Fight Aging! Newsletter, September 3rd 2018

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 is a partial explaination for 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 had the effect of consistently hindering 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.

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."

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.

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.

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.

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.

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.

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.

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.

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.

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.

During evolution, Muller's ratchet permanently generates rising levels of 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.

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.

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.

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.

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."

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.