Fight Aging! Newsletter, September 3rd 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • An Examination of the Link Between Chronic Inflammation and Cognitive Decline
  • First Generation Pharmaceutical Treatments for Transthyretin Amyloidosis Continue to Make Progress
  • The Futility of Attempts to Rigorously Distinguish Age-Related Disease from Aging
  • The State of Evidence for a Novel TP53-DHEAS Anti-Cancer Mechanism in Primates
  • Cellular Senescence is One of the Causes of Age-Related Decline of Liver Regeneration
  • An Update on a Human Telomerase and Follistatin Gene Therapy
  • Mitochondrial Mechanisms Link Oxidative Stress and Chronic Inflammation
  • Deep Wrinkles in Skin Associated with Higher Cardiovascular Mortality Risk
  • Remote Ischemic Conditioning as a Means to Beneficially Upregulate Stress Responses
  • Arguing for Aging to Influence Natural Selection through Loss of Parental Contributions to Early Life Evolutionary Fitness
  • Two New Species Found to Undergo Menopause
  • An Example of Efforts to Develop an Immunotherapy to Target Tau Aggregates
  • TransVision 2018 Takes Place in Madrid this October
  • Articles on Senolytics are Starting to Look Just Like Articles on any Other Field of Medical Research and Development
  • Regulation and Loss of Freedom are to Blame for Much of the Poor Strategy of Past Decades of Cancer Research

An Examination of the Link Between Chronic Inflammation and Cognitive Decline

Chronic inflammation is thought to be one of the major roads by which a few forms of low-level molecular damage, the root causes of aging, give rise to a much broader and more varied range of cell and tissue dysfunctions. Short-term inflammation is a necessary part of both regeneration and the protective activities of the immune system, and is vital to health. Long-term chronic inflammation that arises as a maladaptive reaction to the damage of aging is a different story, however. It changes the behavior of cells for the worse, disrupting regenerative processes, damaging organs, and accelerating the development and progression of age-related disease.

Inflammation is particularly well studied in the context of neurodegeneration, the gradual failure of the brain and the mind that it hosts. The central nervous system, brain included, is segregated from the rest of the body by the blood-brain barrier, and, accordingly, the immune system of the brain is somewhat different to that of the rest of the body. Cells that carry out the usual functions expected of the immune system, including mounting a defense against pathogens and clearing up debris, also participate in neural activity, such as by assisting in creation and maintenance of synaptic connections. Thus chronic inflammation in the brain can have worse and more complex detrimental effects than is the case in other organs.

The open access paper noted here is an example of continued efforts to understand the exact signals and causes that underlie the well established relationship between chronic inflammation in aging and the progression of neurodegenerative conditions. Inflammation arises as the result of signals passed between cells, most of which are at least cataloged at this time, even if a complete picture of this highly dynamic web of signaling is still under construction. Which of these signals are important, and is cognitive decline a function of the presence of these signals regardless of age, or are older individuals more negatively affected by a given level of inflammatory signaling, indicating that other mechanisms of deterioration are at work?

Systemic Inflammation Mediates Age-Related Cognitive Deficits

Mounting evidence associates cognitive impairment with systemic immune activation. For example, elevated serum levels of pro-inflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP), lead to impairments in overall cognition as well as impairments in specific functions, such as reduced processing speed, executive function, and memory. These associations between systemic inflammation and cognitive impairment have been found in young, middle-aged, and older adults. Furthermore, within older adults, this inflammation-cognition link has also been documented. However, to our knowledge, previous studies have not directly examined the mediatory role of systemic inflammation on cognitive aging.

Systemic inflammation leads to elevated circulating pro-inflammatory cytokines, including IL-6, TNF-α, and CRP, which can interact with the central nervous system through three three pathways that, when stimulated peripherally, will activate microglia and astrocytes in the brain to produce pro-inflammatory cytokines, propagating the signal into the neural environment. This leads to comparable inflammation levels in the brain and the periphery. Elevated neuroinflammation can result in structural and functional impairment in the brain, such as hippocampal atrophy and increased substantia nigra activity, both of which have been associated with cognitive deficits.

Going beyond previous work, the present study took a novel methodological approach by examining the mediation of systemic inflammation (i.e., serum levels of IL-6, TNF-α and CRP) on age-related cognitive impairments (i.e., deficits in processing speed and short-term memory). We found that systemic inflammation partially explained differences in cognitive performance associated with increased age. In particular, IL-6 levels accounted for the age-group difference in processing speed. Further, IL-6 levels accounted for the age-related differences in processing speed within the older but not the young age group. Neither of the remaining two examined inflammatory biomarkers (i.e., TNF-α, CRP) nor short-term memory yielded any significant effects.

Two possible mechanisms may underlie the observed moderated mediation. First, age may increase the impact of systemic inflammation on cognition. However, in the present study we did not find a significant age-moderation of the effect of IL-6 levels on processing speed. That is, the association between IL-6 levels and processing speed was comparable between young and older adults. Similarly, a previous study showed that an experimentally-induced elevation in inflammatory cytokine response consistently hindered reaction times among young participants. This suggests that systemic inflammation produces similar impairments regardless of individual age.

Second, systemic inflammation levels increase with age, possibly because older adults face more immune challenges and become increasingly likely to display mild chronic inflammation. With chronic conditions, primed microglia can yield deleterious effects on their local neuro-environment, eliciting even greater inflammation, which may further prime microglia. This, in combination with continued accumulation of immune challenges, implies that inflammation levels, and their subsequent influence on cognition, may accelerate with time. Previous longitudinal studies, however, found no associations between systemic inflammation levels and the rate of cognitive decline. Importantly, these earlier studies focused on cohorts of older adults only. Further, while participants were tracked for about 10 year periods, this time span may have been too short to capture causal effects. Following from this argument, findings from the present study, which investigated a wider age range, showed that IL-6 levels partially accounted for the variance in processing speed between young and older adults.

First Generation Pharmaceutical Treatments for Transthyretin Amyloidosis Continue to Make Progress

Perhaps a score of the countless proteins in the human body misfold in large amounts in later life. The misfolded form is insoluble, leading to solid deposits of the protein in and around cells. These problem proteins are known as amyloids, and the accumulation of amyloids is one of the root causes of aging. Amyloidosis conditions arise from the presence of amyloid and the disruptive effect it has on cellular biochemistry. The best known form of amyloid is the amyloid-β thought to cause Alzheimer's disease, but the research community is beginning to appreciate that other forms may be just as big a problem over the course of aging. The topic for today is transthyrein amyloid, and the efforts to produce therapies to address it and its consequences.

Transthyretin, or TTR, amyloid is of particular note in the cardiovascular system. Evidence suggests that transthretin amyloidosis is the full stop at the upper end of the natural human life span; the majority of the tiny fraction of people who survive everything else that aging can throw at the human form, and manage to become supercentenarians living to age 110 or later, will die because TTR amyloid clogs their cardiovascular system to the point of failure. In earlier old age, studies have suggested that at least 10% of heart failure patients suffered that outcome as the result of TTR amyloid. Beyond this, TTR amyloid may contribute to osteoarthritis, spinal stenosis, and cartilage degeneration.

The first generation of pharmaceutical therapies targeting transthyretin started out as efforts to target the hereditary form of this amyloidosis, in which genetic mutation greatly speeds up the process of amyloid formation. Not all of these development initiatives are applicable to the natural, age-related form of the condition. Those that are function by attempting to stabilize the protein, preventing it from assuming the harmful, misfolded configuration. Generally this results in marginal, incremental gains; it can only slow progression, and has little impact on existing amyloid deposits.

Alternative approaches that can remove existing amyloid deposits should be far superior for all the obvious reasons. A range of methods are at various stages in development, but it has been (and continues to be) slow going. Pentraxin's work on CPHPC as a therapy is ten years in, with a successful clinical trial a few years ago, but the folk in charge seem to be in no hurry to move ahead. Covalent's work on catalytic antibodies has been around for some time, but has not yet made the leap to very active and focused translational development. Other antibody-based efforts are still at earlier stages in development. So for now, the inferior approaches are those gaining all of the funding, and those advancing most rapidly to the clinic.

Drug Reduces Deaths from Underdiagnosed Form of Heart Failure

A phase three clinical trial has shown that a drug called tafamidis significantly reduces deaths and hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive form of heart failure that may be more common than doctors realize. If tafamidis receives FDA approval for transthyretin amyloid cardiomyopathy, it would be the first medical therapy for this life-threatening disease. Compared to a placebo, the drug reduced deaths by 30 percent, reduced cardiovascular-related hospitalizations by 32 percent, and slowed the decline in quality of life among the 441 patients enrolled in the 2.5-year study.

ATTR-CM occurs when a protein called transthyretin becomes unstable and clumps together and forms sticky amyloid in heart muscle. (Amyloid deposits also occur in Alzheimer's disease, but those develop through a different mechanism and cannot be treated with the drug tested in this study). The disease is most common in men over the age of 60 and is caused by heritable genetic mutations or age-related changes in the regulation of transthyretin. Tafamidis acts by stabilizing transthyretin, preventing its dissociation and ability to form amyloid. "Tafamidis prevents progression of the disease, and like other preventive drugs, it should be given as early as possible. We'll need to diagnose people with ATTR-CM earlier for this drug to have the biggest benefit. Currently, patients are diagnosed with advanced disease, and we need to change that."

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy

In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalization. In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo. Tafamidis was associated with lower all-cause mortality than placebo (29.5% versus 42.9%; hazard ratio, 0.70) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68.

Pfizer surprises ATTR rivals with tafamidis success

Over the course of the past several years, Alnylam and Ionis have pushed their respective treatments for hereditary TTR amyloidoisis (ATTR) through late-stage clinical testing to regulatory review by the Food and Drug Administration. Alynlam's drug, called patisiran, is seen by many analysts as more potent and efficacious in easing the symptoms of the rare disease - which causes progressively more severe organ damage, leading to neuropathy and cardiomyopathy. Ionis may win FDA approval for its rival candidate inotersen first, while Alnylam won't be far behind. But Pfizer's results could complicate the competitive mix.

The Futility of Attempts to Rigorously Distinguish Age-Related Disease from Aging

Aging is caused by damage. Age-related diseases are the end result of sizable amounts of that damage, branched out into a network of interacting downstream consequences and system failures. Aging and age-related disease are points on a continuum; age-related disease is an integral part of aging. Yet the predominant way in which researchers and clinicians view aging and age related disease remains one in which an artificial, arbitrary line is drawn between these two things. There is "normal aging" and there is disease. What to make of this when there is very little difference between the level of damage and dysfunction in two people who stand just on either side of that line? Further, the line is subjective, argued over, and interpreted in different ways by different groups, even in fields that apply reliable metrics and a cutoff point.

This business of arbitrary lines is driven by regulation, and the regulation of medicine still proceeds from the basis that aging is distinct from age-related disease - that aging is not a medical condition, should not be treated, is natural, normal, and beyond the bounds of medicine. The result is the present situation, in that regulators such the FDA will grant permission to treat the damage of aging provided that a treatment is only used on one specific tiny part of the constellation of symptoms that result from that damage, and only used for patients who are past a certain point of degeneration, so that their suffering can be stamped with a particular designation. People with a lesser amount of damage, just on the wrong side of the line, are out of luck. It is forbidden to work on prevention by addressing the causes of aging prior to the point at which they and their consequences become very harmful. This is ridiculous, and I think a sizable fraction of the participants in this broken system recognize that it is ridiculous. They nonetheless seem powerless to change it.

This paper on Alzheimer's disease is a fair example of the distracting nature of the dividing line between aging and disease; harmful processes are discounted because they are not harmful enough. Only the exception declines are worthy of note, of treatment. This sort of incentive steers researchers into poor ethical and strategic choices. If the underlying cause of disease, meaning underlying cause of aging, can be addressed, then every older person should be treated, and long before their degeneration becomes threatening to health and mind.

Distinguishing normal brain aging from the development of Alzheimer's disease: inflammation, insulin signaling and cognition

Normal aging is associated with deterioration of cognitive function and accumulation of neuropathological lesions that can also occur in Alzheimer's disease (AD). Distinguishing AD from normal aging, particularly in the earliest stages, allows for more thorough clinical characterization of abnormal cognitive decline and can also provide insights into AD pathophysiology that may ultimately support drug discovery, an element of the AD field that is currently lacking. Since its inception, the amyloid cascade hypothesis has bolstered AD research and helped progress the field immensely, however a fixation on this model may be hindering scientific advances and drug development.

Traditional neuropathological lesions in the AD brain include senile plaques, consisting of aggregated amyloid-β (Aβ) and neurofibrillary tangles (NFT) of tau protein, which accumulate extracellularly and intraneuronally, respectively. Enhanced neuroinflammation is also consistently observed in AD and evidence suggests that early hyperactivity of pro-inflammatory pathways in the brain precedes the development of plaques and tangles in AD. Muddying the waters, however, is the fact that aging itself is associated with similar aberrations in the brain, that may or may not lead to cognitive deterioration. Accumulating evidence suggests that Aβ plaques and neurofibrillary tau tangles are not uncommon in the brains of non-demented, cognitively healthy older people. Evidence has also shown that Aβ deposition correlates poorly with cognitive impairment in elderly cohorts, suggesting that Aβ per se does not directly influence cognitive function.

Classical pathological lesions in AD brain, amyloid and tau deposits are used as measures of disease progression and also as an indicator of therapeutic efficacy. However, given the paucity of consistent correlations between these markers and cognitive decline, future studies may wish to consider alternative pathological measures.

The State of Evidence for a Novel TP53-DHEAS Anti-Cancer Mechanism in Primates

Are there any comparatively simple ways in which natural cancer suppression mechanisms can be greatly enhanced? This is an interesting question to consider. The current repertoire of the cancer research and medical communities include what are arguably a few examples of an enhanced natural suppression mechanism, such as the various ways to drive more cancerous cells into a state of senescence than would normally make that transition. The study of the comparative biology of aging has uncovered a variety of suppression mechanisms in naked mole rats and elephants that might lead to human therapies, but I suspect that "simple" will not describe the programs needed to make any of those therapies a reality. More practical are means to enhance the immune system's capacity to attack cancer, spurring greater creation or greater replication of immune cells; examples include present IL-7 recombinant protein therapies, or potential future FOXN1 gene therapies.

The author of the open access paper below hypothesizes the existence of a cancer kill switch that has been overlooked largely because it exists in primates but not mice. If he is correct, then this would seem to offer an approach to therapy that falls squarely into the category of a potentially simple approach to enhance a natural mechanism. I feel that one should always treat single author papers with a certain polite skepticism until verified, however, even if, as seems to be the case here, it is reporting on work carried out by a team. The short version of the hypothesis is that (a) high levels of DHEAS can trigger the death of cells in which the primary tumor suppressor TP53 is disabled by mutation, (b) humans have unusually high levels of DHEAS in comparison to short-lived mammals such as mice, and (c) in humans, DHEAS levels fall with age, and thus the mechanism ceases to operate.

This has the look of a mechanism expensive enough to verify to discourage most teams from attempting to replicate findings in the absence of further supporting data. The only primate species in which the author believes the mechanism to exist are all endangered, protected, and cannot be easily studied in this context. The mechanism may exist in dogs, but that variant may or may not be close enough to the human variant to be useful. Further, the mechanism might almost be designed to be hard to work with in cell cultures and tissue models of cancer. There is also the very important question of the size of the effect: even if this is all as described, is it a significant effect in comparison to other issues that increase cancer risk in aging? Will it make enough of a difference if pursued and reactivated?

Detection of a novel, primate-specific 'kill switch' tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53

Cancer risk as a function of increasing age in elephants, wildebeest, moose and most other long-lived animals is linear, with little increase in slope with advancing age. This is in sharp contrast to cancer risk in humans, which increases in conformance with a logistic curve with a 30-year lag phase followed by steep exponential kinetics until very late in the life span. Taken together, these observations suggest that tumor suppression mechanisms in non-human species are generally of a type that does not substantially diminish over their lifespan, whereas those in humans do diminish with increasing age.

The p53 tumor suppressor is an ancient protein found in organisms ranging from Caenorhabditis elegans to Homo sapiens. Over the past four decades, a paradigm has evolved in which p53 is thought to function in a very similar manner across widely disparate species. More than half of all human tumors have been found to have mutations in TP53 (the human version of p53), and TP53 appears to be inactivated by other means in the remaining tumors where such mutations are absent. Findings have encouraged an exceptional degree of confidence among workers in the field that mouse models of tumor suppression offer reasonable approximations of mechanisms of tumor suppression in humans.

Thus, for the past several decades, the guiding paradigm with respect to the p53 tumor suppressor has been that it functions in a more or less similar manner across species at least as diverse as man and mouse, and probably across species even more diverse than that. It is our belief, however, that the establishment of this paradigm has come at the expense of ignoring more fundamental paradigms, and the prevailing p53 paradigm may have misled the endeavor of cancer research. The concept of species-specific mechanisms of tumor suppression is gaining increasing support. Recent evidence in the elephant, the blind mole rat, and canines, all support the concept that species-specific mechanisms of tumor suppression may in fact be relatively common.

Exposure to significant cellular stress is well known to activate the p53 tumor suppressor to induce apoptosis. We have recently reported our detection in canines of a rudimentary form of an otherwise primate-specific adrenal androgen-mediated 'kill switch' in which cell death is triggered by the inactivation of p53. It has been hiding in plain sight within the p53 repertoire and may have kept so well hidden because it depends on the unique, primate-specific evolution of extraordinarily high post-natal levels of circulating DHEAS. In humans, this begins at about age 6 years with the advent of adrenarche, the development of the adrenal zona reticularis, a tissue the only apparent function of which is to synthesize DHEAS. True adrenarche may only occur in the human, chimpanzee, and bonobo.

Nevertheless, dogs have a rudimentary zona reticularis and a homologue of adrenarche has been reported in them. Based upon this finding, we formulated the hypothesis that canines might also possess a homologue of the otherwise primate-specific adrenal androgen-mediated tumor suppressor system and that at least some canine tumors might retain sensitivity to triggering of this system.

Circulating DHEAS does not occur in common laboratory rats or mice, and the near exclusive use of such rodent models in cancer research over the past 40 years clearly contributed to the delay in the discovery of the primate-specific, adrenal androgen-mediated kill switch tumor suppression system. Additional research impediments have also contributed to the kill switch mechanism remaining occult throughout these decades of p53 research. Thus, it cannot be studied in transformed cells, because these have already escaped succumbing to it because of kill switch failure; following such failure, such transformed cells have also incurred an obfuscating patchwork of follow-on mutations and epigenetic variations. The kill switch tumor suppressor system is also a single cell phenomenon, and single cell analysis techniques have not yet reached the level of sophistication required to detect in real time a unique event occurring at a low rate in a vast excess of unaffected cells; let alone an event designed to extinguish that cell from existence. Our detection of this kill switch tumor suppression mechanism depended upon a rudimentary form of it occurring in dogs, and the fact that our laboratory works exclusively with dogs with spontaneous cancer.

Cellular Senescence is One of the Causes of Age-Related Decline of Liver Regeneration

Tissue regeneration falters with age throughout the body, and there are numerous contributing factors to this decline. It is uncertain as to exactly how these factors layer in terms of cause and effect, however. One can point to the loss of stem cell activity, for example, and then ponder the degree to which that is secondary to rising levels of chronic inflammation. That chronic inflammation is in part inherent disarray and misconfiguration in the immune system stemming from exposure to persistent pathogens, but also arises from the accumulation of senescent cells that secrete strongly inflammatory signals. Now consider that immune cells are generated by stem cells and that one of the jobs of the immune system is to remove senescent cells, and you can see why it becomes challenging to definitively assign causes and consequences when examining the messy later stages of aging. Everything influences everything else, and many dysfunctions interact with one another to form feedback loops.

When it comes to regeneration in mammals, the liver is something of a special case. It is highly regenerative, the only organ that in adults can regrow entire missing sections. Its regenerative processes are somewhat more complex and spread out across the cell populations of the organ when compared with the usual situation in other tissues. Other organs rely on small stem and progenitor cell populations that take on the burden of producing new cells as needed. Nonetheless, liver regeneration fails with age just as in other tissues. Points of comparison are almost always quite helpful in fundamental research, and scientists examine the aging of the liver in order to better understand why regeneration declines with age.

The open access paper here lists cellular senescence as an important contributing cause of declining regeneration, and this is likely mediated by the inflammatory signals produced by these cells. Regeneration is a complex dance involving different cell populations, and immune cells have a role to play. Short-term local inflammatory signaling is a necessary part of that process, and the temporary appearance of senescent cells is normal and expected when healing from injury. The long-term presence of lingering senescent cells and the consequent production of chronic inflammation disrupts normal regeneration, however.

Liver regeneration in aged mice: new insights

Although adult hepatocytes are characterized by a very low replicative rate, they can rapidly reenter into the cell cycle following tissue loss or death. The best characterized experimental model to study liver regeneration consists of removal of 2/3 of hepatic parenchyma in rodents. In response, the remnant liver cells proliferate until the tissue mass is recovered (within 7 to 10 days). Since aging affects the regenerative response of the liver after chronic tissue injury or following surgical resection, it represents a critical problem in aged patients with liver disease. The first studies focusing on the effect of aging on liver regeneration date back to more than 50 years ago. At that time, it was found that the regenerative response, though preserved, was considerably reduced and retarded in aged rodents.

The long standing concept that hepatocytes lose their proliferative capacity with ageing has been challenged by experimental evidence based on a successful expansion of hepatocyes even after several rounds of transplantation. Remarkably, aged hepatocytes also retain their fully proliferative capacity if exposed to the treatment with direct mitogenic stimuli, such as ligands of the nuclear receptor CAR, which do not cause liver injury.

More recently, increasing evidence suggests that the age-dependent decline of the liver regeneration capacity is the consequence of multiple intertwining factors, both intra and extra-cellular, that cooperate to affect liver mass recovery after tissue damage. From the analysis of the latest literature reports, it emerges that the mass recovery of the injured liver in aged animals is compromised by at least three factors: (i) decreased expression of cell adhesion proteins leading to weakened microstructural adaptation after tissue injury and p21-dependent cell cycle arrest; (ii) change of hepatic stellate cell morphology which results in reduced liver perfusion and, consequently, leads to an impairment of tissue reconstitution after damage; (iii) chronic release of stemness-inducing pro-inflammatory proteins by senescent hepatocytes, which accumulate in the elderly due to a decline of the autophagy program. This senescence-associated secretory phenotype (SASP) maintains the neighboring recipient cells locked in a stem like state in aged tissues, affecting their capacity to replace lost cells.

On these bases, a potential therapeutic approach of direct mitogens to relieve the proliferative decline taking place in aged injured liver could be proposed. Treatment with nuclear receptor ligands could also be useful in liver transplantation and hepatic failure in order to restore liver function. Furthermore, therapeutic interventions aimed at eliminating senescent cells or blocking their effects may be useful to treat or delay age-related diseases. In this regard, it also would be interesting to evaluate if ligands of nuclear receptors could have a role in this process. Indeed, as nuclear receptors are ligand-induced transcription factors, their activation could unlock SASP-mediated senescence-stem locked cells by reprogramming their gene expression thus eliciting a similar hepatocyte proliferation response in young and aged livers.

An Update on a Human Telomerase and Follistatin Gene Therapy

Bioviva didn't succeed as originally envisaged, as a vehicle to bring human telomerase and follistatin gene therapy to the clinic; a recent article gave an outline of this history. At the moment I think few people are working on follistatin delivery, more is the pity, and the telomerase gene therapy banner has been taken up by another group. The original volunteer test subject, Liz Parrish, continues to perform a public service by publishing data on the outcome of her gene therapy - though I have to say that average telomere length as presently measured in sample of white blood cells is just about the least interesting of any measure one might propose to take following gene therapy with telomerase and follistatin.

Telomerase acts to lengthen telomeres, but average telomere length in immune cells is a terrible metric for age and tissue status. Average telomere length is an outcome of the pace at which cells are created from their stem cell populations, fresh with long telomeres, and the pace at which they divide, losing a little telomere length each time. In immune cells these behaviors are highly variable, greatly influenced by many transient health and environmental circumstances that have little to do with aging. Study after study shows immune cell telomere length to have a very poor correlation with age and age-related disease.

So instead, how about metrics of stem cell activity, or immune function, for example? The rationale for telomerase gene therapy is largely that it increases stem cell activity in tissue maintenance, and since it also reduces cancer risk in mice, one might suspect it is improving the ability of the immune system to destroy cancerous cells. Average telomere length on its own is interesting, but it cannot be used to claim rejuvenation, as is done here. It is too disconnected from meaningful metrics of aging, those that are actually closely tied to function and damage.

Before I underwent the therapy procedure, my white blood cell telomeres were measured in September, 2015 by SpectraCell's Texas laboratory, using a blood sample. They were determined to be unusually short, meaning that I was aging much faster than others my age. According to my telomeres, I was supposed to be in my mid-sixties. In March 2016, my telomeres were again measured by SpectraCell. I had already started at a disadvantage, which multiplied the anticipation anxiety. Thankfully, the results exceeded all my expectations. They showed that my telomeres had been extended from an initial 6.71kb to 7.33kb, meaning that my cells grew younger by about 20 years in only 6 months. The gene therapies had restored my telomeres in these cells to my normal age.

I hardly dared to hope there was room for improvement still. In 2018 I went again for testing at SpectraCell. My telomeres further increased from 7.33kb in 2016 to 8.12kb in 2018, equivalent to another decade of cellular rejuvenation. This outcome has exceeded all my expectations. First, because there have so far been no negative effects of my therapy. That is, no cancer, the alleged danger with activating the telomerase enzyme. But second, because my telomeres have continued to get longer without any additional treatment.

The same improvement was obtained following the muscle deterioration treatments: not only did my muscle mass increase after the myostatin inhibitor therapy, but continues to be robust 3 years after it took place. From pre-treatment to post treatment a growth in overall muscle mass and a reduction of intramuscular fat content was observed over a period of three years. This loss of intramuscular fat, also known as 'marbling', is associated with beneficial metabolic changes and improved musculature. My overall body weight did not decrease during this period. As my personal experience shows, a single treatment stimulated the telomerase and the myostatin inhibitor enzymes for at least 3 years after being administered, with no adverse effect. This can be a proof of concept that these two therapies, amply tested in animal models, are safe and efficient in humans.

Mitochondrial Mechanisms Link Oxidative Stress and Chronic Inflammation

Aging is characterized by rising levels of oxidative stress, the presence of oxidative molecules and the damage they cause to molecular machinery in cells, and rising levels of chronic inflammation, an inappropriate and harmful overactivation of the immune system. It is noted that these two aspects of aging and age-related disease appear to go hand in hand, when one is elevated, so is the other. Why is this the case?

The obvious place to start any such investigation is the mitochondrion. Every cell is populated by hundreds of mitochondria, responsible for packaging chemical energy store molecules in a process that produces reactive oxygen species (ROS) as a byproduct. While the cell uses ROS production as a signaling mechanism under normal circumstances, dysfunctional mitochondria produce too great a flux of ROS. Equally, mitochondria are also involved in many other vital cellular processes. For example, there are well-mapped pathways of protein interactions that lead directly from mitochondrial activity to the activation of inflammatory signaling on the part of their host cell.

This is the explanation for the observation that inflammatory disease is accompanied by oxidative stress, and the ability of mitochondrially targeted antioxidants such as SkQ1 to succeed as a treatment for inflammatory eye conditions. Preventing excessive ROS leaving mitochondria helps to dampen signaling processes that lead to inflammation. Reducing inflammation helps tissues to recover at least somewhat from the disease state.

Neurodegenerative diseases have certain characteristics in common. These include a state of inflammation and impaired elimination of defective mitochondrial organelles. Researchers now report their investigation of mice that have alterations in genes linked to Parkinson's disease. The authors identify a direct connection between the cellular process that eliminates damaged mitochondria - called mitophagy - and inflammation.

The enzymes PINK1 and parkin act in a pathway that attaches a protein called ubiquitin to cellular proteins; such ubiquitin-tagged components are targeted for cellular destruction. These enzymes assist with the process of mitophagy, in which non-functional mitochondrial fragments are recycled. Mutations that prevent the normal expression of PINK1 or parkin are linked to an early-onset form of Parkinson's disease, and there is evidence that failure to successfully eliminate damaged mitochondria results in a higher risk of developing the disease. However, mice that are deficient in PINK1 or parkin do not develop symptoms.

The finding that the loss of PINK1 or parkin has a minimal effect on animals was surprising, because it was long thought that the removal of damaged mitochondria serves a key role in protecting cells from oxidative damage. Defective mitochondria represent a severe threat to cells because ruptured mitochondria might release reactive oxygen species (ROS) that cause substantial cellular damage. Defective mitochondria might also release components that are not normally present in the cytoplasm, such as mitochondrial DNA. Indeed, the intrusion of mitochondrial DNA into the cytoplasm can trigger inflammation mediated by the protein STING. This raises the question of whether protection from inflammation, rather than from oxidative damage, might be the key role of mitophagy in the context of Parkinson's disease.

When researchers imposed mitochondrial stress on animals lacking PINK1 or parkin, they found that the bloodstream level of inflammation-driving molecules called cytokines was much higher than it was in mice that were not subjected to this mitochondrial stress. However, if mice lacked STING, as well as PINK1 or parkin, the expression of inflammatory cytokines did not increase as a result of mitochondrial stress. This indicated that STING is required to drive the inflammation mediated by this type of stress. Moreover, an absence of STING prevented the movement defects and neuronal losses that usually occur in old mitochondrial mutator mice that lack parkin.

Deep Wrinkles in Skin Associated with Higher Cardiovascular Mortality Risk

Aging is a global phenomenon throughout the body, a cascade of increasing complexity that starts with comparatively simple causes. Each of these distinct causes contributes to many age-related conditions, and all interact with one another. So on the one hand it is easy to find correlations between different aspects of aging - it would be surprising if that wasn't the case. On the other hand, different aspects of aging in different organs will turn out to share the same subset of important root causes, so it should be also possible to identify correlations that stand apart from the rest of the progression of aging.

Intrinsic skin aging and cardiovascular disease are two such linked manifestations of aging. Both are driven by loss of flexibility of tissues. Skin and blood vessel walls suffer issues due to the very similar accumulation of cross-links in the extracellular matrix and the presence of senescence cells and their inflammatory signaling. In skin, the loss of elasticity leads to wrinkles as its most evident manifestation. In the cardiovascular system, the consequences are more severe: failure of feedback mechanisms controlling blood pressure; remodeling of the heart and blood vessels; pressure damage to sensitive tissues; and ultimately the fatal structural failure of a major blood vessel - a stroke or heart attack.

The authors of the current prospective study investigated a different visible marker of age - horizontal forehead wrinkles - to see if they had any value in assessing cardiovascular risk in a group of 3,200 working adults. Participants, who were all healthy and were aged 32, 42, 52, and 62 at the beginning of the study, were examined by physicians who assigned scores depending on the number and depth of wrinkles on their foreheads. A score of zero meant no wrinkles while a score of three meant "numerous deep wrinkles."

The study participants were followed for 20 years, during which time 233 died of various causes. Of these, 15.2% had score two and three wrinkles. 6.6% had score one wrinkles and 2.1% had no wrinkles. The authors found that people with wrinkle score of one had a slightly higher risk of dying of cardiovascular disease than people with no wrinkles. Those who had wrinkle scores of two and three had almost 10 times the risk of dying compared with people who had wrinkle scores of zero, after adjustments for age, gender, education, smoking status, blood pressure, heart rate, diabetes, and lipid levels.

Furrows in your brow are not a better method of evaluating cardiovascular risk than existing methods, such as blood pressure and lipid profiles, but they could raise a red flag earlier, at a simple glance. The researchers don't yet know the reason for the relationship, which persisted even when factors like job strain were taken into account, but theorise that it could have to do with atherosclerosis, or hardening of the arteries due to plaque build-up. Atherosclerosis is a major contributor to heart attacks and other cardiovascular events. Changes in collagen protein and oxidative stress seem to play a part both in atherosclerosis and wrinkles. Also, blood vessels in the forehead are so small they may be more sensitive to plaque build-up meaning wrinkles could one of the early signs of vessel ageing.

Remote Ischemic Conditioning as a Means to Beneficially Upregulate Stress Responses

Prior to the advent of senolytic therapies, all of the methods shown to improve long-term health and increase life span in laboratory animals involved triggering increased levels of stress response mechanisms. These include cell maintenance activities such as autophagy, responsible for recycling damaged cell components and removing unwanted metabolic waste. Calorie restriction is the best studied of means to beneficially stress an organism, but it is far from the only approach that might be taken. Inducing transient ischemia, a reduction in blood flow to a tissue, has been shown to trigger many of the same stress response mechanisms, and researchers here review the evidence from this part of the field.

Recently, attention has been focused on an innovative approach, termed as ischemic conditioning (IC), particularly remote ischemic conditioning (RIC), knowing that repetitive, transient and sublethal series of ischemia-reperfusion (IR) bursts can trigger endogenous protection and tolerance against subsequent ischemic threats. RIC may benefit multiple organs of the body at the same time. It seems to be a promising non-pharmaceutical and non-surgical therapy for preventing and treating age-related systemic vascular diseases such as combined lesions in the brain, heart, and kidney, and also arteriosclerosis-induced neurodegenerative disorders.

Decreased physiological reserve and tissue resilience are characteristics of biological ageing, which render the human system more susceptible to pathological threats. Given the fact that elderly patients usually have at least two afflicted organs or tissues, therapeutic approaches with systemic actions (inducing protective responses in a wide range of organs and tissues) are warranted. The emerging area of RIC builds upon this foundation. The capability of this non-pharmaceutical and non-surgical intervention to protect vital organs simultaneously by enhancing the body's powers to adapt to pathological threats could provide a safe, less burdensome, minimally-invasive way for ageing-related disorders. Currently, RIC is being evaluated in a variety of clinical settings such as cerebrovascular disease, coronary artery disease, and renal injury that predominantly influence the older population.

To date, regarding the safety and tolerability of the methodology, no RIC-associated adverse events have been reported in the published clinical studies. Although the prospect of clinical transformation of RIC on multi-organ protection is promising, challenges still exist. For instance, although previous experimental work has implied that the number and duration of IR cycles might affect the efficacy of RIC, there is a paucity of clinical data comparing the effectiveness of different RIC protocols, and no convincing evidence of the most favorable conditioning strategy has been established.

Future experimental or clinical work should focus on addressing the issues that may influence the translation of RIC from test bench to bedside, such as identifying the protective mechanism underlying ischemic conditioning, optimizing the conditioning regimen, establishing biomarkers to accurately evaluate the efficacy of RIC, and figuring out the impact of potential comorbidities, medications, and other factors on RIC.

Arguing for Aging to Influence Natural Selection through Loss of Parental Contributions to Early Life Evolutionary Fitness

It seems that ever more people these days argue for aging to influence natural selection through effects on the group, or at least on offspring. The core argument made here, as I understand it, is that a sort of inverse Grandmother effect can allow a rapid pace of aging to reduce fitness in early life by reducing parental or grandparental contributions to survival. If the case, then this means that age-related diseases are not just side-effects of a relentless evolutionary focus on early life at the expense of later life, but are actively involved in selection in some way, perhaps as a buffer against more subtly harmful mutations. Like most of the more abstruse discussion of evolution, proof is hard to come by - most arguments at this level are a matter of model versus model and assumption versus assumption. The line between hypothesis and opinion is more blurred than it might be elsewhere in the life sciences.

During evolution, Muller's ratchet permanently generates deleterious germline mutations that eventually must be defused by selection. It seems widely held that cancer and aging-related diseases (ARDs) cannot contribute to this germline gene selection because they tail reproduction and thus occur too late, at the end of the life cycle. Here we posit however that by lessening the offspring's survival by proxy through diminishing parental care, they can still contribute to the selection.

The widespread occurrence of aging in animals suggests that it is an adaptation. But to what benefit? Aging seems to have only drawbacks. In humans, ARDs cause today almost all mortality; they include heart disease, cerebrovascular disease, Alzheimer's disease, kidney disease, and cancer. Compensation seems unthinkable.

For cancer, the author proposed in a previous study a benefit to the species: purifying selection against deleterious germline genes. We generalize, motivated by the parallels between cancer and aging, the purifying selection posited for cancer to aging. An ARD would be initiated in the organ by multicausal disruption of homeostasis, and be followed by dormancy and senescence until its onset near the end of the life cycle. Just as for cancer, the ARD gives a benefit to the species through the selection against germ line genes that disrupt homeostasis.

Two New Species Found to Undergo Menopause

Menopause is an important topic in considerations of the evolution of aging, alongside the unusual longevity of humans in comparison to other primates. Any evolutionary theory worthy of the name has to explain why both of these features exist. The Grandmother hypothesis has been deployed to try to explain human longevity, that our intelligence and culture allows for the selection of increased lifespan through the influence of older individuals on the evolutionary fitness of their descendants. Lacking that intelligence and culture, other primates are not as long-lived as we are. What of menopause, however, and how to explain the observation that we share it with some toothed whales, but with none of our closest primate relatives?

Scientists have discovered that beluga whales and narwhals go through the menopause, taking the total number of species known to experience this to five. Aside from humans, the species now known to experience menopause are all toothed whales - belugas, narwhals, killer whales and short-finned pilot whales. Almost all animals continue reproducing throughout their lives, and scientists have long been puzzled about why some have evolved to stop.

The new study suggests menopause has evolved independently in three whale species (it may have evolved in a common ancestor of belugas and narwhals). "For menopause to make sense in evolutionary terms, a species needs both a reason to stop reproducing and a reason to live on afterwards. In killer whales, the reason to stop comes because both male and female offspring stay with their mothers for life - so as a female ages, her group contains more and more of her children and grandchildren. This increasing relatedness means that, if she keeps having young, they compete with her own direct descendants for resources such as food. The reason to continue living is that older females are of great benefit to their offspring and grand-offspring. For example, their knowledge of where to find food helps groups survive."

The existence of menopause in killer whales is well documented due to more than four decades of detailed study. Such information on the lives of belugas and narwhals is not available, but the study used data on dead whales from 16 species and found dormant ovaries in older beluga and narwhal females. Based on the findings, the researchers predict that these species have social structures which - as with killer whales - mean females find themselves living among more and more close relatives as they age. Research on ancestral humans suggests this was also the case for our ancestors. This, combined with the benefits of "late-life helping" - where older females benefit the social group but do not reproduce - may explain why menopause has evolved.

An Example of Efforts to Develop an Immunotherapy to Target Tau Aggregates

The buildup of misfolded or altered proteins is an important contributing cause of aging and age-related disease. Now that immunotherapies targeting amyloid-β in the aging brain are finally starting to show results, it seems likely that immunotherapies targeting tau will catch up rapidly. The necessary lessons have been learned, and the wheel will not need to be reinvented. The present consensus view of Alzheimer's disease is that amyloid-β aggregates are more important in the earlier stages of the condition, while the real damage is done by tau aggregates in later stages. It is plausible that reliable, meaningful prevention or reversal of cognitive decline will only be possible given the application of therapies that clear both types of protein aggregate. The first tests of that with combined immunotherapies are hopefully not all that distant in the future, but it is always possible that approaches based on restoring drainage of cerebrospinal fluid may get there first.

Tau, the main component of the neurofibrillary tangles (NFTs), is an attractive target for immunotherapy in Alzheimer's disease (AD) and other tauopathies. MC1/Alz50 are currently the only antibodies targeting a disease-specific conformational modification of tau. Passive immunization experiments using intra-peritoneal injections have previously shown that MC1 is effective at reducing tau pathology in the forebrain of tau transgenic JNPL3 mice. In order to reach a long-term and sustained brain delivery, and avoid multiple injection protocols, we tested the efficacy of the single-chain variable fragment of MC1 (scFv-MC1) to reduce tau pathology in the same animal model, with focus on brain regional differences.

ScFv-MC1 was cloned into an AAV delivery system and was directly injected into the hippocampus of adult JNPL3 mice. Specific promoters were employed to selectively target neurons or astrocytes for scFv-MC1 expression. ScFv-MC1 was able to decrease soluble, oligomeric and insoluble tau species, in our model. The effect was evident in the cortex, hippocampus, and hindbrain. The astrocytic machinery appeared more efficient than the neuronal, with significant reduction of pathology in areas distant from the site of injection. To our knowledge, this is the first evidence that an anti-tau conformational scFv antibody, delivered directly into the mouse adult brain, is able to reduce pathological tau, providing further insight into the nature of immunotherapy strategies.

TransVision 2018 Takes Place in Madrid this October

If you are a recent arrival to the rejuvenation research community, then it is possible you do not know that you are entering one of the expanding fields of thought and endeavor seeded by the transhumanist community of the 1990s. The passage of ideas and people and influence as it took place back then is far harder to discern now than was the case even a decade ago, as the core ideals of the transhumanist vision - radical life extension, artificial general intelligence, the use of technology to transcend the present limits of the human condition - have by now suffused every corner of our culture. It has become hard to see where the concepts were incubated and popularized: the handful of people, the few mailing lists, the few books and novels. The transhumanists won, in other words; they spoke their vision for a better future to the world, and the world listened.

The TransVision conference series has spanned much of this period of time. As a consequence, if you look at the speaker list and the attendees for this year's TransVision 2018, you'll see a range of influential folk in aging research, biotech, artificial intelligence, and other fields, and if unfamiliar with the way in which the recent history of these fields is entwined with transhumanism you might be surprised. But transhumanism was always about changing the world, building the future. It shouldn't be a surprise to find that some fraction of the people capable of vision in the 1980s and 1990s then set out to try to make their part of that vision a reality.

Spain will host the next global futurist summit during October 19-20-21, 2018. HumanityPlus will be the main international organizer of this world congress, TransVision 2018, with the help of other leading associations and organizations working on futurist concepts like longevity extension, artificial intelligence, human enhancement, and other technologies and future trends. The first TransVision conference was held during 1998 in The Netherlands.

During the last 20 years, we have seen phenomenal advances, and we expect to see much more during the next 20 years. What will the future bring? Science and technology should lead the way! Now we are planning to host in Spain the 20th anniversary of the TransVision conferences, an international summit open to people from all continents, with participants coming from the United States to the United Kingdom, from Argentina to Australia, from Africa to China, from Russia to Venezuela.

The topics considered will be very broad, ranging from recent medical advances to artificial intelligence and robotics. The first keynote speaker will be Sophia, the first humanoid robot that was awarded citizenship last year. TransVision 2018 will have other keynote speeches by pioneers of the futurist movement like Natasha Vita-More and Ben Goertzel, among many others, both members of HumanityPlus and other leading institutions.

Articles on Senolytics are Starting to Look Just Like Articles on any Other Field of Medical Research and Development

It is probably worthy of note that press articles on the treatment of aging via senolytic therapies are becoming similar in tone and content to press articles on any other active field of medical development. Take this example, publicity for Unity Biotechnology and their work on senolytic therapies to clear senescent cells from old tissues and thus remove one of the contributing causes of aging and age-related disease. It is formatted as a discussion of trials, funding, and this company or that company, this lab or that lab. It exhibits little of the breathless nonsense as to why we shouldn't address aging and its consequences, a regular feature of the past decade of coverage, and is more a matter of business as usual. Whether this heralds a sweeping change in the way in which the world views aging is anyone's guess, but the existence of major investment and sizable companies working on therapies for aging does serve to make it increasingly challenging to be a naysayer on the topic of extended healthy longevity without appearing foolish.

Osteoarthritis is the first disease Unity Biotechnology is tackling, and that one disease represents a huge opportunity: By 2026, the market for osteoarthritis drugs will be 2.6 billion in the U.S. alone. The company is currently in a phase 1, government-approved safety trial with about 40 patients in multiple sites across the U.S. The goal is to show that the drug Unity is developing - what's called a senolytic agent - can be injected into the knee and tolerated by patients in gradually higher doses. Ultimately, the thinking is that such a drug can destroy senescent cells, effectively halting or reversing osteoarthritis in the knee. In the future the same drug might be effective in treating pain elsewhere in the body.

"Osteoarthritis standard of care begins with ibuprofen, then steroids, and then most people's standard of care is just accepting it: you're old, that sucks, and you're now in pain for the rest of your life. But we think there's a better way, by looking through the lens of biological insight of why those diseases happen in the first place."

Over the last decade the titans of the tech industry have dedicated money toward cutting-edge research focused on curing disease as well as slowing, delaying and, possibly one day, reversing the conditions of old age. Perhaps the most visible example is Calico, short for the California Life Company, a spin-out from Google launched in 2013 and funded with 1.5 billion to study the causes of aging and what to do about them. "People in Silicon Valley look at problems as solvable, with enough time and enough steps. And, obviously, the size of the return is huge. If you're able to bring anything like that to the market, you have something that's universally needed. Senescent cells are really one of the first bona fide targets of aging that we've found we've been able to do something about."

Taking aim at senescent cells is a treatment paradigm being used not only by Unity Biotechnology, but also by research hospitals in the U.S. A team at the Kogod Center on Aging at the Mayo Clinic is currently testing the use of senolytic drugs in treating chronic kidney disease in humans. "The time has finally arrived that our knowledge of biology and our sophistication level is sufficient that we can attack some of these fundamental, underlying causes of aging."

Regulation and Loss of Freedom are to Blame for Much of the Poor Strategy of Past Decades of Cancer Research

FDA bureaucrats see the role of their organization as that of a shield, removing as much risk as possible from medicine. Since it is impossible to remove all risk from any medicine, what this mission means in practice is that no individual bureaucrat ever wants to be held accountable for approving a therapy that later turns out to have unexpected consequences. It doesn't matter if those consequences occur in just a few individuals, while countless others benefit, or even if the medicine in question is actually responsible: the fickle press will rise up in arms; the lawyers will flock. Thus those FDA bureaucrats will always move in the direction of requiring ever greater proof from companies - the cost of commercial development has doubled for no reason other than this in the past decade. Along the way, they also remove the right to choose from patients, the ever-present authoritarian side to the goal of protection. No-one is permitted their own risk assessment, and no organization is permitted to help those patients willing to take educated risks.

There are more subtle, reaching, and harmful effects beyond the obvious ones noted above. The structure of regulation has changed the strategy of research and development for the worse. As the article here argues, it is the major contributing factor to the lack of progress in treatment of cancer over the last half century. The present regulatory environment incentivizes the sort of development programs that produce marginal, incremental results, that build on existing approaches. Bold new directions need not apply. The FDA makes the cost of development so high that only large organizations can follow through to the clinic, and large organizations are risk averse. Few leaders will be willing to take the sort of risks that lead to real, revolutionary progress.

Look at the history of chemotherapy research and you'll find a very different world than the one that characterizes cancer research today: fast bench-to-bedside drug development; courageous, even reckless researchers willing to experiment with deadly drugs on amenable patients; and centralized, interdisciplinary research efforts. Cancer research was much more like a war effort before the feds officially declared war on it. The whole cycle, from no chemotherapies at all to development, trial, and FDA approval for multiple chemotherapy drugs, took just six years, from 1948 to 1953. Modern developments, by contrast, can take decades to get to market.

Today, the National Cancer Institute and various other national agencies now largely fund research through grants. The proliferation of organizations receiving grants means cancer research is no longer primarily funded with specific treatments or cures (and accountability for those outcomes) as a goal. With their funding streams guaranteed regardless of the pace of progress, researchers have become increasingly risk-averse. As the complexity of the research ecosystem grew, so did the bureaucratic requirements. "16.8 percent of the total costs of an observational protocol are devoted to institutional review board interactions, with exchanges of more than 15,000 pages of material, but with minimal or no impact on human subject protection or on study procedures."

As R&D gets more expensive and compliance more onerous, only very large organizations - well-funded universities and giant pharmaceutical companies, say - can afford to field clinical trials. Even these are pressured to favor tried-and-true approaches that already have FDA approval and drugs where researchers can massage the data to just barely show an improvement over the placebo. (Since clinical trials are so expensive that organizations can only do a few, there's an incentive to choose drugs that are almost certain to pass with modest results - and not to select for drugs that could result in spectacular success or failure.) Of course, minimal improvement means effectively no lives saved.

The problem is clear: Despite tens of billions every year spent on research, progress in combating cancer has slowed to a snail's pace. So how can we start to reverse this frustrating trend? One option is regulatory reform, and much can be done on that front. Streamline the process for getting grant funding and institutional review board approval. Cut down on reporting requirements for clinical trials, and start programs to accelerate drug authorizations for the deadliest illnesses. One proposal is "free-to-choose medicine." Once drugs have passed Phase I trials demonstrating safety, doctors would be able to prescribe them while documenting the results in an open-access database. Patients would get access to drugs far earlier, and researchers would get preliminary data about efficacy long before clinical trials are completed.

More radically, it might be possible to repeal the 1962 Kefauver-Harris amendment to the Federal Food, Drug, and Cosmetic Act, a provision that requires drug developers to prove a medication's efficacy (rather than just its safety) before it can receive FDA approval. Since this more stringent authorization process was enacted, the average number of new drugs greenlighted per year has dropped by more than half, while the death rate from drug toxicity stayed constant. The additional regulation has produced stagnation, in other words, with no upside in terms of improved safety. Years ago, a Cato Institute study estimated the loss of life resulting from FDA-related drug delays from 1962 to 1985 in the hundreds of thousands. And this only included medications that were eventually approved, not the potentially beneficial drugs that were abandoned, rejected, or never developed, so it's probably a vast underestimate.


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