Fight Aging!

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.

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 of dollars 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.

Link: https://reason.com/archives/2018/05/12/when-cancer-was-conquerable/

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."

Link: https://www.cnbc.com/2018/08/29/jeff-bezos-backs-silicon-valley-scientist-working-on-a-cure-for-aging.html

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.

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.

Link: https://transvisionmadrid.com/

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.

Link: https://doi.org/10.1186/s40478-018-0585-2

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.

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.

Link: http://www.exeter.ac.uk/news/featurednews/title_677275_en.html

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.

Link: https://doi.org/10.1016/j.mehy.2018.07.020

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.

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.

Link: https://doi.org/10.18632/aging.101527

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.

Link: https://www.eurekalert.org/pub_releases/2018-08/esoc-dfw082318.php

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.

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.

Link: https://doi.org/10.1038/d41586-018-05988-z

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.

Link: https://bioviva-science.com/blog/new-telomere-length-results-a-2018-update-by-liz-parrish/

There are many failures on the path from early study in cells to successful medical technology applied to humans. A success in cell cultures often turns out to be infeasible in animals, as cells in culture are not a part of a larger tissue and organism and thus not subject to the same signals, stresses, and influences. Work in organoids, tiny sections of living tissue, can certainly help to bridge this gap, but even an organoid that accurately reflects the structure and function of an organ is still not subject to the real ebb and flow of a living animal, all of the interactions with other tissues and systems.

Success in animal studies, usually carried out in mice, can fail in larger mammals for any number of reasons. While there are many similarities between mammals, there are just as many differences. The popular science article below focuses on the biochemical differences between species as a reason for the leap between mice and humans to fail so often. I think it overemphasizes the point, and fails to offer viable suggestions for an alternative. In the field of aging, I'd have to say that there are two important factors for a high failure rate, only one of which is really an issue of species differences, and both can be traced back to a poor high level strategy for the development of means to treat aging and age-related disease.

The first is that short-lived species exhibit vastly greater slowing of aging and life extension when stress response mechanisms are upregulated. So calorie restriction, increased autophagy, heat stress, and other hormetic effects produce sizable gains in life span, up to 40% or more in mice. Where direct comparisons can be made, we know that these methods produce no such result in humans. While beneficial for health, the existence of effect sizes of larger than five years of additional life is very implausible given the existing data. Yet members of the aging research community continue to put the majority of their effort into developing therapies that boost these stress responses. Results fail to translate because effect sizes in humans are much smaller and much less reliable, and clinical trials are looking for sizable, reliable outcomes.

The second issue is that most of the work on age-related conditions starts with the end stage disease state and works backward. Researchers end up trying to develop therapies based on manipulating proximate causes that are very late in the development of pathology, far removed from root causes. This tinkering with the operation of the disease state is far more vulnerable to small differences in cellular biochemistry between species, and tends to produce marginal results at the best of times. Small benefits based on tinkering with a complex, disarrayed biochemistry have a way of vanishing or becoming highly unreliable firstly in the move between species, and secondly in clinical trials once larger numbers of people and their individuals differences become involved. Again, this is a problem that exists because of the way in which research and development is conducted: it is the result of a poor choice of strategy.

The right approach to aging is to target and repair the known root causes. Many of these are the same in their important aspects in all mammals, such as the accumulation of senescent cells, or the class is the same and only the importance of different members of the class varies, such as accumulation of cross-links or lipofuscin, in which the specific molecules to target are different in mice and humans. Further, the effect sizes resulting from successfully reversing root causes of aging and age-related disease should be larger and more reliable in any species: it covers many downstream consequences, and even if those consequences are different in different species, they will still be reduced. This gives a greater expectation of success in future human clinical trials based on the existence of mouse data only.

Don't believe the mice

When you read that a lab animal with a human disease has been cured with a new drug candidate, do not get your hopes up. The stats for converting these successes into human patients are appalling. Results in animals are often the opposite of those seen in humans. For example: corticosteroids were shown to treat head injuries in animals, but then increase deaths in new-born babies in trials. This is a big deal. A staggering 95% of drugs tested in patients fail to reach the market, despite all the promising animal studies that precede their use in humans. "There are lots of reasons why, but in essence we are not 70 kilogram rats and we are not inbred strains."

Mice are the most popular lab animals, but their brains and biology are quite different from our own. Surprisingly, rats and mice predict each other for complex measures with only 60%. Different animals, different effects. Newspapers headlines heralding cures for Alzheimer's to autism, on the back of rodent studies, can be taken with a pinch of salt. Neurodegenerative disorders such as Alzheimer's were one of the first areas to turn against the animal models. "It was shown that the animal tests were misleading with respect to what is a cure and what is not." After hundreds of human trials for promising treatments for Alzheimer's, almost none helped patients. This is a colossal waste of money. Industry has noticed. "The pharma industry is now using about one-sixth the number of animals that they used in the past for drug studies. They go very late into these models."

One problem is that scientists often take a simple approach to mimicking a disease in mice, by just finding a gene that when knocked out stamps the mice with hallmarks of the human disease. This is how the first Alzheimer's disease mouse was created, but the animal did not reflect the true Alzheimer's condition of most patients. "Single gene mouse models are different from the illness that we experience in humans. This has been a failed strategy."

Sometimes scientists discover therapies to cure mice, but not people. The record for inflammatory disease is especially striking. More than 150 trials have tested agents to block inflammation in critically ill patients. The candidates worked in animals, but all failed in patients. With this in mind, researchers decided to compare how all genes in mice and all genes in people react when they encounter trauma, burns or bacterial toxins. There was almost no connection whatsoever. Mice genes did one thing; human genes did another.

In situ cell reprogramming is an interesting approach to the treatment of degenerative blindness conditions in which photoreceptor cells are lost, but the retinal structure is otherwise largely intact. A number of demonstrations have been carried out in the past five years, in cell cultures and in mice. Here is the latest example of this line of work, in which preliminary evidence indicates that some degree of vision is restored. It is of course not all that easy to determine the quality of vision obtained in mice though any successful therapy for blindness; light sensitivity is one thing, but what exactly do they see in this scenario? Those quantifying efforts still lie ahead.

In vertebrates, Müller glia cells are the most common type of non-neuronal cells found in the retina and provide structural and functional stability for photoreceptor rods and cones. In cold-blooded vertebrates, such as zebrafish, Müller glia act as retinal stem cells, multiplying after retinal injury and reprogramming themselves as photoreceptor cells to replace damaged ones. In mammals, however, Müller glia cells do not spontaneously reprogram themselves into stem cells and then photoreceptor cells to replace damaged ones after injury.

Based on the data in zebrafish and other nonmammalian species, researchers have been looking for the correct cocktail of gene products to coax Müller glia to revert to a stem-cell-like state and then differentiate into retinal cells in mammals. In this study, researchers reprogrammed Müller glia cells into rod photoreceptors in the retinas of uninjured mice, both in wildtype mice and in two strains that serve as models of congenital blindness. The team developed a two-step technique, first injecting an adeno-associated virus with a gene that expresses β-catenin, a protein that helps the glia re-enter the cell cycle, into the retinas of the four-week-old mice. Two weeks later, the mice received a second injection of an adeno-associated virus with the genes that express the transcription factors Otx2, Crx, and Nrl - shown in past studies to aid in the development of rod photoreceptors.

After the second injection, when Müller glia divided, one daughter cell became a rod photoreceptor while the other remained a Müller glia cell. The new rods produced proteins characteristic of the light-sensing retinal cells. Recording light responses from retinal ganglion cells in the retinas of mutant mice that got the gene therapy showed that some of the cells responded, whereas none of the cells responded in mutant mice that did not receive the treatment. The team also detected light responses in the primary visual cortex of the brains of the treated mutant mice but not in the same brain region of untreated blind mice.

Link: https://www.the-scientist.com/news-opinion/reprogrammed-mu-ller-glia-restore-vision-in-mice-64644

If you have been following the development of mitochondrially targeted antioxidants as a potential therapy to modestly slow aging, you might find this open access paper interesting. MitoQ is one of the readily available compounds, with SkQ1 as the other. My impression from the papers is that SkQ1 and closely related plastoquinones have a larger effect size on life span in animal studies, but it still isn't more than a fraction of that produced by calorie restriction.

Mitochondrially targeted antioxidants appear to function by improving mitochondrial metabolism, but the most medically relevant effect observed so far is their ability to dampen the consequences of inflammation, particularly in inflammatory eye conditions. Inflammation and excessive levels of oxidative molecules go hand in hand. This same underlying mechanism may allow these compounds to reduce stiffness of blood vessels in older individuals, by reducing the impact of inflammation and the aged tissue environment on smooth muscle cells responsible for contraction and dilation. A human trial of MitoQ produced interesting data on this front. The paper here looks at a broader range of biomarkers and outcomes.

The postulated relationship between cellular decline and reactive oxygen species (ROS) has been well explored in the free radical theory of aging, which suggests that human lifespan and degenerative disease are tied to the adverse effects of ROS on cell structure and function. Once produced, ROS react with lipids, proteins, and nucleic acids causing oxidative damage to these macromolecules, over time contributing to the aging process.

Mitochondria are among the most metabolically active organelles in the body and are a primary source of energy production and oxidative phosphorylation. Oxidative phosphorylation, a process in energy production, results in the production of ROS. As both the major producer and primary target of ROS, mitochondria are thought to play an important role in aging.

Generally speaking, decreasing the concentration of ROS and thereby potential damaging capabilities, it is hypothesised that the aging process can be delayed. This concept has inspired a host of nutraceuticals aimed at alleviating oxidative damage, particularly in the mitochondria. To decrease mitochondrial oxidative damage, a number of mitochondria-targeted antioxidants have been developed. One such mitochondria-targeted antioxidant is MitoQ.

This review has examined the effect of MitoQ on oxidative stress markers related to the aging process. Our findings indicate that MitoQ has a statistically significant reduction in concentrations of 3-NT, a biomarker of protein oxidation produced upon the nitration of protein residues, which alters protein structure and function. This is of interest as nitration of protein residues has been shown to inhibit enzyme catalytics, and so MitoQ may promote efficiency of cellular processes as well as help decrease the concentration of reactive oxygen species.

Mitochondrial membrane potential has been shown to significantly increase upon administration of MitoQ, suggesting an upregulation in the functioning capacity of mitochondria with supplementation. Mitochondrial membrane potential is commonly used as an indication of functional status. While decreased membrane potential (depolarization) indicates damaged, dysfunctional mitochondria that cannot meet cellular energy demands, increased membrane potential (hyperpolarization) suggests increased functional capacity and work conducted.

Link: https://doi.org/10.1155/2018/8575263

Over the past few years researchers have demonstrated, numerous times, that using senolytic therapies to remove a significant fraction of senescent cells from old tissues in mice can reverse aspects of aging, successfully treat multiple age-related diseases that presently have no viable treatment options, and extend healthy life. In an exciting recent addition to this field of research, scientists used the dasatinib and quercetin combination in mouse models of Alzheimer's disease. The result is a restoration of function and a reduction of the characteristic tau aggregation that is a feature of this condition. The researchers in fact report that there is a two-way relationship between tau aggregation and cellular senescence: targeting either one reduces the other.

Even allowing for the fact that mouse models of Alzheimer's are highly artificial, as no such analogous condition naturally occurs in that species, this might be taken as good evidence for senescent cell accumulation to provide a meaningful contribution to neurodegeneration. Further, I think it important to note that the particular senolytics used here are very cheap. Dasatinib is a generic drug with years of human usage data resulting from the treatment of cancer, and can be obtained for $100-200 per senolytic dose from some sources. Add an equal amount to pay for validation of the identity of the ordered compound via mass spectroscopy. One dose every few years will probably be optimal for this class of drug; more frequent dosing likely wouldn't help much. These economics mean that self-experimentation with senolytics continues to look ever more like an interesting option, at least for those people willing to carefully think about the trade-off between risk and benefit, and accept responsibility for their actions.

In this context, here is an interesting question: given a working, first generation rejuvenation therapy that targets a fundamental cause of aging and is piling up considerable evidence for impressive across-the-board benefits in diseases of aging in animal studies, how long will it take the tens of millions of older people who could easily obtain and use dasatinib and quercetin to actually start obtaining and using these compounds in large numbers? I feel that the basis for some form of revolutionary change in the relationship between regulators and regulated is brewing. FDA functionaries are unlikely to allow widespread off-label use of dasatinib without a fight, but can any authority really stop a cheap, mass-produced compound from being widely available? History suggests no.

Stressed, toxic, zombie cells seen for 1st time in Alzheimer's

Cellular senescence is associated with harmful tau protein tangles that are a hallmark of 20 human brain diseases, including Alzheimer's and traumatic brain injury. Researchers have identified senescent cells in postmortem brain tissue from Alzheimer's patients and then found them in postmortem tissue from another brain disease, progressive supranuclear palsy. "When cells enter this stage, they change their genetic programming and become pro-inflammatory and toxic. Their existence means the death of surrounding tissue."

The team confirmed the discovery in four types of mice that model Alzheimer's disease. The researchers then used a combination of drugs to clear senescent cells from the brains of middle-aged Alzheimer's mice. The drugs are dasatinib, a chemotherapy medication that is U.S. Food and Drug Administration-approved to treat leukemia, and quercetin, a natural flavonoid compound found in fruits, vegetables, and some beverages such as tea.

After three months of treatment, the findings were exciting. "The mice were 20 months old and had advanced brain disease when we started the therapy. After clearing the senescent cells, we saw improvements in brain structure and function. This was observed on brain MRI studies and postmortem histology studies of cell structure. The treatment seems to have stopped the disease in its tracks. The fact we were able to treat very old mice and see improvement gives us hope that this treatment might work in human patients even after they exhibit symptoms of a brain disease."

In Alzheimer's disease, patient brain tissue accumulates tau protein tangles as well as another protein deposit called amyloid beta plaques. The team found that tau accumulation was responsible for cell senescence. Researchers compared Alzheimer's mice that had only tau tangles with mice that had only amyloid beta plaques. Senescence was identified only in the mice with tau tangles. In other studies to confirm this, reducing tau genetically also reduced senescence. The reverse also held true. Increasing tau genetically increased senescence. Importantly, the drug combination reduced not only cell senescence but also tau tangles in the Alzheimer's mice. This is a drug treatment that does not specifically target tau, but it effectively reduced the tangle pathology.

Tau protein aggregation is associated with cellular senescence in the brain

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis, which suggests secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction.

Using four AD transgenic mouse models, we found that NFTs, but not amyloid-β plaques, display a senescence-like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

The existence of actual, working rejuvenation therapies will eventually chase out the fraud and lies from the "anti-aging" marketplace, and what will be left is just plain old medicine - but much better, more advanced medicine than we have today. This will take years, however, and the established hucksters will continue to have a fine old time on their way out. They will continue to cherry-pick studies, cloak the junk that doesn't work in a thin veneer of science, mimicking the voices and marketing of legitimate ventures. The basic lie that is loudly propagated by the "anti-aging" business, that their products can make a difference, has been spoken for so long that is accepted as a part of the tapestry of society. Few people can bring themselves to be irate about it these days. It is another part of the ridiculous nonsense that we are subjected to on a daily basis.

This does mean, however, that anyone entering the realm of longevity science, whether wanting to improve their health or make a difference in the pace of progress, is faced with a much tougher uphill battle than should be the case. How to distinguish the lies of the "anti-aging" marketplace from the real science given no background in the field? How to pick out research projects and classes of therapy with a high expectation value from those that are good science that cannot possibly greatly influence the aging process? For every advocate who tries to help by presenting a realistic view of the field, there are twenty paid shills out there trying to persuade the world that blueberries hold back aging, or that apple stem cells are medically useful - or whatever the product they are selling today might be, regardless of the facts.

Now that we are starting to see the arrival of actual therapies aimed at targeting the processes of aging directly in order to prevent age-related diseases, it has become easier to separate two very distinct groups.

The first group consists of the snake oil salesmen peddling unproven supplements and therapies to whoever is foolish enough to buy and take things on faith without using the scientific method. The hucksters have long been a plague on our field, preying on the gullible and tainting legitimate science with their charlatanry and nonsense. One example is the "biotech company" that makes bold claims yet never delivers on those claims in practice, offering data based on poorly designed experiments and tiny cohorts that are statistically irrelevant; another example is the supplement peddler selling expensive supplement blends with flashy names, which, on inspection, turn out to be commonly available herbs and minerals mixed and sold at a high markup. These sorts of people have plagued our community and given the field a reputation of snake oil.

The second group are the credible scientists, researchers, and companies who have been working on therapies for years and sometimes more than a decade. Many of these therapies are following the damage repair approach advocated by Dr. Aubrey de Grey of the SENS Research Foundation over a decade ago. The basic idea is to take an engineering approach to the damage that aging does to the body and to periodically repair that damage in order to keep its level below that which causes pathology. These therapies are now starting to arrive, with some already in human trials right now, and this marks a milestone in our field: the credible science has finally outstripped the snake oil, and the focus can move from pseudoscience to real, evidence-based science.

While it will be some years yet before all therapies to end age-related diseases are here and available, and the hucksters are still peddling their wares, you can arm yourself with knowledge and protect yourself and our community from these people. Learn to evaluate science rather than taking things at face value, and avoid expensive scams and bad science.

Was the claim first announced through mass media or through scientific channels? Are the claimants transparent about their testing, and is there sufficient published data for reproduction? A properly developed technology will take years of development to reach release; is there a clear paper trail of studies and clinical trials supporting it? How good is the quality of data supporting the claim, and is it of statistical significance? Are the claimants reputable, and are they published in credible journals? The snake oil sellers will be with us for a few years yet, but by working together as a community and thinking critically about claims, we can help filter these people out and ultimately clean up the field for the benefit of legitimate scientists working on the real solutions to aging that will benefit us all.

Link: https://www.leafscience.org/snake-oil/

Immunotherapies that target aggregation of amyloid-β in order to treat Alzheimer's disease have a long and expensive history of failure. The tide finally seems to be turning, however, with the advent of several treatments that can reduce amyloid-β levels without resulting in an unacceptable level of risk for the patients. This newfound incremental success is taking place at the same time as the years of frustration with the lack of progress have finally blossomed into a variety of alternative theories on the causes of Alzheimer's disease, such as blocked drainage of cerebrospinal fluid or persistent microbial infection, some of which have advanced to the point of development of therapies.

The challenge for amyloid-β clearance therapies is now to show benefits in patients, and there are good reasons to believe that this will be challenging in the late disease state. The present consensus on Alzheimer's disease is that amyloid-β accumulation is an early phase, damaging yes, but nowhere near as damaging as the tau aggregation that occurs later on. Further, Alzheimer's patients also tend to have other forms of neurodegeneration, such as vascular dementia, that are unlikely to be greatly affected by amyloid-β clearance. It is a challenging business: therapies for neurodegeneration will most likely have to tackle most or all of the important mechanisms in the aging brain in order to be reliably beneficial.

After years of fits and starts, anti-amyloid immunotherapies are finally hitting their target effectively. At least four drugs have now demonstrated the ability to clear plaques from the brain: aducanumab, gantenerumab, Lilly's LY3002813, and BAN2401. At the Alzheimer's Association International Conference, held in July, researchers presented new data from gantenerumab and LY3002813, aka N3pG. It clinched the case that these antibodies can mop up brain amyloid, bringing many people with early symptomatic Alzheimer's disease (AD) below the threshold for amyloid positivity. At one to two years, this clearance took a long time. But still: researchers claimed that two years of treatment with high-dose gantenerumab essentially resets a person's trajectory of amyloid accumulation. "We are setting back the clock by 15 years."

To achieve these rates of clearance, researchers have had to greatly boost antibody dose, in many cases quadrupling the amounts used in earlier, unsuccessful trials. These high doses bring a greater risk of infusion site reactions and ARIA-E, the occurrence of leaky blood vessels causing edema in the brain. Scientists argued that these side effects are manageable with careful monitoring of patients. Moreover, ARIA-E can be lessened by gradually titrating up the antibody dose. However, clinicians noted that the jury is still out on how much this will help AD patients. "Several of the antibodies are looking good at removing amyloid, but the clinical efficacy still needs to be demonstrated."

Link: https://www.alzforum.org/news/conference-coverage/four-immunotherapies-now-banish-amyloid-brain

The Life Extension Advocacy Foundation volunteers hosted their first conference, Ending Age-Related Diseases 2018, in New York City a month ago. It was attended by a mix of advocates, scientists, entrepreneurs, and investors, all interested in seeing greater progress take place in the field of rejuvenation research. For those of us starting or running biotech companies to work on ways to treat aspects of aging, it was a good opportunity to network and make connections.

The presentations given at the conference were recorded, and are being tidied up and released for general viewing, as is the case for most of the conferences in our community. There was a greater emphasis on the business side of the house than usual at this event, and it is certainly the case that commercial biotechnology is becoming ever more important to efforts to treat aging as a medical condition. All of the fields of damage and damage repair described in the SENS rejuvenation research proposals are arguably at the stage where at least some part of the program might be commercially developed, given suitable levels of funding, or is being actively pursued by one or more companies.

Keith Comito at Ending Age-Related Diseases 2018 - One Second, One Life

Keith Comito, President of the Life Extension Advocacy Foundation and the Lifespan.io crowdfunding platform, discusses the emerging longevity biotech landscape at the Ending Age-Related Diseases conference in NYC.

Dr. Aubrey de Grey at Ending Age-Related Diseases 2018 - Rejuvenation is Finally an Industry

Some people in our community make the mistake of jumping right into a conversation about repairing the damage of aging without considering if the listener has any prior knowledge of the subject. Dr. Aubrey de Grey begins, as all good speakers should, in a mixed audience of experienced hands and those totally new to the topic of aging, with the basics about aging and works towards more complex topics. If you're familiar with his work, you may wish to skip to around the 17:55 mark, where he talks about new developments in the field and topics you may not have heard before.

Steven A. Garan at Ending Age-Related Diseases 2018 - Silicon Valley's Role in Fighting Aging

Steven A. Garan is the Director of Bioinformatics at the Center for Research and Education on Aging (CREA) and a researcher at UC Berkeley National Laboratory. In his talk at Ending Age-Related Diseases, he discussed the impact of various present and future Silicon Valley technology breakthroughs on overcoming aging. He gave a somewhat future-facing talk at the conference, which may surprise some people given his senior position at Berkeley. Ten years ago, talking about ending aging would potentially have damaged your career and gotten you unfairly labeled as fringe, much as Dr. Aubrey de Grey was for many years until many others joined his crusade to end aging. It was therefore refreshing to hear Steven talk so positively about the future of biomedical science and about doing something about aging itself in order to end age-related diseases.

Kelsey Moody at Ending Age-Related Diseases 2018 - Antibody Mimetic for Parkinson's Disease

Kelsey Moody is a process-oriented biotechnology executive who has specialized in the study of aging and aging mechanisms for over a decade. Since 2013, he has successfully built Ichor Therapeutics from a living room start-up into a premier, vertically integrated contract research organization that focuses on preclinical research services for aging pathways. Proceeds from this work are used to self-fund initiatives that constitute Ichor's portfolio companies in enzyme therapy (Lysoclear), small molecule drug discovery (Antoxerene), and protein engineering (RecombiPure). In this talk, Kelsey discusses Ichor's protein engineering platform, how Ichor has used it, and Ichor's plans for using it to discover new classes of drugs for age-related diseases.

There is a fair amount of evidence in mice for antidepressants to work via increased plasticity in the brain. This means greater generation and integration of new neurons, and more restructuring of synaptic connections between neurons. In mice, plasticity is lost with age, and here researchers show that a commonly used antidepressant can restore some of that loss. It remains an interesting question as to how much of this mouse research does in fact translate to humans; of late the data regarding plasticity of the human brain has been mixed, suggesting that there may be significant differences between humans and mice in this matter.

In the study the researchers focused on the aging of inhibitory interneurons which is less well understood than that of excitatory neurons, but potentially more crucial to plasticity. The team counted and chronically tracked the structure of inhibitory interneurons in dozens of mice aged to 3, 6, 9, 12 and 18 months (mice are mature by 3 months, live for about 2 years, and 18-month-old mice are already considered quite old). Previous work has shown that inhibitory interneurons retain the ability to dynamically remodel into adulthood. But the team now shows that new growth and plasticity reaches a limit and progressively declines starting at about 6 months. The study also shows that as mice age there is no significant change in the number or variety of inhibitory cells in the brain.

While the decline of dynamic remodeling and plasticity appeared to be natural consequences of aging, they were not immutable, the researchers showed. Prior work had shown that fluoxetine promotes interneuron branch remodeling in young mice, so they decided to see whether it could do so for older mice and restore plasticity as well.

To test this, researchers put the drug in the drinking water of mice at various ages for various amounts of time. Three-month-old mice treated for three months showed little change in dendrite growth compared to untreated controls, but 25 percent of cells in six-month-old mice treated for three months showed significant new growth (at the age of 9 months). But among 3-month-old mice treated for six months, 67 percent of cells showed new growth by the age of 9 months, showing that treatment starting early and lasting for six months had the strongest effect.

"Our finding that fluoxetine treatment in aging mice can attenuate the concurrent age-related declines in interneuron structural and visual cortex functional plasticity suggests it could provide an important therapeutic approach towards mitigation of sensory and cognitive deficits associated with aging, provided it is initiated before severe network deterioration."

Link: https://picower.mit.edu/news/antidepressant-restores-youthful-flexibility-aging-inhibitory-neurons-mice

One of the major areas of focus in regenerative research is finding ways to enhance the ability of transplanted cells to integrate with tissue, survive, and induce healing and growth. In early, first generation stem cell therapies, near all cells die quite quickly. The span of benefits that result is a reaction of native cells to the molecular signals briefly generated by the transplanted cells. The anti-inflammatory effects of mesenchymal stem cell therapies as presently practiced is a good example.

One way to improve cell survival is to build an artificial environment that to some degree mimics the extracellular matrix. Given that starting point, however, one can start adding additional features, such as molecular signals that enhance cell resilience, or structures that isolate cells for a time from hostile surroundings. Scaffolding materials are evolving to primarily provide protection for transplanted cells, rather than just a familiar three-dimensional structure.

A car accident leaves an aging patient with severe muscle injuries that won't heal. Treatment with muscle stem cells from a donor might restore damaged tissue, but doctors are unable to deliver them effectively. A new method may help change this. Researchers engineered a molecular matrix, a hydrogel, to deliver muscle stem cells called muscle satellite cells (MuSCs) directly to injured muscle tissue in patients whose muscles don't regenerate well. In lab experiments on mice, the hydrogel successfully delivered MuSCs to injured, aged muscle tissue to boost the healing process while protecting the stem cells from harsh immune reactions. The method was also successful in mice with a muscle tissue deficiency that emulated Duchenne muscular dystrophy.

Simply injecting additional muscle satellite cells into damaged, inflamed tissue has proven inefficient, in part because the stem cells encounter an immune system on the warpath. "Any muscle injury is going to attract immune cells. Typically, this would help muscle stem cells repair damage. But in aged or dystrophic muscles, immune cells lead to the release a lot of toxic chemicals like cytokines and free radicals that kill the new stem cells. "Our new hydrogel protects the stem cells, which multiply and thrive inside the matrix. The gel is applied to injured muscle, and the cells engraft onto the tissues and help them heal."

"Muscle satellite cells are resident stem cells in your skeletal muscles. They live on muscle strands like specks, and they're key players in making new muscle tissue. As we age, we lose muscle mass, and the number of satellite cells also decreases. The ones that are left get weaker. It's a double whammy. At a very advanced age, a patient stops regenerating muscle altogether. With this system we engineered, we think we can introduce donor cells to enhance the repair mechanism in injured older patients. We also want to get this to work in patients with Duchene muscular dystrophy."

Link: https://www.news.gatech.edu/2018/08/15/matrix-delivers-healing-stem-cells-injured-elderly-muscles

In recent years, researchers working on forms of telomerase gene therapy have produced evidence to show that increased levels and activity of telomerase does not raise cancer risk in mice. The open access paper and publicity materials noted below report the latest example. Extra telomerase increases the sort of activities that are beneficial in the context of improved regenerative capacity, but might be thought to raise the risk of cancer when they take place in the damaged environment of old tissue. This means more stem cell activity, more cellular replication, and so forth.

Somatic cells are limited in the degree to which they can replicate by the length of their telomeres, repeated DNA sequences at the ends of chromosomes. A little of that length is dropped with each cell replication, and a cell with short telomeres will become senescent or self-destruct, and in either case cease replicating. The primary function of telomerase is to extend telomeres, so the operation of telomerase in somatic cells will act to push them past their evolved limits to replication. Stem cells, on the other hand, naturally deploy telomerase to bypass the telomere countdown and retain the ability to replicate indefinitely.

All higher animals depend upon this split between a small number of privileged cells and the vast majority of limited cells. It is the primary means by which incidence of cancer is kept to a low enough rate, and pushed off far enough into later life, for evolutionary success. Near all cells that suffer random DNA mutation are somatic cells, and thus are removed from circulation long before they can become damaged enough to be a threat. Unless they are full of telomerase, and replicating for far longer, in which case the odds change for the worse.

Why, then, does telomerase gene therapy in mice fail to increase cancer risk? In fact in some studies it dramatically reduces cancer risk. One theory is that the increased cellular activity and replication in the immune system more than offsets the increased risk elsewhere. Immune cells are an important line of defense against cancer, seeking out and destroying cancerous cells. Cancer risk correlates fairly well with measures of immune system decline with age.

Does this mean that we should embrace telomerase gene therapies for human use, as way to enhance regeneration in the damaged tissues of old individuals? Not yet, I think, or at least not yet if we are cautious. Mice have very different telomere and telomerase dynamics when compared to humans. It is still possible that the balance of evolved cellular metabolism plus added telomerase works out to less cancer in mice, but more cancer in humans. There is work yet to be done, some of which might take the form of more brave individuals self-experimenting with gene therapies, if the last few years are any guide.

Researchers prove that gene therapy vectors carrying the telomerase gene do not increase the risk of cancer in cancer-prone mouse models

For years now researchers have been investigating the possibility of using the enzyme telomerase to treat pathological processes related with telomere shortening, as well as diseases associated with ageing - cardiovascular and neurodegenerative diseases, among others - and even the ageing process itself. In 2012, they designed a highly innovative strategy: a gene therapy that reactivates the telomerase gene using adeno-associated viruses (AAV). These gene therapy vectors do not integrate in the genome of the host cell, thus telomerase only performs its telomere-reparative actions during a few cell divisions before the vector is diluted out. In this manner, a potential risk associated with the activation of telomerase, such as promoting cancer, it is minimized. But to what extent?

The paper being published now specifically tackles this question by applying gene therapy to an animal model, a mouse, which reproduces human lung cancer and which, therefore, already has a greater risk of developing this disease. The results are negative: "The activation of telomerase by means of this gene therapy does not increase the risk of developing cancer", not even in these mice, where tumours are forced to appear in a relatively short time.

"These findings suggests that gene therapy with telomerase appears to be safe, even in a pro-tumour context. In our research, we were already seeing that this gene therapy does not increase the risk of cancer, but we wanted to conduct what is known as a 'killer experiment', an experiment that creates the worst conditions for your hypothesis to hold true; if it survives even under those circumstances, the hypothesis is truly solid. That is why we chose these mice; they are animals that spontaneously develop a type of lung cancer that is very similar to the human form, which normally never appears in normal mice. We can't think of any other experiment that would provide a better demonstration of the safety of this therapy".

AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer

The ends of our chromosomes, or telomeres, shorten with age. When telomeres become critically short cells stop dividing and die. Shortened telomeres are associated with onset of age-associated diseases. Telomerase is a retrotranscriptase enzyme that is able to elongate telomeres by coping an associated RNA template. Telomerase is silenced after birth in the majority of cells with the exception of adult stem cells. Cancer cells aberrantly reactivate telomerase facilitating indefinite cell division. Mutations in genes encoding for proteins involved in telomere maintenance lead the so-called "telomere syndromes" that include aplastic anemia and pulmonary fibrosis, among others.

We have developed a telomerase gene therapy that has proven to be effective in delaying age-associated diseases and showed therapeutic effects in mouse models for the telomere syndromes. Given the potential cancer risk associated to telomerase expression in the organism, we set to analyze the effects of telomerase gene therapy in a lung cancer mouse model. Our work demonstrates that telomerase gene therapy does not aggravate the incidence, onset and progression of lung cancer in mice. These findings expand on the safety of AAV-mediated telomerase activation as a novel therapeutic strategy for the treatment of diseases associated to short telomeres.

Raised blood pressure is to be avoided; the overwhelming weight of evidence associates it with a higher risk of age-related disease and shorter life expectancy. Some of that is because the proximate causes of raised blood pressure damage long term health in other ways as well, but in and of itself, even if there were no proximate causes, higher blood pressure is harmful. It damages delicate tissues in the brain, kidneys, and other organs. It causes remodeling and weakening of the heart and blood vessels. It increases the pace at which capillaries rupture in the brain, producing tiny areas of damage that contribute to cognitive decline. There is much more - the aforementioned consequences are only a sample of the full range of downstream issues.

The causes of raised blood pressure with advancing age are the mechanisms that produce stiffening of blood vessels, such as loss of elasticity in the extracellular matrix, dysfunction in vascular muscle cells, and so on. They cannot be entirely evaded at the present time, not until the presently very narrow range of available rejuvenation therapies expands considerably, but they can be slowed through lifestyle choices. Don't get fat; avoid smoking and other environmental factors that reliably increase chronic inflammation; the usual suspects, in other words. The research here demonstrates the relationship between excess visceral fat tissue and raised blood pressure.

Body mass index is positively associated with blood pressure, according to the ongoing study of 1.7 million Chinese men and women. In individuals who were not taking an antihypertensive medication, the researchers observed an increase of 0.8 to 1.7 mm Hg in blood pressure per additional unit of body mass index (BMI). Overall, the population had a mean BMI of 24.7 and a mean systolic blood pressure of 136.5, which qualifies as stage I hypertension.

Researchers recorded the participants' blood pressure from September 2014 through June 2017 as part of the larger China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project, which captures at least 22,000 subgroups of people based on age (35-80), sex, race/ethnicity, geography, occupation, and other pertinent characteristics - such as whether or not they are on antihypertensive medication. "The enormous size of the dataset - the result of an unprecedented effort in China - allows us to characterize this relationship between BMI and blood pressure across tens of thousands of subgroups, which simply would not be possible in a smaller study."

In China, the frequency of obesity is expected to more than triple in men - from 4.0% in 2010 to 12.3% in 2025 - and more than double in women - from 5.2% to 10.8%. Meanwhile, high blood pressure already affects one-third of Chinese adults, and only about one in 20 of those with hypertension have the condition under control. According to the researchers, one way for the Chinese healthcare system to address these risk factors would be the management of high blood pressure with antihypertensive drugs. A study compared the widespread and successful use of antihypertensive drugs in the United States for blood pressure management to their infrequent use in China, suggesting that by prescribing antihypertensives earlier and more frequently, China might begin to take control of its high blood pressure crisis.

Link: https://news.yale.edu/2018/08/17/body-mass-index-increases-blood-pressure-may-well

Blood vessels stiffen with age, and this appears to be the primary cause of age-related hypertension, or raised blood pressure. That raised blood pressure in turn damages delicate tissues, increasing the pace at which ruptures occur in capillaries throughout the body. In the brain this causes many tiny, silent strokes over the years, adding up to create cognitive decline. Eventually hypertension combines with the corrosive effect of atherosclerosis on blood vessel walls to cause some form of fatal structural failure in a major blood vessel.

The causes of stiffening of blood vessels include cross-linking that disrupts the physical properties of the extracellular matrix, the related loss of elastin in the matrix, and dysfunction in the vascular smooth muscle cells responsible for constriction and dilation of blood vessels. That cellular dysfunction has a whole set of deeper causes, not all of which are well understood at this time. The chronic inflammation and harmful signaling generated by senescent cells seems to be involved, but it isn't the whole story by any means.

Aging is associated with a progressive decline in vasoconstrictor responses in central and peripheral arteries. The mechanism responsible for the age-related decrease in vasoconstrictor function has not been fully elucidated but may involve an impaired ability of vascular smooth muscle (VSM) cells to develop contractile tension. This hypothesis is supported by evidence indicating that myogenic constrictor responses in skeletal muscle arterioles declined with age. In addition, agonist-induced vasoconstrictor responses to norepinephrine (NE), phenylephrine (PE), and angiotensin II (Ang II) were impaired in endothelium intact skeletal muscle feed arteries (SFA) from old rats when compared to young rats.

Arterial aging results in progressive changes in the mechanical properties of the vessel wall leading to increased wall stiffness and an impaired ability of aged blood vessels to control local blood flow and pressure. At the microscopic level, this translates to decreased responsiveness of VSM and endothelial cells to mechanical stimuli. This impairment, in turn, induces compensatory hypertrophic or hyperplastic remodeling of aged arteries. The discrete VSM cell mechanical properties and their ability to adapt to external mechanical signals (e.g., blood pressure and flow) directly contribute to maintaining vessel tone.

Vascular smooth muscle cells play an integral role in regulating matrix deposition and vessel wall contractility via interaction between the actomyosin contractile unit and adhesion structures formed at the cell membrane that mechanically link the cell to the matrix. The actin cytoskeleton is responsible for maintaining cell shape and provides the platform for the distribution of mechanical signals throughout the cell. This mechanical load-bearing cell-matrix interaction is key to maintaining the contractile state of resistance arteries. Most studies to date on arterial aging have focused on the role played by endothelial dysfunction or changes in the extracellular matrix, and less on the contribution of VSM cells that control vessel tone. However, there is emerging interest in the role VSM cells play in regulating vessel wall stiffness.

Link: https://doi.org/10.3389/fphys.2018.00856

Today, I'll point out an open access commentary in which the authors survey a number of lines of research into age-related dysfunction in the liver, all of which lead back to elevated levels of cyclin-dependent kinase 4 (CDK4). Some of this work involves investigation of the mechanisms of fatty liver disease, more properly known as hepatic steatosis. This is most commonly caused by being overweight in this age of cheap calories, but, setting aside the morbidly obese, the condition nonetheless tends to emerge later rather than earlier in life. Other research programs look at more directly age-associated measures of liver function, such as senescent cell burden, changes in gene expression, and proteins and lipids in the bloodstream. Inhibition of CDK4 in late life to some degree reverses many of these declines.

Manipulation of specific proteins and genes is an intervention with widely varying expectations of ease and safety. The ideal gene and its protein product has little influence over anything other than the one disease-associated mechanism of interest. Or at the least, it only has that one relationship in the organ suffering from the disease state, even if it has other roles elsewhere in the body. Unfortunately that can be said for all too few genes. CDK4 is a dangerous-looking target, showing up in considerations of cancer via its close relationship to retinoblastoma proteins, and because it is involved in cell replication. Growth and replication genes tend to be hard to safely target as downstream effects of change are unpredictable, and their influence on cancer risk is one of those unpredictable items. This is the challenge for any gene involved in vital low-level cellular processes, and is one of the reasons why adjusting gene expression to form new metabolic states is an expensive, slow process.

The question remains as to why CDK4 levels rise with age in the liver. This is a reaction to which of the root causes of aging, mediated by which intermediary mechanisms? Just because chronic inflammation is important in liver aging, and the inflammation-producing accumulation of senescent cells is measured here doesn't mean that cellular senescence is the most important of underlying causes. As is usually the case, the approach of fixing root causes and observing the results is likely to be a faster path to answers than working backwards through pathways and relationships in the cell.

Correction of aging phenotype in the liver

The earliest stage of Non-Alcoholic Fatty Liver Disease (NAFLD), hepatic steatosis (or non-alcoholic fatty liver, NAFL) has no evidence of liver injury, but is characterized by an accumulation of triglycerides in hepatocytes. In some patients, NAFL can progress in age-dependent manner to fibrosis and then to non-alcoholic steatohepatitis (NASH) and cirrhosis. Mechanisms of development of hepatic steatosis are not well understood and approaches to treat hepatic steatosis are not developed.

Researchers have investigated the role of the endogenous ligand of growth hormone Ghrelin in development of age-associated hepatic steatosis. The authors clearly demonstrated the deletion of ghrelin prevents development of hepatic steatosis. This prevention is mediated by down-regulation of C/EBPα-p300 axis suggesting that the inhibition of ghrelin activities or C/EBPα-p300 pathway might be considered as a therapeutic approach. In agreement with these findings, other scientists have recently reported that blocking cdk4, a direct activator of C/EBPα-p300 complex, eliminates age-associated hepatic steatosis as well as several age-associated disorders of the liver.

Researchers have investigated age-associated development of hepatic steatosis in mice with deletion of ghrelin. At young age, no significant differences were observed. However, while wild type (WT) mice developed severe steatosis, Ghrelin knockout (KO) mice showed significant inhibition of steatosis. Further studies revealed that the enzyme of the last step of synthesis of triglycerides, DGAT1, is not elevated in livers of Ghrelin KO mice, while it is elevated with age in livers of old mice. Activation of DGAT1 promoter does not occur in ghrelin KO mice due to a lack of C/EBPα-p300 complexes. The lack of these complexes is associated with failure of Ghrelin KO mice to phosphorylate C/EBPα, the event that is required for the formation of C/EBPα-p300 complexes. This phosphorylation is typically under control of cdk4 and it is likely that the deletion of ghrelin leads to the inhibition of cdk4, suggesting that cdk4 is a key mediator of ghrelin-dependent hepatic steatosis.

Researchers examined the role of cdk4 in age-dependent hepatic steatosis using three settings: liver biopsies from old patients with NAFLD, cdk4-resistant C/EBPα-S193A mice, and inhibition of cdk4 in old WT mice. These three experimental settings showed that cdk4 is elevated in old patients and degree of elevation correlates with severity of NAFLD. Work with S193A mice and the inhibition of cdk4, revealed that cdk4 is a key driver of the age-associated hepatic steatosis. Surprisingly, the authors found that inhibition of cdk4 not only eliminates hepatic steatosis, but also corrects several other age-dependent liver disorders including cellular senescence, heterochromatin structures, E2F1 and RB-dependent pathways of proliferation, liver/body weight ratio, and several blood parameters.

We all, to some degree, accumulate harmful protein aggregates in the brain with age, but only some people develop severe neurodegenerative disease as a result. The rest of the population remains mildly impaired. Why is this? Some have suggested that Alzheimer's disease and the like are to some degree lifestyle conditions, aggravated by the presence of excess visceral fat tissue and the abnormal metabolism that results. Alternatively the microbial hypothesis suggests that only some people have sufficient persistent infection by herpesviruses or lyme spirochetes to result in high levels of protein aggregates. Theories of impaired cerebrospinal fluid drainage point to differing levels of structural failure in fluid channels leading from the brain. Researchers here propose another mechanism, in that some people have synapses that are resilient to the harms inflicted by tau aggregation, thought to be the most damaging mechanism in late stage Alzheimer's disease.

People suffering from Alzheimer's disease (AD) develop a buildup of two proteins that impair communications between nerve cells in the brain - plaques made of amyloid beta proteins and neurofibrillary tangles made of tau proteins. Intriguingly, not all people with those signs of Alzheimer's show any cognitive decline during their lifetime. The question became, what sets these people apart from those with the same plaques and tangles that develop the signature dementia?

"In previous studies, we found that while the non-demented people with Alzheimer's neuropathology had amyloid plaques and neurofibrillary tangles just like the demented people did, the toxic amyloid beta and tau proteins did not accumulate at synapses, the point of communication between nerve cells. When nerve cells can't communicate because of the buildup of these toxic proteins that disrupt synapse, thought and memory become impaired. The next key question was then what makes the synapse of these resilient individuals capable of rejecting the dysfunctional binding of amyloid beta and tau?"

The researchers analyzed the protein composition of synapses isolated from frozen brain tissue donated by people who had participated in brain aging studies. The participants were divided into three groups - those with Alzheimer's dementia, those with Alzheimer's brain features but no signs of dementia, and those without any evidence of Alzheimer's. The results showed that resilient individuals had a unique synaptic protein signature that set them apart from both demented AD patients and normal subjects with no AD pathology. "We don't yet fully understand the exact mechanisms responsible for this protection. Understanding such protective biological processes could reveal new targets for developing effective Alzheimer's treatments."

Link: https://www.utmb.edu/newsroom/article11851.aspx

Small, short doses of damaging cellular stress, such as that achieved through the application of heat, toxins, lack of nutrients, or raised levels of oxidative molecules, produce a net benefit to cell and tissue function. This is called hormesis. It occurs because cells react to short periods of stress with a lasting upregulation of maintenance activities and other altered behavior. Hormetic behaviors are the basis for many of the benefits of exercise, calorie restriction, and other related interventions shown to slow aging to some degree in animal studies.

In the research noted here, scientists report on an investigation into the way in which mitochondrial activity changes in response to cellular stress. Mitochondria are the power plants of the cell, and their function is central to cellular health. With age, mitochondria become dysfunctional in a number of different ways. Periodic hormetic stress may slow down or attenuate this progressive decline by, for example, increasing the housekeeping processes of mitophagy, responsible for recycling damaged mitochondria. Other signaling processes that more directly determine mitochondrial function are also likely involved, however.

Researchers report that brief exposures to stressors can be beneficial by prompting the cell to trigger sustained production of antioxidants, molecules that help get rid of toxic cellular buildup related to normal metabolism. Short-term stress to cells leads to remodeling mitochondria, the powerhouses of the cell that deteriorate with age, so they generate fewer toxic byproducts. The findings could lead to new approaches to counter the cellular effects of aging, possibly even extending lifespan.

"The novelty of this study is that we've generated a model in which we can turn off antioxidant production in mitochondria but in a reversible way. So we were able to induce this stress for specific time windows and see how cells responded." In the process of converting food into chemical energy, mitochondria produce a chemical called superoxide, which has a critical role in cells but is toxic if it builds up. For this reason, mitochondria also produce an enzyme - superoxide dismutase, or SOD - to convert superoxide to a less toxic form.

In a group of genetically identical mice in utero, half with a molecular "off" switch for SOD experienced brief stress when the enzyme was deactivated. After the mice were born and continued to grow to adulthood, the two groups looked very similar. But liver samples taken when they were four weeks old told a strikingly different story: the mice whose SOD enzyme had been turned off briefly to trigger stress in mitochondria had - surprisingly - higher levels of antioxidants, more mitochondria and less superoxide buildup than the mice who had not experienced stress.

When the team analyzed which genes were being activated in both the lab dishes and the liver samples of all the mice, they found unexpected molecular pathways at work in the SOD group that were reprogramming mitochondria to produce fewer toxic molecules while simultaneously increaseing the cells' antioxidant capacity. The work suggests that short-term mitochondrial stress may lead to long-term adaptations (a concept called "mitohormesis") that could keep cells healthy longer, staving off aging and disease. Researchers next plan to study whether the mechanism elucidated here can delay the effects of aging in mammals.

Link: https://www.salk.edu/news-release/cells-agree-what-doesnt-kill-you-makes-you-stronger/

The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed Didier Coeurnelle of the Healthy Life Extension Society (HEALES), a long-standing advocate on the European side of our community who has promoted research and development of therapies to treat aging for many years now.

Insofar as the treatment of aging goes, we are living through the early stages of an enormously important transition, a tipping point in the progress of medicine. It will be of far greater impact than the advent of antibiotics. The development of rejuvenation therapies, treatments that can reverse or repair or bypass the known root causes of aging, will bring sweeping change and improvement to the human condition. The first legitimate, functioning rejuvenation therapies already exist, senolytic drug candidates that can remove a sizable fraction of senescent cells from old tissues. These drugs are in some cases very cheap, being generic and widely manufactured for other uses, but the world at large has not yet caught up to this point. The millions of older individuals who might benefit from removal of senescent cells do not yet appreciate that with just a modest effort, they could most likely experience significantly improved health, a reduction in the burden of aging.

Nothing happens quickly. It will take time for the realization to percolate. For the human trials to complete and be publicized, and then for people to understand the implications of the results. The usual suspects are ahead of the wave, by which I mean some researchers, some self-experimenters, some venture capitalists, some advocates. Their job at the present time is still largely to persuade everyone else, the people who will one day be customers, developers, and investors. An enormous industry is waiting in the wings to come into being. It will ultimately provide the majority of all medicine and medical services, approaches that will control the progression of aging and put an end to age-related disease. It is inevitable, but the necessary steps along this road are running all too slowly, for reasons that have little to do with the technology and everything to do with human nature.

An Interview With Didier Coeurnelle

You have been an advocate for quite some time now; how successful do you think collective advocacy efforts have been over the years?

Not enough yet and not fast enough. The "pro-aging" narrative is, sadly, powerful. Defeating aging looks "too good to be true" and makes people feel uneasy. However, there are changes. For example, in the French-speaking world, sometimes we see articles about "amortalité" (life without senescence) in the press; a few years ago, you would see only articles speculating about billionaires wanting "immortality" (which makes people afraid).

In November, HEALES will organize the next Eurosymposium on Healthy Ageing (EHA). EHA and Undoing Aging each have a section focused on advocacy. Why did you decide to include it?

I think most scientists wanting big progress for longevity know that having public opinion on our side will help. Also, PR is useful in order to raise money. However, many scientists feel uneasy about these issues. That's why we decided to have a day dedicated to social aspects. Not all scientists will stay for the last day, and we will also try to reach a larger public on the last day. Another aspect is that Brussels is the European capital. One of our goals is to convince people there. Let's be honest: there is a long way to go. However, for a year or two now, some European civil servants who have been promoting "healthy aging" (we know it is an oxymoron) seem to be very interested in big data on health and scientific research. We will be keeping an eye on these developments.

You don't need to convince people that saving the lives of children is a good thing to do; however, you do need to convince them that saving elderly lives is a good thing. Why do you think this difference exists?

Nor do you need to convince people that defeating cancer or Alzheimer's disease would be good, but death by old age is a step too far. For me, the fundamental reason is a variant of Stockholm syndrome called the terror management theory. Death by old age is awful and unavoidable. We must think that longevity is not better, otherwise it would be too awful to die. This process is unconscious.

How far do you think we are from the point when people won't need persuading anymore, if ever?

Aubrey de Grey said it will be when a mouse becomes "immortal", because people will feel that rejuvenation therapies will be available soon. I think that it could be sooner if more and more scientists start to speak out more about it.

With some luck, the effects of first-generation rejuvenation therapies, such as senolytics, will be tangible soon. Assuming that the effects are measurably positive, how do you think the world will react to the news, and how do you think that this will affect advocacy?

It would be interesting even if senolytics have only a moderate effect. I think some groups who are not in the "longevity camp" will start asking to use them. Maybe, in some countries, they will even start asking for reimbursement from social security programs. Some groups on the other side will probably ask not to use these products or will stress risks, but it will be especially difficult for "deathists" to fight against senolytics, which are, in a way, very classical drugs.

The involvement of In Silico Medicine in the formation of Napa Therapeutics to run drug discovery based on advances in understanding of mitochondrial metabolism in aging is an example of the premium placed on any approach that might plausibly reduce the cost and time involved in finding drug candidates. We will no doubt see a lot more of this sort of thing as computational methodologies become a plausible replacement for greater portions of the existing costly, hands-on, mechanical screening processes.

Draw a triangle in the present field of aging research with the three points set at calorie restriction mimetics, exercise mimetics, and general tinkering with energy metabolism, then efforts to increase NAD+ levels in mitochondria might be found somewhere in the midst of that space. That line of work is growing in popularity, and the early human trials of compounds like nicotinamide riboside suggest that the effect size might be worth chasing if the costs are low. (Though of course the development costs are never low for any approach that must pass through the full regulatory process).

Helping mitochondria to function more effectively in old tissues may help modestly with a variety of issues, given that faltering energy generation is a feature of aging, though it remains to be seen as to just how large the effect sizes are at the end of the day. This is not rejuvenation; this is pushing a damaged engine a little harder, this is overriding an aspect of the aged state of metabolism without addressing the underlying damage that causes that aged state. Sometimes that can work to some degree, sometimes it doesn't.

The Buck Institute for Research on Aging, Insilico Medicine, and Juvenescence Ltd announced today that they have formed Napa Therapeutics, Ltd to develop drugs against a novel aging-related target. The Buck Institute is one of the leading research centers in the world focused solely on research on aging and the elimination of age-related disease. Insilico Medicine is an AI company focused on a range of verticals devoted to aging. Juvenescence is a company focused on developing drugs to modify aging and the diseases of aging.

Napa Therapeutics is based on groundbreaking research in NAD metabolism conducted in the lab of Eric Verdin, MD, President and CEO of the Buck Institute. The Verdin lab will collaborate with Napa, using Insilico's drug development engine to speed the discovery of new compounds. "I am most excited by this model and the ability to combine the quality science of the Buck Institute with the remarkable deep learning engine at Insilico Medicine. To me this is another big step in the evolving process of using AI with human intelligence to extract the best of both systems. Napa Therapeutics lets Juvenescence deepen our collaboration with the Buck Institute and with Insilico Medicine. We hope to shorten the time required to identify molecules that can be brought to the clinic and most importantly help patients."

Link: https://www.prnewswire.com/news-releases/the-buck-institute-insilico-medicine-and-juvenescence-found-napa-therapeutics-to-develop-drugs-to-impede-age-related-disease-300696495.html

The present consensus on the inheritance of longevity is that genetic influences over aging only rise to importance in later life. Even then it is perhaps more a matter of resistance to accumulated molecular damage and its consequences than a slower pace of aging per se. Environment and choice throughout life are the overwhelming determinants of the course of aging leading into middle age, meaning exposure to pathogens, amount of visceral fat tissue, smoking, and similar line items. That of course raises the question as to the degree to which inherited longevity is a cultural rather than genetic phenomenon. Only a tiny minority of individuals can legitimately blame their genes for the sort of shape they are in at 65. Health and survival status at 95 are a different story, however, and genetics plays a larger role - at least in the context of a world lacking rejuvenation therapies, but that will cease to be the case soon enough.

Researchers report that women whose mothers lived to at least age 90 were more likely to also live to 90, free of serious diseases and disabilities. The study found women whose mothers lived into their ninth decade enjoyed 25 percent increased likelihood of also doing so without suffering from serious or chronic illness, including heart disease, stroke, diabetes, cancer, hip fractures or other debilitating disabilities.

Interestingly, the study also found that if only the father lived to 90, it did not correlate to increased longevity and health in daughters. However, if both the mother and father lived to 90, the likelihood of the daughter achieving longevity and healthy aging jumped to 38 percent. The study did not address parental life span effects on sons. Rather, it analyzed data from approximately 22,000 postmenopausal women participating in the Women's Health Initiative, a large, national study investigating major risk factors for chronic diseases among women. Limitations included no knowledge of the health or cause of death of the participants' parents.

Researchers believe a combination of genetics, environment, and behaviors passed to subsequent generations may influence aging outcomes among offspring. At baseline, the women in the study whose mothers lived to at least 90 were more likely to be college graduates, married with high incomes and incorporated physical activity and a healthy diet into their lives. "We now have evidence that how long our parents live may predict our long-term outcomes, including whether we will age well, but we need further studies to explore why. Although we cannot determine our genes, our study shows the importance of passing on healthy behaviors to our children. Certain lifestyle choices can determine healthy aging from generation to generation."

Link: https://ucsdnews.ucsd.edu/pressrelease/parental_life_span_predicts_daughters_living_to_90_without_chronic_disease_or_disability

Hair cells are the sensors of the ear, picking up vibrations with tiny fibers that give the cells their name. Unfortunately, these cells are not replaced when lost in adult mammals. Loud noise, toxins, and some infectious diseases can cause sufficient loss of hair cells to induce deafness - a condition that currently lacks effective treatments. A sizable fraction of research into the causes of hearing loss has focused on hair cells in the ear, particularly with the growth of the regenerative medicine community. The restoration of lost cell populations is on the horizon, and hair cell regrowth is further advanced than many other lines of work in this field.

Is this approach useful for the types of hearing loss most frequently observed in older individuals, however? The results in today's open access paper can be used to argue that hair cell regrowth may not be sufficient on its own. The authors present evidence for inner hair cells to remain largely intact, while the underlying issue is the death of neurons and their axons connecting these cells to the brain. Reintegration of new hair cells with the complex auditory system of the brain has the look of a much harder problem to solve than the lesser challenge of creating the new hair cells. Rebuilding the connecting axons may not be sufficient on its own, and even that is a hard task to contemplate in comparison to the introduction of new hair cells.

This is one of many examples in which it is an open question as to whether the next generation of regenerative strategies will be sufficient to address specific forms of degeneration that span different organs and tissue types. Will we be fortunate, and find that approaches spurring coordinated localized regrowth do in fact cause reconnection of the nervous system to new tissues and cells? The answer will no doubt be different in each case, and depend on the fine details. The effort must be made, and if it fails, then the more sophisticated efforts of later years will have to be designed, constructed, and take their turn.

Primary Neural Degeneration in the Human Cochlea: Evidence for Hidden Hearing Loss in the Aging Ear

Although sensorineural hearing loss (SNHL) can involve damage to either sensory cells or sensory neurons of the inner ear, a longstanding dogma in acquired SNHL was that loss of sensory cells is the primary event, and that degeneration of auditory nerve fibers (ANFs) occurs only secondarily to the loss of peripheral targets. This view arose because, after cochlear insults such as acoustic injury or ototoxic drugs, the degeneration of sensory cells can be seen within hours post-exposure, whereas degeneration of spiral ganglion cells (SGCs), the cell bodies of the ANFs, is not visible for weeks to months.

Animal work challenged the dogma by showing that hair cell loss in acquired SNHL is neither necessary nor sufficient for loss of ANFs. Firstly, in acoustic injury models, overexposures causing only reversible threshold shifts, and no hair cell loss, can nevertheless cause significant ANF degeneration. The neural damage is visible immediately as loss of synaptic connections between ANFs and inner hair cells (IHCs). In the aging mouse ear, as in the noise-damaged ear, it is the connections between SGCs and IHCs that degenerate first, rather than the hair cells themselves. This primary neural degeneration, or partial de-afferentation of IHCs, has negligible effect on thresholds until it exceeds 80-90%, thus it "hides" behind the audiogram.

The observation that ANF degeneration precedes and/or exceeds hair cell loss in animal models of acquired SNHL has suggested why two people with the same threshold audiogram, whether normal or abnormal, can have very different abilities to understand speech in a noisy environment. i.e. that partial de-afferentation of IHCs, a.k.a. "hidden hearing loss", compromises hearing ability in complex listening environments without changing the ability to detect a pure tone in quiet.

Here we take a direct approach to the question of whether hidden hearing loss is as important in humans as in animal models. We study temporal bones from a group of 20 "normal-aging" humans, ranging in age from birth to 86 years, without any explicit history or ear diseases or ototoxic exposures. We prepare these autopsy specimens in ways that allow us to accurately quantify the survival of hair cells and ANF peripheral axons in the same cochlear regions.

Mean loss of outer hair cells was 30-40% throughout the audiometric frequency range in subjects over 60 yrs, with even greater losses at both apical (low-frequency) and basal (high-frequency) ends. In contrast, mean inner hair cell loss across audiometric frequencies was rarely more than 15%, at any age. Neural loss greatly exceeded inner hair cell loss, with 7 of 11 subjects over 60 years showing more than 60% loss of peripheral axons, and with the age-related slope of axonal loss outstripping the age-related loss of inner hair cells by almost 3:1. The results suggest that a large number of auditory neurons in the aging ear are disconnected from their hair cell targets. This primary neural degeneration would not affect the audiogram, but likely contributes to age-related hearing impairment, especially in noisy environments. Thus, therapies designed to regrow peripheral axons could provide clinically meaningful improvement in the aged ear.

Elephants and whales are in their own way just as interesting a target of study for cancer researchers as naked mole-rats. Cancer risk is a numbers game, based on incidence of mutation and capacity of cancer suppression mechanisms to destroy cancerous cells before they can form a tumor. Given that elephants have many more cells than humans, but a lower rate of cancer, what are the differences in cellular biochemistry that explain that outcome? Might any one or more of those differences form the basis for therapies in human medicine? It is a little early to say at this stage whether or not the comparative biology of cancer will lead to meaningful advances in control over human cancer, but a number of lines of research are underway in this part of the field.

An estimated 17 percent of humans worldwide die from cancer, but less than five percent of captive elephants - who also live for about 70 years, and have about 100 times as many potentially cancerous cells as humans - die from the disease. Humans, like all other animals, have one copy of the master tumor suppressor gene p53. This gene enables humans and elephants to recognize unrepaired DNA damage, a precursor of cancer. Then it causes those damaged cells to die. Unexpectedly, however, researchers found that elephants have 20 copies of p53. This makes their cells significantly more sensitive to damaged DNA and quicker to engage in cellular suicide.

Now, researchers describe a second element of this process: an anti-cancer gene that returned from the dead. "Genes duplicate all the time. Sometimes they make mistakes, producing non-functional versions known as pseudogenes." While studying p53 in elephants, researchers found a former pseudogene called leukemia inhibitory factor 6 (LIF6) that had somehow evolved a new on-switch. LIF6, back from the dead, had become a valuable working gene. Its function, when activated by p53, is to respond to damaged DNA by killing the cell. The LIF6 gene makes a protein that goes, quite rapidly, to the mitochondria, the cell's main energy source. That protein pokes holes in the mitochondria, causing the cell to die.

LIF6 seems to have emerged around the time when the fossil record indicates that the small groundhog-sized precursors of today's elephants began to grow bigger. This started about 25 to 30 million years ago. This supplementary method of suppressing cancer may have been a key element enabling enormous growth, which eventually led to modern elephants. Bigger animals have vastly more cells, and they tend to live longer, which means more time and opportunities to accumulate cancer-causing mutations. When those cells divide, their DNA makes copies of itself. But those copies don't match the original. Errors get introduced and the repair process can't catch up. "Large, long-lived animals must have evolved robust mechanisms to either suppress or eliminate cancerous cells in order to live as long as they do, and reach their adult sizes."

Link: https://www.eurekalert.org/pub_releases/2018-08/uocm-zgp080818.php

Samumed is noteworthy for the breadth of their regenerative medicine development pipeline, based as it is on a single technology platform, the manipulation of Wnt signaling. Their trials to date are attempts to use variations on this approach to increase regenerative capacity in aging and damaged tissues. The company might be viewed as an early example of the fork in the road for the regenerative medicine community, arising after first generation stem cell therapies have matured. Some groups will produce better, more advanced cell therapies, aiming to improve the survival and utility of transplanted cells. Others, like Samumed, will abandon cell transplants in favor of ways to manipulate native cell populations to produce similar outcomes.

At least a few of the future successful companies in the rejuvenation research space should come to look quite similar to Samumed in structure. Most legitimate rejuvenation therapies, those capable of at least partially reversing one of the root causes of aging, will be applicable to scores of age-related diseases. Companies will be limited in size and activity only by the amount of funding they can raise. It will not be unusual to see the likes of Samumed or Unity Biotechnology raising hundreds of millions of dollars for very broad pipelines, with trials of their technology for a dozen or more age-related conditions running in parallel.

Samumed, LLC, announced today that it has closed its A-6 Round of equity issuance with $438 million, bringing its total equity raised to date to more than $650 million.The pre-money valuation for the round was $12 billion. "We appreciate the strong support from our investors, and we are now in a fortunate position to both move our later stage programs to commercialization, as well as expand on our earlier stage science and clinical portfolio."

Samumed is developing small-molecule drugs that target the regenerative potential of the Wnt pathway in order to reverse the progression of various age-related diseases. Its development pipeline includes therapies focused on osteoarthritis, degenerative disc disease, idiopathic pulmonary fibrosis, and Alzheimer's disease. A number of these therapies are currently in human trials, and some of them are currently in phase 2 testing.

The Wnt pathway is a primary signaling pathway that regulates the self-renewal and differentiation of adult stem cells. It plays a key role in tissue repair and upkeep, and it helps the body repair and regenerate following injury. As we age, the Wnt pathway becomes deregulated, which leads to a decline of tissue regeneration and supports the progression of various age-related diseases. Samumed is focused on modulating the Wnt pathway in order to promote the restoration and health of diseased tissues by spurring effective regeneration.

Link: https://www.leafscience.org/samumed/

The protein α-synuclein, like amyloid-β and tau, forms into an increasing amount of solid aggregates in the aging brain. These aggregates and their surrounding biochemistry cause neural dysfunction and cell death. Every older individual has raised levels of these protein aggregates, and the pathology they cause rises to the level of named condition when one or another is present in great enough amounts. The age-related diseases associated with α-synuclein are termed synucleinopathies, though one can argue that all neurodegeneration is to some degree influenced by all protein aggregates. Where the research, medical, and regulatory communities choose to draw the line between "normal" and "pathological" is somewhat arbitrary. If methods of reliably removing protein aggregates existed, every older individual should undergo treatment on a periodic basis, not just people with notably high levels of aggregates.

Parkinson's disease is the best known of the synucleinopathies, alongside dementia with Lewy bodies, and a few other less common conditions. Arguably α-synuclein is a meaningful cause of pathology in Alzheimer's patients as well. It might be better to think of the named conditions as rough, shifting territories outlined on a broad map of brain aging that combines differing levels of protein aggregation, vascular dysfunction, mitochondrial aging, immune system failure, and other causative processes. They are shorthand descriptions for large and varied chunks of a complicated landscape.

In today's open access paper, researchers present evidence for inhibition of TLR2 as a potential strategy to dampen the progression of synucleinopathy. TLR2 is a part of mechanisms that trigger the immune system into action, and in this case the activities of glial cells of the brain are the focus point. Glial cells are known to become dysregulated and inflammatory in the aging brain, and suppressing that inappropriate behavior is one possible path towards a slowing of progression towards pathology. Therapies of this nature don't directly address the underlying damage that causes immune dysfunction, but any effort that at least somewhat sets the immune system back on track may result in increased repair and maintenance by immune cells. The size of the effect is very much dependent on the details of the case at hand, of course.

Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation

Following Alzheimer's Disease (AD), synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are the second most common group of neurodegenerative disorders of the aging population. Overall, they represent heterogeneous group of neurological conditions, characterized by progressive accumulation of α-synuclein in neuronal and glial cells. The mechanisms through which the various species of α-synuclein aggregates lead to selective neurodegeneration and neuroinflammation is not completely understood. Transmission of α-synuclein aggregates from neuron-to-neuron and neuron-to-glia has been suggested as the underlying mechanism of the neurodegeneration and neuroinflammation in synucleinopathy.

We have previously shown that the oligomeric forms of extracellular α-synuclein interact with Toll-like receptor 2 (TLR2) on the surface of neurons and glial cells. This results in neuro-inflammatory responses with TNFα and IL-6 production. TLR2 belongs to a family of pattern recognition receptor which modulate responses to exogenous pathogens as well as endogenous misfolded proteins released following damage and cellular stress. In the central nervous system, TLR2 is expressed in glial cells and neuronal populations, and recent studies have shown that the levels of TLR2 are elevated in neurodegenerative disorders such as AD and PD.

We have recently shown that inhibition of TLR2 by gene deletion or siRNA-mediated knock down rescues the pathology associated with α-synuclein accumulation in cellular models and transgenic mice. Therefore, TLR2 and downstream signaling have been suggested a new therapeutic target for synucleinopathy. Neutralizing TLR2 with a monoclonal antibody has been recently shown to ameliorate the pathology in a murine model of AD.

The main objective of this study was to evaluate the therapeutic effects of targeting TLR2 with a functional inhibitory antibody (anti-TLR2). We show that the administration of anti-TLR2 was able to decrease the accumulation of neuronal and astroglial α-synuclein, resulting in reduced neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein transgenic mouse model of PD/DLB. Moreover, the anti-TLR2 blocked neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission and reduced pro-inflammatory responses in a cell based model. Therefore, TLR2 might be a viable target and TLR2 immunotherapy is a novel therapeutic strategy for synucleinopathies of the aging population.

Theory and evidence for persistent infection as a cause of Alzheimer's disease continues to grow in scope and plausibility. In general this supports rather than replaces past thinking on amyloid-β and its role in the development of Alzheimer's. It provides an explanation as to why it is that levels of amyloid-β rise over time to produce the early disruptions and changes in the biochemistry of the brain that are necessary for later neurodegeneration to take place. Other compelling lines of work provide evidence for entirely separate mechanisms by which levels of amyloid-β can grow in later life, such as declining drainage of cerebrospinal fluid. It seems plausible that all may be correct to some degree, and that many of these proposed processes are significant, each adding their own contribution to the progressive decline of the brain.

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of phosphorylated tau (pTau). These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease.

Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients.

Link: https://doi.org/10.3389/fnagi.2018.00224

Persistent cytomegalovirus (CMV) infection is thought to cause a sizable amount of the age-related decline of the immune system. Latent infection by this sort of herpesvirus causes few to no immediate and obvious symptoms in the vast majority of individuals, but the virus cannot be permanently cleared by the immune system. Over time ever more T cells of the adaptive immune system become uselessly specialized to CMV, unavailable for other tasks. Coupled with the much reduced pace of creation of new T cells in later life, this results in an increasingly dysfunctional immune system.

Researchers here point to one specific consequence of the accumulation of a problematic class of T cell noted to occur with aging, increased risk of cardiovascular disease, and present evidence to show that this accumulation occurs because of persistent CMV infection. All told, the evidence for CMV to be a major issue, a slow corrosion of immune function and health, is quite compelling. What to do about it? The most effective approach might not be to tackle CMV directly, but rather to clear out and replace the problem immune cells via some form of targeted cell destruction followed by cell therapy.

A recent publication shows that Cytomegalovirus (CMV) infection increases the risk of cardiovascular death by over 20% but no specific mechanisms explaining this effect were identified. CMV infection, however, is notorious for promoting large expansions of terminally differentiated effector T-cells, including CD4 T-cells. This is particularly observable in older people. Moreover, there is good evidence that terminally differentiated T-cells may cause vascular damage, to the extent that therapies specifically targeting T-cells in advanced atherosclerosis are being developed.

Among activated CD4 T-cells, cardiologists are particularly interested in CD28null CD4 T-cells. These terminally differentiated effector cells do not express CD28, a co-stimulatory receptor molecule, which antigen-presenting cells engage during early T-cell activation. CD28null CD4 T-cells were initially discovered in rheumatoid arthritis, but later associated with unstable angina and coronary artery plaque instability. Multiple links between these cells and cardiovascular complications have since been reported. Down-regulation of CD28 on CD4 T-cells is thought to be triggered by continuous/repetitive antigen exposure, which could be the result of a persistent viral infection, for example with CMV.

CD28null CD4 T-cells accumulate in older people and show reduced proliferative capacity among many other signs of cellular senescence. Large frequencies of these cells are, therefore, primarily attributed to normal (immune system) aging. While an association of CMV infection with increased numbers of CD28null CD4 T-cells was repeatedly reported in the literature, this link is generally considered to be indirect and explained by the fact that older people are more likely to be CMV infected. Nobody has yet studied CD28null CD4 or CD8 T-cells in a large enough number of CMV-seronegative (CMV-) older people to resolve this issue. However, several smaller studies in the fields of autoimmune and cardiovascular disease offer some insight.

It was not the purpose of our work to show that CD28null CD4 T-cells are associated with cardiovascular (CV) morbidity or mortality, since there is overwhelming evidence for this association in the literature. Instead, we examined the frequencies of CD28null CD4 T-cells in 93 CMV- and 122 CMV+ generally healthy older people and a corresponding cohort of young people; CD28null CD8 T-cells were evaluated in parallel. Our investigation was focused on the intriguing possibility that, independently of aging, CMV infection is a major risk factor for the expansion of the highly pro-atherogenic CD28null CD4 T-cell subset.

Our results show that CMV infection is significantly associated with the accumulation of CD28null CD4 T-cells. Our data further suggest that CMV may directly drive this subset with a significant proportion of these cells recognizing CMV-antigens. The frequencies of CD28null CD4 T-cells were an order of magnitude higher in CMV+ compared to CMV- individuals, but only marginally affected by age. These observations seem to refute the idea that accumulation of CD28null CD4 T-cells is a result of normal immune system aging.

Link: https://doi.org/10.7150/thno.27428

Spermidine is one of many compounds identified to date that trigger some of the same beneficial stress response mechanisms that are upregulated by calorie restriction. For example, spermidine is known to boost the operation of autophagy, a collection of cellular maintenance processes responsible for recycling damaged structures and unwanted proteins. Keeping the level of damage lower means a lesser a chance of generating further detrimental consequences. The outcome, at least in short-lived species, is a longer healthy life span.

Unfortunately, the strategy of enhancing stress responses produces diminishing returns as species life span increases. The effects on longevity become ever smaller, even while the short term benefits to health tend to look quite similar. Why this is the case is not fully understood, but the data is inarguable. Humans cannot reliably live to see 150 on the basis of calorie restriction, though mice gain as much as a 40% increase to life span as a result of that intervention. Mice engineered to lose growth hormone or growth hormone receptor function live even longer yet, but the human population of Laron syndrome growth hormone receptor loss of function mutants do not appear to live significantly longer than the rest of us.

On the basis of the data noted in today's open access paper, we might tentatively add spermidine to the list of interventions that can be directly compared between humans and mice. As one might expect, these are not large effect sizes, and require continued intake over decades. Our first reaction to anything of this nature should be that we can do better than this. Indeed, we can. Instead of altering metabolism to slightly slow the pace of aging, we should be identifying the damage that causes aging and working towards therapies that can periodically repair it. That strategy has a far greater potential benefit - it can in principle achieve rejuvenation and indefinite extension of healthy life span, given sufficiently good repair technologies.

Spermidine delays aging in humans

Polyamines including spermidine play an essential role in intermediate metabolism. Since they are synthesized by higher eukaryotic cells, they are not vitamins. However, the levels of polyamines are profoundly influenced by their external supply. Our groups have shown over the past decade that supplementing spermidine by adding it to culture media (as we did for the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster) or to the drinking water (as we did for the rodent Mus musculus) is sufficient to extend longevity and to improve health span at multiple levels. Thus, in mice, the supplementation was able to suppress the age-related decline in cardiovascular function (as measured at 24 months of age) and increased overall longevity by approximately 10%.

The molecular and cellular mechanisms through which spermidine delays age-related disease and death have been elucidated to some extent. Spermidine can act as an inhibitor of EP300. EP300 acts as an inhibitor of autophagy by acetylating lysine residues within multiple proteins that are involved in autophagy-regulatory or autophagy-executing circuitries. As a result, the inhibition of EP300 by spermidine stimulates autophagy. Autophagy is required for the anti-aging effect of spermidine as indicated by the fact that genetic inhibition of autophagy abolishes the longevity-extending effects of spermidine on yeast, worms, and flies.

Until now the literature on the longevity-enhancing effects of spermidine has been limited to model organisms. Now, two prospective population-based studies report for the first time that nutritional spermidine uptake is also linked to reduced overall, cardiovascular and cancer-related mortality in humans. Both studies were based on the use of food questionnaires that allowed to calculate for each individual the nutritional uptake of polyamines including spermidine. Importantly, high spermidine uptake constituted an independent favourable prognostic parameter for reduced mortality, meaning that this variable predicted a reduced incidence of death even after correction for possible confounding factors.

In addition to the aforementioned epidemiological results, there are further, though admittedly indirect arguments in favour of a health-improving role for spermidine in human health. Thus, spermidine has been classified as a "caloric restriction mimetic" that has broad health-promoting effects due to its capacity to induce similar biochemical changes as does caloric restriction. Second, the proximal pharmacological target of spermidine is the same as that of salicylic acid, the active metabolite of aspirin (both inhibit EP300). The health-improving effects of aspirin have been initially attributed to act as an anti-coagulant. Since spermidine has not been reported to have similar anti-coagulant activity, we prefer the hypothesis that aspirin may mediate its broad pro-health effects via the inhibition of EP300.

The consensus on the progressive blindness of glaucoma is that the primary cause is rising pressure in the eye, resulting from an age-related failure of fluid flow in surrounding structures. Medications that reduce pressure in the eye, such as by reducing the pace of creation of new fluid, slows down the loss of sight associated with glaucoma, but even after successful treatment the condition can still progresses towards blindness. Researchers may now have identified why this is the case, and here present evidence to suggest that a form of autoimmunity is the process that causes loss of vision.

One of the biggest risk factors for glaucoma is elevated pressure in the eye, which often occurs as people age and the ducts that allow fluid to drain from the eye become blocked. The disease often goes undetected at first; patients may not realize they have the disease until half of their retinal ganglion cells have been lost. Most treatments focus on lowering pressure in the eye (also known as intraocular pressure). However, in many patients, the disease worsens even after intraocular pressure returns to normal.

"That led us to the thought that this pressure change must be triggering something progressive, and the first thing that came to mind is that it has to be an immune response." To test that hypothesis, the researchers looked for immune cells in the retinas of mice exhibiting glaucoma and found that indeed, T cells were there. This is unusual because T cells are normally blocked from entering the retina, by a tight layer of cells called the blood-retina barrier, to suppress inflammation of the eye. The researchers found that when intraocular pressure goes up, T cells are somehow able to get through this barrier and into the retina.

The researchers generated high intraocular pressure in mice that lack T cells and found that while this pressure induced only a small amount of damage to the retina, the disease did not progress any further after eye pressure returned to normal. Further studies revealed that the glaucoma-linked T cells target proteins called heat shock proteins, which help cells respond to stress or injury. Normally, T cells should not target proteins produced by the host, but the researchers suspected that these T cells had been previously exposed to bacterial heat shock proteins.

The researchers then turned to human patients with glaucoma and found that these patients had five times the normal level of T cells specific to heat shock proteins, suggesting that the same phenomenon may also contribute to the disease in humans. The researchers' studies thus far suggest that the effect is not specific to a particular strain of bacteria; rather, exposure to a combination of bacteria can generate T cells that target heat shock proteins.

Link: http://news.mit.edu/2018/glaucoma-autoimmune-disease-0810

Since the advent of low-cost accelerometers, like the one in near every modern phone, the data obtained from studies of exercise has improved greatly. In the scientific world of the study of exercise and aging, in which it can take a decade or two for enough epidemiological evidence to accumulate to change minds, accelerometers are still a comparatively recent innovation. The study noted here is an example of the sort of work being accomplished in this context. Like most such studies, the data strongly suggests that exercise slows the onset of cardiovascular aging, and thus lowers the risk of cardiovascular disease.

Should we view it as a failure of the established, mainstream approach to research and development of therapies to treat age-related disease that exercise remains one of the best and most reliable options on the table? Quite possibly. This is an era of accelerating, revolutionary progress in the tools and capabilities of biotechnology. The research community should have achieved far more than it has to date. The failure to do so is arguably due to the adoption of an ineffective strategy, one that largely revolves around attempts to adjust the late stage disease state rather than seeking to address root causes.

Adults in their early 60s, who spend less time sitting and more time engaged in light to vigorous physical activity, benefit with healthier levels of heart and vessel disease markers. Physical inactivity is a well-known risk factor for cardiovascular disease and premature death from cardiovascular disease. Physical activity's protective effect is likely due in part to its impact on biomarkers in the blood that help predict atherosclerosis risk.

"The 60 to 64 age range represents an important transition between work and retirement, when lifestyle behaviors tend to change. It may, therefore, be an opportunity to promote increased physical activity. In addition, cardiovascular disease risk is higher in older adults. It's important to understand how activity might influence risk in this age group. We found it's important to replace time spent sedentary with any intensity level of activity."

Researchers studied more than 1,600 British volunteers, age 60 to 64, who wore heart rate and movement sensors for five days. The sensors revealed not only how much physical activity, in general, they were doing, but also how much light physical activity, such as slow walking, stretching, golfing, or gardening, versus moderate-to-vigorous activity, such as brisk walking, bicycling, dancing, tennis, squash, lawn mowing, or vacuuming.

Researchers analyzed participants' blood levels for markers of cardiovascular disease, including inflammatory markers and cholesterol markers. Each additional 10-minutes spent in moderate-to-vigorous intensity activity was associated with leptin levels that were 3.7 percent lower in men and 6.6 percent lower in women. Each additional 10-minutes spent sedentary was associated with 0.6 percent higher IL-6 levels in men and 1.4 percent higher IL-6 levels in women. Each additional 10-minutes spent in light intensity activity was associated with around 0.8% lower tissue-plasminogen activator levels in both men and women. Based on the study's findings, physical activity might lower cardiovascular disease risk by improving blood vessel function. Increased sedentary time may be adversely related to endothelial function.

Link: https://newsroom.heart.org/news/older-adults-who-get-physical-can-lower-their-heart-disease-risk

Myostatin inhibition and upregulation of the myostatin inhibitor follistatin are approaches to spurring increased muscle growth. This class of approach has been shown to work in humans to at least some degree, and there are numerous heavily muscled myostatin loss of function mutants in various animal species, both naturally occurring and created via genetic technologies. SMAD2 is a related regulatory protein, and some efforts to increase muscle growth have targeted it. Further exploration in this same cluster of regulatory proteins leads to JNK, the subject of today's open access paper.

This portion of mammalian biochemistry is an area of interest to researchers as a potential means to treat sarcopenia, the characteristic loss of muscle mass and strength that occurs with aging. If muscle growth can be dialed up as needed, something that seems a plausible goal at this point, then that capability would deal with half of the problem of sarcopenia, leaving just the quality of the muscle to be addressed. It might also be deployed as a compensatory therapy for forms of muscle wasting, such as that occurring as a result of cancer and its treatment. Of course, one suspects that use by younger people as an enhancement therapy would eventually become just as widespread. Who wouldn't want a little extra muscle without having to put in the effort to gain it?

It remains to be seen which of the variety of efforts to manipulate the regulation of muscle growth ultimately succeed in reaching clinical application. The established forms of treatment, such as follistatin gene therapy or myostatin antibodies, are conceptually simple enough. The question is more one of when gene and antibody therapies in general pass the point of cost and reliability that leads to widespread availability via medical tourism, as occurred for early stem cell therapies nearly twenty years ago. Now is about when it should start to happen, given the state of the science for delivery or upregulation of proteins.

JNK regulates muscle remodeling via myostatin/SMAD inhibition

The adaptation of muscle to endurance or resistance exercise is a highly variable trait in humans and animals. As a means to discover the molecular mechanisms that regulate endurance adaptations in skeletal muscle, our previous work utilized rodent models generated by selective breeding for low- or high-adaptive response to endurance exercise. The failure to improve aerobic capacity in low responders to endurance training occurred in conjunction with a less oxidative muscle phenotype and deficiencies in exercise-induced angiogenesis in skeletal muscle. Importantly, blunted endurance remodeling in the skeletal muscle of low responders to endurance exercise was associated with increased risk for chronic metabolic disease. Our data demonstrated that hyper-activation of the mitogen-activated protein kinase, c-Jun N-terminal kinase (JNK), was associated with the failure of muscle to undergo endurance remodeling with exercise. Thus, we hypothesized that JNK activation during exercise is a negative regulator of endurance adaptations in muscle.

The present investigation aimed to directly test the hypothesis that JNK is a critical mediator of muscle remodeling. We employed a multi-disciplinary approach to determine the effect of JNK hyper-activation and loss of function on muscle phenotype and remodeling, including tissue culture systems, animal models, and human subjects. This work identifies JNK as a molecular switch that, when active, stimulates muscle fibers to grow, leading to increased muscle mass. Conversely, when JNK is inhibited, an alternative adaptive program is induced, leading to endurance adaptations and enhanced aerobic capacity.

We find that JNK exerts its effects on muscle phenotype via phosphorylation of the transcription factor, SMAD2, at specific linker-region residues. JNK-mediated SMAD2 phosphorylation results in negative regulation of the myostatin/TGFβ pathway, thus allowing for muscle growth. In addition, we demonstrate that in human skeletal muscle, this JNK/SMAD signaling axis is activated by resistance exercise, but not endurance exercise, therefore identifying JNK/SMAD signaling as a target to induce muscle remodeling. These data enhance our understanding of the fundamental mechanisms that mediate muscle reprogramming and remodeling in vivo.

The SENS view of aging is a synthesis of decades of evidence produced by the research community. It is that aging is caused at root by an accumulation of molecular damage in and around cells, damage that occurs as the result of the normal operation of cellular metabolism. The logical approach to aging is therefore to repair this damage, but, sad to say, only a small fraction of the research community pursues work of this nature.

Why is this case? Perhaps because the dominant paradigm of investigative research involves picking one age-related disease and then working backwards from the disease state, trying to uncover contributing factors that occur in the final stages of the progression of disease. The first opportunities to produce therapies as a result of increased understanding therefore involve changes in cells and tissue that are far downstream of the root causes of aging, have limited relevance to aging beyond the specific disease, and offer only limited potential benefits. It is not the right path forward if we want to see meaningful progress in our lifetimes.

Autophagy is a process of destruction and processing of damaged cell components by the cells themselves. It is used by a cell to clean itself of excessive organelles and sometimes for programmed cell death. This adaptive mechanism supports a healthy phenotype on the cellular level. Autophagy is activated in certain cases of acute kidney failure (e.g., caused by the administration of antibiotics or anti-cancer drugs), sepsis, or kidney ischemia. Scientists already know that it is the activation of autophagy that reduces kidney damage manifestation.

However, while an organism is aging, the efficiency of autophagy declines as well. Though the number of lysosomes (the organelles that digest damaged cell components) is increased in old cells, they fail to perform their function. Oxidized proteins and damaged organelles (including mitochondria that participate in the respiration and energy production) start to pile up.

A team of scientists considered kidney pathologies that accompany aging - first of all, acute kidney failure that is several times more likely to be observed in patients over 60. "In our article we demonstrated that aging is associated with the accumulation of damaged biological structures (proteins, lipids, nucleic acids, organelles) in the kidney. The replacement of a young (healthy) phenotype with an old one takes place when a certain threshold level of such changes is reached."

Link: https://www.eurekalert.org/pub_releases/2018-08/lmsu-msu081018.php

Antagonistic pleiotropy is the name given to a particular view on the evolution of aging. Natural selection will favor optimization of capacity in early life, when reproduction is possible, but not the optimization of capacity in late life. Given a system in which the decline of aging is already happening to some degree, there will be further selection of processes that work well at the outset but cause harm later on in life. The adaptive immune system is an example of the type: it is highly effective in youth, due to its capacity for memory, but runs down and malfunctions in the later life context of trying to maintain memory of a lifelong exposure to countless varieties of pathogen.

Researchers here present evidence for the cellular maintenance processes of autophagy to be pleiotropic in this way, at least in nematode worms. In this species autophagy works well in the context of a youthful low level of damage, but then becomes actively harmful in the later life context of high levels of damage and dysfunction. Early life capacity for reproduction has a much greater influence on the traits that are selected than late life capacity, and this sort of thing is the outcome.

Ageing in worms mainly results from the direct action of genes and not from random wear and tear or loss of function, and the same is likely to be true in humans, according to research. The study shows that normal biological processes which are useful early on in life, continue to 'run-on' pointlessly in later life causing age-related diseases. The deteriorative part of ageing, called 'senescence', is the main cause of disease and death worldwide as it leads to dementia, cancer, cardiovascular disease, and chronic obstructive pulmonary disease, but scientists have struggled to identify what causes it.

To address this, researchers have focused on discovering the basic principles of ageing by studying simple animals such as Caenorhabditis elegans, a nematode worm used in this study which lives on fruit, and dies of old age after only 2-3 weeks. Specifically, they focused on autophagy, where body cells consume their own biomass to recycle components and extract energy. They found that the worms' intestine consumes itself (autophagy) to create the yolk needed for eggs, and in elderly worms, this process causes severe deterioration of the intestine and obesity from a build-up of pooled fats. In turn, this further impacts on the health of the worm by promoting growth of tumours in the uterus, and shortens lifespan.

"This really surprised us since autophagy is usually thought to protect against ageing rather than cause it. It seems that worms crank-up autophagy, which is considered good, to maximise reproductive success, which is good too, but they end up overdoing it, causing senescence." When useful biological programmes run-on in later life, they can become disease-causing 'quasi-programmes'. Such programmes were recently proposed and the findings support that they are indeed a major underlying cause of ageing. This does not mean that aging is programmed but instead, that it is a continuation of developmental growth driven by genetic pathways to the point where these becomes harmful. Other examples include an increase in blood pressure causing hypertension and an increase to the eyes' near vision point causing long-sightedness and a need for reading glasses.

Link: http://www.lancaster.ac.uk/news/genes-drive-ageing-making-normal-processes-damaging

I had promised a short update on progress at Repair Biotechnologies, the company that Bill Cherman and I founded earlier this year to help advance the state of therapies to treat aging, and here it is. We recently closed a seed round with a number of investors in our close-knit community, and are presently setting up our modest headquarters near Syracuse, NY, alongside our allies at Ichor Therapeutics. The staff at Ichor, fresh from a sizable investment made by Juvenescence in their subsidiary Antoxerene, have launched an incubator, Grapeseed.bio, to encourage the development of new companies focused on the treatment of aging. Repair Biotechnologies is the first such company to be accepted to the program.

Our initial development program at Repair Biotechnologies progresses, and I'm pleased to be able to say that we have made our first scientific hire. We were fortunate to near immediately connect with a very talented protein biochemist in Syracuse, who will be joining us later this month. We continue to interview in search of another entrepreneurial scientist, someone with a cell biology and gene therapy background. If you know of scientists with an interest in aging and the talent to make a difference, please do point them in our direction.

Repair Biotechnologies, Inc., a startup developing therapies with the goals of reversing atherosclerosis and atrophy of the thymus, is proud to announce it has raised a seed round from leading institutions and angel investors in the growing longevity science community, including Methuselah Foundation and others.

Founded by Reason and Bill Cherman in April 2018, Repair Biotechnologies will use these new funds to expand its foundational gene therapy development work with the addition of a recombinant protein engineering program, as it proceeds towards proof of concept results in animal models.

Additionally, Repair Biotechnologies is pleased to announce that the company has been accepted to the Grapeseed.bio incubator, recently launched by Ichor Therapeutics. The company is relocating to Upstate New York, to work hand in hand with the Ichor team towards the success of the Repair Biotechnologies development programs. Repair Biotechnologies is now hiring scientists for several positions in Lafayette, NY, just outside Syracuse.

"At Repair Biotechnologies, we are committed to developing treatments for aging and age-related diseases that address the root causes of these conditions. We are grateful for the financial support from top investors in our community, and look forward to working together with our friends at Ichor Therapeutics. We intend to draw upon their considerable experience in the field, and learn from their demonstrable success in structuring and executing challenging development programs," said Reason, CEO.

Nothing in this post should be construed as an offer to sell, or a solicitation of an offer to buy, any security or investment product. Certain information contained herein may contains statements, estimates and projections that are "forward-looking statements." All statements other than statements of historical fact in this post are forward-looking statements and include statements and assumptions relating to: plans and objectives of Repair Biotechnologies' management for future operations or economic performance; conclusions and projections about current and future economic and political trends and conditions; and projected financial results and results of operations. These statements can generally be identified by the use of forward-looking terminology including "may," "believe," "will," "expect," "anticipate," "estimate," "continue", "rankings" or other similar words. Repair Biotechnologies does not make any representations or warranties (express or implied) about the accuracy of such forward-looking statements. Accordingly, you should not place reliance on any forward-looking statements.

Neurogenesis is the production and integration of new neurons into neural networks in the brain. Along with synaptic plasticity, it determines the ability of the brain to recover from damage. There is some controversy over the degree to which it occurs in adult humans; the consensus is that it does, but the vast majority of research on this topic has been carried out in mice, not humans. If there is little or no natural neurogenesis in the adult human brain, a situation quite different from that of mice, then the prospects diminish for the development of therapies to hold back aging that work by increasing neurogenesis. This is an important topic in the field of regenenerative research.

The open access paper noted here offers an interesting hypothesis: that humans and a range of other larger-brained mammals exhibit lesser (or possibly absent) adult neurogenesis because they have lost olfactory function over evolutionary time. We should consider adult neurogenesis to be a co-evolved feature of large and capable olfactory systems in the brain, and we do not have a large and capable olfactory system. Mice do. This is a tenuous hypothesis, in need of considerable support, but it is worth thinking over for a few moments.

The majority of mammals show adult hippocampal neurogenesis to some extent, with exceptions in dolphins, humans, and some bats. Neurogenesis seems to be under selective pressure. Under an evolutionary profile, humans have it during the youngest ages that likely had the greatest phylogenetic importance in the past. Open questions about adult human neurogenesis include: (i) are low levels of neurogenesis functionally relevant? (ii) are there vestigial/quiescent remnants of stem cell niches and can these be reactivated in some way? Some authors, considering that the new neurons within the dentate gyrus, even a low number, can be highly functional (at least in animal models), argue that "there has been evolution toward neurogenesis-based plasticity rather than away from it". At present, no systematic, fully comparable studies are available on a wide range of mammalian species to support this view.

The most likely explanation for the general reduction of adult neurogenesis in humans when compared to rodents might be related to the reduced importance of specific brain functions linked to survival, replaced by other (higher) cognitive functions. This potential explanation acquires relevance when olfaction/olfactory brain structures, such as subventricular zone (SVZ) neurogenesis, are concerned. Although olfaction in humans is considered more impactful than previously thought (in term of total amount of neurons), the relative size of the olfactory bulb with respect to the whole brain volume (0.01% of the human brain compared to 2% of the mouse brain) and the importance of olfaction for survival are quite reduced when compared to rodents.

Dolphins are large-brained mammals. Among several aspects worthy of a comparative study on neurogenic activity in dolphins, we focused on a unique trait: the absence of olfaction/olfactory brain structures. We recently expressly searched the periventricular region of dolphins for neurogenic processes. The persistence of a vestigial remnant (functionally inactive) of the SVZ neurogenic niche in dolphins strongly suggests that periventricular neurogenesis reduction or disappearance occurs in parallel with reduction or disappearance of olfactory brain structures across evolution.

In conclusion, three features of adult neurogenesis are crucial when considering its translational value: (i) its substantial decrease in humans and other long-living, large-brained mammals; (ii) its decrease with the age of the individuals (in both SVZ and hippocampus); and (iii) a scarce propensity/efficacy for lesion-induced repair in mammals. These constraints seem to strongly depend on evolutionary pathways. Evolution drives the occurrence, rate, and type of plasticity among mammals, and interspecies differences must be taken into account when translating results from mice to humans.

Link: https://doi.org/10.3389/fnins.2018.00497

Juvenescence is one of the more recent venture groups to become enthusiastically involved in supporting the development of means to treat aging, and the organization's principals are now beginning to build their positions in earnest. As this unfolds, we obtain insight into their interpretation of the field of longevity science, the lines of development that they believe to be plausible and interesting. The founding members have expressed a strong interest in SENS rejuvenation research programs, but will they follow up with the investments to match? It always seems impolite to ask that question, but our community has been disappointed in the past.

You might recall that Juvenescence invested in AgeX Therapeutics not so long ago. AgeX aims to build out an platform that is intended as an incremental advance over present approaches to regenerative medicine, mixing in telomerase upregulation with the production and deployment of cell therapies. Juvenescence has now expanded their support of AgeX Therapeutics. It will be interesting to see how this line of work matures, and whether the AgeX staff choose to explore some of the surprising outcomes that are emerging from the induced pluripotency field these days, particularly those resulting from inducing pluripotency in vivo - something that sounds like a terrible idea, but has in fact produced initially intriguing results in mice.

BioTime, Inc., a clinical-stage biotechnology company focused on degenerative diseases, today announced a new strategic alignment between AgeX Therapeutics and Juvenescence Limited, a global leader in developing therapeutics focused on improving and extending human lifespans. Under the terms of the agreement, Juvenescence will purchase, in a single transaction, 14.4 million shares of AgeX Therapeutics from BioTime for $43.2 million. "We feel it is a great fit with the Juvenescence team of drug developers and scientists. First and foremost, we look forward to developing and bringing products to the patients as novel treatments to potentially offset some of the maladies of getting old."

AgeX Therapeutics, Inc., a subsidiary of BioTime, Inc., is a biotechnology company focused on the development of novel therapeutics for age-related degenerative disease. The company's mission is to apply the proprietary technology platform related to telomerase-mediated cell immortality and regenerative biology to address a broad range of diseases of aging. The products under development include two cell-based therapies derived from telomerase-positive pluripotent stem cells and two product candidates derived from the company's proprietary induced Tissue Regeneration (iTR) technology.

AGEX-BAT1 and AGEX-VASC1 are cell-based therapies in the preclinical stage of development comprised of young regenerative cells designed to correct metabolic imbalances in aging and to restore vascular support in ischemic tissues respectively. AGEX-iTR1547 is a drug-based formulation in preclinical development intended to restore regenerative potential in a wide array of aged tissues afflicted with degenerative disease using the company's proprietary iTR technology. Renelon is a first-generation iTR product designed to promote scarless tissue repair which the Company plans to initially develop as a topically-administered device.

Link: http://www.agexinc.com/biotime-to-receive-43-million-from-juvenescence/

Sarcopenia is the name given to loss of muscle mass and strength that occurs with age. When it comes to assembling evidence for causes of the condition, this is one of the better examples of the present state of understanding in aging. A sizable number of potential causes have convincing evidence, all may be relevant, but the degree to which they are important relative to one another is hard to discern. Further, the layering of the causative mechanisms, how they interact, and whether and to what degree some are secondary to others, is also hard to discern. The only truly reliable method of answering such questions is to fix just one contributing cause, and observe the results. The field of biotechnology is on the verge of being able to achieve that goal for sarcopenia and a number of other age-related conditions, but not quite there yet.

What is the usual approach given the inability to fix a cause of age-related disease in isolation? Make it worse instead. The research community can break cellular biochemistry in ways that exaggerate certain manifestations of aging - such as the oxidative stress under examination in today's open access paper. It is, however, very challenging to say whether or not such a study produces results that are useful or actionable. Forms and amounts of damage that do not occur in normal aging produce results that might superficially resemble aspects of aging, might tell us something, or might be completely irrelevant to our understanding of aging. The details matter, and they are wildly different in every case, and sometimes the research community simply doesn't have a good enough understanding of the specific mechanisms to be able to mount a good argument as to whether or not the study is useful.

Among the candidates for contributing causes of sarcopenia are chronic inflammation, loss of stem cell activity, dysregulation of dietary protein processing necessary for tissue growth, decline of nerve-muscle junctions, and reduced density of capillary networks and thus a reduction in nutrient supply to tissues. There are others. The paper here looks at rising levels of oxidative stress, increased amounts of reactive oxidizing molecules generated by cells and roaming throughout tissues; these molecules cause damage that must be repaired, but more importantly trigger all sorts of cellular reactions that, collectively, don't help the situation. This is an aspect of aging that goes hand in hand with chronic inflammation, and is secondary to deeper causes that include mitochondrial dysfunction and cellular senescence.

Oxidative stress-induced dysregulation of excitation-contraction coupling contributes to muscle weakness

Sarcopenia, the age-related loss of muscle mass and strength, is a major cause of morbidity and mortality in the elderly population. While muscle atrophy contributes to weakness, the decline in muscle strength is more rapid than the atrophy, suggesting a deficit in intrinsic force-generating properties of the muscle. The age-related muscle weakness independent of loss of mass is defined as dynapenia and involves the excitation-contraction coupling machinery of the muscle fibres. A progressive increase in cellular oxidative stress during ageing has been implicated as a major contributor to sarcopenia.

Excitation-contraction coupling involves a sequence of events whereby action potential-driven excitation of the sarcolemma results in rapid changes in cytoplasmic calcium concentration leading to activation of force-generating machinery in the sarcomere. In mammalian skeletal muscle, this process may dictate the rates of relaxation and a termination of a variety of Ca2+-dependent signalling pathways and gene transcription events that influence muscle quality and quantity. These processes imply the critical importance of calcium handling in the muscle fibre as dysregulation of calcium homoeostasis has been associated with reduced specific force in ageing and conditions of increased oxidative stress.

Our lab has previously used a mouse model of oxidative stress that was created by deleting cellular antioxidant enzyme Cu/Zn superoxide dismutase (Sod1-/-) resulting in many features of rapid and accelerated sarcopenia. The reduction in specific force in these mice is only partially rescued via direct muscle stimulation that bypasses the neuromuscular junction, suggesting a loss of functional innervation in these mice but also defects within fibres. Moreover, interrogation of the function of single permeabilized fibres showed no difference between Sod1-/- and wild-type (WT) mice indicating no impairment in the Sod1-/- mice in the inherent function of the contractile machinery and suggests that there may be declines in the functioning of the excitation contraction machinery.

The goal of this study was to determine whether the loss of innervation and the chronic increase in cellular oxidative stress in the Sod1-/- mice affect the excitation-contraction apparatus in a manner similar to muscles of old WT mice. We report that the disruption of excitation-contraction coupling contributes to impaired force generation in the mouse model of Sod1 deficiency. Briefly, we found a significant reduction in sarcoplasmic reticulum Ca2+ ATPase (SERCA) activity as well as reduced expression of proteins involved in calcium release and force generation. Another potential factor involved in EC uncoupling in Sod1-/- mice is oxidative damage to proteins involved in the contractile response.

In summary, this study provides strong support for the coupling between increased oxidative stress and disruption of cellular excitation contraction machinery in mouse skeletal muscle. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.

Neurogenesis is the process by which new neurons are created and then integrated into existing neural circuits. Does neurogenesis take place in the adult human brain? That is once again a subject for debate after two decades of consensus, with the arrival of solid evidence for the absence of neurogenesis in adult humans, even as other researchers continue to produce data showing that it does take place. This newfound uncertainty contrasts with the well-established presence of neurogenesis in adult mice, the species that is the focus of the vast majority of research on this topic.

This an important topic. Along with synaptic plasticity, it determines the ability of the brain to repair itself, to recover from the variety of losses that occur with aging or injury. If neurogenesis does occur in adult humans, then there may be comparatively straightforward approaches that can boost the operation of this process in order to slow the impact of aging. If it does not occur in adult humans, then the prospect of repairing the aging brain becomes harder and more distant.

The main reason behind the continuing interest in understanding the process of mammalian adult neurogenesis is the notion that similar processes might be involved in the human brain. Whether neurogenesis in humans exists has been investigated using several and distinct approaches that brought compelling evidence about the presence of adult hippocampal neurogenesis in human brains. Interestingly, two very recent - but opposing - publications brought back the debate concerning the existence of human adult neurogenesis. The first, using postmortem and fresh tissue, reported that there was no evidence of neurogenesis in humans after adolescence whatsoever, while the second demonstrated the exact opposite by showing that adult neurogenesis persists during life in humans, albeit with a small decrease with aging. Further exploration of this complex question is necessary in order to conclude on the processes underlying the timeline and the mechanisms of neurogenesis in humans.

Recently, in addition to the study of the overall process of neurogenesis, much effort has focused on deciphering the intrinsic regulation of stem cells in the brain, both in the hippocampus as well as the subventricular zone (SVZ) niche. Aging negatively affects neurogenesis by inducing a sharp and continuous decrease in cell production in both the SVZ and hippocampal neurogenic niches of the brain. With aging, activated neural stem cells (NSCs) lose their proliferative potential and become quiescent, but, remarkably, they can be reactivated to a certain extent upon stimulation, such as exercise or even seizure, indicating that NSC plasticity is preserved to a certain extent in the aged organism.

Because of the enormous consequences of aging on NSCs, a lot of effort has focused on identifying mechanisms that could potentially reset the aging clock. Systemic manipulations such as exercise, calorie restriction, and heterochronic blood transfer have demonstrated that it is possible to reactivate the intrinsic program in order to rejuvenate NSCs and, consequently, the brain. The delicate balance between NSC quiescence and activation is easily shifted depending on the different stimuli and could be used to better manipulate NSC fate in vitro and in vivo. Moreover, recent findings point to the conclusion that aging is not necessarily a permanent state, but could be malleable, and that finding ways to interfere in the cell intrinsic machinery in order to slow down or even reverse this process will be the challenge for years to come.

Link: https://doi.org/10.1016/j.conb.2018.07.006

Autophagy is a collection of cellular maintenance processes that recycle damaged or unwanted proteins and structures. It is generally considered to become less effective with age, and that this decline is an important aspect of aging, but nothing is simple in cellular biochemistry. For any well supported topic there are always exceptions and there is always at least some opposing evidence. Here, researchers report on data that shows autophagy to be just as active in old dermal fibroblasts as it is in the younger versions of such cells. It is hard to say what to make of that, given the sizable weight of all of the existing evidence for age-related dysfunction in autophagy, whether taken as a whole, or examining specific subsystems vital to the overall process.

Autophagy is an intracellular stress response that is enhanced under starvation conditions, and also when the cellular components are damaged. Aging accompanies an increase in intracellular stress and has significant impact on the skin. Since dermal fibroblasts are a powerful indicator of skin aging, we compared the autophagic activity of human skin fibroblasts between the young and old. The number of autophagosomes per cytoplasmic area was similar between young and aged fibroblasts. The amount of LC3-II, a form associated with autophagic vacuolar membranes, was also similar between the groups. Although residual bodies were more common in aged dermal fibroblasts, LC3 turnover and p62 assay showed little difference in the rate of lysosomal proteolysis between the young and old. RNA-seq analysis revealed that the major autophagy-modulating genes were not differentially expressed with age.

Our results suggest that the basal autophagic flux in aged dermal fibroblasts is largely comparable to that of young fibroblasts. However, with a higher speed and amount of waste production in aged cells, we postulate that such autophagic flux may not be sufficient in keeping the old cells "clean", resulting in skin aging. Aging is a complex process and, as such, the relationship between autophagy and aging is not straightforward. That is to say, autophagy does not simply decline with age. Regardless of the controversies on autophagic activity with age, autophagy plays a crucial role in counteracting aging, and strategies aimed at its modulation should hold promise for the prevention of skin aging.

Link: http://dx.doi.org/10.3390/ijms19082254

The evidence of the past decades, and particularly the past seven years, strongly supports the idea that the accumulation of senescent cells is a root cause of aging. Cells become senescent in large numbers day in and day out, a normal end of life state for somatic cells that have reached the Hayflick limit. Cells also become senescent as the result of damage, or a toxic environment, and there is ever more of that with advancing age. Near all of these cells are destroyed quite quickly after they enter a senescent state, but enough linger to ensure that a few percent of all cells are senescent in old age. These problem cells secrete a potent mix of signals that induces chronic inflammation, degrades tissue structure, and alters the behavior of normal cells for the worse.

Senescent cells are not the only component of aging, but given enough time senescent cells alone would be able to kill you. Senescent cells are a prominent cause of fibrosis and declining function of organs such as the lungs, kidneys, liver, and heart. They cause arthritis. Ever more immune cells are senescent in later life. The list goes on, and scientists are adding to it with each passing month, as ever more is discovered of the role of senescent cells in specific age-related conditions. The research I'll point out today is an example of the type, in this case early evidence that indicates senescent microglia in the brain are a contributing cause of synucleinopathies such as Parkinson's disease.

Synucleinopathies are associated with the aggregation of solid deposits of α-synuclein in the aging brain. Neurons are harmed by the halo of surrounding biochemistry that arrives alongside the presence of these protein aggregates. This is a similar story to that related to amyloid-β and tau: deposits in the brain; an associated collection of molecules and interactions that harm neurons; the association with age-related neurodegeneration. It will be most interesting to see how the exploration of cellular senescence in the supporting cells of the brain plays out in this context over the years ahead. How much of this protein aggregation in aging is driven by the secretions of senescent cells, and how greatly can the onset of these conditions be delayed by targeted destruction of those senescent cells?

Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity

An example of the changing environment in the aging brain is the changes in the supporting cells in the brain, including microglia. Healthy microglia monitor their environment, phagocytosing debris, and releasing numerous molecules that can impact other cells. Activated microglia can act as antigen presenting cells and activate T-cells. After an infection has been dealt with microglia can recruit cells that are involved in neuronal repair and secrete anti-inflammatory cytokines. The idea of aging microglia stems from histological observations of healthy aged brains where the cells often develop dystrophic phenotypic characteristics. Dystrophic microglia have also been associated with the increased release of toxic reactive oxygen species and inflammatory cytokines and impaired phagocytic ability. However, one of the most unique changes observed in dystrophic microglia in the aging brain is the very high accumulation of iron, which is found to be stored in proteins, such as ferritin.

The presence of healthy glial cells is critically important to neuronal wellbeing. Microglia maintain homeostasis in the healthy brain and fight infection, when it is present, through a complicated system of signalling molecules. The importance of microglia to neurons is supported by higher incidence of dystrophic microglia and microglial apoptosis in Alzheimer's disease. The inflammation of the nervous system in neurodegenerative disease was thought to be due to activated microglia. However, low, but sustained, release of inflammatory factors and impaired neuroprotective ability of microglia seen in neurodegeneration could be due to dystrophic changes instead.

The cytosolic protein alpha-synuclein (α-syn) is associated with a range of neurodegenerative diseases, including Parkinson's disease (PD). In PD there has been discussion of the possible involvement of microglia and experiments with rodent PD models have shown that microglial activation can cause PD-like symptoms. In the current work, we establish iron overload as a mechanism to switch microglial phenotype to one that has many of the characteristics of senescent microglia. Iron overload was achieved by growing microglia in high concentrations of iron. We also show that iron overloaded (iron-fed) microglia release factors, including increased levels of the cytokine TNFα that caused an increased expression of α-syn, altered its activity, and increased its aggregation.

Developing a model of senescent/dystrophic microglia in vitro has numerous issues. Chief among these is the lack of clarity in defining dystrophic microglia. There is currently no single molecular marker that would define a dystrophic or senescent microglial cell. Proteomics/transcriptomics based studies comparing microglia from old and young brains have been carried out for both mouse and human but have yielded conflicting results. However, there is a general cellular senescence signature that all cells show and this is no different for microglia, which also show characteristics aligning with a senescence-associated secretory phenotype.

Synucleinopathies are associated with the aggregation of α-syn in cells and this is believed to stem from two causative processes. The first and most well recognized is an increased expression of α-syn, resulting in molecular crowding. Using conditioned medium from our model dystrophic microglia, we were able to induce increased α-syn expression and increased aggregation in SH-SY5Y cells. Thus, by the incorporation of an aspect of brain aging we were able to induce several aspects of the disease state in neuronal cells. For this reason, we believe that we have developed a simple and valuable tool for the exploration of the molecular mechanisms behind synuclein related diseases and possibly other neurodegenerative diseases.

Aggregation of altered tau protein is arguably the primary cause of brain cell death in the late stages of Alzheimer's disease. It is quite fundamental in cells, involved in maintaining the cytoskeletal structure of microtubules, but nonetheless can be removed without any great disruption of function - though the evidence is mixed on whether that means no unwanted side-effects. This approach has been tried in mice altered to generate similar pathology to that of human Alzheimer's disease. Researchers here instead examine the outcome of removing tau in young mice and find that it actually improves the metabolism of the brain and measures of cognitive function. Mice are not humans, but perhaps it is the case that we might all be enhanced by some form of therapy that can greatly reduce levels of tau in the brain, and not just through a greater ability to resist the onset of age-related neurodegeneration.

Tau is a protein that associates with microtubules and is found prominently in the axons of neurons. Abnormal modifications of tau are involved in a number of neurodegenerative diseases, known as tauopathies, which are characterized by the formation of pathological deposits of tau. Hyperphosphorylated or cleaved forms of tau are the principal components of neurofibrillary tangles, one of the neuropathological hallmarks of Alzheimer's disease (AD). Pathological forms of tau generate serious alterations in neuronal activity, affecting synaptic transmission and learning and memory processes, which finally leads to neurodegeneration.

Genetic deletion of tau could be protective. Studies in a mouse model of AD have shown that ablation of tau expression prevents neurotoxicity induced by the amyloid-β peptide and improves cognitive damage. Similarly, tau deletion protects against the effects of stress on neuronal structure and working memory. However, other reports suggest that the absence of tau could have a negative effect on normal brain function.

Pathological forms of tau can impair mitochondrial function, including mitochondrial morphology, transport, and bioenergetics. Interestingly, we found that the expression of pathological tau species, in particular truncated tau, induces mitochondrial fragmentation and bioenergetics failure in neurons. Similarly, phosphorylated tau induces mitochondrial fragmentation and affects the bioenergetics function of mature neurons. Thus, the absence of tau protein in neural cells could prevent the effects on mitochondrial structure and function produced by post-translationally-modified tau.

Considering that limited research has used tau-deficient mouse models and the role of tau on the regulation of mitochondrial function and the resulting implications on cellular and cognitive processes are not entirely clear, a study examining the impact of tau ablation will contribute to the understanding of the physiological function of tau protein in vivo. The present study was conducted in litters of young mice (3 months old) to investigate the effects of tau reduction in hippocampal tissue, to identify the implications of tau on mitochondrial function and behavior during youth.

Our results showed that tau deletion had positive effects on hippocampal cells by decreasing oxidative damage, favoring a mitochondrial pro-fusion state, and inhibiting mitochondrial permeability transition pore (mPTP) formation by reducing cyclophilin D (Cyp-D) protein. More importantly, tau deletion increased ATP production and improved the recognition memory and attentive capacity of juvenile mice. Therefore, the absence of tau enhanced brain function by improving mitochondrial health, which supplied more energy to the synapses. Thus, our work opens the possibility that preventing negative tau modifications could enhance brain function through the improvement of mitochondrial health.

Link: https://doi.org/10.1016/j.redox.2018.07.010

In this open access paper, researchers report that compounds delivering hydrogen sulfide into cells slow the pace at which those cells become senescent in culture. The mechanisms involved are not fully explored but involve splicing factors, proteins that have a strong influence over gene expression. As the biochemistry of cellular senescence is explored, and researchers find ways to potentially hold back the transition of cells into the senescent state, we might ask whether or not this is a good idea. Lingering cellular senescence is a cause of aging, but most cells become senescent for a good reason - they are damaged, potentially cancerous, have replicated too many times for continued safety, or the surrounding environment is toxic. Most self-destruct rather than remaining to contribute to the aging process.

Will it be helpful rather than harmful to prevent senescence? Current approaches to senescent cells involve destroying them, which seems the better path forward. Cells that become senescent are not, on balance, the sort of cell that one would want to keep around. Better to remove them, I think. So how to interpret the evidence here regarding the influence of hydrogen sulfide on cellular senescence and aging in general? It seems positive and also suppresses cellular senescence. What does it actually achieve under the hood, what is the full balance of relevant mechanisms? It is perhaps a little early to say, and we should continue to watch the accumulation of evidence on this topic.

The biochemical and functional pathways most dysregulated by age in the human peripheral blood transcriptome are enriched for transcripts encoding the regulatory machinery that governs splice site choice. Changes in splicing regulation have also been linked with lifespan in both mammalian and invertebrate model systems. Evidence that these changes are functional is provided by the observation that large-scale dysregulation of patterns of alternative splicing is characteristic of many age related diseases.

The accumulation of senescent cells is emerging as an important driving factor of the ageing process in multiple species. Senescent cells do not divide, are viable and metabolically active, but have altered physiology. This includes the secretion of the SASP, a cocktail of pro-inflammatory cytokines and tissue remodelling factors that induces senescence in neighbouring cells in a paracrine manner. Senescent cells also show dysregulation of splicing regulator expression in vitro, and restoration of splicing factor expression to levels comparable with those seen in younger cells has recently been demonstrated to be associated with reversal of multiple senescence phenotypes in senescent human primary fibroblasts.

There is now enormous interest in compounds with the potential to kill senescent cells or ameliorate their effects. The endogenous gaseous mediator hydrogen sulfide (H2S) has been described to exert a protective effect against cellular senescence and ageing phenotypes, and accordingly, to have protective effects against several age related diseases, although many of these studies have been carried out using non-physiological conditions, using very high levels of H2S. Plasma H2S level declines with age, is associated with hypertension in animals and humans and shows a significant inverse correlation with severity of coronary heart disease.

Here, we aimed to assess the effect of the H2S donor Na-GYY4137, and since mitochondria are a source and a target of H2S, three novel H2S donors, AP39, AP123, and RT01 previously demonstrated to be targeted specifically to the mitochondria, on splicing regulatory factor expression and cell senescence phenotypes in senescent primary human endothelial cells. Treatment with Na-GYY4137 resulted in an almost global upregulation of splicing factor expression in treated cells. Conversely, H2S donors targeted to the mitochondria also resulted in rescue from senescence but each demonstrated a very specific upregulation of transcripts encoding the splicing activator protein SRSF2 and the splicing inhibitor protein HNRNPD.

Abolition of either SRSF2 or HNRNPD expression in primary endothelial cells in the absence of any treatment resulted in increased levels of cellular senescence. None of the H2S donors were able to reduce senescent cell load in cells in which SRSF2 or HNRNPD expression had been abrogated. These data strongly suggest that mitochondria-targeted H2S is capable of rescuing senescence phenotypes in endothelial cells through mechanisms that specifically involve SRSF2 and HNRNPD.

Link: https://doi.org/10.18632/aging.101500

A sizable amount of effort is devoted to the comparative biology of aging, and in particular mapping the noteworthy differences between naked mole-rats and other similar-sized rodent species. Naked mole-rats live nearly ten times longer than mice and are near immune to cancer. It is possible that a sufficiently comprehensive understanding of why this is the case could result in therapies for humans, though I believe the odds of this coming to pass in the near future of the next couple of decades are much larger for cancer than aging. Research into calorie restriction mimetic drugs has demonstrated that safely inducing even small shifts in the operation of metabolism, even when aiming to mimic states that occur naturally and are very well studied, is very expensive and very slow work. While naked mole-rat resistance to cancer may boil down to just a couple of mechanisms, any one of which might be exploited alone, their longevity most likely has many contributing factors, and will be much harder to map and understand.

The open access papers noted here report on what are fairly standard fishing expeditions into the cellular biochemistry of the naked mole-rat, comparing it with that of the guinea pig. This sort of work takes place throughout the research community, and in many contexts. Researchers pick likely tissues and processes to examine, and then compare as much genetic, epigenetic, and proteomic data as they have the capacity to produce and process. Differences are pulled up from the depths for examination, and theories advanced based on what is presently known. Of the findings in these papers, some reinforce earlier theories on the damage resistance of specific cellular components in naked mole-rats, particularly mitochondria, while the most interesting item is the presence of raised levels of enzymes that are protective against oxidative damage. Past research has shown that older naked mole-rats appear to have all the signs of high levels of oxidative stress, but are largely unaffected by it.

Naked mole-rat transcriptome signatures of socially suppressed sexual maturation and links of reproduction to aging

Naked mole-rats (NMRs) are eusocially organized in colonies. Although breeders carry the additional metabolic load of reproduction, they are extremely long-lived and remain fertile throughout their lifespan. This phenomenon contrasts the disposability theory of aging stating that organisms can invest their resources either in somatic maintenance, enabling a longer lifespan, or in reproduction, at the cost of longevity. Here, we present a comparative transcriptome analysis of breeders vs. non-breeders of the eusocial, long-lived NMR vs. the polygynous and shorter-lived guinea pig (GP).

Comparative transcriptome analysis of tissue samples from ten organs showed, in contrast to GPs, low levels of differentiation between sexes in adult NMR non-breeders. NMRs show functional enrichment of status-related expression differences associated with aging. Lipid metabolism and oxidative phosphorylation - molecular networks known to be linked to aging - were identified among most affected gene sets. Remarkably and in contrast to GPs, transcriptome patterns associated with longevity are reinforced in NMR breeders.

Species comparison of liver proteomes reveals links to naked mole-rat longevity and human aging

Our cross-species analysis revealed that the liver of NMRs possesses three major characteristics compared to GP: (i) lower rate of mitochondrial respiration, due to reduced protein levels of complex I; (ii) higher reliance on fatty acids for energy production, deriving from increased abundance of enzymes responsible for lipid turnover; and (iii) increased expression of detoxifying enzymes.

Naked mole-rats have a very low metabolic rate, which reaches only 40% of the value predicted for a mammal in relation to body mass. They further have a very poor ability of thermoregulation and one of the lowest body temperatures of 32°C known among mammals. These traits likely serve as energy-saving adaptations to their arid environment. An inverse relationship between body temperature and expected lifespan has been reported, which suggests a contribution of the low body temperature of NMR to their longevity. These adaptations, as well as their high resistance to hypoxia, may account for a large proportion of the unique metabolic differences of NMR compared to other mammals.

Consistent with the established and published knowledge on NMR phenotypes at old age, we have shown a clear impact of aging on the NMR liver proteome that negatively affects the abundance of proteins involved in lipid metabolism and detoxification processes. The same pathways are similarly affected with aging also in mice and humans. Our observations support the notion of an extremely low, but detectable, rate of aging in NMRs.

Two major questions arise from our work: how NMRs have evolved their particular liver metabolism, and how does this contribute to the extreme longevity of these animals? Multiple studies have previously linked the composition of the mitochondrial respiratory chain to lifespan extension in multiple species. Similarly, lipid homeostasis and signaling has been linked to health and longevity, and changes in lipid metabolism have been shown to mediate the positive effects of anti-aging dietary interventions. Our data show that in both NMR and human liver, there is a progressive decline of enzymes responsible for fatty acid turnover. These alterations might contribute to changes in energy metabolism that favor the accumulation of adipose tissue and increased inflammation at older age.

From a mechanistic point of view, it is conceivable that adaptation to the particular ecosystem of NMRs has selected for characteristics of energy metabolism that in turn enabled extreme longevity via activation of stress pathways. Among these, the NFE2L2 pathway, which controls the expression of many of the detoxifying enzymes that we found increased in NMR vs. GP, was shown to have enhanced activity in NMR. The activities of the same pathways tend to decline during aging, as shown here by the decline of their target genes in both NMR and humans and in different model organisms. It is therefore tempting to speculate that their higher basal activity in the NMR might contribute to its enhanced stress resistance and ultimately delay the aging process.

One of the small paradoxes of aging is that older people are on balance more satisfied with this business of being alive, despite suffering a growing burden of the consequences of degeneration. A related paradox is that most people, if asked, will say that they want to age, decline, and die on the same schedule as their parents and grandparents. It is possibly the case that we humans are just not very good at the important things, the ideas and decisions that really matter. Conformity is more important than life. We readily sabotage the person that we will be a decade from now. Progress happens by accident, and we collectively random walk towards an incrementally better world because we are collectively incapable of taking the logical, direct path - whether that is towards an end to violence, an end to suffering, or an end to aging.

Ask people if they would like to live longer, perhaps even much longer, so that they could have more time. Initially, they'll say that the problem is quality, not quantity. Once you've convinced them to focus only on the benefits, you're bound to still face some skepticism. Nearly everyone grew up in a cultural context in which the fact that human life is limited is depicted as a blessing in disguise. There really isn't any proof, or even convincing evidence, that living longer than we do now would wind up being demotivating or boring, yet it's something that people commonly believe.

As avid a lover of life as I am, there are dull moments, moments that I'd rather forget, moments that don't count at all, and moments at which I'd rather lie down and slack off than "live to the fullest". I am okay with that, because life is made of ups and downs. We've got needs that periodically require taking care of. That's why you don't want a party to last forever; after a while, you need quiet and privacy. Later on, you'll feel more social again. This is the point at which people are likely to draw a false analogy and say that life is just like that party: at some point, you'll want to leave.

Life should be enjoyed. This doesn't mean that you should expect to be hyped all the time, but if you have a choice between enjoying any given moment and hating it fiercely, why not the former? If you can maximize your own enjoyment without harming anyone, why not? That's something to think about in general and something that people who are skeptical about life extension should ask themselves. Being sick hardly helps you enjoy yourself; so, if you want to maximize your enjoyment, you want to stay disease-free as much as possible. This is the point at which people need to understand that elimination of disease and life extension are one and the same: you can't really have one without the other.

As life extension technologies would likely allow us to live much longer, they would allow us to maximize our enjoyment by maximizing its duration; of course, this is only a possibility, as your enjoyment of your extra time depends very much on what you do with it. This is the point at which another objection is likely to be brought up: Are the extra years granted by life extension going to be more of the same old stuff? I don't have the foggiest clue, because it depends upon a number of unknown factors, one of which is you. If you're afraid that you'll spend your additional years doing the same old boring job, I'd say that you've got a problem with your job, not with life extension.

Link: https://www.leafscience.org/time-is-precious-so-lets-enjoy-more-of-it/

"Use it or lose it" applies as much to the mind as to the body. Evidence suggests that a fair fraction of the observed loss of physical strength and fitness with age is lack of activity and training rather than inexorable processes of aging - though those inexorable processes exist, and will kill you if nothing is done about them. The situation is most likely similar for the brain. Not all of the observed loss is necessary or inevitable, even given the present lack of effective rejuvenation therapies that can address the causes of age-related neurodegeneration. Some fraction of the decline occurs because people choose to not to stretch their minds as much as they might. How large is this fraction? That is an interesting question without any precise answer at this time.

For a long time, it has been assumed that brain plasticity peaks at young age and then gradually decreases as one gets older. Interestingly, thanks to tremendous advances in medical imaging techniques for assessment of brain structure and function, mounting evidence for lifelong brain plasticity has been generated over the past years. In the context of practice-induced task learning, a key question is how brain plasticity can be optimized and this is an even more important consideration for older adults. The gold standard to elicit brain plasticity is to practice new tasks intensively and to organize the training epochs in such a way that skill learning and retention are maximized.

A critical requirement for neuroplasticity to emerge is to make the practice context sufficiently difficult for the learner. One way to challenge the environmental context is to confront learners with practicing more than one task within each practice session. More specifically, rather than performing subtasks in a sequential or blocked manner, one after the other (less challenging), one can also apply a more demanding random practice regime such that learners have to switch tasks from trial to trial during practice (more challenging). The latter condition has led to the apparent paradox that reduced performance levels are obtained during the training phase but better long-term retention and memory formation of the skill are observed at later stages as a result of more profound inter-task information processing strategies. This is generally known as 'contextual interference' (CI). Even though CI seemingly induces complication of the learning environment, it has been shown that older adults can equally cope with this increased contextual complexity as young adults do and that it benefits longer-term skill retention

Using magnetic resonance spectroscopy (MRS), we explored the neurochemical basis of the CI effect via determination of the practice-induced modulation of gamma-aminobutyric acid (GABA), i.e. the chief inhibitory neurotransmitter that also plays a major role in brain plasticity. We found that the MRS data demonstrated a training-induced decrease in occipital GABA level during random practice but an increased GABA level during blocked practice and this effect was even more pronounced in older adults. First, the data suggest that older adults can indeed cope with more complex random practice contexts that challenge their instantaneous performance but boost their learning potential and skill retention. Second, training-induced modulations in GABA appear to be a function of degree of contextual challenge and this effect is even amplified by aging. This modulatory capability is preserved in spite of the fact that initial GABA levels were lower in older as compared to young adults.

These data provide additional confirmation for task-training induced lifelong plasticity. New motor and other skills can be acquired at any age even though the progress may be somewhat attenuated in older as compared to young populations. In view of the demographic evolution of society, characterized by a steadily increasing proportion of older adults, the evidenced lifelong brain plasticity provides a critical foundation for a sustained role of older adults in society and for securing prolonged functional independence and quality of life.

Link: https://doi.org/10.18632/aging.101514

Selective destruction of senescent cells in old tissues offers the promise of some degree of rejuvenation, coupled with effective therapies for a range of age-related diseases that currently cannot be controlled. In the past few years, a number of companies have raised venture funding for the development of senolytic therapies, those capable of removing some portion of senescent cells with an acceptable side-effect profile. The potential market is enormous, and thus despite the many potential competitors, any new mechanism by which senescent cells can be destroyed might be the pathway to success and revenue for the individuals and organizations involved in that research. A great deal more attention and funding is being devoted to the biochemistry of senescent cells than was the case even five years ago.

Cellular senescence is also of great interest to cancer researchers. Senescence in response to DNA damage is a way in which our biochemistry removes the riskiest cells from circulation. Senescence irreversibly shuts down the ability to replicate, senescent cells secrete signals to attract the immune system to the vicinity, so that problem cells can be destroyed, and in any case most senescent cells self-destruct shortly after entering this state. This works quite well at the outset, but not all senescent cells are destroyed. Eventually, there are enough of them that their signaling results in significant inflammation and disarray in the surrounding tissue - and that actually helps the development of cancer.

Nonetheless, at the front line of cancer research, any reliable approach that can force cancer cells into senescence is a win. Today's paper describes the possible foundation for such a treatment. While this isn't good for the patient in the long term - much of the shortened life expectancy of chemotherapy patients is most likely due to their high burden of senescent cells - it is a much better option than the outcome of uncontrolled cancer. It seems quite plausible that one of the results of the present raised level of interest in senescent cell biochemistry will be a range of more selective, more reliable, better ways to force cancer cells into senescence; approaches that rely on cellular biochemistry that is common to many or all cancers. That can then be coupled with senolytic therapies: turn the cancerous cells senescent and immediately destroy them. Might there be a practical end to cancer somewhere in the senescence research of the next decade or two? Maybe so.

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. Among the genes coding for the MYST family of KATs are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF). KAT6A has essential roles in normal haematopoietic stem cells and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers.

KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus, a function that requires its KAT activity. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer.

Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

In summary, using high-throughput screening followed by medicinal chemistry optimization, in-cell assays, biochemical assessment of target engagement, and tumour models in mice and fish, we have developed a novel class of inhibitors for a hitherto unexplored category of epigenetic regulators. These inhibitors engage the MYST family of lysine acetyltransferases in primary cells, specifically induce cell cycle exit and senescence, and are effective in preventing the progression of lymphoma in mice.

If we are to judge from the findings of genetic association studies, natural variation in human longevity occurs due to countless distinct factors, each of which provides a small contribution, is highly dependent on environmental circumstances, and is highly linked to other factors. Scientists have struggled to replicate more than a few known associations across different study populations, and those that have been replicated between study groups have small effects.

Blood group is genetically determined, and data on patient blood group is included in many of the data sets that report on disease incidence and mortality. A number of research groups have attempted to find robust associations between blood group and longevity, but on the whole the results seem fairly nebulous to date. Blood group B in particular keeps showing in correlations, but as an association for either longevity or a shorter life expectancy, depending on the study. That suggests that there is no useful underlying association that might be universally applied and, as is the case for the broader study of genetics and longevity, different patient populations have quite different characteristics.

The ABO blood group polymorphism has been associated with different diseases, cancer included. The cancer developments are variegated processes associated with aging. Protection from cancer and atherosclerosis is the main longevity reason. Long-survivors are an important group for the evaluation of genetic markers in cancer pathogenesis. Population studies have demonstrated that the ABO group phenotypes frequencies vary widely from one ethnicity to another.

The ABO genes control the expression of part of the carbohydrates by the epithelial cells in the respiratory, genitourinary, and gastrointestinal systems; the carbohydrate variability acts as a potential receptor for non-pathogenic and pathogenic microorganisms influencing immune responses. The first report on the relation between the ABO blood group and cancer indicated the A blood group to increase the risk of stomach cancer, while the O blood type was protective. Thereafter, the correlation between the ABO blood type and other malignancies, such as gastric and pancreatic, has been continuously reported. A total of 1.6 million healthy blood donors were followed in Denmark and Sweden: the A, B and AB blood groups were associated either with the increased or decreased risk of cancer at 13 anatomical sites as compared with the O blood group. Multiple mechanisms have been indicated to explain the blood type role in cancer progression, including altered immune response, inflammation, and cellular adhesion.

The role of the specific genetic differences contributing to life expectancy is hardly known. Several genome sequencing and GWAS studies compared the total number of disease variants in centenarians and controls, indicating that there are some evidences that centenarians harbor the anti-aging polymorphisms which protect them from diseases, although long-survivors may show numerous disease variants at a rate similar to normal people, but they are protected from their effects. The single nucleotide polymorphism defining the most common allele responsible for the O blood group is related with longevity; the centenarians are more likely than controls to have the O blood group.

The aim of the present study was to assess the ABO blood group polymorphism association with prostate, bladder, and kidney cancer, and longevity. The following data groups were analyzed: Prostate cancer (n=2,200), bladder cancer (n=1,530), renal cell cancer (n=2,650), oldest-old (n=166) and blood donors (n=994) groups. The data on the ABO blood type frequency and odds ratio in prostate cancer patients revealed a significantly higher blood group B frequency. A comparison of the oldest-old and blood donor groups revealed that blood group A was significantly more frequent and blood type B was significantly rarer in the oldest-olds. The results of the present study indicated that blood type B was associated with the risk of prostate and bladder cancer, and could be evaluated as a determinant in the negative assocation with longevity. Blood types O and A may be positive factors for increasing the oldest-old age likelihood.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063046/

Researchers recently reported initial success in a transplant of decellularized lungs in pigs, though there is still a way to go in order to prove the ability to produce a completely functional lung in this way. In the decellularization process, donor lungs are stripped of their cells, leaving behind the extracellular matrix and its chemical cues for cell growth. The lung is then repopulated with cells derived from samples taken from the eventual recipient of the transplant. This minimizes the risk of transplant rejection.

Decellularization is a short-cut technology, a way to work around the present inability to produce sufficiently structured and chemically correct scaffolds for tissue engineering of complex organs. It will allow for a higher fraction of donor organs to be transplanted than is currently the case, make the logistics of organ transplant somewhat easier, as decellularized tissue is much more amenable to longer term storage, and also opens the door for the development of viable xenotransplantation, such as from pigs to humans.

Researchers have transplanted bioengineered lungs into pigs successfully for the first time. The team harvested lungs from dead pigs to construct a scaffold for the bioengineered lung to hold fast to. They used a solution of soap and sugar to wear away all the cells of the lungs, leaving behind only collagen, a protein that forms the support structure of the organ. Next, they removed one lung from every recipient pig, and used cells from those lungs, together with the collagen scaffold, growth factors, and media, to grow a new lung in a bioreactor. After a month, the lungs were transplanted into the recipient pigs.

As the cells came from the same animal that then received a bioengineered lung, there was no organ rejection. The researchers euthanized the recipient animals and tested their lungs 10 hours, two weeks, and one and two months following transplantation. The team found that before the pigs were euthanized, the transplanted lungs developed without any outside help, building blood vessels they needed for survival. However, even the two-month-old transplanted lung, while not showing any fluid collection that would indicate an underdeveloped organ, had not developed enough to independently supply the animal with oxygen. The researchers hope that bioengineered lung transplants will be feasible in humans within a decade. But first the team will "need to prove that the animals can survive on the oxygen provided by the engineered lung alone."

Link: https://www.the-scientist.com/news-opinion/lab-grown-lungs-transplanted-into-pigs-64607

The long years of failure in Alzheimer's research, in which trial after trial of immunotherapies targeting amyloid-β produced no meaningful benefits in Alzheimer's patients, has sown the seeds of change in the research community. In the past couple of years, promising human data for amyloid-β clearance has finally arrived, but the damage is done. The amyloid hypothesis for Alzheimer's disease is now challenged, and alternative theories are thriving. One of particular note is built upon the point that generation of amyloid in the brain appears to be a defensive mechanism of the innate immune system, and thus its proponents see Alzheimer's as the end result of persistent infection, such as by herpesviruses or the bacteria of lyme disease.

In this view of the world, Alzheimer's is just another of the many unpleasant late consequences of a high disease burden sustained throughout life. We are, after all, far better off than our recent ancestors thanks to increased control over infectious disease. Chronic inflammation and other consequences of the burden of parasitism and infectious disease resulted in earlier frailty in later life and shortened life expectancy until the advent of widespread antibiotics and other, similarly influential 20th century medical advances. Nonetheless, many infectious agents remain uncontrolled or poorly controlled - the ones whose effects are sufficiently subtle and slow to have evaded early notice. Numerous herpesviruses have few to no immediate symptoms, but may be slowly corroding the immune system or other aspects of our biology over the years, as cytomegalovirus is thought to do.

Why do only some people develop full blown Alzheimer's disease, while others never progress beyond the symptoms of mild cognitive impairment? Those researchers who favor an infectious disease model would say that it is because only some people carry a high burden of the most relevant infectious agents, such as lyme spirochetes. It is a compelling argument in many ways.

It's Never Too Early or Too Late - End the Epidemic of Alzheimer's by Preventing or Reversing Causation From Pre-birth to Death

Historically, infectious diseases were the cause of morbidity and mortality. Infectious disease arguably continues to be the major driver of morbidity and mortality however this connection is largely ignored because of the occult nature of many of the causative agents and the cryptic cause and effect between organism and disease. The concept of evolutionary fitness actually points to infection as being the major cause of disease in modern society. Genetic traits that may be unfavorable to an organism's survival or reproduction do not persist in the gene pool for very long. Natural selection weeds them out and any inherited disease or trait that has a serious impact on fitness must fade over time. Therefore, when diseases have been present in human populations for many generations and still have a substantial negative impact on people's fitness, they are likely to have infectious causes.

Immune system vitality may be the most important risk factor in any chronic disease including Alzheimer's. Apart from symbiotic coexistence of human with micro-organisms, disease causing organisms breed in man-made unhygienic conditions of air water and soil. People with low immunity, weak, and living in unhygienic conditions are at greater risk for contracting the infections from surroundings. This model of disease fits equally well with Alzheimer's and other chronic diseases but has been limited because source of the infection is less obvious and diagnosis is not frequently enough made or considered.

Chronic inflammation is considered a cause of chronic disease, including Alzheimer's. Chronic inflammation continues to be blamed for tissue damage but this complex cascade, stimulated by internal and external mediators, results in the release of danger signals that promote immune responses to antigens. Chronic, occult infection is a significant stimulator of chronic inflammation. Any chronic disease, then, is potentially a measure of the stress on the biological system and its ability, or lack thereof, to cope.

Chronic disease incidences, including Alzheimer's, increases with older age and are linked to immunosenescence. Numerous studies show that the pathology of Alzheimer's disease is present decades before a clinical diagnosis of dementia can be made. Predisposition to Alzheimer's, therefore, is established prior to the acceleration of immunosenescence that starts around age 65. The vulnerability to disease due to an immature immune system during the ages 0-5 is also relevant. It is during these times that the antecedents of Alzheimer's and other chronic diseases, specifically occult infections, may opportunistically infiltrate such vulnerable hosts only to express as disease across the spectrum of time and lead to the a significant upswing in Alzheimer's.

There is plenty of evidence to link the presence of excess visceral fat tissue with cognitive decline over the course of aging. This fat tissue produces chronic inflammation, among other issues, accelerating all of the common forms of age-related decline. Becoming overweight is a reliable way to raise risk of age-related disease, increase lifetime medical costs, and reduce life expectancy. The more weight carried, the worse the prognosis.

A new study using data from the Trinity Ulster Department of Agriculture (TUDA) ageing cohort study comprising over 5,000 individuals has found that a measure of belly fat (waist:hip ratio) was associated with reduced cognitive function in Irish adults older than 60 years. These findings have significant implications as the global prevalence of dementia is predicted to increase from 24.3 million in 2001 to 81.1 million by 2040.

Previous studies have found that people who are overweight do not perform as well on tests of memory and visuospatial ability compared to those who are normal weight. However, it is not well known if this is true in older adults. This is of concern within Ireland, as over half of the over 50s population is classified as being centrally obese, with only 16% of men and 26% of women reported to have a BMI (body mass index) within the normal range.

The researchers used data from the TUDA study, which is a cross-border collaborative research project gathering data from thousands of elderly adults in Northern Ireland and Ireland. They found that a higher waist:hip ratio was associated with reduced cognitive function. This could be explained by an increased secretion of inflammatory markers by belly fat, which has been previously associated with a higher risk of impaired cognition. On the contrary, body mass index (BMI) was found to protect cognitive function. BMI is a crude measure of body fat and cannot differentiate between fat and fat-free mass (muscle), thus it is proposed that the fat-free mass component is likely to be the protective factor.

Link: https://www.tcd.ie/news_events/articles/measure-of-belly-fat-in-older-adults-is-linked-with-cognitive-impairment/

People who undertake no moderate exercise suffer about as much as the heavily overweight, or smokers, when it comes to diminished life expectancy - though there is always the question of direction of causation in these correlations. Past studies have suggested that even a little regular exercise improves matters considerably. But how little? The human dose-response curve for exercise is being mapped out, slowly, through large epidemiological studies. The open access paper reports on data that suggests even very low levels of exercise correlate with a surprisingly large difference in life expectancy in comparison to sedentary individuals. This isn't an excuse to slack off if you happen to be somewhere closer to the recommended level of physical activity, however: there is plenty of evidence to suggest that optimal exercise benefits require twice that amount or more.

Strong evidence shows that physical activity has beneficial effects on well-being, health, and longevity in older ages. The survival effect of physical exercise has received support by a large study of more than 40,000 athletes, which shows that the Standardized Mortality Ratio (SMR) for athletes compared to the standard population was 33% lower. There are also other studies showing that physical exercise decreases mortality. In one study it was found that jogging or brisk walking more than 7.5 hr every week was associated with a higher life expectancy. In another study, for a person engaged in more frequent physical activity, the mortality risk was about 25% lower than for those less frequently active.

The longevity effect of physical activity seems, however, in a number of studies, in which both light and intense physical activity levels have been used, to be U-shaped according to frequency and intensity. Some researchers have tried to establish a dose-response relationship between the amount of exercise and decrease of mortality. Assuming the existence of a U-shaped relationship, moderate activity levels seem most preferable. This assumption has also been empirically supported with regard to the relationship between the amount of exercise and cardiac morbidity, quality of life and cognitive functioning. In addition, people with more frequent moderate physical activity (MPA) were engaged in more cognitive activities. It has also been found that only one to two hours of jogging weekly decreased the risk by 71%.

Assuming the existence of a U-shaped relationship, it has been suggested that while the largest decrease in the risk of death takes place when going from zero to any moderate physical activity, more frequent and intense physical activity is beneficial only for a very small part of the population, such as trained athletes. In this study, a sample of 8,456 individuals aged 60 to 96 years, representative of the Swedish population, was included. Participants were followed from 2004 to 2015. The results show that 82.1% of the total sample performed MPA 2 to 3 times every month or more, and those were, in an 11-year perspective, more often still alive.

In comparison with other studies, the low frequency of MPA needed for an effect on longevity was remarkable, although low levels have been suggested previously. The results do not contradict the general recommendations of daily moderate physical activity, but the present results also indicate that health advantages, at least in terms of longevity, can be achieved by an even lower activity frequency. The previously made suggestion that the strongest difference in health outcomes can be observed between those not active at all and those performing any moderate activity is confirmed by the result of this study.

Link: https://doi.org/10.1177/2333721418786565

The Life Extension Advocacy Foundation (LEAF) volunteers have produced an excellent series of interviews of late, with many of the researchers of note involved in work aimed at better treating and understanding aging. João Pedro de Magalhães is one of the very long-standing members of the original small community of life extension advocates that emerged from the online transhumanist forums of the 1990s. From that small but highly influential movement a surprisingly large number of individuals become scientists or advocates or leaders or entrepreneurs of one sort or another involved in efforts to bring aging under medical control. The list includes Aubrey de Grey of the SENS Research Foundation, Anders Sandberg at the Future of Humanity Institute, Max More now running the Alcor Life Extension Foundation, a good many other people and ventures, too many to list, and of course João de Magalhães, now with his own lab in the UK, and still maintaining a very helpful website on the science of aging after all these years.

Insofar as transhumanist ideals of artificial general intelligence, molecular manufacturing, radical life extension, and the transformation of the human condition have spread out into the broader melange of ideas in our culture, then the original members of the community can count themselves a success. You can't take too many steps through the vast and many-threaded conversation constantly taking place between the peoples of the world today without running into some sign of transhumanist ideas and goals. These concepts, accepted and integrated now, were strange, fringe, new, and assembled by just a handful of folk some thirty plus years ago. Then they escaped into fiction and the growing internet, and it all took off from there. At some point this will make for an interesting study in the history of ideas and people, how they interact - how the goal of radical life extension and human rejuvenation moved from science fiction to reality in half a lifetime.

An Interview With Dr. João Pedro de Magalhães

How do you think we age; are we programmed to die, do we wear out, or is the truth a mixture of both?

I don't think we wear out. Humans and complex animals are made of cells and molecules that, by and large, have some turnover; we can replace most of our components, so I don't think it's correct to see aging as wearing out, at least not in complex animals like humans. That said, I do think that some forms of cumulative damage contribute to the aging process, such as DNA damage. I also think that there are programmatic aspects to aging. That is, I think that genetic programs coordinating some aspects of growth and development persist into adulthood and become detrimental as forms of antagonistic pleiotropy. It is probably a combination of molecular damage and the inadvertent actions of genetic programs that causes aging.

There seems to be an increasing suggestion in academia that directly targeting the underlying aging processes is the most promising strategy.

Absolutely; this is something that biogerontologists have been arguing for a very long time. I also think that the graying of the population means that there is a growing awareness of the need to develop approaches to tackle the process of aging and associated pathologies.

There also seems to be an increasing amount of investment in rejuvenation biotechnology in the last year; what has happened in science to encourage this commitment?

There's more than one reason to explain this recent excitement in anti-aging biotech. One reason is the aforementioned graying of the population, making anti-aging interventions commercially very appealing. In addition, the discoveries of the past couple of decades showing that the process of aging is plastic and can be manipulated in model organisms has generated tremendous excitement. Even in mice, we can tweak one gene and extend lifespan by nearly 50%, retarding a multitude of age-related pathologies. If we could do that in humans, that would mean making people not only live longer but stay healthy for longer. Again, from a financial perspective, that would have huge implications, and any company that were to develop a true anti-aging intervention would make huge profits. My recent review of the business of anti-aging science discusses this topic in more detail.

What is the biggest bottleneck to progress in aging research, in your view?

Most scientists would say lack of funding, but while having more funding would certainly accelerate progress, I think it would only help so much. This is because experiments in aging, and potential human clinical trials, are intrinsically time-consuming. That is not going to change with more funding. I would argue that the biggest bottleneck to progress in aging is the nature of the aging process itself in that it takes quite a long time, which, in turn, means that studies and trials will also take a long time.

Alex Zhavoronkov of In Silico Medicine has written a fair amount on the economics of aging and the urgent need for greater research and development of means to treat aging - to diminish the burdens that fall upon us all as the result of certain degeneration and death in late life. The costs of aging are staggering, and yet here at the dawn of the era of rejuvenation therapies, only tiny amounts of funding are devoted to doing something about it. Spending on competitive sports - or war, the other manifestation of the same urge - is vast in comparison to the resources devoted to slowing or reversing the causes of aging. We fiddle while Rome burns.

In the past, Alex Zhavoronkov claimed that he expected to live to be 150, but now he's more conservative. He's skeptical that we will see such drastic changes to the human lifespan quite so soon. There are too many hurdles left to clear, and he feels that today's political and economic climate isn't exactly conducive to expensive, experimental longevity research. To be clear, he does believe humanity will someday live that long, but not as soon as he thought. Someday, Zhavoronkov argues, we will build a future where humans can all live longer and healthier, enjoying productive lives well past the ages we never thought we'd reach at all. To get there, the powers that be will just need to shift their focus and decide that longevity is worth pursuing. And his company, along with others that are looking into big data, will forge ahead until that happens.

It's hard to argue that scientists shouldn't find ways to help people live longer. Zhavoronkov argues that longevity ought to be a fundamental human right - the right to live as long and well as possible. Living longer and healthier would help people enjoy a better quality of life, but it would also prevent or solve many of the problems facing our economy. Presumably, living longer will fix the economy because people will grow old without growing frail - our eternal descendants will spend less time at the nursing home and more time at the office. The economic argument is a compelling one for the people holding the purse strings for the grants that fund research, but so far it hasn't been enough for them to funnel money into the field, where Zhavoronkov thinks it's most needed.

"This is very frustrating. But this is the nature of today's society. People in the developed countries have most of their basic needs already satisfied but instead of focusing on securing the future, they focus on today's events. Clearly the governments and the people they represent have their priorities misplaced." In an ideal world, transformative changes will ripple through healthcare within ten to fifteen years, Zhavoronkov predicts. But he's disappointed that his company and other teams working on real, science-based, longevity research haven't gotten more hype. "The limitations on what we can do for longevity today come from our current understanding of technology and will not be there in the future. We need to focus on what is available today at the very cutting edge and take it to the next level."

Link: https://futurism.com/artificial-intelligence-longevity-alex-zhavoronkov/

Since it doesn't get much press these days, newcomers to our longevity science community might not be aware of the wager made nearly two decades ago between optimist Steven Austad and pessimist S. Jay Olshansky on the trajectory of future human life expectancy. The core of the wager is whether or not the research and medical communities will develop and implement means of radical life extension sufficient to result in 150-year old humans within next century or so. Given where things stand today, I'd say that betting against this outcome is tough to justify. Fifty years in technology is a very long time in this era of rapid progress in applied science, never mind a century, and the first rejuvenation therapies that work by removing a fundamental cause of aging are already heading to the clinic.

It is possible that someone reading this now will be alive to see the resolution of a $1 billion bet between Jay Olshansky, a University of Illinois at Chicago professor of public health, and Steven Austad, chairman of biology at the University of Alabama at Birmingham. Eighteen years ago, the two friends began their discussion on an issue that long has intrigued scientists and laymen alike: What is the limit of the human life span? Austad, whose research focuses on aging, had made a bold prediction at an academic conference: In the year 2150, he said, there will be a 150-year-old human being. Olshansky, also an expert on aging, wasn't having it.

They decided to make it interesting. They each put $150 into an investment fund, and signed a contract specifying that the heirs of the winner will cash it out in 2150. Early published reports on the wager said the payoff would be from $200 million to $500 million given good market returns, but the men have since doubled their initial investments and they now estimate the final jackpot at roughly $1 billion.

Since they made wager in 2000, average human life spans have inched up. I asked Olshansky if, in light of the galloping progress of medicine on all fronts, he was having any second thoughts about his position. None, he said. If anything he's more certain than ever that his descendants - he has one grandchild so far - will be made fabulously wealthy. "There will certainly be breakthroughs that will slow many of the biological processes of aging. We'll be able to extend the number of years that people can live in good health but the brain is our Achilles heel. There's still no evidence to suggest that we'll be able to halt the effects of the daily loss of nonreplicating neurons, much less reverse it. We can replace hips, knees, hearts and so on, but we can't replace the brain."

Austad, too, believes more firmly than ever in his position. "We're discovering more and more ways every year to make mice live longer through drugs and diet. A 150-year-old person is only about 20 percent older than the current record holder, and we've found dozens of ways to extend the lives of mice by that much. Not all of them will work with humans, of course, but if any of them do, we're going to see dramatic results. All we have to do in the next 30 years is find drugs that dramatically slow the underlying causes of aging. If we give them to people approaching 50, some are going to reach the extreme of 150."

Link: http://www.chicagotribune.com/news/opinion/zorn/ct-perspec-zorn-longevity-aging-olshansky-austad-20180715-story.html

Doug Ethell has a clear and comparatively easily tested hypothesis on an important cause of Alzheimer's disease: that it results from the progressive failure of drainage of cerebrospinal fluid through one particularly crucial pathway in the skull. This traps ever greater levels of metabolic waste in the brain, such as amyloid-β, tau, and α-synuclein, and leads to the spectrum of well-known neurodegenerative diseases characterized by protein aggregates and resultant dysfunction and death of neurons.

Dave Gobel of the Methuselah Foundation backed the first work on this hypothesis a few years back, and the result is Leucadia Therapeutics, a company now well on the way to proving that restored drainage of cerebrospinal fluid can be a basis for treatment. Along the way, supporting evidence for the important of impaired cerebrospinal fluid flow in neurodegeneration has emerged from groups studying the glymphatic system in the brain. Given that the cost of this exercise is a tiny fraction of the funding put into the development of any one anti-amyloid immunotherapy, and it should impact all forms of metabolic waste in the brain, not just one, it seems like a good path forward.

I'd like to thank Aubrey de Grey for inviting me to this wonderful conference, because aging is still the biggest risk factor for Alzheimer's disease. There are 35 million cases in the world today, and another 200 million people are walking around today who will get this disease over the next 30 years. So solving this one is like curing cancer ten times over.

Let's start at the beginning. In 1901, a German psychiatrist working at the Frankfurt asylum had this patient Auguste Deter. Alois Alzheimer was her doctor. She was 51 years old and severely demented; confused, disoriented, paranoid. She couldn't make any new memories. He followed her for five years until she died, and then he took her brain to the Kraepelin lab in Munich, where they discovered the pathology that underlay her condition. He wrote up a paper for that, a small paper, "On a Peculiar Disease of the Cerebral Cortex." It wasn't until a year later that Kraepelin wrote his textbook and mentioned the case, and he referred to it as "Alzheimer's disease." That is how it got its name - he didn't name it after himself.

The most obvious pathological feature, on a gross level, of Alzheimer's disease is a several atrophy or wasting of the cerebral cortex. It is due to the death of billions of neurons. If you take a section of that and you cut it up you find the two pathological features that they identified in Kraepelin's lab. Firstly there are plaques, tiny waxy deposits of amyloid-β protein and some other things, but mostly amyloid-β. Secondly, neurofibrillary tangles. These are the insoluable remnants of the cytoskeletons of neurons that have died. They are a very good marker for where the cell death is happening in the brain, but neurofibrillary tangles are something that sick neurons make. So it doesn't really tell us why they are sick, just that there were sick neurons there.

Amyloid has been the center and a preoccupation in Alzheimer's disease research for 25 years. Unfortunately it has not gone so well. It has been an unbroken string of failed clinical trials, costing $20-30 billion in private and public funding - and the bloodletting continues to this day. In just February of this year, two companies dropped out of their Alzheimer's development program. Close to 1800 clinical trials have been conducted on something related to Alzheimer's disease. Do you know how many of those trials have slowed or stopped the progression of Alzheimer's disease? Zero. Not a single one. That is what I call a systematic error. So a few years ago I began to apply Occam's razor to this, looking for a more simplistic solution. Is there something basic that we are missing, something that can account for the age-dependent incidence of the disease? Something that accounts for the higher risk for people who have traumatic head injuries, and the near certainty that people with specific mutations will develop the disease at an early age, just like Auguste Deter.

I'm going to need to use a little neuroanatomy here, but I'll try to keep it simple. At the top of the slide here we have the right halt of the cerebral cortex, the right is the front and the left is the back. The image below that, since it is just the half, is what it looks like on the medial surface - on the inside. The last image is what it looks like from below. Here we have three columns of such images for the three stages of Alzheimer's disease, early, middle, and late. The coloration is neurofibrillary tangle staining. If you notice on the left hand side, early stage Alzheimer's, the small orange portion of neurofibrillary tangle staining is the specific area where the pathology starts. It is almost like a little campfire; it starts off with a spark that smoulders a bit and then it explodes - it goes to other regions of the brain.

But it starts here, and this is called the medial temporal gyrus. It has the hippocampus in there, and big parts of the olfactory system. So there is something peculiar about this area. No other animal gets this disease, and in humans it starts in this one specific area. This is actually a different part of the cerebral cortex. In the early Alzheimer's images, the unstained yellow area is the neocortex, a six-layered neocortex. But the stained areas with neurofibrillary tangles are allocortex, three layer and five layer cortex. They are a more ancient part of the brain. What is it about this part of the brain that seeds Alzheimer's pathology, seeds the deposition of amyloid-β in the interstitial spaces of this region of the brain?

I think it comes back to the evolutionary origin. Here is an image of an alligator brain. The blue area is where the olfactory system is. It used to be a third of the forebrain - very important. If we look at other animals, we can see that in most mammals it is very large, because it is important for smell, which is important for survival, breeding, and evolutionary fitness. But in humans, notice how small the olfactory system is in the brain. It is just a tiny thing, and sits just below the prefrontal cortex, where executive function and abstract reasoning happen. So it is almost as it there was a turf war for space, and the olfactory system lost. So we think very well, but we can't smell very well. This is my dog Rex; when I take him for a walk, he smells as if it is an 80" plasma ultra-high-definition TV, and I smell like it is a little 1950s black and white with the fuzzy lines and stuff - a dog is 700-800 times better than the average human in sense of smell.

Now, the olfactory system is where Alzheimer's disease starts. In the image, these are the olfactory bulbs here, the little bulbs. So what is it about this area that seeds Alzheimer's pathology? I think it might have to do with the clearance of interstitial spaces. Here is an allegory. Think of a forest; there is a little stream in the forest, and leaves fall down from the trees. If they fall on the ground, they sit there and they rot. If they fall into the stream it carries them away. Later in the summer, the stream starts to dry up, and the leaves keep falling in. Eventually it hits a point at which the water can't carry them away, and then they form mats - or plaques. So I think it has to do with the clearance of the tissue.

In most of the body this is done in the following way: capillaries have these tiny holes, or fenestrations, or some kind of gap between the cells. Blood plasma comes out of these holes, and enters the interstitial compartment, where it becomes interstitial fluid. It passes slowly through there, picks up soluable macromolecules, maybe pieces of apoptotic cells, and other debris, and carries it along to the lymphatic vessels. They take it up, lymph nodes eventually taking it back to the bloodstream. Of course any cancer cells will also take this route, and that his how they so frequently wind up in the lymph nodes.

But in the brain, this system doesn't exist. The blood-brain barrier prevents any formation of fenestrations or gaps between the endothelial cells. The brain does it a different way. It has these large fluid-filled cavities called ventricles, and those have choroid plexuses that produce cerebrospinal fluid (CSF) - about half a liter per day per person. It percolates through the tissue, through the cortex, through all the spaces, and along the blood vessels, and it works its way up to the surface, to the subarachnoid spaces. From there some is resorbed, but some of it passes all the way down to the spinal cord, where you can get a lumbar puncture or a spinal tap to sample the CSF.

Now remember that I said that the olfactory system used to be a very big, very important part of the forebrain. CSF comes into the hippocampus, and works its way up to the surface at the medial temporal gyrus. But then it goes along the olfactory route towards the olfactory bulb, not towards the spinal cord. In this diagram, here is the medial temporary gyrus; fluid comes in, goes towards the surface, goes towards the front, and there is a rudimentary cone here - the lateral olfactory stria. This is a loose fiber bundle, and the CSF passes through little channels in there, along past the basal forebrain, and to the olfactory bulb.

Then what happens to the fluid? Well, here is an image of the interior of a skull, looking downwards. The front is at the top, the back is to the bottom. There are two little depressions or pockets, olfactory fossa, in the front of the skull. The olfactory bulbs sit in there, and the CSF drains through. In this cross-section figure, we can see the olfactory bulbs on top, a small gap, and below the cribriform plate and then nasal mucosa. Here are the olfactory nerves, sending information to the olfactory bulb about the odors they perceive. But there are gaps in there, and the metabolite-laden CSF makes its way through into the nasal mucosa, where there are plenty of lymphatic vessels. For anyone who has ever had a nasal vaccine - the presence of so many lymphatic vessels in the nasal mucosa is why this delivery method is used.

The cribriform plate is a natural choke point for the clearance of this fluid from the brain region where the disease starts. Here is an image of a 26 year old skull, and a CT scan of the same. You can see that there is some thick bone in the cribriform plate here, but not very much. Here is a CT scan of the same region of an 80 year old skull, and you can see that there is a lot more bone deposition in the cribriform plate. This structure at the top of the image is a piece of bone that sticks up, and I'll show you more of it in a minute. It is called the crista galli and notice how much bigger it is in the older person. We have continuing bone deposition in this area. One of the effects of that is that it closes off the holes, the apertures, reducing the ability to clear the CSF.

Here is an image of a CT scan of the skull, and this is seen from the front. The cribriform plate is on the bottom here, and this vertical structure is the crista galli. Notice it goes down the middle, right here, all the way and connects up with the bone in the middle of your nose, the nasal septum. The second image shows a cribriform plate from the interior of the skull. You can see the apertures there. What we've been doing at Leucadia is high resolution micro-CT imaging of about 70 human cribiform plates. These are taken from control subjects at different ages, and from Alzheimer's patients.

The image here is of a 26-year-old control cribriform plate. I actually have a 3-D print with me, as we do a lot of that as well. You can see the holes, plenty of apertures. There is a little thick bone, but lots of apertures - Swiss cheese, practically. If we look at 70-year-old control, we can see that there is a bit of a bony veil that has developed, and there are not so many apertures in here. There is a little bit of bone deposition. If we go a little further, and look at an Alzheimer's disease cribriform plate, notice the big bony veil convering pretty much all of the apertures at the very back of the olfactory fossa.

See also a big bony area in the middle, because this cribriform plate is uneven. The crista galli is in the middle: if you break your nose, it is going to deflect the crista galli, and when it heals there will be extra bone around the injury. So in this case we can tell that it has been deviated due to past injury, and thus there is thicker bone on that side. So it seems that if you injure the cribriform plate, it is going to affect this system. This next image is the cribriform plate for a different Alzheimer's patient. You can see that the channels in the middle are different, but the big bony veil is similar. So we are talking about how much capacity there is to drain the CSF, and that seems to be different in Alzheimer's patients.

We are carrying out these high resolution micro-CT scans on cadavers, but we want to start doing them on humans, because we want to be able to relate what we see in the high resolution samples with what we will see in a lower resolution clinical sample. We do that, we'll get our scans, and the hard-working interns at the company are going through and segmenting these files: I have to go through and say that is bone and that is other tissues. We produce these 3-D models of the cribriform plate, like the one I just showed you, and if we take just the one aperture and expand it like this diagram here, we can see it is made up of dots, and each dot has an (x,y,z) coordinate. We get a big file that contains thousands upon thousands of these coordinates, and that's how we're matching up the samples, using computers.

If we do this, what we should be able to accomplish is, theoretically, when we are all finished with our database, is look at someone's scan and determine the theoretical CSF flow capacity. If we can do that, then we can use CT scans to say, well this person obvious has a lot of occlusion here, or this person is fine. This will come in very handy for mild cognitive impairment, which is the pre-dementia state. Only about 10% of those patients progress on to Alzheimer's disease. The big question has always been which ones? If we can do these scans and say this one and that one and so on, it is going to be a big help. It could also be part of an annual wellness assessment for seniors. Maybe they get a scan every two years or five years, and we can actually watch the progression of ossification, and calculate how long it is going to be before they hit the critical threshold.

The bone is kind of only part of the story, because the other part is the soft tissue. This image is the highest resolution MRI ever done of a human cribriform plate. What we see here is the soft tissue is blue and the bone is a firey color. You can see where the apertures are, but that's not quite good enough, because there are so many apertures, a couple of dozen apertures, and some of them have blood vessels, some of them have nerves, some of them probably have the channels for CSF, but we need to know which are which. So we came up with another method: we figured out a way to enhance the staining, so that we could use CT to resolve bone and nerve and other tissues in the micro-CT images. Then we go in and digitize it. In this digitized image you can see the bone, the nerve, and these blue things here are the fluid-filled conduits where the CSF is actually flowing through. We can use this with our database to figure out how much CSF flow capacity there is.

Here is another digitized image showing the same, you can see the nerves in orange and the flow channels in blue. We can remove the bone from the image to show just the structure within. Now this yellow structure that is something else; it is a little interesting and nobody else have ever seen that before. These are actually channels within the bone, CSF conduits that are connected to the soft tissue drainage channels. It is almost like an equilibriation of the CSF flow mechanism. These CSF conduits in the bone, we can see them in the control cases, but looking at the Alzheimer's patients they are almost completely gone. We are losing these conduits and we're also getting ossification. So there is really something going on here with the CSF flow.

The proof of concept we are doing for this is we are blocking the cribriform plate in ferrets. It turns out that mice and rats, for a number of reasons, are probably the worst model you can pick for Alzheimer's disease. It is ironic, because the NIH has been very draconian about "you must use mice." In this picture you can see our team of human neurosurgeons, who brag now that they are the greatest ferret neurosurgeons in the world. The ferret pictured here has had surgery a few months before; the surgeons go in through the top of the skull, go into the nasal cavity, make a little window, peel the tissue off the cribriform plate, and put bone cement on there to block it up. We want to see after six months do we get plaques and tangles, hopefully so and that would be great. But in the meantime we're doing behavior studies. Pictured here is the maze that they run through. We are assessing them every two weeks, and when we finish this study we'll put it all together.

It is one thing to tell someone that we have done a scan and you are going to get Alzheimer's disease in five years or seven years, or you have a very high risk because of your cribriform plate. It is another thing to be able to do something about it. This slide is an image from Greek mythology, the water nymph Arethusa, and she attracted the attention of a river god, and she couldn't get away from him. Artemis saved her by turning her into a hidden underground stream. That is what we want to do; we want to make a hidden under-the-tissue channel to drain the fluid from this area. We call it Arethusta.

Here is a simple diagram. We go up through the nose, the cribriform plate is up there at the very top of the nasal cavity, and we put in the device. This is a very old version of the device. We have much newer, better ones, but it is in the patent, which is publicly available. What we feel we'll do is put the shunt in maybe in people who have mild cognitive impairment. That should actually reverse their mild cognitive impairment (MCI), because the MCI is happening because the amyloid-β has become oligomeric, which is toxic to synapses. So the synapses aren't working as well. This is even before the formation of plaques. If we restore the flow, we should be able to reduce the level of oligomeric amyloid-β and hopefully prevent the disease from progressing to Alzheimer's disease. That is our plan.

We think it is minimally invasive, although we do have neurosurgeons do it because we are puncturing into a part of the brain, and we have to be very careful about that. We think it should be pretty straightforward, and the trial, since we're targeting MCI, isn't going to be the 10 or 20 year trial for an Alzheimer's study. It will only be a couple of years, because we should see the effects in a matter of weeks to months. Then hopefully five years later they don't progress to Alzheimer's disease.

So in summary, I talked about the cribriform plate as the final outlet for CSF in the region where the disease starts. It is a natural chokepoint. We saw age-dependent changes in the cribriform plate, and the Alzheimer's patients show more occlusion. Then there are the flow channels, the fluidics. Looking at these flow channels is just a lot of work because these files are enormous, and it takes weeks and weeks to go through one and identify all of the channels and all of the nerves. But we are making good progress. Then what we really want to do is use all of our information to make a diagnostic algorithm that will work with an appropriate CT scan from anyone, and figure out where they are in the spectrum - and then treat MCI.

Sarcopenia is the name given to the age-related loss of muscle mass and strength. There are many potential causes of this decline with at least some supporting evidence in the scientific literature. The most compelling are those related to loss of stem cell function, but there is also the question of whether or not older individuals lose the ability to process dietary proteins to produce new muscle tissue. In particular dysfunction in processing of the essential amino acid leucine is a possible mechanism, and some groups have considered dietary leucine supplementation as a possible compensatory treatment. The open access paper here ties in recent findings regarding age-related changes in the microbial populations of the gut to the issue of protein processing in aging. It is by no means settled as to whether or not all of this will fit together sufficiently well to explain a significant fraction of sarcopenia, but it is certainly an active area of research.

Sarcopenia is a geriatric syndrome defined as the age-related loss of skeletal muscle mass and function, quantified by objective measures of muscle mass, strength, and physical function. One major risk factor for the development of sarcopenia is protein-energy malnutrition. A number of factors can lead to reduced protein intake in older age. Patients with sarcopenia are often frail (vulnerable to minor stressors) and the two concepts (frailty and sarcopenia) share an increased risk of adverse outcomes. Three large observational studies have supported an association between protein intake and muscle strength and mass, but multiple trials carried out in healthy, replete, older adults, without an exercise intervention, have been negative.

In those with suboptimal protein intake, the most promising results are for specific essential amino acids, particularly leucine, but also its metabolite β-hydroxy β-methylbutyric acid (HMB). Supplementation with these more targeted regulators of muscle protein synthesis (MPS) may be most effective for overcoming anabolic resistance in this cohort, especially if combined with exercise, a potent stimulator of anabolic response in muscle at all ages. Anabolic resistance refers to the phenomenon whereby older adults require a higher dose of protein to achieve the same response in MPS as a younger adult. The aetiologies and mechanisms for this are not understood, but we propose that the gut microbiome may be implicated in one or many of those suggested in the literature.

With age and frailty in particular, the resilience of the gut microbiome is reduced, as it becomes more vulnerable to medications, disease, and changes in lifestyle, with changed species richness and increased inter-individual variability. Ageing is associated with chronic inflammation, often referred to as 'inflammaging'. Here we suggest that this 'inflammaging', in combination with altered gut microbiome composition and/or diversity, leads to changes in protein metabolism, absorption and availability; ultimately contributing to anabolic resistance and therefore to reduced MPS and the development of sarcopenia.

Link: http://dx.doi.org/10.3390/nu10070929

Efforts to clear amyloid-β from the brains of Alzheimer's patients might have turned the corner these past few years, with immunotherapies beginning to show results that are something other than abject failure. The lengthy period of years in which trial after trial of potential anti-amyloid therapies failed inspired a great deal of theorizing on alternative models for Alzheimer's disease. I think it likely that the condition has several causes, each of which produces a sizable fraction of the overall symptoms. Combine that with the theories that suggest amyloid-β aggregation is an early mechanism that enables tau aggregration to do the real damage later on, and it looks plausible that clearing amyloid is both useful and necessary, but not enough on its own to reliably help patients.

This is why I favor development of the new and as yet unrealized approach of restoring drainage of cerebrospinal fluid, which holds the potential of reducing the buildup of all forms of molecular waste in the brain - amyloid-β, tau, α-synuclein, and so forth. Still, the signs of progress reported here join the 2016 aducanumab results and others as an indication that at some point immunotherapy to remove amyloid-β will become a solved problem, and that it appears possible to produce benefits for patients this way. We can hope that approaches that target more than one form of molecular waste, such as those based on restoring youthful levels of drainage of cerebrospinal fluid, will prove to be even more effective once piloted in humans.

The last full day of the Alzheimer's Association International Conference saw scientists pack a room the size of an aircraft hangar in anticipation of a late addition to the scientific program. They came to see the data behind a tantalizing press release issued earlier this month, which had claimed that BAN2401, the anti-Aβ protofibril immunotherapy, reduced amyloid in early Alzheimer's disease and also slowed cognitive decline. The upshot? According to the results presented, the antibody appears to have done what it was designed to do.

Over 18 months, fibrillar amyloid fell in all treatment groups compared with placebo; indeed, plaques melted by a whopping 93 percent in participants on the highest dose. This dose was reported to have reduced cognitive decline by 47 percent as measured by the ADAS-Cog, and by 30 percent on the ADCOMS, a new composite measure to detect early cognitive decline. At 856 participants with mild cognitive impairment due to AD or mild AD, this trial is the largest one yet to post both amyloid reduction and a downstream benefit on symptoms.

Statisticians and clinicians who gathered in the hallways after the presentation were cautiously upbeat. "Overall the results are positive and the amyloid effect is impressive. I believe this antibody works. In summary, there is dramatic amyloid lowering, with some apparent slowing in decline at the highest dose. The field is clearly moving forward with the ability of a fourth drug to remove amyloid to a normal level, as measured by PET. Now with aducanumab, gantenerumab, and n3pg, BAN2401 has demonstrated reversal of amyloid plaques to normal levels, representing a milestone in the history of Alzheimer's disease."

Link: https://www.alzforum.org/news/conference-coverage/ban2401-removes-brain-amyloid-possibly-slows-cognitive-decline