. Not surprisingly though because of its target breadth the use of broad-spectrum antibiotics has a higher probability of developing antibiotic resistant bacteria. Therefore it is standard operating procedure for broad-spectrum antibiotics to only be assigned when the pathogen is unidentified or if unresponsive to any narrow-spectrum antibiotics. For instance gram negative bacteria are typically treated with broad-spectrum antibiotics due to the structural differences in the cellular wall and internal reproduction machinery, which make more narrow-spectrum antibiotics, which are designed to treat gram positive bacteria, ineffective.
Antibiotics are also separated into three classifications derived from their application: surface, oral or intravenous. Surface applications are placed on the skin, in the eyes or mucous membrane in the nose and are typically limited to the local area around where the antibiotic is applied. Oral applications are pills, tablets and gel-caps that are swallowed breaking down in the small intestine and are later absorbed by the bloodstream. Intravenous application is the most powerful application because there is little residence or lag time between application and absorption into the bloodstream. However, intravenous application typically only occurs at a hospital and is largely reserved for critical or uniquely specific conditions.
Of the three classifications oral application is one of the principle elements responsible for the development of bacterial resistance because despite warnings a number of patients continue to prematurely cease oral treatments due to a disappearance of illness related symptoms. Basically patients take some of the assigned dosage start to feel better and fail to finish the remainder of the dose due to a belief of non-necessity. Unfortunately not completing the dosage increases the probability of surviving bacteria becoming resistant.
Although antibiotics are normally used to treat illness they are also prescribed in certain situations to reduce the potential for infection and illness. The most common scenario for this preventative strategy is antibiotic treatment before major surgery to reduce probabilities of current operative and post-operative infection. Also combination therapy is popular where multiple drugs are administered together where one mechanism aids the effectiveness of the other in a synergistic relationship. An example of such a relationship is penicillin weakening or destroying cell walls allowing aminoglycoside entry into the cell. Typically synergistic activity is not an effective treatment strategy outside of circumventing non-pathway resistant mutations because normally a single antibiotic and the innate immune system can neutralize an illness. Also while effective combination therapy failure increases resistant probabilities for multiple drugs instead of just one.
Unfortunately the second most common pathway for bacterial resistance has developed from the widespread use of antibiotics in animal and milk production. In short farmers and corporate entities apply large amounts of antibiotics to healthy dairy cows and other livestock in an attempt to reduce their probability of contracting illness and increase their weight. The weight increases come from eliminating the current microbiota (gut bacteria population) through antibiotic treatment and re-establishing a weight-gain favoring microbiota through diet. However, the haphazard application of antibiotics in such a fashion increases the probability that resistant bacteria emerge and because resistance is just a matter of probability frivolous application strategies like the one above have net detrimental outcomes over the long-term.
Although the tools exist to synthetically create antibiotics from a new base core, a vast majority of antibiotics in use are derived from living organisms, mostly molds, fungi and other bacteria. The two major reasons synthetic antibiotics have not become prominent are safety and functionality concerns along with the financial cost associated with creating antibiotics versus the “lack” of a market for pharmaceutical profit. One of the most common and reliable ways of producing an antibiotic is biosynthesis where the specific organisms themselves manufacture the antibiotic under optimized growing and conditions with additional elements/stressors that will increase the rate and probability for production of the desired elements.
Industrial mass production of antibiotics through biosynthesis is carried out by fermentation where the antibiotics, which are typically secondary metabolites, are collected before cell death. The typical isolation process involves killing the cell, thereby production schemes require large amounts of cell growth to maximize product collection to ensure efficiency and profitability. Collection first involves extraction and then purification into a crystalline product. Organic solvents are used to increase the efficiency of collecting soluble products, but non-soluble products must be removed through additional steps like precipitation, ion exchange and/or adsorption.
The synthesis of synthetic antibiotics typically follows the same methodology. First, an existing antibiotic is selected for modification. The reason behind selecting an existing antibiotic is two-fold: first, there is already empirical certainty that the selected antibiotic has some form of activity against bacteria, thus there is no wasted money developing random chemical structures that have unknown activity profiles. Second, the existing antibiotic is safe enough for human consumption due to widespread use with relatively known side effects.
The second step for synthetic generation is to identify the chemical structure of the active portion of the antibiotic in order to determine what structural modifications could be made to change activation potentials against resistant organisms. Third, the operational pathway of the antibiotic is identified and confirmed. Finally, alterations are made to some part of the structure of the antibiotic to possibly change its response to a given infection. For example all members of the penicillin family have identical rings, but the chemical chain (R group) attached to the ring will be different for different members of the family. So modification of that particular chemical chain is frequently the target of synthetic strategies for penicillin.
After their production these new synthetic derivatives are tested for effectiveness and to ensure retention of safety due to the changes in the chemical formula. In addition to this general methodology new techniques are being used to alter the genetic structure of certain bacteria so the bacteria itself produces a similar, but different antibiotic.
Pharmaceutical companies use computers to data mine and test modifications in the ring to observe chemical compatibility and probability. A standardized testing structure known as 'rational design program' is frequently used now. Such a program focuses on more in-depth analysis of how the favorable agent inhibits by looking at specific targets. In addition to making slight changes in chemical composition to increase antibiotic effectiveness against resistance emergence, another common goal of synthetic antibiotic creation involves increasing the half-life of the drug so that lasts longer in the bloodstream, which will increase the probability for effective treatment.
Identification of side effects and efficiency of treatment is carried out through a screening process that uses a large number of isolates of microorganisms and the secondary products of these organisms are tested in diffusion and growth limitation studies on test organisms. Molecules that show favorable results in both of these areas are then tested for selective toxicities. Afterwards the best candidates are isolated for more rigorous study, which enter the standard three clinical trial phase testing methodology for clinical drugs. However, recently there has been some momentum for changing antibiotic specific testing protocols to speed the application of new antibiotics to the market in effort to better address increasing bacterial resistance.8
Realistically a large amount of natural and synthetic antibiotics have been created at one time or another, but only a select handful have been proven safe and effective. The ideal characteristic of an antibody is a selective bacteria-unique target that negatively influences a critical system required to maintain life. This method of action will lead to the death of the bacteria, but should not interact with any eukaryotic cell targets thus heavily limiting, if not eliminating, any side effects associated with the use of the antibiotic. However, due to the general effectiveness of the immune system antibiotics that lack selective targeting are still useful if administered in a controlled and proper dose. Even if dosage is proper there is valid probability for the development of side effects, thus these changes must also be monitored.
When determining whether or not to treat with antibiotics the first step is to identify what type of organism is responsible for the illness. Under normal circumstances once identification has concluded available treatment options and treatment is rather straightforward. There are typically two elements that complicate treatment strategies. First, if the cause of the illness is viral most treatment options are no longer viable limiting options to a small number of interferons. Second, if the patient is allergic to the primary option of treatment a secondary, more than likely, less effective option will need to be utilized. If the illness is caused by an unidentified pathogen treatment is usually applied using broad-spectrum antibiotics, a strategy commonly called empiric therapy. Overall once a treatment is applied its effectiveness is determined by how well the drug is absorbed into the bloodstream, the diffusion rate of the drug and the half-life of the drug.
Some of the more common classes of antibiotics that have been used in the past or are currently in use are:
Penicillins:
Alexander Fleming discovered the penicillin group from the fungi Pencillium in 1928 (specifically penicillin G was isolated first and later followed by procaine penicillin, benzathine penicillin and penicillin V). Penicillin functions by damaging or destroying bacterial cell walls while the bacterium are in the process of reproduction. The mechanism of action is the inactivation transpeptidase, which is necessary for cross-linking and proper cell wall synthesis. The bacterium accepts penicillin as a substrate and then alkanolates a nucleophilic oxygen of the enzyme, rendering it inactive. Cell wall construction and maintenance ceases leaving multiple holes in the existing cell wall due to continuing natural degradation. This process is also aided by negative feedback where increasing osmotic pressure increases the probability of cytolysis and excess peptidoglycan precursor, due to limited cell wall synthesis, triggers hydrolases and autolysin activation further breaking down the cell wall.
The antibiotic nature of the penicillin is due to the strained beta-lactam ring; when the ring opens, strain is reduced making penicillin more reactive than ordinary amides. Based on its method of action penicillins do not act against organisms lacking cell walls like eukaryotic cells and certain types of bacteria (like most Gram-negative). Due to their ability to facilitate cell wall breakdown, penicillin works well in combination treatments with intracellular acting antibiotics that attack DNA, RNA and/or protein synthesis. Unfortunately due to unsurprising overuse, penicillin has been used for over half a century most bacteria have become resistance on a large-scale.
While the lack of cell walls in eukaryotic cells limits the side effects from these antibiotics, some mild side effects can occur from their use like diarrhea, rashes and hives (which usually indicates an allergy). The most rare and dangerous side effect is an “anaphylactic” allergy, which results in labored breathing due to swelling in the airway born from a severe allergic reaction. Normally allergic reactions eliminate the availability of a given antibiotic, but if the situation demands the use of an antibiotic that will result in an allergic reaction a desensitization strategy is used where the patient receives small doses with a high frequency of administration and slight increases in the overall dosage.
Cephalosporins:
Along with cephamycins, cephalosporins are a class of beta-lactam antibiotic that originally acted against Gram-positive bacteria, but through modern synthetic synthesis newer formulations have increased action effectiveness against Gram-negative bacteria while weakening their action against Gram-positive bacteria. While its method of action is similar to penicillin due to a small structural difference cephalosporins are less susceptible to penicillinases making it more difficult for bacteria to neutralize its bactericidal action. Differing generations of cephalosporins have been created by largely modifying its nucleus to reduce the probability that bacteria develop resistance. Currently, although somewhat disputed, five different generations of cephalosporins have been created with the fourth and fifth generations classified as having broad-spectrum action.
Quinolones:
Quinolones, the largest sub-class being fluoroquinolones, are synthetic broad-spectrum antibiotic that was first developed in 1962 as a distillate byproduct in chloroquine synthesis. Quinolones are typically reserved for secondary application in community-acquired infections due to concerns over peripheral neuropathy along with other strong side effects and increasing bacterium resistance development along with enhancing probability of Clostridium difficile and MRSA infections. However, when used quinolones function occurs through blocking the action of DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive. For treatment quinolones can stand alone due to their increased probability of cell entry through porins, but in Gram-positive bacteria combination treatment with a beta-lactam antibiotic also increases treatment outcomes. Unfortunately numerous pathogens now demonstrate resistance to quinolones due to overuse in that they were the principle treatment of Gram-negative bacteria from the 60s until the 90s until the development of synthetic broad-spectrum beta lactam antibiotics and continued misuse in the 00s.
Aminoglycosides:
Aminoglycosides are molecules composed of amino-modified sugars and typically can act as antibiotics through two different mechanisms: first the ability to bind irreversibly to the 30S ribosomal subunit in bacteria interfering with successful mRNA interaction reducing the effectiveness of translation (i.e. protein synthesis). There is also some evidence that they also interfere with proofreading and inhibit ribosomal translocation. Second, aminoglycosides are thought to competitively displace magnesium and calcium that link polysaccharides within lipopolysaccharide groups creating transient holes disrupting cell wall permeability.
Aminoglycosides are primarily effective against Gram-negative aerobes and mycobacteria, but while effective antibiotics they are unfortunately rapidly dissolved in the stomach, which eliminates oral consumption, limiting their administration to IVs or injections. Also aminoglycosides have some fairly damaging side effects including kidney and auditory damage. Due to these side effects aminoglycosides are typically used as a last resort antibiotic against unknown or multi-drug resistant pathogens.
Polymyxins:
Polymyxins damages cell walls through interaction between lipopolysaccharide in the outer membrane and its hydrophobic tail in a similar method as detergent/soap. Polymyxin appears to work best in combination treatments with intracellular acting antibiotics for the disruption of the outer membrane allows for easier entry to the cell. Unfortunately similar to aminoglycosides, polymyxins are typically reserved for late stage treatments due to serious neurotoxic side effects.
Tetracyclines:
Tetracyclines (tetracycline, doxycycline) bind to the 16S portion of the 30S ribosomal subunit and block polypeptide chain elongation by preventing the attachment of charged aminacyl-tRNA. They are typically used when treating Gram-positive cocci, chlamydia, mycoplasma, and rickettsia. A secondary mechanism of function involves tetracyclines binding to ions on the membrane and generating additional ionophores disrupting calcium flow into and out from the bacteria. Unfortunately bacteria resistance has developed rapidly against tetracyclines significantly limiting their functionality.
Rifampicin:
Rifampicin binds strongly to DNA-dependent RNA polymerase leading to the inhibition of RNA synthesis. It is largely used in combination treatments against Mycobacterium infections most notably tuberculosis. Due to its mechanism of action rifampicin is also used in secondary combination treatments against more resistant bacteria. Combination treatments are the norm with rifampicin because when used alone bacterial resistance builds quickly.
Macrolides:
Macrolides are molecules with a macrolide ring and a standard construct of a linear molecule that later form a large ring induced by activation of an enzyme on the terminus molecule. These rings are linked through glycoside bonds with amino sugars usually cladinose and desosamine. The linear molecule is constructed similar to that of a protein with small molecules combined on a biological assembly line. Most macrolides function by interfering with bacterial ribosomes by binding reversibly to the P site on the 50S subunit preventing ribosomal initiation complex formation or amino-acyl translocation. In low doses it is typically bacteriostatic, but at higher concentrations it becomes bactericidal, but obviously side effects become more prominent as well. Leukocyte accumulation and interaction aid in transporting macrolides to infection sites increasing efficacy.
Sulfonamides:
Not all sulfonamides are antibacterial, but those that are typically have structures that resemble para-aminobenzoic acid (PABA), which is a precursor in folic acid synthesis. Sulfonamides compete (competitive inhibitors) with PABA to bind to dihydropteroate synthase, an enzyme involved in folate synthesis. Reduction of folate synthesis efficiency makes sulfonamides bacteriostatic. Sulfonamides are typically used in combination treatment, usually erythromycin or trimethoprim, due to recent escalation in resistance. There are few side effects associated with sulfonamide use due to the lack of biosynthesis of folate in humans; folate is instead acquired through diet.
Trimethoprim:
Trimethoprim (TMP) is a synthetic antibiotic. Similar to sulfonamide, trimethoprim selectively inhibits the dihydrofolic acid reductase of bacteria, which converts dihydrofolic acid to tetrahydrofolic acid, a precursor of purines stopping DNA synthesis and replication. TMP is normally bacteriostatic, but can be bactericidal and is commonly used in combination with sulfamethoxazole (SMX). This combination is useful because bacteria that are partly resistant to either TMP or SMX can still be killed by the combination of the two.
Vancomycin:
Vancomycin is a glycopeptide that inhibits cell wall synthesis in Gram-positive bacteria by preventing the synthesis of the long polymers N-acetylmuramic acid and N-acetylglucosamine and preventing polymer cross-linking. Through most of its lifetime vancomycin was viewed as a treatment of last-resort due to its poor oral bioavailability requiring intravenous treatment, which reduced the probability of bacteria resistance. Unfortunately in recent years bacteria resistance has grown exponentially significantly limiting the usefulness of vancomycin.
Resistance has become one of the biggest “rarely talked about” problems in the modern world. A bacterium becomes resistant to an antibiotic when it alters a portion of its genetic structure to neutralize the method of antibiotic action. The genetic change can neutralize antibiotic activity in multiple ways: the target is eliminated entirely, a new defense element is created to eliminate the ability of the antibiotic to target the molecule (deactivating it or removing it) or a change occurs in the pathway of operation eliminating the necessity of the target for growth and survival.1,9 There are typically two major categories that bacteria can alter their genetic structure to create resistance.
Random genetic mutation is the most basic way resistance is acquired. Basically random genetic mutation is the egg in the chicken and the egg question regarding bacterial resistance as no other forms of resistance could occur without the original underlying mutation. Unfortunately these mutations are random and do not require previous exposure to the antibiotic to become resistant. The spontaneous mutation of a susceptibility gene has a frequency of occurrence of anywhere from 10-12 - 10-7 which for some species increases to 10-7 to 10-5 under selective pressure during or after exposure to a specific antibiotic.10 This increased resistance probability is what creates concern by certain parties when discussing frivolous antibiotic administration on healthy organisms.
Another means of mutation that generates resistance is genetic transposition. Transposition is the recombination of genetic material due to transposons which are DNA segments with specific insertion sequences at each end. Using these sequences, transposons are able to migrate or jump between DNA strands in the same bacterium. Sometimes the new sequences that are created due to this movement produce antibiotic resistance.
The second method that leads to resistance is acquisition of a plasmid with the appropriate resistance. Bacteria commonly exchange circular pieces of DNA smaller than their chromosomes otherwise referred to as plasmids. Plasmid acquisition typically occurs in one of three ways: 1) bacterium in close contact with each other freely transfer various plasmids typically referred to as transduction. If the receiving bacterium transfers a plasmid back then the process is referred to as retrotransfer; 2) the unilateral transfer of a plasmid between bacterium during reproduction typically referred to as conjugation; 3) the absorption of a portion or entire chromosome by another bacterium typically referred to as transformation;
Overall there are five major mechanisms in which a bacterium uses these genetic additions or mutations to acquire resistance. 1) Antibiotic Modification - The antibiotic is inactivated typically by the production of a new enzyme that targets the antibiotic changing its structure; 2) Antibiotic Entry Restriction – Modification lowers the probability that the antibiotic is able to enter the cell to target intracellular molecules; this mechanism is more common in Gram-negative bacteria where porins that typically allow diffusion of antibiotics through the membrane are altered disallowing antibiotic entry; 3) Enhanced efflux of the antibiotic – efflux pumps are augmented or synthesized at faster rates to remove antibiotics from the intracellular space and cytoplasm before it can reach the target molecule; 4) Alteration of Drug Target – the mutation changes the structure of the target molecule so the antibiotic can no longer bind triggering its effect; 5) Pathway Alteration – This is the least common mutation due to its complexity, the bacterium produces an alternate redundant pathway mitigating the effectiveness of antibiotic blocking of the initial pathway.
One troubling element of resistance is how rapid it appears to be developing. For example in the 1940s when penicillin use was first becoming standard protocol for all isolates of S. Aureus <1% of isolates were resistant, but by 1951 approximately 75% of isolates were resistant which is why synthetic penicillin was created. For S. pneumoniae only 2% of isolates in 1981 were penicillin resistant versus 12% in 1995. It is thought that similar types of resistance development curves exist for other bacteria and other antibiotics. Of bacteria that have developed resistances the Infectious Diseases Society of America (IDSA) believes that Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter and E. coli are the most advanced and dangerous.11
The Gram-negative Acinetobacter, Pseudomonas, Enterobacter are becoming increasingly resistant to existing antibiotics at a much faster pace than their Gram-positive brethren. According to the CDC methicillin-resistance Staphylococcus aureus (MRSA) kills approximately 11,000 more than emphysema, AIDS, Parkinson’s or homicides.12 An additional 100,000 die from hospital acquired infections where a vast majority of those infections are resistant to at least one type of antibiotics.13,14
Antibiotics are misused primarily through excessive use of prophylactic strategies for travelers, failure to prescribe correct dosages through history of use and weight, failure to complete the prescribed dosage regardless of existing symptoms and inappropriate prescription of antibiotics for non-necessary conditions. In addition to misuse, the crisis among antibiotic resistant bacteria has largely come about due to a vast majority of pharmaceutical companies electing not to continue antibiotic research programs to develop new antibiotics. Not surprisingly without a continuous stream of new antibiotics, especially those with new core structures, increasing bacteria resistance has narrowed the available treatment options for existing bacteria infections. To highlight this deficiency in new antibiotics from 2008 to early 2013 only two systemic antibacterial agents were approved by the FDA versus the approval of sixteen from 1983-1987.14 Of at least 20 pharmaceutical companies that had large research and development programs in 1990 only AstraZeneca and GlaxoSmithKline remain today.15,16
One could argue that with the progression of time novel antibiotic discoveries become more difficult so it is understandable that fewer antibiotics would be developed now versus 20-30 years ago; while this rationality is correct a drop off of 87.5% in a 25-year span cannot be explained by such a rationality. In fact there are three principle reasons why a vast majority of pharmaceutical companies no longer focus on producing antibiotics.
First, there is little profitability in creating a new antibiotic largely because its application is single use over a short period of time versus the blockbuster (billion dollar+ per year) drugs that focus on chronic health or lifestyle conditions (statins, erectile dysfunction, high blood pressure etc.). In modern capitalism businesses prefer to sell a product that stabilizes a negative state/condition rather than cures it because the stabilizing agent can be sold in perpetuity. However, a counterpoint is that in the current market individuals pay $100,000 for an extra four months of life when facing stage-4 cancer, but balk at paying $125 for antibiotics that will help treat an infection. In this vein consumer priorities do appear misguided, based on fear rather than rationality ($100,000 for four more months and then death versus $125 for potentially decades of more life). This pricing difference is neither rational nor data-driven; there is no cost analysis that supports cancer drug pricing. Rather, drug pricing in the U.S. is based on public perception and fear. People are terrified of cancer, but not terrified by a multi-antibiotic resistant form of TB, which has much higher levels of virulence and a comparable fatality rate.
Second, drug research in general is expensive, especially now that most of the “low-hanging” fruit has been scooped off of the ground. The principle antibiotics that were first utilized in treatment (sulfonamides and penicillin) were derived from other species making their isolation and manufacture into a human applicable form straightforward. These compounds also provided effective core/lead compounds that could be slightly manipulated to produce new drugs, which had the potential to evade certain resistances bacteria developed for the initial principle compound. However, the manipulation of those core compounds has run fairly dry demanding more complexity, data mining and high throughput screening (i.e. computer power) to develop the next generation of antibiotics. Of course this complexity demands excess resources and financial capital increasing the costs of even attempting to create new antibiotics.
Third, some individuals believe that the regulatory system, especially in the United States, creates a sufficient obstacle for pharmaceutical companies. Critics cite that antibiotic approval by the FDA is confusing, unnecessarily complex and does not recognize the specialty of the antibiotic field of drug development versus other developmental fields. One of the more problematic elements of regulation is the narrow “approved for use” window assigned to antibiotics. For example when an anti-cholesterol drug is approved it is for broad use not high cholesterol values in the heart versus in the lower leg. When an antibiotic is approved it is approved to treat a specific single condition like pneumonia instead of the specific organism that the antibiotic or anti-bacterial targets.
Due to the volume based sales strategy with antibiotics and the narrow “approved for use” FDA rules where about one of every 72 new antibiotics are approved versus one of every 15 for other types of drugs, pharmaceutical companies would be encouraged to develop broad-spectrum antibiotics, which have higher resistance development profiles, the exact opposite of what antibiotic treatments should be striving for. Based on all of these elements: sales potential and regulation/research costs some estimate that in current market environment the production of a new antibiotic will actually cost a pharmaceutical company millions dollars over the life cycle of that given drug. Part of the problem with the additional regulatory steps demanded by the FDA could be what occurred after the approval of Telithromycin (brand name Ketek), which involved the use of fraudulent data to speed its approval resulting in numerous deaths and liver failures. Due to this incident the FDA has become more cautious when approving new antibiotics.
Passed in 2012 the GAIN act attempted to address some of the concerns with the deficiency in antibiotic research and development by extending marketing protections for select “qualified infectious disease products” by increasing levels of exclusivity (12 years to 17 years further delaying generics). Also there is an additional six months of exclusivity for drugs with a companion diagnostic test is approved. Basically this additional exclusivity tacks on to any Hatch-Waxman, orphan drug or pediatric exclusivity. This legislation also produced an expedited review awarding appropriate antibiotic candidates with priority review and fast track status.
In addition the FDA is responsible for revising guidelines for future antibiotic clinical trials to accurately reflect the latest scientific and clinical knowledge. So far in response to GAIN the FDA has created an anti-bacterial drug development task force to study future guidelines for drug development, released a list of high warning pathogens and reviewed with appropriate updates to numerous antibiotic drug development guidelines.
The problem with the GAIN act is it only focuses on one of the two important elements of the bacteria resistance issue, creating new antibiotics. There are no new regulations regarding the stewardship and application of existing and new antibiotics during the course of their administration. Without new rules new antibiotics will simply suffer the same fate as existing antibiotics and squander a percentage of their potential due to misuse.
Some may argue that FDA documents Final Guidance #209 and Draft Guidance #213 address this second element of usage and administration. However, voluntary recommendations are not effective rules and policy. #209 recommends that food/animal producers stop the use of medically important drugs (chiefly antibiotics) for growth promotion or feed efficiency purposes. It also suggests these producers seek veterinary oversight when application of any medical important drug is used for treatment or prevention. Not surprisingly it stands to reason that as only recommendations producers will only apply these actions if profitable. Seeing that a number of individuals/groups tend to ignore the antibiotic resistant problem and even violate existing usage law in the first place one cannot be confident that most producers will abide by these recommendations.
Draft Guidance #213 recommends that drug companies aid the application of Final Guidance #209 by removing any use suggestions on their drug labels pertaining to growth promotion. However, companies in the future will have the ability to list therapeutic uses, including disease prevention, on their labels. With antibiotic sales as a volume driven business it is difficult to see many companies voluntarily reducing the probability of sales of these products.
The FDA does acknowledge that making these guidelines voluntary is a significant handicap on their potential effectiveness, but claims that creating guidelines that have significant penalties associated with non-compliance will require time consuming formal hearings and legal processes that will more than likely see numerous evidentiary hearings and drag out for years partly because it would have to focus on one drug at a time . If this is the case then voluntary recommendations may be the best option to actually producing change.
In an attempt to combat the lack of new antibiotics the IDSA has proposed a specialized regulatory mechanism called the Special Population Limited Medical Use (SPLMU) exclusively for antibiotics that they wanted to be included in GAIN, but was not. The chief aspect of this new plan would change the approval process from two Phase III “lack of inferiority” trials to smaller Phase III trials using narrowly defined test subjects (those suffering from a condition born from a resistant bacteria). Despite the lack of safety information on these new antibiotic compounds it is thought that because these patients are already out of options due to the resistance the benefits derived from consuming the experimental compound will outweigh the risks. The thought is that through this direct treatment methodology safety and efficacy information can be derived for the experimental compound hastening the determination regarding whether or not it would be suitable for large-scale release.
This new testing regimen has been compared to the regimen utilized for development and approval of drugs for “orphan” conditions. However, orphan drugs will always remain a niche treatment area whereas these new antibiotics would eventually be used by millions of people with wide ranging characteristics that could produce a variety of side effects. Such a situation creates one of two strategies: 1) conduct secondary testing after initial approval to identify serious potential side effects and address any of these outcomes appropriately or 2) react and track new side effects when they occur in a broader public administration of the drug. Clearly the first strategy is more costly for it involves traditional Phase III testing, which in a sense is just postponed for a time after approval, but the second strategy creates legitimate questions of legal liability for any life altering side effects.
The two chief problems with this testing strategy are differentiating between drug related and bacterial related detrimental effects and off-label distribution. Phase III trials are tightly controlled, especially with regards to patient health, so effective rationalities can be made regarding the side effects associated with the tested drug and its usefulness in overall treatment. Direct treatment against very sick patients will create numerous problems determining whether future negative conditions are born from the experimental compound, the bacterium or a combination of both.
Off-label usage is a continuous problem as well. Despite the belief that specialized labeling, instructions to physicians and limited marketing should provide a sufficient barrier, the problem is that off-label usage is already widespread with existing drugs, so there is little to prevent the same behavior with these new experimental drugs. Very strict record keeping would be required including the IDSA suggested post-market surveillance plan. Off-label application should result in heavy sanctions against the offending party and if the sponsor company is responsible immediate cessation of the trial.
Some individuals have suggested that the future antibiotic research and development will depend on appropriate incentives to make the research and development economically sustainable. Some of the suggested incentives involve tax credits, special grants and improved intellectual property protections. While enhancing intellectual property protections is suitable and appropriate simply expecting the government to pay private pharmaceutical companies to develop antibiotics is not appropriate. What most individuals who clamor for direct financial incentives forget is that antibiotic development is direct income poor indirect income rich. In short a pharmaceutical company cannot sell their other drugs to a corpse, keeping the consumer alive is of utmost importance. Therefore, focusing on creating statins and other chronic no-cure (stasis) drugs over antibiotics is foolish because the consuming population will die making even the most profitable blockbuster drug not profitable. In addition most of the large pharmaceutical companies are not making “skin of their teeth” profit margins, thus to expect government, which is still running deficits, to incentivize antibiotic production is a short-term feasible long-term foolish strategy.
An interesting funding idea would involve all pharmaceutical companies that fail to develop new antibiotics to pay a royalty to those that do in effort to support antibiotic research and development. In addition this royalty would also allow successful companies to refrain from deployment of these new antibiotics until necessary. Furthermore this royalty could increase for novel mechanisms, which would also receive expedited approval from the FDA focusing on a new safety and efficacy track.
In addition to developing new antibiotics new usage policies need to be developed to ensure that these new antibiotics remain as fit as possible. There are numerous strategies that can and should be applied to limit the probability of resistance for new antibiotics. First, all nations must ban the use of antibiotics on non-human life despite the aforementioned reservations of the FDA. The shallow benefits provided by injecting mass quantities of antibiotics into healthy farm animals and the like are completely outweighed by the selective pressures these antibiotics provide for a more rapid development of resistance. The European Union has already done its part on this issue, it is time for the rest of the world to follow suit.
Second, the development of diagnostic and metabolic biometrics to create an “antibiotic floor” in order to prevent the foolish and unnecessary prescription of antibiotics to patients that should recover in a suitable fashion through standard non-antibiotic therapeutic strategies (hydration, sleep, exercise, etc.). This floor is important because it is more common than it should be for individuals suffering from viral infections to demand antibiotics that will do nothing but either be disposed of or increase resistance probability for current non-pathogenic bacteria residing in the patient. Third, sewage treatment methodologies should develop an additional step or agent that will increase the degradation rate for antibiotics in the waste stream or remove them entirely. Fourth, a standardized treatment methodology should be created to understand the timeline regarding the dosage and treatment pattern for how existing and new antibiotics attack a given infection. Establishing such a methodology will increase treatment rates and efficiencies and working in combination with the above second step should further limit over-prescription of antibiotics.
One longstanding idea regarding clinical trials in general is the lack of a centralized repository where clinical specimens from patients could be housed during and after clinical trials. These specimens would be used to reduce redundancy, increase efficiency in utilized dosage reducing costs and allow effective comparisons between drugs and/or control groups. This repository idea has also been proposed by the National Cancer Institute to retain samples from cancer patients undergoing various treatments.
Overall bacterial resistance is similar to global warming in the fact that it will have a significant detrimental influence on individuals and society as a whole, yet the global public at large does not view either as important problems that need to be solved in the near-future. Solving bacterial resistance will demand pharmaceutical companies stop being penny smart dollar stupid and realize that new antibiotics are essential to the profit maximization of other blockbuster chronic drugs. The FDA needs to realize that antibiotics require a specific pathway for approval and cannot simply be thrown into a generic approval pathway. Finally countries and companies have to work together to maximize information exchange to limit the spread of new resistant bacteria outbreaks and develop new treatments both through antibiotics and non-antibiotics to limit the probability of future resistance development.
Citations –
1. Walsh, C. Antibiotics: actions, origins, resistance. ASM Press; Washington, D.C: 2003.
2. Mukhtar, T, and Wright, G. “Streptogramins, oxazolidinones, and other inhibitors of bacterial protein synthesis.” Chem Rev. 2005. 105:529–42.
3. Tomasz, A. “The mechanism of the irreversible antimicrobial effects of penicillins: how the beta-lactam antibiotics kill and lyse bacteria.” Annu Rev Microbiol. 1979. 33:113–37.
4. Kohanski, M, Dwyer, D, and Collins, J. “How antibiotics kill bacteria: from targets to networks.” Nat. Rev. Microbiol. 2010. June: 8(6):423-435.
5. Nissen, P, et Al. “The structural basis of ribosome activity in peptide bond synthesis.” Science. 2000. 289:920–30.
6. Espeli, O, and Marians, K. “Untangling intracellular DNA topology.” Mol Microbiol 2004. 52:925–31.
7. Campbell, E, et Al. “Structural mechanism for rifampicin inhibition of bacterial RNA polymerase.” Cell. 2001. 104:901–12.
8. Food and Drug Administration. FDA's Strategy on Antimicrobial Resistance - Questions and Answers. http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm216939.htm
9. Coates, A, and Hu, Y. “Novel approaches to developing new antibiotics for bacterial infections.” British Journal of Pharmacology. 2007. 152:1147-1154.
10. Livermore, D. “Bacterial resistance: origins, epidemiology, and impact.” Clinical Infectious Diseases. 2003. 36(Suppl 1):S11-23.
11. Infectious Diseases Society of America’s (IDSA) Statement Promoting Anti-Infective Development and Antimicrobial Stewardship through the U.S. Food and Drug Administration Prescription Drug User Fee Act (PDUFA) Reauthorization Before the House Committee on Energy and Commerce Subcommittee on Health. March 8, 2012.
12. U.S. Department of Health and Human Services - Centers for Disease Control and Prevention. “Antibiotic Resistance Threats in the United States, 2013.” 2013.
13. Eisenstein, B, and Hermsen, E. “Resistant infections: a tragic irony in modern medicine.” APUA Clinical Newsletter. 2012. 30(1):11-12.
14. Centers for Disease Control and Prevention. “Estimating health care-associated infections and deaths in U.S. hospitals.” Public Health Rep. 2002. 122:160-166.
15. Choe, J. “Fewer drugs, more superbugs: strategies to reverse the problem.” APUA Clinical Newsletter. 2012. 30(1):16-19.
16. McArdle, M. “Resistance is futile.” The Atlantic. Oct. 2011. http://www.theatlantic.com/magazine/archive/2011/10/resistance-is-futile/8647/
Most of the early work concerning antibiotics occurred between the years 1928 and 1942 with the initial work of Sir Alexander Fleming in 1928 who accidentally empirically discovered the anti-bacterial properties of the mold, Penicillium and Gerhard Domagk who discovered the first class of antibacterial agent, sulfonamides, in 1935. In 1939 Rene Dubos discovered the first naturally derived antibiotic, tyrothricin, but after testing was deemed too toxic for human administration. The substance utilized by the mold to achieve such properties was isolated and unsurprisingly named penicillin by Ernst Chain and Howard Florey in 1942. By the early 1940s both sulfonamides and penicillin began clinical use in treatment of diseases. Later penicillin was first chemically synthesized in 1957 by John C. Sheehan, which generated the basic information required to begin synthesis of synthetic penicillin derived antibiotics to combat resistance.
Antibiotics have two modes of function: prevention of bacterial growth (bacteriostatic) and bacterial death (bactericidal). In normal immune systems typically either function is sufficient for recovery as the patient’s immune system should be able to neutralize the bacteria after antibiotic application. However, in those individuals who have weaker immune systems, elderly, very young children or other immunocompromised, bacteriostatic antibiotics may not be enough to fully treat the illness. The bactericidal behavior of penicillin is largely why it was the favored antibiotic over sulfonamides before bacterial resistance started to emerge.
Antibiotics have a wide range of functional pathways to influence bacterial growth: 1) destroy cell wall either through the production of pores or negation of synthesis elements; 2) neutralize aspects of protein synthesis including blocking ribosome production or their binding to appropriate targets; 3) neutralize DNA synthesis and other nucleic acid metabolism functions.1-4 When identifying a new antibiotic agent testing is important to determine the functionality of the antibiotic, how long it works and how large of a dose is required to receive an effective treatment response. Dosage is important because a large enough dose of antibiotic administered against a non-resistant target will kill it, but will also generate significantly detrimental side effects as well.
One of the major targets for antibiotics currently utilized in treatment is the bacterial ribosome largely because of its significant structural differences relative to its mammalian cousin. Bacterial ribosomes are 70S with a 30S and 50S subunit that are comprised from three types of rRNA (5S, 16S and 23S) versus the 80S mammalian ribosome.2,5 This difference makes antibiotics that target ribosomes attractive candidates as the probability of antibiotic interaction against mammalian (friendly) ribosomes leading to unpleasant side effects is low. Antibiotics that target DNA synthesis can also be attractive candidates because of the ability to target molecules that are not utilized in mammalian cells like bacterial DNA girase (topoisomerase II),6 which packs and unpacks supercoiled bacterial DNA, or bacterial DNA-dependent RNA polymerase.7 Other antibiotics neutralize bacteria through indirect means like targeting unique secondary products that are required for DNA like the metabolism of tetrahydrofolic acid. Tetrahydrofolic acid is essential for the synthesis of purines, pyrimidines and some amino acids. Anti-metabolites interfere with tetrahydrofolic acid synthesis and, therefore, inhibit DNA synthesis.
There are two classifications for antibiotics: narrow-spectrum that only work on a small number of specific bacteria and broad-spectrum that work against a large number of bacteria. Not surprisingly though because of its target breadth the use of broad-spectrum antibiotics has a higher probability of developing antibiotic resistant bacteria. Therefore it is standard operating procedure for broad-spectrum antibiotics to only be assigned when the pathogen is unidentified or if unresponsive to any narrow-spectrum antibiotics. For instance gram negative bacteria are typically treated with broad-spectrum antibiotics due to the structural differences in the cellular wall and internal reproduction machinery, which make more narrow-spectrum antibiotics, which are designed to treat gram positive bacteria, ineffective.
Antibiotics are also separated into three classifications derived from their application: surface, oral or intravenous. Surface applications are placed on the skin, in the eyes or mucous membrane in the nose and are typically limited to the local area around where the antibiotic is applied. Oral applications are pills, tablets and gel-caps that are swallowed breaking down in the small intestine and are later absorbed by the bloodstream. Intravenous application is the most powerful application because there is little residence or lag time between application and absorption into the bloodstream. However, intravenous application typically only occurs at a hospital and is largely reserved for critical or uniquely specific conditions.
Of the three classifications oral application is one of the principle elements responsible for the development of bacterial resistance because despite warnings a number of patients continue to prematurely cease oral treatments due to a disappearance of illness related symptoms. Basically patients take some of the assigned dosage start to feel better and fail to finish the remainder of the dose due to a belief of non-necessity. Unfortunately not completing the dosage increases the probability of surviving bacteria becoming resistant.
Although antibiotics are normally used to treat illness they are also prescribed in certain situations to reduce the potential for infection and illness. The most common scenario for this preventative strategy is antibiotic treatment before major surgery to reduce probabilities of current operative and post-operative infection. Also combination therapy is popular where multiple drugs are administered together where one mechanism aids the effectiveness of the other in a synergistic relationship. An example of such a relationship is penicillin weakening or destroying cell walls allowing aminoglycoside entry into the cell. Typically synergistic activity is not an effective treatment strategy outside of circumventing non-pathway resistant mutations because normally a single antibiotic and the innate immune system can neutralize an illness. Also while effective combination therapy failure increases resistant probabilities for multiple drugs instead of just one.
Unfortunately the second most common pathway for bacterial resistance has developed from the widespread use of antibiotics in animal and milk production. In short farmers and corporate entities apply large amounts of antibiotics to healthy dairy cows and other livestock in an attempt to reduce their probability of contracting illness and increase their weight. The weight increases come from eliminating the current microbiota (gut bacteria population) through antibiotic treatment and re-establishing a weight-gain favoring microbiota through diet. However, the haphazard application of antibiotics in such a fashion increases the probability that resistant bacteria emerge and because resistance is just a matter of probability frivolous application strategies like the one above have net detrimental outcomes over the long-term.
Although the tools exist to synthetically create antibiotics from a new base core, a vast majority of antibiotics in use are derived from living organisms, mostly molds, fungi and other bacteria. The two major reasons synthetic antibiotics have not become prominent are safety and functionality concerns along with the financial cost associated with creating antibiotics versus the “lack” of a market for pharmaceutical profit. One of the most common and reliable ways of producing an antibiotic is biosynthesis where the specific organisms themselves manufacture the antibiotic under optimized growing and conditions with additional elements/stressors that will increase the rate and probability for production of the desired elements.
Industrial mass production of antibiotics through biosynthesis is carried out by fermentation where the antibiotics, which are typically secondary metabolites, are collected before cell death. The typical isolation process involves killing the cell, thereby production schemes require large amounts of cell growth to maximize product collection to ensure efficiency and profitability. Collection first involves extraction and then purification into a crystalline product. Organic solvents are used to increase the efficiency of collecting soluble products, but non-soluble products must be removed through additional steps like precipitation, ion exchange and/or adsorption.
The synthesis of synthetic antibiotics typically follows the same methodology. First, an existing antibiotic is selected for modification. The reason behind selecting an existing antibiotic is two-fold: first, there is already empirical certainty that the selected antibiotic has some form of activity against bacteria, thus there is no wasted money developing random chemical structures that have unknown activity profiles. Second, the existing antibiotic is safe enough for human consumption due to widespread use with relatively known side effects.
The second step for synthetic generation is to identify the chemical structure of the active portion of the antibiotic in order to determine what structural modifications could be made to change activation potentials against resistant organisms. Third, the operational pathway of the antibiotic is identified and confirmed. Finally, alterations are made to some part of the structure of the antibiotic to possibly change its response to a given infection. For example all members of the penicillin family have identical rings, but the chemical chain (R group) attached to the ring will be different for different members of the family. So modification of that particular chemical chain is frequently the target of synthetic strategies for penicillin.
After their production these new synthetic derivatives are tested for effectiveness and to ensure retention of safety due to the changes in the chemical formula. In addition to this general methodology new techniques are being used to alter the genetic structure of certain bacteria so the bacteria itself produces a similar, but different antibiotic.
Pharmaceutical companies use computers to data mine and test modifications in the ring to observe chemical compatibility and probability. A standardized testing structure known as 'rational design program' is frequently used now. Such a program focuses on more in-depth analysis of how the favorable agent inhibits by looking at specific targets. In addition to making slight changes in chemical composition to increase antibiotic effectiveness against resistance emergence, another common goal of synthetic antibiotic creation involves increasing the half-life of the drug so that lasts longer in the bloodstream, which will increase the probability for effective treatment.
Identification of side effects and efficiency of treatment is carried out through a screening process that uses a large number of isolates of microorganisms and the secondary products of these organisms are tested in diffusion and growth limitation studies on test organisms. Molecules that show favorable results in both of these areas are then tested for selective toxicities. Afterwards the best candidates are isolated for more rigorous study, which enter the standard three clinical trial phase testing methodology for clinical drugs. However, recently there has been some momentum for changing antibiotic specific testing protocols to speed the application of new antibiotics to the market in effort to better address increasing bacterial resistance.8
Realistically a large amount of natural and synthetic antibiotics have been created at one time or another, but only a select handful have been proven safe and effective. The ideal characteristic of an antibody is a selective bacteria-unique target that negatively influences a critical system required to maintain life. This method of action will lead to the death of the bacteria, but should not interact with any eukaryotic cell targets thus heavily limiting, if not eliminating, any side effects associated with the use of the antibiotic. However, due to the general effectiveness of the immune system antibiotics that lack selective targeting are still useful if administered in a controlled and proper dose. Even if dosage is proper there is valid probability for the development of side effects, thus these changes must also be monitored.
When determining whether or not to treat with antibiotics the first step is to identify what type of organism is responsible for the illness. Under normal circumstances once identification has concluded available treatment options and treatment is rather straightforward. There are typically two elements that complicate treatment strategies. First, if the cause of the illness is viral most treatment options are no longer viable limiting options to a small number of interferons. Second, if the patient is allergic to the primary option of treatment a secondary, more than likely, less effective option will need to be utilized. If the illness is caused by an unidentified pathogen treatment is usually applied using broad-spectrum antibiotics, a strategy commonly called empiric therapy. Overall once a treatment is applied its effectiveness is determined by how well the drug is absorbed into the bloodstream, the diffusion rate of the drug and the half-life of the drug.
Some of the more common classes of antibiotics that have been used in the past or are currently in use are:
Penicillins:
Alexander Fleming discovered the penicillin group from the fungi Pencillium in 1928 (specifically penicillin G was isolated first and later followed by procaine penicillin, benzathine penicillin and penicillin V). Penicillin functions by damaging or destroying bacterial cell walls while the bacterium are in the process of reproduction. The mechanism of action is the inactivation transpeptidase, which is necessary for cross-linking and proper cell wall synthesis. The bacterium accepts penicillin as a substrate and then alkanolates a nucleophilic oxygen of the enzyme, rendering it inactive. Cell wall construction and maintenance ceases leaving multiple holes in the existing cell wall due to continuing natural degradation. This process is also aided by negative feedback where increasing osmotic pressure increases the probability of cytolysis and excess peptidoglycan precursor, due to limited cell wall synthesis, triggers hydrolases and autolysin activation further breaking down the cell wall.
The antibiotic nature of the penicillin is due to the strained beta-lactam ring; when the ring opens, strain is reduced making penicillin more reactive than ordinary amides. Based on its method of action penicillins do not act against organisms lacking cell walls like eukaryotic cells and certain types of bacteria (like most Gram-negative). Due to their ability to facilitate cell wall breakdown, penicillin works well in combination treatments with intracellular acting antibiotics that attack DNA, RNA and/or protein synthesis. Unfortunately due to unsurprising overuse, penicillin has been used for over half a century most bacteria have become resistance on a large-scale.
While the lack of cell walls in eukaryotic cells limits the side effects from these antibiotics, some mild side effects can occur from their use like diarrhea, rashes and hives (which usually indicates an allergy). The most rare and dangerous side effect is an “anaphylactic” allergy, which results in labored breathing due to swelling in the airway born from a severe allergic reaction. Normally allergic reactions eliminate the availability of a given antibiotic, but if the situation demands the use of an antibiotic that will result in an allergic reaction a desensitization strategy is used where the patient receives small doses with a high frequency of administration and slight increases in the overall dosage.
Cephalosporins:
Along with cephamycins, cephalosporins are a class of beta-lactam antibiotic that originally acted against Gram-positive bacteria, but through modern synthetic synthesis newer formulations have increased action effectiveness against Gram-negative bacteria while weakening their action against Gram-positive bacteria. While its method of action is similar to penicillin due to a small structural difference cephalosporins are less susceptible to penicillinases making it more difficult for bacteria to neutralize its bactericidal action. Differing generations of cephalosporins have been created by largely modifying its nucleus to reduce the probability that bacteria develop resistance. Currently, although somewhat disputed, five different generations of cephalosporins have been created with the fourth and fifth generations classified as having broad-spectrum action.
Quinolones:
Quinolones, the largest sub-class being fluoroquinolones, are synthetic broad-spectrum antibiotic that was first developed in 1962 as a distillate byproduct in chloroquine synthesis. Quinolones are typically reserved for secondary application in community-acquired infections due to concerns over peripheral neuropathy along with other strong side effects and increasing bacterium resistance development along with enhancing probability of Clostridium difficile and MRSA infections. However, when used quinolones function occurs through blocking the action of DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive. For treatment quinolones can stand alone due to their increased probability of cell entry through porins, but in Gram-positive bacteria combination treatment with a beta-lactam antibiotic also increases treatment outcomes. Unfortunately numerous pathogens now demonstrate resistance to quinolones due to overuse in that they were the principle treatment of Gram-negative bacteria from the 60s until the 90s until the development of synthetic broad-spectrum beta lactam antibiotics and continued misuse in the 00s.
Aminoglycosides:
Aminoglycosides are molecules composed of amino-modified sugars and typically can act as antibiotics through two different mechanisms: first the ability to bind irreversibly to the 30S ribosomal subunit in bacteria interfering with successful mRNA interaction reducing the effectiveness of translation (i.e. protein synthesis). There is also some evidence that they also interfere with proofreading and inhibit ribosomal translocation. Second, aminoglycosides are thought to competitively displace magnesium and calcium that link polysaccharides within lipopolysaccharide groups creating transient holes disrupting cell wall permeability.
Aminoglycosides are primarily effective against Gram-negative aerobes and mycobacteria, but while effective antibiotics they are unfortunately rapidly dissolved in the stomach, which eliminates oral consumption, limiting their administration to IVs or injections. Also aminoglycosides have some fairly damaging side effects including kidney and auditory damage. Due to these side effects aminoglycosides are typically used as a last resort antibiotic against unknown or multi-drug resistant pathogens.
Polymyxins:
Polymyxins damages cell walls through interaction between lipopolysaccharide in the outer membrane and its hydrophobic tail in a similar method as detergent/soap. Polymyxin appears to work best in combination treatments with intracellular acting antibiotics for the disruption of the outer membrane allows for easier entry to the cell. Unfortunately similar to aminoglycosides, polymyxins are typically reserved for late stage treatments due to serious neurotoxic side effects.
Tetracyclines:
Tetracyclines (tetracycline, doxycycline) bind to the 16S portion of the 30S ribosomal subunit and block polypeptide chain elongation by preventing the attachment of charged aminacyl-tRNA. They are typically used when treating Gram-positive cocci, chlamydia, mycoplasma, and rickettsia. A secondary mechanism of function involves tetracyclines binding to ions on the membrane and generating additional ionophores disrupting calcium flow into and out from the bacteria. Unfortunately bacteria resistance has developed rapidly against tetracyclines significantly limiting their functionality.
Rifampicin:
Rifampicin binds strongly to DNA-dependent RNA polymerase leading to the inhibition of RNA synthesis. It is largely used in combination treatments against Mycobacterium infections most notably tuberculosis. Due to its mechanism of action rifampicin is also used in secondary combination treatments against more resistant bacteria. Combination treatments are the norm with rifampicin because when used alone bacterial resistance builds quickly.
Macrolides:
Macrolides are molecules with a macrolide ring and a standard construct of a linear molecule that later form a large ring induced by activation of an enzyme on the terminus molecule. These rings are linked through glycoside bonds with amino sugars usually cladinose and desosamine. The linear molecule is constructed similar to that of a protein with small molecules combined on a biological assembly line. Most macrolides function by interfering with bacterial ribosomes by binding reversibly to the P site on the 50S subunit preventing ribosomal initiation complex formation or amino-acyl translocation. In low doses it is typically bacteriostatic, but at higher concentrations it becomes bactericidal, but obviously side effects become more prominent as well. Leukocyte accumulation and interaction aid in transporting macrolides to infection sites increasing efficacy.
Sulfonamides:
Not all sulfonamides are antibacterial, but those that are typically have structures that resemble para-aminobenzoic acid (PABA), which is a precursor in folic acid synthesis. Sulfonamides compete (competitive inhibitors) with PABA to bind to dihydropteroate synthase, an enzyme involved in folate synthesis. Reduction of folate synthesis efficiency makes sulfonamides bacteriostatic. Sulfonamides are typically used in combination treatment, usually erythromycin or trimethoprim, due to recent escalation in resistance. There are few side effects associated with sulfonamide use due to the lack of biosynthesis of folate in humans; folate is instead acquired through diet.
Trimethoprim:
Trimethoprim (TMP) is a synthetic antibiotic. Similar to sulfonamide, trimethoprim selectively inhibits the dihydrofolic acid reductase of bacteria, which converts dihydrofolic acid to tetrahydrofolic acid, a precursor of purines stopping DNA synthesis and replication. TMP is normally bacteriostatic, but can be bactericidal and is commonly used in combination with sulfamethoxazole (SMX). This combination is useful because bacteria that are partly resistant to either TMP or SMX can still be killed by the combination of the two.
Vancomycin:
Vancomycin is a glycopeptide that inhibits cell wall synthesis in Gram-positive bacteria by preventing the synthesis of the long polymers N-acetylmuramic acid and N-acetylglucosamine and preventing polymer cross-linking. Through most of its lifetime vancomycin was viewed as a treatment of last-resort due to its poor oral bioavailability requiring intravenous treatment, which reduced the probability of bacteria resistance. Unfortunately in recent years bacteria resistance has grown exponentially significantly limiting the usefulness of vancomycin.
Resistance has become one of the biggest “rarely talked about” problems in the modern world. A bacterium becomes resistant to an antibiotic when it alters a portion of its genetic structure to neutralize the method of antibiotic action. The genetic change can neutralize antibiotic activity in multiple ways: the target is eliminated entirely, a new defense element is created to eliminate the ability of the antibiotic to target the molecule (deactivating it or removing it) or a change occurs in the pathway of operation eliminating the necessity of the target for growth and survival.1,9 There are typically two major categories that bacteria can alter their genetic structure to create resistance.
Random genetic mutation is the most basic way resistance is acquired. Basically random genetic mutation is the egg in the chicken and the egg question regarding bacterial resistance as no other forms of resistance could occur without the original underlying mutation. Unfortunately these mutations are random and do not require previous exposure to the antibiotic to become resistant. The spontaneous mutation of a susceptibility gene has a frequency of occurrence of anywhere from 10-12 - 10-7 which for some species increases to 10-7 to 10-5 under selective pressure during or after exposure to a specific antibiotic.10 This increased resistance probability is what creates concern by certain parties when discussing frivolous antibiotic administration on healthy organisms.
Another means of mutation that generates resistance is genetic transposition. Transposition is the recombination of genetic material due to transposons which are DNA segments with specific insertion sequences at each end. Using these sequences, transposons are able to migrate or jump between DNA strands in the same bacterium. Sometimes the new sequences that are created due to this movement produce antibiotic resistance.
The second method that leads to resistance is acquisition of a plasmid with the appropriate resistance. Bacteria commonly exchange circular pieces of DNA smaller than their chromosomes otherwise referred to as plasmids. Plasmid acquisition typically occurs in one of three ways: 1) bacterium in close contact with each other freely transfer various plasmids typically referred to as transduction. If the receiving bacterium transfers a plasmid back then the process is referred to as retrotransfer; 2) the unilateral transfer of a plasmid between bacterium during reproduction typically referred to as conjugation; 3) the absorption of a portion or entire chromosome by another bacterium typically referred to as transformation;
Overall there are five major mechanisms in which a bacterium uses these genetic additions or mutations to acquire resistance. 1) Antibiotic Modification - The antibiotic is inactivated typically by the production of a new enzyme that targets the antibiotic changing its structure; 2) Antibiotic Entry Restriction – Modification lowers the probability that the antibiotic is able to enter the cell to target intracellular molecules; this mechanism is more common in Gram-negative bacteria where porins that typically allow diffusion of antibiotics through the membrane are altered disallowing antibiotic entry; 3) Enhanced efflux of the antibiotic – efflux pumps are augmented or synthesized at faster rates to remove antibiotics from the intracellular space and cytoplasm before it can reach the target molecule; 4) Alteration of Drug Target – the mutation changes the structure of the target molecule so the antibiotic can no longer bind triggering its effect; 5) Pathway Alteration – This is the least common mutation due to its complexity, the bacterium produces an alternate redundant pathway mitigating the effectiveness of antibiotic blocking of the initial pathway.
One troubling element of resistance is how rapid it appears to be developing. For example in the 1940s when penicillin use was first becoming standard protocol for all isolates of S. Aureus <1% of isolates were resistant, but by 1951 approximately 75% of isolates were resistant which is why synthetic penicillin was created. For S. pneumoniae only 2% of isolates in 1981 were penicillin resistant versus 12% in 1995. It is thought that similar types of resistance development curves exist for other bacteria and other antibiotics. Of bacteria that have developed resistances the Infectious Diseases Society of America (IDSA) believes that Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter and E. coli are the most advanced and dangerous.11
The Gram-negative Acinetobacter, Pseudomonas, Enterobacter are becoming increasingly resistant to existing antibiotics at a much faster pace than their Gram-positive brethren. According to the CDC methicillin-resistance Staphylococcus aureus (MRSA) kills approximately 11,000 more than emphysema, AIDS, Parkinson’s or homicides.12 An additional 100,000 die from hospital acquired infections where a vast majority of those infections are resistant to at least one type of antibiotics.13,14
Antibiotics are misused primarily through excessive use of prophylactic strategies for travelers, failure to prescribe correct dosages through history of use and weight, failure to complete the prescribed dosage regardless of existing symptoms and inappropriate prescription of antibiotics for non-necessary conditions. In addition to misuse, the crisis among antibiotic resistant bacteria has largely come about due to a vast majority of pharmaceutical companies electing not to continue antibiotic research programs to develop new antibiotics. Not surprisingly without a continuous stream of new antibiotics, especially those with new core structures, increasing bacteria resistance has narrowed the available treatment options for existing bacteria infections. To highlight this deficiency in new antibiotics from 2008 to early 2013 only two systemic antibacterial agents were approved by the FDA versus the approval of sixteen from 1983-1987.14 Of at least 20 pharmaceutical companies that had large research and development programs in 1990 only AstraZeneca and GlaxoSmithKline remain today.15,16
One could argue that with the progression of time novel antibiotic discoveries become more difficult so it is understandable that fewer antibiotics would be developed now versus 20-30 years ago; while this rationality is correct a drop off of 87.5% in a 25-year span cannot be explained by such a rationality. In fact there are three principle reasons why a vast majority of pharmaceutical companies no longer focus on producing antibiotics.
First, there is little profitability in creating a new antibiotic largely because its application is single use over a short period of time versus the blockbuster (billion dollar+ per year) drugs that focus on chronic health or lifestyle conditions (statins, erectile dysfunction, high blood pressure etc.). In modern capitalism businesses prefer to sell a product that stabilizes a negative state/condition rather than cures it because the stabilizing agent can be sold in perpetuity. However, a counterpoint is that in the current market individuals pay $100,000 for an extra four months of life when facing stage-4 cancer, but balk at paying $125 for antibiotics that will help treat an infection. In this vein consumer priorities do appear misguided, based on fear rather than rationality ($100,000 for four more months and then death versus $125 for potentially decades of more life). This pricing difference is neither rational nor data-driven; there is no cost analysis that supports cancer drug pricing. Rather, drug pricing in the U.S. is based on public perception and fear. People are terrified of cancer, but not terrified by a multi-antibiotic resistant form of TB, which has much higher levels of virulence and a comparable fatality rate.
Second, drug research in general is expensive, especially now that most of the “low-hanging” fruit has been scooped off of the ground. The principle antibiotics that were first utilized in treatment (sulfonamides and penicillin) were derived from other species making their isolation and manufacture into a human applicable form straightforward. These compounds also provided effective core/lead compounds that could be slightly manipulated to produce new drugs, which had the potential to evade certain resistances bacteria developed for the initial principle compound. However, the manipulation of those core compounds has run fairly dry demanding more complexity, data mining and high throughput screening (i.e. computer power) to develop the next generation of antibiotics. Of course this complexity demands excess resources and financial capital increasing the costs of even attempting to create new antibiotics.
Third, some individuals believe that the regulatory system, especially in the United States, creates a sufficient obstacle for pharmaceutical companies. Critics cite that antibiotic approval by the FDA is confusing, unnecessarily complex and does not recognize the specialty of the antibiotic field of drug development versus other developmental fields. One of the more problematic elements of regulation is the narrow “approved for use” window assigned to antibiotics. For example when an anti-cholesterol drug is approved it is for broad use not high cholesterol values in the heart versus in the lower leg. When an antibiotic is approved it is approved to treat a specific single condition like pneumonia instead of the specific organism that the antibiotic or anti-bacterial targets.
Due to the volume based sales strategy with antibiotics and the narrow “approved for use” FDA rules where about one of every 72 new antibiotics are approved versus one of every 15 for other types of drugs, pharmaceutical companies would be encouraged to develop broad-spectrum antibiotics, which have higher resistance development profiles, the exact opposite of what antibiotic treatments should be striving for. Based on all of these elements: sales potential and regulation/research costs some estimate that in current market environment the production of a new antibiotic will actually cost a pharmaceutical company millions dollars over the life cycle of that given drug. Part of the problem with the additional regulatory steps demanded by the FDA could be what occurred after the approval of Telithromycin (brand name Ketek), which involved the use of fraudulent data to speed its approval resulting in numerous deaths and liver failures. Due to this incident the FDA has become more cautious when approving new antibiotics.
Passed in 2012 the GAIN act attempted to address some of the concerns with the deficiency in antibiotic research and development by extending marketing protections for select “qualified infectious disease products” by increasing levels of exclusivity (12 years to 17 years further delaying generics). Also there is an additional six months of exclusivity for drugs with a companion diagnostic test is approved. Basically this additional exclusivity tacks on to any Hatch-Waxman, orphan drug or pediatric exclusivity. This legislation also produced an expedited review awarding appropriate antibiotic candidates with priority review and fast track status.
In addition the FDA is responsible for revising guidelines for future antibiotic clinical trials to accurately reflect the latest scientific and clinical knowledge. So far in response to GAIN the FDA has created an anti-bacterial drug development task force to study future guidelines for drug development, released a list of high warning pathogens and reviewed with appropriate updates to numerous antibiotic drug development guidelines.
The problem with the GAIN act is it only focuses on one of the two important elements of the bacteria resistance issue, creating new antibiotics. There are no new regulations regarding the stewardship and application of existing and new antibiotics during the course of their administration. Without new rules new antibiotics will simply suffer the same fate as existing antibiotics and squander a percentage of their potential due to misuse.
Some may argue that FDA documents Final Guidance #209 and Draft Guidance #213 address this second element of usage and administration. However, voluntary recommendations are not effective rules and policy. #209 recommends that food/animal producers stop the use of medically important drugs (chiefly antibiotics) for growth promotion or feed efficiency purposes. It also suggests these producers seek veterinary oversight when application of any medical important drug is used for treatment or prevention. Not surprisingly it stands to reason that as only recommendations producers will only apply these actions if profitable. Seeing that a number of individuals/groups tend to ignore the antibiotic resistant problem and even violate existing usage law in the first place one cannot be confident that most producers will abide by these recommendations.
Draft Guidance #213 recommends that drug companies aid the application of Final Guidance #209 by removing any use suggestions on their drug labels pertaining to growth promotion. However, companies in the future will have the ability to list therapeutic uses, including disease prevention, on their labels. With antibiotic sales as a volume driven business it is difficult to see many companies voluntarily reducing the probability of sales of these products.
The FDA does acknowledge that making these guidelines voluntary is a significant handicap on their potential effectiveness, but claims that creating guidelines that have significant penalties associated with non-compliance will require time consuming formal hearings and legal processes that will more than likely see numerous evidentiary hearings and drag out for years partly because it would have to focus on one drug at a time . If this is the case then voluntary recommendations may be the best option to actually producing change.
In an attempt to combat the lack of new antibiotics the IDSA has proposed a specialized regulatory mechanism called the Special Population Limited Medical Use (SPLMU) exclusively for antibiotics that they wanted to be included in GAIN, but was not. The chief aspect of this new plan would change the approval process from two Phase III “lack of inferiority” trials to smaller Phase III trials using narrowly defined test subjects (those suffering from a condition born from a resistant bacteria). Despite the lack of safety information on these new antibiotic compounds it is thought that because these patients are already out of options due to the resistance the benefits derived from consuming the experimental compound will outweigh the risks. The thought is that through this direct treatment methodology safety and efficacy information can be derived for the experimental compound hastening the determination regarding whether or not it would be suitable for large-scale release.
This new testing regimen has been compared to the regimen utilized for development and approval of drugs for “orphan” conditions. However, orphan drugs will always remain a niche treatment area whereas these new antibiotics would eventually be used by millions of people with wide ranging characteristics that could produce a variety of side effects. Such a situation creates one of two strategies: 1) conduct secondary testing after initial approval to identify serious potential side effects and address any of these outcomes appropriately or 2) react and track new side effects when they occur in a broader public administration of the drug. Clearly the first strategy is more costly for it involves traditional Phase III testing, which in a sense is just postponed for a time after approval, but the second strategy creates legitimate questions of legal liability for any life altering side effects.
The two chief problems with this testing strategy are differentiating between drug related and bacterial related detrimental effects and off-label distribution. Phase III trials are tightly controlled, especially with regards to patient health, so effective rationalities can be made regarding the side effects associated with the tested drug and its usefulness in overall treatment. Direct treatment against very sick patients will create numerous problems determining whether future negative conditions are born from the experimental compound, the bacterium or a combination of both.
Off-label usage is a continuous problem as well. Despite the belief that specialized labeling, instructions to physicians and limited marketing should provide a sufficient barrier, the problem is that off-label usage is already widespread with existing drugs, so there is little to prevent the same behavior with these new experimental drugs. Very strict record keeping would be required including the IDSA suggested post-market surveillance plan. Off-label application should result in heavy sanctions against the offending party and if the sponsor company is responsible immediate cessation of the trial.
Some individuals have suggested that the future antibiotic research and development will depend on appropriate incentives to make the research and development economically sustainable. Some of the suggested incentives involve tax credits, special grants and improved intellectual property protections. While enhancing intellectual property protections is suitable and appropriate simply expecting the government to pay private pharmaceutical companies to develop antibiotics is not appropriate. What most individuals who clamor for direct financial incentives forget is that antibiotic development is direct income poor indirect income rich. In short a pharmaceutical company cannot sell their other drugs to a corpse, keeping the consumer alive is of utmost importance. Therefore, focusing on creating statins and other chronic no-cure (stasis) drugs over antibiotics is foolish because the consuming population will die making even the most profitable blockbuster drug not profitable. In addition most of the large pharmaceutical companies are not making “skin of their teeth” profit margins, thus to expect government, which is still running deficits, to incentivize antibiotic production is a short-term feasible long-term foolish strategy.
An interesting funding idea would involve all pharmaceutical companies that fail to develop new antibiotics to pay a royalty to those that do in effort to support antibiotic research and development. In addition this royalty would also allow successful companies to refrain from deployment of these new antibiotics until necessary. Furthermore this royalty could increase for novel mechanisms, which would also receive expedited approval from the FDA focusing on a new safety and efficacy track.
In addition to developing new antibiotics new usage policies need to be developed to ensure that these new antibiotics remain as fit as possible. There are numerous strategies that can and should be applied to limit the probability of resistance for new antibiotics. First, all nations must ban the use of antibiotics on non-human life despite the aforementioned reservations of the FDA. The shallow benefits provided by injecting mass quantities of antibiotics into healthy farm animals and the like are completely outweighed by the selective pressures these antibiotics provide for a more rapid development of resistance. The European Union has already done its part on this issue, it is time for the rest of the world to follow suit.
Second, the development of diagnostic and metabolic biometrics to create an “antibiotic floor” in order to prevent the foolish and unnecessary prescription of antibiotics to patients that should recover in a suitable fashion through standard non-antibiotic therapeutic strategies (hydration, sleep, exercise, etc.). This floor is important because it is more common than it should be for individuals suffering from viral infections to demand antibiotics that will do nothing but either be disposed of or increase resistance probability for current non-pathogenic bacteria residing in the patient. Third, sewage treatment methodologies should develop an additional step or agent that will increase the degradation rate for antibiotics in the waste stream or remove them entirely. Fourth, a standardized treatment methodology should be created to understand the timeline regarding the dosage and treatment pattern for how existing and new antibiotics attack a given infection. Establishing such a methodology will increase treatment rates and efficiencies and working in combination with the above second step should further limit over-prescription of antibiotics.
One longstanding idea regarding clinical trials in general is the lack of a centralized repository where clinical specimens from patients could be housed during and after clinical trials. These specimens would be used to reduce redundancy, increase efficiency in utilized dosage reducing costs and allow effective comparisons between drugs and/or control groups. This repository idea has also been proposed by the National Cancer Institute to retain samples from cancer patients undergoing various treatments.
Overall bacterial resistance is similar to global warming in the fact that it will have a significant detrimental influence on individuals and society as a whole, yet the global public at large does not view either as important problems that need to be solved in the near-future. Solving bacterial resistance will demand pharmaceutical companies stop being penny smart dollar stupid and realize that new antibiotics are essential to the profit maximization of other blockbuster chronic drugs. The FDA needs to realize that antibiotics require a specific pathway for approval and cannot simply be thrown into a generic approval pathway. Finally countries and companies have to work together to maximize information exchange to limit the spread of new resistant bacteria outbreaks and develop new treatments both through antibiotics and non-antibiotics to limit the probability of future resistance development.
Citations –
1. Walsh, C. Antibiotics: actions, origins, resistance. ASM Press; Washington, D.C: 2003.
2. Mukhtar, T, and Wright, G. “Streptogramins, oxazolidinones, and other inhibitors of bacterial protein synthesis.” Chem Rev. 2005. 105:529–42.
3. Tomasz, A. “The mechanism of the irreversible antimicrobial effects of penicillins: how the beta-lactam antibiotics kill and lyse bacteria.” Annu Rev Microbiol. 1979. 33:113–37.
4. Kohanski, M, Dwyer, D, and Collins, J. “How antibiotics kill bacteria: from targets to networks.” Nat. Rev. Microbiol. 2010. June: 8(6):423-435.
5. Nissen, P, et Al. “The structural basis of ribosome activity in peptide bond synthesis.” Science. 2000. 289:920–30.
6. Espeli, O, and Marians, K. “Untangling intracellular DNA topology.” Mol Microbiol 2004. 52:925–31.
7. Campbell, E, et Al. “Structural mechanism for rifampicin inhibition of bacterial RNA polymerase.” Cell. 2001. 104:901–12.
8. Food and Drug Administration. FDA's Strategy on Antimicrobial Resistance - Questions and Answers. http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm216939.htm
9. Coates, A, and Hu, Y. “Novel approaches to developing new antibiotics for bacterial infections.” British Journal of Pharmacology. 2007. 152:1147-1154.
10. Livermore, D. “Bacterial resistance: origins, epidemiology, and impact.” Clinical Infectious Diseases. 2003. 36(Suppl 1):S11-23.
11. Infectious Diseases Society of America’s (IDSA) Statement Promoting Anti-Infective Development and Antimicrobial Stewardship through the U.S. Food and Drug Administration Prescription Drug User Fee Act (PDUFA) Reauthorization Before the House Committee on Energy and Commerce Subcommittee on Health. March 8, 2012.
12. U.S. Department of Health and Human Services - Centers for Disease Control and Prevention. “Antibiotic Resistance Threats in the United States, 2013.” 2013.
13. Eisenstein, B, and Hermsen, E. “Resistant infections: a tragic irony in modern medicine.” APUA Clinical Newsletter. 2012. 30(1):11-12.
14. Centers for Disease Control and Prevention. “Estimating health care-associated infections and deaths in U.S. hospitals.” Public Health Rep. 2002. 122:160-166.
15. Choe, J. “Fewer drugs, more superbugs: strategies to reverse the problem.” APUA Clinical Newsletter. 2012. 30(1):16-19.
16. McArdle, M. “Resistance is futile.” The Atlantic. Oct. 2011. http://www.theatlantic.com/magazine/archive/2011/10/resistance-is-futile/8647/
Saturday, November 30, 2013
Is War Inevitable?
The question of whether or not war among humans is unescapable is a troubling one for it goes to the core of who we are as a supposedly logical and rational species. Some argue that conflict is inherent in our makeup with deep biological roots that cannot be overcome. However, others believe that no creature with any level of rationality is destined to yield to their supposed aggressive nature. So who is right and what elements contribute to such a reality?
The idea that humans have a predisposition towards violence, either intraspecies or interspecies, has been debated for decades. Both sides attempt to utilize the behaviors of other primates as empirical support for their positions, but different primate species demonstrate different levels of innate violence even within the same genus as rhesus macaques are very violent, but stump tail macaques are generally non-violent. Overall studying primate behavior does suggest that environment shapes behavior almost exclusively versus genetics for even when rhesus macaques are transplanted into a stump tail troop the rhesus change and adapt reducing their violent behavior.1,2
Based on this information there appears to be two driving keys to conflict: survival and expression of dominence. Interestingly enough both of these keys involve the acquisition of resources. Initially one could state that all violence and aggression boils down to resource collection. Looking at all of the conflict over history rarely, if ever, can one characterize a conflict where resources were not the driving force initating that conflict regardless of whether the war was on of conquest or independence. Resource motivation for wars of conquest are self-explanatory where motivations in wars of independence are to “unshackle” resource access controlled by the ruling parties so one can control his or her future.
If an individual has enough resources to survive the need for violence is reduced because the weighted necessity of those resources is reduced. For example what is the probability of acceptance if someone with 10,000 dollars in the bank is offered 10 dollars to do 100 pushups verses someone who has 100 dollars in the bank? Although the cost benefit ratio of the deal for both individuals is generally the same, the overall weight is different for the 10 dollars is more valuable to the second individual than the first; therefore the second individual is more likely to accept the arrangement.
The same can be said for displays of aggression and conflict engagement. When an individual or group has a lot of resources the costs of war seem greater than when that entity has few resources even if the costs are the same. This psychology is especially true when resources are scarce to the point where survival is at stake because the aggressor rationalizes three options: 1) a low quality life leading to a hastened death due to lack of resources; 2) a quicker death due to the conflict; 3) a longer live due to new resources acquired through victory; in all negative scenarios death is the worst outcome, but conflict does create a pathway to more resources and continued survival where the status quo does not.
This cost element can also be regarded as only a secondary element to initiating a war. While war is costly, especially in the most extreme fashion (the loss of life) and most cost benefit analysis reject war, most individuals do not first consider a cost-benefit analysis, but instead question whether or not they the war will be successful. What is the point of conducting a war, no matter what the benefits, if one cannot win? A low probability of victory is what stops a vast majority of individuals/groups from engaging in conflict; however, it is also what allows inequality and injustice to persist as well.
Clearly resource allocation and shortage heavily influence aggressive tendencies in creatures, even those of higher intelligence, because if one has an abundance of resources then violent action is unbenefical because the gains are mitigated, one can solve problems with the abundance of available resources. While this reasoning is logical it still begs the question of why do different groups initiate aggressive actions against other parties even when they have enough resources to survive? Even though resources play the major role in aggressive and violent behavior there are clearly other factors that initiate violence. What are these additional elements?
The secondary elements that catalyze aggressive behavior appear to be pride/ego and freedom. Even if a creature has adequate resources to survive, if they lack the freedom to use those resources or acquire more resources they may resort to aggression to change this situation. One could acknowledge that such action is also influenced by a lack of resources, but not isolated to that situation. Pride/ego induces aggression in one of two ways: 1) when one feels wronged on some level by another, which then deamnds some level of consequence against the offending party; 2) when one wants to prove that he/she is better than other individuals;
Further exploring the human psychological aspect to conflict when resources are not the sole driving force, ego is an interesting element to conflict because it is not insinctive instead it is brought on by cultural or soceital triggers. For example everyone at some level wants to be respected, but not everyone feels the need to consider him/herself better than someone else. The expansion of ego drives the desire to compare each other in effort to judge self-worth, which then drives conflict. The acquisition of resources, chiefly money, is the principle measuring factor used by humans when distinguishing superiority between individuals. Remove this relative judgment standard in favor of a self-absolute standard and it stands to reason that conflict would decrease. Instead of judging each other on a comparison basis, one would only judge the possessed number of resources against a self-imposed standard ignoring all others. The need to be regarded as better than another human drives people, even when equal, to seek more and war/conflict is one way to acquire that more. In one respect the problem is not that aggression or violence is in human nature, but instead it is in our complexity, consciousness and society.
There in lies the chief problem when attempting to eliminate conflict among humans; resource allocation is a fixable problem, but is made much more complicated because of this personal ego attribute. For example most societies use capitalism as their economic system, a system the demands competition and unequality between the members of that society due to the necessity to assign winners and losers in such a system. Therefore, in this system even if resources are abundant enough that everyone could receive what is necessary to survive individuals could be (and are frequently) outcompeted for those resources by those who already have significant resources. This enhanced competition factor is largely the reason why more inequality exists in the first place.
Not surprisingly capitalism has a notorious feedback system where those who have resources increase their probaibility of getting more resources while those who don’t have resources decrease their probability of getting resources in the future. Sadly while some continue to believe that capitalism is principly a meriticracy such a characterization can no longer be accurately applied in modern society, for numerous examples exist where smart and determined individuals fail to acquire suitable resources because those who already have resources force the use of special connections and secret handshakes to enhance resource acquisition probabilities. Unfortunately as long as capitalism retains its competitive characteristic and individuals are free to compete for all resources despite their personal resource standing (i.e. no resource acquisition ceiling) there is little reason to suspect a lasting and significant reduction in conflict within a capitalistic system.
While human psychology provides a significant barrier to reducing conflict it can also provide hope through the same mechanisms. Interestingly studies find that people in general are more cooperative than economic rationality within a capitalistic system would predict3-6 creating meaningful questions within the study of reciprocity. One theory to explain this gap is that individuals utilize altruism as a signal to indicate their quality.7 Such a signal is meaningful because the demonstration of the altruistic action has cost to the actor and this cost is viewed as creating a sense of sincerity in the actor. This altruistic action is thought to bridge the gap between strangers who cannot rely on friendships to explain a lack of point-for-point reciprocity.
One can also use the application of altruism to shift the relative nature of superiority that capitalism promotes. Instead of individuals using their acquired wealth and resources as a signal for superiority they could use their ability to give to others as that signal. Such a mindset has been the general hope of some, but clearly has not come to pass possibly because it has only been passively applied by society rather than actively. Unfortunately while the complete elimination of relative self-worth would be ideal it appears that the transference of how realitve self-worth is evaluated is the best one can expect.
Some may argue that threats of war between major powers has declined demonstrating that aggression is not purely biological. The problem is that these declines can be attributed not to a change in biology or even one in societal behavior instead a change in weaponary. It is the advancement of weaponry used to wage war and a conscious understanding that one must use these weapons to win, but their use reduces the resource gains from war due to excessive levels of collaterial damage. Interestingly enough these new weapons make it less likely for a major power to conduct war, but more likely for a single individual or small group to conduct war. Thus the advancement of weaponry may actually shift the nature of large-scale aggression and conflict. If this shift actually occurs it will displace the long standing belief that when the benefits of war outweigh the costs, war occurs, versus when the costs of war outweigh the benefits war will not occur. With pride continuing to be a catalyst the cost of war become almost microscopic and if we turn that corner as a species, aggression, conflict and war become inevitable.
Overall ending general conflict among humans will be incredibly difficult because of the competitive nature of capitalism and how that nature is applied with human psychology and social relationships as well as war having become a formal part of human culture. While the frequency and ferocity of war conducted by human ancestors can be debated, it cannot be debated that in recent history war has been conducted constantly on both large and small scales. This empirical application of the process of war makes it more difficult to end war because individuals do see winners and losers not just losers from the conflict. It would be easier to argue against the benefits of war if humans had never engaged in it in the first place. However, despite the realities of ego, experience and survival it is possible for humans to throw off the “yolk” of conflict, but it will demand a perspective change and an active effort of utilitarian sacrifice.
==
Citations
1. Kummer, Hans. In quest of the sacred baboon: A scientist's journey. Princeton. University Press. 1997.
2. Chaffin, C, Friedlen, K, and De Waal, F. “Dominance style of Japanese macaques compared with rhesus and stumptail macaques.” American Journal of Primatology. 1995. 35(2):103-116.
3. Colman, A. M. “Cooperation, psychological game theory, and limitations of rationality in social interaction.” Behavioral and Brain Sciences. 2003. 26:139–198.
4. Fehr, E, and Fischbacher, U. “The nature of human altruism.” Nature. 2003. 425:785–791.
5. Ostrom, E. A. “Behavioral approach to the rational choice theory of collective action.” American Political Science Review. 1998. 92:1–22.
6. Palameta, B, and Brown, W. “Human cooperation is more than by-product mutualism.” Animal Behaviour. 1999. 57:F1–F3.
7. Roberts, G. “Cooperation through interdependence.” Anim. Behav. 2005. 70:901–908.
The idea that humans have a predisposition towards violence, either intraspecies or interspecies, has been debated for decades. Both sides attempt to utilize the behaviors of other primates as empirical support for their positions, but different primate species demonstrate different levels of innate violence even within the same genus as rhesus macaques are very violent, but stump tail macaques are generally non-violent. Overall studying primate behavior does suggest that environment shapes behavior almost exclusively versus genetics for even when rhesus macaques are transplanted into a stump tail troop the rhesus change and adapt reducing their violent behavior.1,2
Based on this information there appears to be two driving keys to conflict: survival and expression of dominence. Interestingly enough both of these keys involve the acquisition of resources. Initially one could state that all violence and aggression boils down to resource collection. Looking at all of the conflict over history rarely, if ever, can one characterize a conflict where resources were not the driving force initating that conflict regardless of whether the war was on of conquest or independence. Resource motivation for wars of conquest are self-explanatory where motivations in wars of independence are to “unshackle” resource access controlled by the ruling parties so one can control his or her future.
If an individual has enough resources to survive the need for violence is reduced because the weighted necessity of those resources is reduced. For example what is the probability of acceptance if someone with 10,000 dollars in the bank is offered 10 dollars to do 100 pushups verses someone who has 100 dollars in the bank? Although the cost benefit ratio of the deal for both individuals is generally the same, the overall weight is different for the 10 dollars is more valuable to the second individual than the first; therefore the second individual is more likely to accept the arrangement.
The same can be said for displays of aggression and conflict engagement. When an individual or group has a lot of resources the costs of war seem greater than when that entity has few resources even if the costs are the same. This psychology is especially true when resources are scarce to the point where survival is at stake because the aggressor rationalizes three options: 1) a low quality life leading to a hastened death due to lack of resources; 2) a quicker death due to the conflict; 3) a longer live due to new resources acquired through victory; in all negative scenarios death is the worst outcome, but conflict does create a pathway to more resources and continued survival where the status quo does not.
This cost element can also be regarded as only a secondary element to initiating a war. While war is costly, especially in the most extreme fashion (the loss of life) and most cost benefit analysis reject war, most individuals do not first consider a cost-benefit analysis, but instead question whether or not they the war will be successful. What is the point of conducting a war, no matter what the benefits, if one cannot win? A low probability of victory is what stops a vast majority of individuals/groups from engaging in conflict; however, it is also what allows inequality and injustice to persist as well.
Clearly resource allocation and shortage heavily influence aggressive tendencies in creatures, even those of higher intelligence, because if one has an abundance of resources then violent action is unbenefical because the gains are mitigated, one can solve problems with the abundance of available resources. While this reasoning is logical it still begs the question of why do different groups initiate aggressive actions against other parties even when they have enough resources to survive? Even though resources play the major role in aggressive and violent behavior there are clearly other factors that initiate violence. What are these additional elements?
The secondary elements that catalyze aggressive behavior appear to be pride/ego and freedom. Even if a creature has adequate resources to survive, if they lack the freedom to use those resources or acquire more resources they may resort to aggression to change this situation. One could acknowledge that such action is also influenced by a lack of resources, but not isolated to that situation. Pride/ego induces aggression in one of two ways: 1) when one feels wronged on some level by another, which then deamnds some level of consequence against the offending party; 2) when one wants to prove that he/she is better than other individuals;
Further exploring the human psychological aspect to conflict when resources are not the sole driving force, ego is an interesting element to conflict because it is not insinctive instead it is brought on by cultural or soceital triggers. For example everyone at some level wants to be respected, but not everyone feels the need to consider him/herself better than someone else. The expansion of ego drives the desire to compare each other in effort to judge self-worth, which then drives conflict. The acquisition of resources, chiefly money, is the principle measuring factor used by humans when distinguishing superiority between individuals. Remove this relative judgment standard in favor of a self-absolute standard and it stands to reason that conflict would decrease. Instead of judging each other on a comparison basis, one would only judge the possessed number of resources against a self-imposed standard ignoring all others. The need to be regarded as better than another human drives people, even when equal, to seek more and war/conflict is one way to acquire that more. In one respect the problem is not that aggression or violence is in human nature, but instead it is in our complexity, consciousness and society.
There in lies the chief problem when attempting to eliminate conflict among humans; resource allocation is a fixable problem, but is made much more complicated because of this personal ego attribute. For example most societies use capitalism as their economic system, a system the demands competition and unequality between the members of that society due to the necessity to assign winners and losers in such a system. Therefore, in this system even if resources are abundant enough that everyone could receive what is necessary to survive individuals could be (and are frequently) outcompeted for those resources by those who already have significant resources. This enhanced competition factor is largely the reason why more inequality exists in the first place.
Not surprisingly capitalism has a notorious feedback system where those who have resources increase their probaibility of getting more resources while those who don’t have resources decrease their probability of getting resources in the future. Sadly while some continue to believe that capitalism is principly a meriticracy such a characterization can no longer be accurately applied in modern society, for numerous examples exist where smart and determined individuals fail to acquire suitable resources because those who already have resources force the use of special connections and secret handshakes to enhance resource acquisition probabilities. Unfortunately as long as capitalism retains its competitive characteristic and individuals are free to compete for all resources despite their personal resource standing (i.e. no resource acquisition ceiling) there is little reason to suspect a lasting and significant reduction in conflict within a capitalistic system.
While human psychology provides a significant barrier to reducing conflict it can also provide hope through the same mechanisms. Interestingly studies find that people in general are more cooperative than economic rationality within a capitalistic system would predict3-6 creating meaningful questions within the study of reciprocity. One theory to explain this gap is that individuals utilize altruism as a signal to indicate their quality.7 Such a signal is meaningful because the demonstration of the altruistic action has cost to the actor and this cost is viewed as creating a sense of sincerity in the actor. This altruistic action is thought to bridge the gap between strangers who cannot rely on friendships to explain a lack of point-for-point reciprocity.
One can also use the application of altruism to shift the relative nature of superiority that capitalism promotes. Instead of individuals using their acquired wealth and resources as a signal for superiority they could use their ability to give to others as that signal. Such a mindset has been the general hope of some, but clearly has not come to pass possibly because it has only been passively applied by society rather than actively. Unfortunately while the complete elimination of relative self-worth would be ideal it appears that the transference of how realitve self-worth is evaluated is the best one can expect.
Some may argue that threats of war between major powers has declined demonstrating that aggression is not purely biological. The problem is that these declines can be attributed not to a change in biology or even one in societal behavior instead a change in weaponary. It is the advancement of weaponry used to wage war and a conscious understanding that one must use these weapons to win, but their use reduces the resource gains from war due to excessive levels of collaterial damage. Interestingly enough these new weapons make it less likely for a major power to conduct war, but more likely for a single individual or small group to conduct war. Thus the advancement of weaponry may actually shift the nature of large-scale aggression and conflict. If this shift actually occurs it will displace the long standing belief that when the benefits of war outweigh the costs, war occurs, versus when the costs of war outweigh the benefits war will not occur. With pride continuing to be a catalyst the cost of war become almost microscopic and if we turn that corner as a species, aggression, conflict and war become inevitable.
Overall ending general conflict among humans will be incredibly difficult because of the competitive nature of capitalism and how that nature is applied with human psychology and social relationships as well as war having become a formal part of human culture. While the frequency and ferocity of war conducted by human ancestors can be debated, it cannot be debated that in recent history war has been conducted constantly on both large and small scales. This empirical application of the process of war makes it more difficult to end war because individuals do see winners and losers not just losers from the conflict. It would be easier to argue against the benefits of war if humans had never engaged in it in the first place. However, despite the realities of ego, experience and survival it is possible for humans to throw off the “yolk” of conflict, but it will demand a perspective change and an active effort of utilitarian sacrifice.
==
Citations
1. Kummer, Hans. In quest of the sacred baboon: A scientist's journey. Princeton. University Press. 1997.
2. Chaffin, C, Friedlen, K, and De Waal, F. “Dominance style of Japanese macaques compared with rhesus and stumptail macaques.” American Journal of Primatology. 1995. 35(2):103-116.
3. Colman, A. M. “Cooperation, psychological game theory, and limitations of rationality in social interaction.” Behavioral and Brain Sciences. 2003. 26:139–198.
4. Fehr, E, and Fischbacher, U. “The nature of human altruism.” Nature. 2003. 425:785–791.
5. Ostrom, E. A. “Behavioral approach to the rational choice theory of collective action.” American Political Science Review. 1998. 92:1–22.
6. Palameta, B, and Brown, W. “Human cooperation is more than by-product mutualism.” Animal Behaviour. 1999. 57:F1–F3.
7. Roberts, G. “Cooperation through interdependence.” Anim. Behav. 2005. 70:901–908.
Wednesday, November 20, 2013
Advancement of Information and Quality Ideas in Society
Although it is the primary responsibility of those that seek information to properly acquire and utilize it by filtering out bias and misinformation, initial information providers can make these tasks easier and increase the efficiency of information collection by presenting information in a straightforward and organized manner. In general there are three categories of information presentation based on the intent and motivation of the provider: review, problem solving or debate. Each presentation method has its own strengths and weaknesses that need to be explored.
Information in a review form is the simplest means of transmission because there is no motivator the information is simply presented without opinion. In this style the goal of the presenter is to ensure as much accurate information about the given topic is made available to whoever wishes to acquire it. There are no judgments made about the information presented, outside of its factual accuracy, and no significant attempt to apply the information for any type of solution. There are three key points to maximizing the importance of distributing this type of information. First, define the exact context of the subject matter for presentation. Second, create a hierarchy outline of what information would be required to or aid in understanding the presented information and what information could be better understood after understanding the presented information. Third, the easiest step to say and most difficult to do, present all of the relevant and accurate information on the defined subject.
Currently the online dictionary Wikipedia does an excellent job at covering step one and a good portion of step three largely because of the efforts of the entire global community who continue to add information and continually check the accuracy of that information. Wikipedia has an advantage in raw information availability over print material, which should be taken advantage of when supplying information without application. This advantage allows Wikipedia users to continue to add information without having to subtract information that may not be as important, but still relevant.
Thus the information library regarding the particular subject matter is continually increased increasing the probability that individuals who seek out this information will find a lack of gaps in the overall amount of information pertinent to the overall subject. Two elements that Wikipedia could incorporate to improve its already significantly useful information distribution system would be to integrate step two indicating what specific knowledge would enhance the ability for a user to understand the current topic. Also the addition of a more specific categorization regarding what information is essential to understanding the basics of the topic at hand and what information is supplemental and what exactly does it teach.
Problem solving is a motivation that strives to solve a problem and presents all of the necessary information and methodology to solve that problem. The goal of problem solving is to first find at least one significant and workable solution and then to identify the optimal solution among all solutions, if multiple ones are found. When presenting information with this motivation the first and third step utilized in the review motivation is presented to act as a base for understanding the solutions presented later. Next the provider presents a number of different solutions to the problem highlighting their strengths and weaknesses. Unlike debate none of these solutions are presented with bias or any level of emotional favoritism, but instead just “cold hard” facts. Defining strengths and weaknesses for certain solutions can be difficult because responses to certain problems may rely on anticipating how outside parties will react which, despite what a number of individuals want to believe, are frequently unknown. In such cases it is best to simply present what would be the best course of action for the particular party based on how the presenter interprets the behavior of that particular party. Due to the lack of bias it is important for the presenter to clearly define the boundary conditions that will be applied to the presented solutions.
Solving problems can also be difficult because if one wants to create elaborate and specific solutions significant details will have to be provided. For smaller problems that only affect a single individual or a very small community these solutions can be crafted by a single person; however, when addressing large societal problems it is very difficult to expect a single person to devise a detailed solution methodology that will be successful both because of factors that may evade said person due to a lack of experience and knowledge or just the pure labor intensity of documenting the steps themselves.
Therefore, to solve the large much more meaningful problems successfully numerous parties need to study the issue and contribute solution pieces which can then be incorporated into a grand solution. Unfortunately this mindset for creating effective solutions has been abandoned in most sectors, especially the political sector, in recent years in favor of entire solutions being created by individuals who derive their experiences from only a small collection of knowledge and life events. Not surprisingly solutions born from these individuals are ineffective and a waste of time and resources, yet because they speak to a specific group of individuals egotism allows them to gain undeserved traction.
Currently there is no Wikipedia-like database that focuses on solving problems using the aforementioned methodology, but such a database could be and should be created. Overall the creation of such a database would be an extremely useful tool when making decisions and drawing conclusions on complicated matters such as foreign or domestic policy, economics and technology. With access to such a database of potential solutions for various concerns and problems it would allow the citizenry of a given country more control to pressure their government if they believe the government is not attempting to solve a given problem with the best solution. Knowledge is indeed power and it is time that people give themselves the means to acquire and wield that power in a more effective manner.
Debate is obviously driven by intent to convince others that the viewpoint of the presenter regarding information or a solution is correct. This method can be a useful motivation because those that utilize it are typically very passionate about the particular subject at hand and can potentially be receptive to new information about the subject. However, it can also be dangerous and counter-productive for the probability that the presented information contains unnecessary bias is much higher than review or problem solving motivation. Also the presenter may be invested in his/her particular viewpoint to an extent where it will not listen to any opposing evidence and/or even be willing to carry out an inferior solution just to get his/her way even if it creates negative consequences for others. Unfortunately these negatives have come to cast a large pall over the positives in modern times for debate information motivations.
Since the goal of debate is to convince listening parties that a particular viewpoint is the correct one, the presenter should focus heavily on highlighting key issues that demonstrate the strength of that position relative to the applied realistic boundary conditions. Significant weaknesses should also be identified and their flaws mitigated through the use of facts and logic regarding the existing boundary conditions that will be present when the solution is applied and during the source of its application. One of the worst things for an individual can do when questioned about a weakness in an argument is to utilize cognitive dissidence or something similar to avoid acknowledging it because it is impossible to improve an idea if one ignores its legitimate problems. The point in a debate is not to “win” the discussion, but to produce the best idea that matches an individual’s core beliefs; being stubborn and clinging to a clearly flawed idea disrupts the very point of a debate in the first place and cheapens the beliefs of those who retain these flawed ideas.
Overall more details can certainly be provided in the discussion of these different motivations behind information distribution, but the purpose of this post was simply to introduce the concept and argue for a more public venue of organization for the problem solving perspective. Current organization largely involves various scattered message boards or blogs (like this one) that offer little efficiency for those new to the topic at hand and can become environments of groupthink or needless conflict. Society is facing bigger problems as it continues to grow both from itself, wealth inequality and food distribution inefficiencies to name a few, and from the environment, human-induced global warming. These problems demand a concerted effort to develop effective solutions that cannot be solely assigned to academia. Therefore, it is important for the public to actively involve themselves in the development of these solutions and one of the most important steps is creating a public arena that is able to sort through the bias of arguments and apply the contents to reviews and problem solving.
Information in a review form is the simplest means of transmission because there is no motivator the information is simply presented without opinion. In this style the goal of the presenter is to ensure as much accurate information about the given topic is made available to whoever wishes to acquire it. There are no judgments made about the information presented, outside of its factual accuracy, and no significant attempt to apply the information for any type of solution. There are three key points to maximizing the importance of distributing this type of information. First, define the exact context of the subject matter for presentation. Second, create a hierarchy outline of what information would be required to or aid in understanding the presented information and what information could be better understood after understanding the presented information. Third, the easiest step to say and most difficult to do, present all of the relevant and accurate information on the defined subject.
Currently the online dictionary Wikipedia does an excellent job at covering step one and a good portion of step three largely because of the efforts of the entire global community who continue to add information and continually check the accuracy of that information. Wikipedia has an advantage in raw information availability over print material, which should be taken advantage of when supplying information without application. This advantage allows Wikipedia users to continue to add information without having to subtract information that may not be as important, but still relevant.
Thus the information library regarding the particular subject matter is continually increased increasing the probability that individuals who seek out this information will find a lack of gaps in the overall amount of information pertinent to the overall subject. Two elements that Wikipedia could incorporate to improve its already significantly useful information distribution system would be to integrate step two indicating what specific knowledge would enhance the ability for a user to understand the current topic. Also the addition of a more specific categorization regarding what information is essential to understanding the basics of the topic at hand and what information is supplemental and what exactly does it teach.
Problem solving is a motivation that strives to solve a problem and presents all of the necessary information and methodology to solve that problem. The goal of problem solving is to first find at least one significant and workable solution and then to identify the optimal solution among all solutions, if multiple ones are found. When presenting information with this motivation the first and third step utilized in the review motivation is presented to act as a base for understanding the solutions presented later. Next the provider presents a number of different solutions to the problem highlighting their strengths and weaknesses. Unlike debate none of these solutions are presented with bias or any level of emotional favoritism, but instead just “cold hard” facts. Defining strengths and weaknesses for certain solutions can be difficult because responses to certain problems may rely on anticipating how outside parties will react which, despite what a number of individuals want to believe, are frequently unknown. In such cases it is best to simply present what would be the best course of action for the particular party based on how the presenter interprets the behavior of that particular party. Due to the lack of bias it is important for the presenter to clearly define the boundary conditions that will be applied to the presented solutions.
Solving problems can also be difficult because if one wants to create elaborate and specific solutions significant details will have to be provided. For smaller problems that only affect a single individual or a very small community these solutions can be crafted by a single person; however, when addressing large societal problems it is very difficult to expect a single person to devise a detailed solution methodology that will be successful both because of factors that may evade said person due to a lack of experience and knowledge or just the pure labor intensity of documenting the steps themselves.
Therefore, to solve the large much more meaningful problems successfully numerous parties need to study the issue and contribute solution pieces which can then be incorporated into a grand solution. Unfortunately this mindset for creating effective solutions has been abandoned in most sectors, especially the political sector, in recent years in favor of entire solutions being created by individuals who derive their experiences from only a small collection of knowledge and life events. Not surprisingly solutions born from these individuals are ineffective and a waste of time and resources, yet because they speak to a specific group of individuals egotism allows them to gain undeserved traction.
Currently there is no Wikipedia-like database that focuses on solving problems using the aforementioned methodology, but such a database could be and should be created. Overall the creation of such a database would be an extremely useful tool when making decisions and drawing conclusions on complicated matters such as foreign or domestic policy, economics and technology. With access to such a database of potential solutions for various concerns and problems it would allow the citizenry of a given country more control to pressure their government if they believe the government is not attempting to solve a given problem with the best solution. Knowledge is indeed power and it is time that people give themselves the means to acquire and wield that power in a more effective manner.
Debate is obviously driven by intent to convince others that the viewpoint of the presenter regarding information or a solution is correct. This method can be a useful motivation because those that utilize it are typically very passionate about the particular subject at hand and can potentially be receptive to new information about the subject. However, it can also be dangerous and counter-productive for the probability that the presented information contains unnecessary bias is much higher than review or problem solving motivation. Also the presenter may be invested in his/her particular viewpoint to an extent where it will not listen to any opposing evidence and/or even be willing to carry out an inferior solution just to get his/her way even if it creates negative consequences for others. Unfortunately these negatives have come to cast a large pall over the positives in modern times for debate information motivations.
Since the goal of debate is to convince listening parties that a particular viewpoint is the correct one, the presenter should focus heavily on highlighting key issues that demonstrate the strength of that position relative to the applied realistic boundary conditions. Significant weaknesses should also be identified and their flaws mitigated through the use of facts and logic regarding the existing boundary conditions that will be present when the solution is applied and during the source of its application. One of the worst things for an individual can do when questioned about a weakness in an argument is to utilize cognitive dissidence or something similar to avoid acknowledging it because it is impossible to improve an idea if one ignores its legitimate problems. The point in a debate is not to “win” the discussion, but to produce the best idea that matches an individual’s core beliefs; being stubborn and clinging to a clearly flawed idea disrupts the very point of a debate in the first place and cheapens the beliefs of those who retain these flawed ideas.
Overall more details can certainly be provided in the discussion of these different motivations behind information distribution, but the purpose of this post was simply to introduce the concept and argue for a more public venue of organization for the problem solving perspective. Current organization largely involves various scattered message boards or blogs (like this one) that offer little efficiency for those new to the topic at hand and can become environments of groupthink or needless conflict. Society is facing bigger problems as it continues to grow both from itself, wealth inequality and food distribution inefficiencies to name a few, and from the environment, human-induced global warming. These problems demand a concerted effort to develop effective solutions that cannot be solely assigned to academia. Therefore, it is important for the public to actively involve themselves in the development of these solutions and one of the most important steps is creating a public arena that is able to sort through the bias of arguments and apply the contents to reviews and problem solving.
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