Fight Aging! Newsletter, February 11th 2019

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

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  • Thoughts on the Longevity Therapeutics Conference, January 2019
  • Acute Myeloid Leukemia Produces Senescent Cells to Promote its Own Growth, and is Thus Vulnerable to Senolytics
  • Autophagy is Everywhere in Aging
  • Notes on the Longevity Leaders Event, January 2019
  • Curcumin Analogs and Expectations About Natural Senolytics
  • PU.1 Inhibition as a Potential Therapy to Suppress Fibrosis
  • Arguing for Exercise to be a Useful Treatment for Sarcopenia Because it Affects Mitochondria, Unlike Most Other Attempted Interventions
  • Delivery of Senolytics Can Help Following Acute Kidney Injury, but Tissue Damage and Loss of Function Remains
  • Arguing that Public Desire for Greater Longevity is Growing
  • Age-Related Diseases are Just the Names we Give to Portions of Aging
  • Calorie Restriction Reduces Neuroinflammation
  • Considering the MouseAge Project
  • $100 Million Longevity Vision Fund Launches
  • An Interview with Sebastian Aguiar of Apollo Ventures
  • Reporting on the Longevity Leaders Conference

Thoughts on the Longevity Therapeutics Conference, January 2019

I attended the small Longevity Therapeutics conference in San Francisco last week, there to talk a little about the work taking place at Repair Biotechnologies. This was another first conference of a forthcoming series, but, unlike most of the prior conferences in our community, this was organized by Hanson-Wade, a company that specializes in hosting conferences. The company finds areas of growing interest in business and science, sets up conferences, and tries to make a business out of that process. It is a sign of growth that companies of this nature are arriving in our community to launch conferences relating to the development of treatments to enhance longevity and slow or reverse aging. Greater funding is flowing, more people are participating, and more outsiders are paying attention.

The other attendees were largely a mix of researchers, entrepreneurs, businesspeople from larger companies, and individuals in the process of transition from one of those categories to another. As one researcher-soon-to-be-entrepreneur I spoke to noted, the tone of the conference was one of optimism, of the desire to make progress towards concrete benefits for patients - and this is quite different to what one might find at scientific community events. I think that this is a good thing. The drive and the vision is necessary for progress to occur. Despite the tremendous influx of capital and interest into the field of longevity science and development of therapies to treat aging, it remains a backwater of development, underfunded by several orders of magnitude in comparison to its importance and potential.

As one might expect, there was a sizable senolytics contingent at the conference to discuss their various approaches and the state of the field. This is an exciting topic, and we're going to see a big jump in both the number of companies and potential senolytic therapies and mechanisms over the next year. It is already the case that when I turn up at one of these events, there is a company or two I hadn't heard of, involved in some form of senolytics development I was unaware of. This growth will be coupled with results from the first human trials over the next year, hopefully repeating the robust, positive results on a range of age-related diseases achieved in mice in recent years. For better or worse, senolytics will be the flagship of the rejuvenation biotechnology community for the next decade: as senolytics succeed, there will be more interest for the development of other rejuvenation therapies; as any specific company or development program stumbles, it will harm the industry as a whole.

Beyond senolytics, the topics varied widely, from fundamental science related to known drugs (such as metformin or mTOR inhibitors) that slow aging to some degree, to more recently discovered mechanisms yet to produce therapies, such as splicing factor changes in older individuals, to efforts on biomarker development that are aimed at making biomarkers of aging practical to use in evaluation of therapies. The machine learning contingent had their representatives as well. As I've mentioned in the past, a sizable fraction of present investment in the field of therapeutics for aging relates to the use of machine learning methodologies to improve the efficiency of small molecule drug discovery programs. The larger investors seem most interested in setting up an initial presence in the field that is based on producing large numbers of small molecule drug candidates: new senolytics, new mTOR inhibitors, and the like.

Mixed in with these topics were presentations from a number of noteworthy individuals from the field presenting; people from Unity Biotechnology and Life Biosciences, for example, and well known scientists such as Judith Campisi and Aubrey de Grey. A wide range of views on aging and the prospects for development were represented, from people who see metformin as ambitious new technology, and adding a few years to be the greatest that can be achieved in the near future, to people who wish to see true rejuvenation biotechnology after the SENS model realized, and would aim at decades and more added to the human life span.

A topic that came up in several discussions is the challenge (the present failure) of moving basic science to the clinic. All of the players in this process do things poorly: the scientists are bad at packaging up research for commercialization; the funding entities and universities fail to identify, cultivate, and fund truly valuable, novel work; the venture industry and entrepreneurs fail to reach into the research community in any systemic way to identify new technologies that can be development. The Life Biosciences representative argued that their way of doing things is a model that can help to address this problem, and it may well be a good attempt, even given my disagreement with the value of some of the programs they have chosen to support. I am given to think the onus largely falls on the venture and corporate world to do this work, as they have the resources and the will.

On the whole, I think this event worked well. The conference organizers profit, and people came to find their own benefits via networking and discussion of the state of the field. I met some new faces, and had a chance to pitch the primacy of damage repair as an approach to aging. We will see more of this in the years ahead, as the community continues to grow rapidly, driven by clinical success in the first attempts at generating rejuvenation in human patients.

Acute Myeloid Leukemia Produces Senescent Cells to Promote its Own Growth, and is Thus Vulnerable to Senolytics

Accumulation of lingering senescent cells is one of the causes of aging; these cells secrete a potent mix of molecules that produce inflammation, disrupt tissue structure and function, and alter the behavior of other cells for the worse. This signaling is useful during wound healing, where senescent cells are created and then destroyed once they have served their purpose, but like most such processes it becomes quite harmful when sustained over the long term. Researchers are presently hotly engaged in developing senolytic therapeutics to destroy senescent cells, and thereby achieve a narrow form of rejuvenation.

Prior to the present focus on senescent cells in aging, most work on cellular senescence was carried out in the context of cancer research. Senescent cells have quite the interesting relationship with cancer. While the state of senescence is an anti-cancer mechanism, shutting down replication in cells that are damaged and may become cancerous, the presence of too many senescent cells makes the tissue environment more hospitable to cancer, more amenable to cancer growth and survival. Along with the age-related decline of the immune system, this is one of the reasons why cancer is an age-related condition.

The work here demonstrates an addition complexity to the relationship between cancer and senescence. Since senescence is contagious to some degree, meaning that a senescent cell can drive nearby cells into senescence as well, why not a cancer that co-opts that mechanism in order to make the local environment more conducive to its growth? That is what researchers observe here in the case of acute myeloid leukemia (AML). This suggests that, for at least some cancers, senolytic treatments capable of destroying senescent cells might be a useful a way to weaken the cancer, make it more vulnerable to other therapies. Existing standard treatments such as chemotherapy and radiotherapy will create numerous further senescent cells, either forcing cancer cells into senescence, or damaging bystander cells that become senescent as a consequence. Senolytics will be useful after the fact as well, cleaning tissues of therapy-induced senescence to prevent the long-term harm to the patient that results from cancer treatments.

Cancer causes premature ageing

New findings show that healthy bone marrow cells were prematurely aged by cancer cells around them. It is well known that ageing promotes cancer development. But this is the first time that the reverse has been shown to be true. Importantly, the aged bone marrow cells accelerated the growth and development of the leukaemia - creating a vicious cycle that fuels the disease. The study also identified the mechanism by which this process of premature ageing occurs in the bone marrow of leukaemia patients and highlights the potential impact this could have on future treatments.

NOX2, an enzyme usually involved in the body's response to infection, was shown to be present in acute myeloid leukemia (AML) cells - and this was found to be responsible for creating the ageing conditions. The research team established that the NOX2 enzyme generates superoxide which drives the ageing process. By inhibiting NOX2, researchers showed the reduction in aged neighbouring non-malignant cells resulted in slower cancer growth.

Acute myeloid leukemia induces pro-tumoral p16INK4a driven senescence in the bone marrow microenvironment

Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of pro-inflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the bone marrow microenvironment. We report that the bone marrow stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feedback to promote AML blast survival and proliferation via the SASP.

Importantly, selective elimination of p16INK4a-positive senescent bone marrow stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model we show that by targeting NOX2 we reduced bone marrow stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia generated NOX2 derived superoxide as a driver of pro-tumoral p16INK4a-dependent senescence in bone marrow stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs which specifically target the 'benign' senescent cells that surround and support AML.

Autophagy is Everywhere in Aging

Researchers who work on autophagy might well feel justified in issuing the claim that the processes of autophagy are involved in near every aspect of aging. Autophagy is cellular housekeeping, the recycling of damaged or unwanted structures and molecules inside the cell. In chaperone-mediated autophagy, very selective chaperone proteins pick up other molecules and carry them to lysosomes. In macroautophagy, materials to be broken down are engulfed in an autophagosome, which then travels to the lysosome and fuses with it. In microautophagy, the lysosome engulfs materials directly. In all cases, the lysosome is the end of the journey, where a mix of enzymes will slice up the waste material into parts suitable for reuse. The result of smoothly running autophagy is a cell that is less cluttered with damaged parts and waste, and thus a cell that causes fewer issues to the tissue it is a part of.

This business of keeping molecular wear and tear inside cells to a minimal level appears a noteworthy determinant of aging. Many of the methods shown to slow aging in laboratory species such as flies, nematodes, and mice involve increased autophagy. Cells react to stress by increasing autophagy, largely regardless of the type of stress. This is one of the reasons why short and mild exposure to stress improves health, the process known as hormesis. Radiation, lack of nutrients, heat, cold ... it all can lead to improved long-term health and lengthened life span. Autophagy is an important part of this outcome, and in some cases it is a necessary part: animals with disabled autophagy do not gain the benefits to health and longevity provided by calorie restriction, for example.

In the open access paper here, the authors walk through the Hallmarks of Aging, linking them to autophagy. While, yes, one can link autophagy to near everything in aging, and particularly given that autophagy declines with age, it is important to remember that there is a limited upside to increased autophagy as a therapeutic approach. The rough location of that limit is illustrated by calorie restriction; one can imagine a therapy that does twice as well as calorie restriction at upregulating autophagy, but that isn't going to add decades to the human life span. In fact stress responses in our species have only small effects on life span in comparison to those observed in mice. Calorie restriction may increase maximum life span by 40% in mice, but it certainly doesn't do that in our species. Five years of additional life expectancy would be about the upper limit of what we might expect - though the health benefits along the way are certainly well worth having.

Hallmarks of Aging: An Autophagic Perspective

Loss of Proteostasis

Proteostasis is one of the major functions of autophagy in normal tissues. Imbalance of proteostasis due to aging leads to protein aggregation, accumulation of misfolded proteins and in the end to cellular dysfunction, among others. Notably, carbonylation due to oxidative stress is one of the changes that leads to loss of proteostasis. To avoid cell death or dysfunction, numerous homeostatic mechanisms turn on, mainly autophagy and the Ubiquitin-Proteasome-System (UPS). Because autophagy is considered one of the most important intracellular homeostatic processes, an alteration or deterioration of this pathway could modify the normal cell functioning, including a variety of diseases and normal cell physiology declination.

Mitochondrial Dysfunction

Mitophagy is a basal process involved in the autophagic degradation of mitochondria. It is necessary in normal differentiation of certain cell types such as red blood cells, in embryogenesis, immune response, cell programming, and cell death. Mitophagy is required not only to remove damaged mitochondria, but also to promote the biosynthesis of new ones, supporting the mitochondrial quality control. Given that mitochondria are implicated in bioenergetics and ROS production, the mitophagy plays an important role in cell homeostasis. Additionally, a decrease in mitophagy is observed in aged animals and this contributes to aging phenotypes.

Deregulated Nutrient Sensing

Because autophagy is a catabolic mechanism, it can be assumed to be implicated in cellular and systemic metabolism. Metabolic stress responses could be compromised due to a decline in autophagic activity. As an important process regulating the general cellular status, autophagy can also link metabolic pathways to maintain homeostasis under a variety of conditions. In this sense, it has been demonstrated that, after nutrient or growth factor deprivation, ULK1 and ULK2 are activated, and these kinases phosphorylate and activate several glycolytic enzymes as well as autophagic proteins. This makes it possible to obtain metabolites thanks to glucose uptake, gluconeogenic pathway blockage, and autophagic degradation of cytosolic components. Supporting this, mTOR hyperactivation was found in several diseases such as obesity, metabolic syndrome, and type 2 diabetes, which highlights the importance of a tight regulation of autophagy as well as the nutrient sensing pathway.

Genomic Instability

In the last decade, several studies have demonstrated that autophagy or autophagic-related molecules act as a "safeguard" of genome stability both directly (DNA repair modulation) and indirectly (by acting as a homeostatic response). Several mouse models have provided substantial information regarding genomic instability and its connection with healthy and pathological aging.

Epigenetic Alterations

Taken together, organismal models as well as in vitro studies highlight the importance of epigenetics throughout life. The relationship between epigenetic changes and autophagy needs to be deeply studied in order to understand the regulatory loop that seems to be involved in development and aging.

Telomere Attrition

Telomerase activity can support cell cycle progression by preventing the arrest due to short telomeres, leading to a putative malignancy. Remarkably, overexpression of Beclin1 in HeLa cells revealed that telomerase activity is reduced after autophagy induction. This approach argues in favor of the hypothesis that autophagy plays an important tumor suppressor role by the modulation of telomerase activity in somatic cells. This autophagic response arises in order to avoid genome instability and telomeric dysfunction, thus promoting cell survival.

Cellular Senescence

Autophagy regulates the senescence of vascular smooth muscle cells. Intriguingly, autophagy can mediate the transition to a senescent phenotype in oncogene-induced senescence fibroblasts, making possible the protein remodeling needed to establish the senescent phenotype under oncogene activation. It is proposed that type of autophagy, the exact moment when it acts, and the place where it occurs can define the pro or anti-senescence role of autophagy.

Stem Cell Exhaustion

Self-renewal is important to maintain the population of tissue-specific stem cells throughout life. Importantly, as we age, stem-cell activity decreases. It has been shown that autophagy is necessary for preservation and quiescence of hematopoietic stem cells (HSCs). Autophagy is also important to maintain stemness in bone marrow-derived mesenchymal stem cells. In addition, Atg7 loss in aged muscle stem cells (satellite cells) of transgenic mice caused altered mitophagy and an accumulation of ROS, all features of senescence that diminish the regenerative potential of aged satellite cells.

Notes on the Longevity Leaders Event, January 2019

LSX, a life science and biotechnology business networking organization, runs a yearly conference that took place in London this week. As a part of the festivities this year, the organizers added the Longevity Leaders event. This is one of a number of new conference series recently launched, in response to the great influx of funding and interest in the development of means to treat aging. Not all of that is rejuvenation biotechnology after the SENS model of damage repair, but a growing percentage is, even if that is near all a growing fleet of senolytics startups. A few years from now, we'll all have lost count of myriad methods of achieving rejuvenation via removal of senescent cells, scores of small molecule drug candidates and numerous startup companies. Even this first thin slice of the full rejuvenation biotechnology industry ahead of us will be massive and energetic.

The community of supporters and folk interested in the intersection of biotechnology and aging are getting quite organized; since this conference was on a Monday and thus going to see a lot of people flying in a day or two beforehand, the Aikora Health principals organized a large meet and greet for investors, entrepreneurs, and others on Sunday night. It went very well, and was a most useful addition to the normal conference schedule. I don't get over to the other side of the pond all that often, and met many new and interesting people. I came away with a great sense of anticipation on the part of the business community: they expect big things from the treatment of aging. We could all learn from this pre-conference meeting exercise, and try to make it a more commonplace occurrence in the community.

Each of the conference series related to biotechnology and aging has its own focus. Undoing Aging is the SENS rejuvenation biotechnology conference; the Ending Age-Related Diseases series has a focus on investor and entrepreneur networking in the context of scientific and technical goals; the Longevity Forum engages the broader public and has explicitly non-profit goals in advancing treatments for age-related disease; and so forth. The Longevity Leaders event was distinguished by a focus on bringing in medical insurance, life insurance, and pension industry people, particularly those who recognize that they have major, systemic, costly problems that could be solved by either (a) grasping the true scope of gains in healthy and overall life span that are possible and plausible in the near future, or (b) the introduction of partially effective treatments to control or reverse mechanisms of aging that produce gains in healthy life span.

The pensions and insurance industries could be strong allies, given the right frame of mind. They have deep pockets, and parts of the industry are capable of spending comparatively large amounts on treatments for older individuals, provided that those treatments saved them from greater losses further down the line. Given that aging produces immense costs, there must be a way to restructure these industries to both fund and benefit from any approach to rejuvenation in the old. Sadly the conference broke out into three groups for much of the day, and since I was presenting in the startup-focused group, I couldn't listen in on the insurance-focused presentations.

A number of biotechnology startup and other companies presented at the event. Insurance giant Prudential was one of the larger ones; they are clearly very engaged with this business of aging. The widely distributed Prudential advertising materials that encouraged people to think about radical life extension, living to 150, are clearly not a flash in the pan. This is an organization in which many groups understand the scope of the change that is coming, and at least some are on their way to being appropriately concerned and active. Among the startups there were Oisin Biotechnologies, Ichor Therapeutics, Repair Biotechnologies (the company Bill Cherman and I founded last year), Cleara Biotech, Senolytx, and many others. When I was up on stage to talk about Repair Biotechnologies, I was actually following right on the heels of three senolytics companies presenting in sequence: perhaps feeling a little subtle peer pressure there, given that I was discussing rejuvenation biotechnologies that had absolutely nothing to do with senescent cells.

I also participated in a very interesting round table discussion on the challenges to commercial development of therapies to treat aging at the present time - and of course what we might do to address those challenges. It was led by Sree Kant of Life Biosciences, and once again the senolytics contingent was the largest distinct group at the table. (This is something of a taste of what is to come; it seems that every group capable of the work is moving towards launching a small molecule senolytic treatment. A few years from now there will be many more startup companies in this space). Now, it is my contention that we have two major issues in development of rejuvenation therapies: (a) all of the entities involved - universities, researchers, entrepreneurs, investors - generally do a poor job of identifying and nurturing highly promising technologies that are currently in the late stages of research, but ready for the leap to a startup company, and (b) there are too few entrepreneurs capable of taking on this work, possibly an order of magnitude too few.

What leads me to this conclusion is that, as a result of my years of watching the field, I know of at least a score of languishing technologies that should be moving ahead. They are easy to find if you have a grasp of the areas of development relevant to aging. Repair Biotechnologies is working on two of them, and we obtained the rights (where that is even needed) very easily. One of them could have been developed in the 1990s, and has failed to make the leap from the labs at least twice that we know of. This sort of situation is enormously frustrating, and worse, deadly. Countless people have suffered and died of age-related diseases younger than might have been the case over the last century, and at root this is because institutions and communities are just not good at the technology transition from laboratory research to corporate development.

Considered as a model of organization, Life Biosciences is an approach to trying to make things better, though as ever I would say that many of the technologies they focus on have limited upside in the matter of human longevity. They are a structure that creates companies around research projects where the researchers have no entrepreneurial leanings, and then provides all of the support and advice to help those companies succeed. Juvenescence represents a different model, in which the companies are more independent, but the principals are still very energetically trying to solve the challenge of identifying the technical opportunities. Another approach is to build an industry-wide culture of companies that run multiple distinct projects, encapsulating each in a subsidiary company structure to obtain funding and become independently run when it achieves success, but at the head is a single team of entrepreneurs. Ichor Therapeutics, for example, now has several spin-off companies, but all of their work is managed by the founders of the original parent company. Many other groups could do this.

Overall, we seem to be in a period of acceleration, of a great influx of venture funding, almost with the tenor of optimism of the early internet years. This year is far more active than last. The people who were convinced early on that the treatment of aging will be a vast industry are well into their land-grab activities, using large funds to engage all the more obvious and high-profile research groups and funding the most evident startups. Their activities act as a signal to other capital ventures, which gravitate towards this space. That in turn will help raise the profile of the treatment of aging with other large industries, such as insurance and pensions. This is all very rewarding and sudden for those of us who went through the past twenty years of slow, incremental advocacy, one day at a time. We chipped away at the flood gates, and now they are breaking, and the speed is surprising when seen at first hand, even given that we knew intellectually that this outcome was exactly the goal.

Curcumin Analogs and Expectations About Natural Senolytics

Senolytic compounds selectively destroy senescent cells to some degree, and thus achieve a narrow form of rejuvenation, as accumulation of senescent cells is one of the root causes of aging. Senolytics produce a reliable reversal of age-related disease and extension of life in mice. As in all such things, quality varies widely: there will be a very large number of marginal senolytics that we should all ignore by the time the first enthusiastic wave of research, exploration, and clinical development is done. Of the senolytic compounds that do have sizable enough effects to care about, and for which there is published data, their effect sizes are at present all in the same ballpark - up to 50% clearance of lingering senescent cells, varying widely tissue by tissue. Another interesting point to consider is that data on senolytic effects in cell cultures is a poor guide as to how well these compounds do in mice. Further, we don't yet know how much variation in effectiveness to expect going from mice to humans.

Fisetin is a supplement that is widely used. Given the recent discovery that fisetin is significantly senolytic in mice - about as good as the dasatinib and quercetin combination - at doses that are ten to twenty times higher than the usual supplement dose used by a great many humans, how should we adjust our expectations regarding the wide range of natural compounds that have been shown in the past to very modestly slow aging or reduce risk of age-related disease in mice? How many of those are in fact senolytic? How many will become meaningfully senolytic if used at much higher doses than is common? These are questions without answers at the present time; the odds are unknown. In the case of curcumin and its analogs, however, I'm much more dubious than I am regarding whether or not fisetin will turn out to be usefully senolytic in humans. Curcumin has a much longer history of widespread use, and it seems unlikely that humanity would have failed to discover that high doses were a reliable treatment for age-related disease, were it as senolytic in humans as fisetin is in mice.

Nonetheless, researchers are now investigating a range of natural compounds and their derivatives that have been claimed to affect aging in mice, even to only very small degrees, and curcumin and its analogs are in that list. This is one of many programs of dubious utility that obtain far too much funding and interest in comparison to the benefits they might plausibly delivery. My suspicion is that this will turn out to be an exercise of largely academic interest, better categorizing a range of marginal ways to influence aging, but until such time as fisetin is rigorously tested in humans, there is always that to point to as a counterargument. Further, since it is much cheaper to develop natural compounds, there will always be those who choose to fish in the shallows just because it is easier to fish in the shallows, regardless of the fact that the rewarding catches are only found further out. This is exactly why we have more research into curcumin than into many of the branches of SENS rejuvenation research. It is a waste in the grand scheme of things, a distraction, but it will nonetheless occupy a great deal of time and resources.

The curcumin analog EF24 is a novel senolytic agent

The mechanisms by which senescent cells (SCs) accumulate with aging have not been fully understood but may be attributable in part to immune senescence that decreases the ability of the body to clear SCs. Although cellular senescence is a tumor-suppressive mechanism, SCs can play a causative role in aging and age-related diseases when they accumulate. This suggestion is supported by the finding that genetic elimination of SCs in naturally aged mice through a transgene can delay various age-dependent deterioration in tissues and organs and extend their lifespan.

This seminal finding stimulates research to identify small molecules termed senolytic agents that can selectively kill SCs as potential therapeutics for age-related diseases. To date, several classes of senolytic agents have been identified, and most of them are natural compounds such as quercetin, fisetin, and piperlongumine. Because natural senolytic compounds have the advantages of low toxicity, they may have a better chance to be translated into clinic to treat age-related diseases or can be used as a lead for the development of more specific and potent senolytic agents.

Curcumin, a natural compound extracted from turmeric, has a broad range of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anti-cancer activities. Numerous studies suggest that curcumin has some health benefits in delaying aging and may be useful in preventing and treating age-related diseases. For example, curcumin was shown to prolong lifespan and extend healthspan in Drosophila melanogaster and Caenorhabditis elegans. To improve the bioavailability and biological activity of curcumin, many curcumin analogs were developed, including EF24, HO-3867, 2-HBA, and dimethoxycurcumin, which have been demonstrated to be more active than curcumin in preventing and treating various diseases and reducing age-dependent deterioration. However, the mechanisms of their anti-aging action have not been fully elucidated.

We hypothesized that curcumin and its analogs may increase healthspan in part by functioning as novel senolytic agents. Therefore, in this study, we examined the senolytic activity of several curcumin analogs and found that EF24 is a novel potent and broad-spectrum senolytic agent in cell culture. We show that EF24 can selectively reduce the viability of human SCs from different tissue origins and induced by different stresses. Its senolytic effect is likely attributable to the induction of apoptosis via proteasome-mediated downregulation of the Bcl-2 anti-apoptotic family proteins such as Bcl-xl. These findings provide new insights into the mechanisms by which curcumin and its analogs function as anti-aging agents and suggest that the curcumin analog EF24 has the potential to be used as a novel senolytic agent for the treatment of age-related diseases.

PU.1 Inhibition as a Potential Therapy to Suppress Fibrosis

Researchers here suggest that PU.1 is a master regulator of fibrosis, and thus inhibition could be an effective treatment for the various fibrotic diseases that presently lack good options for patients. Fibrosis is a dsyregulation of the normal processes of tissue maintenance, in which scar-like deposits of collagen are formed, disrupting tissue structure and function. When this progresses far enough, it is ultimately fatal: consider the fibrotic diseases of heart, lungs, and kidney, for example. There is evidence for the presence of senescent cells to contribute to fibrotic diseases. Given this new information about PU.1 it, it will be interesting to see if the mechanisms by which scarring forms can be traced back to specific signaling on the part of senescent cells, and thus further reinforce senolytics as a therapy for fibrosis.

In connective tissue diseases such as systemic sclerosis, referred to collectively as 'fibrosis', excessive activation of connective tissue cells leads to hardening of the tissue and scarring within the affected organ. In principle, these diseases can affect any organ system and very often lead to disruption of organ function. Connective tissue cells play a key role in normal wound healing in healthy individuals. However, if the activation of connective tissue cells cannot be switched off, fibrotic diseases occur, in which an enormous amount of matrix is deposited in the tissue, leading to scarring and dysfunction of the affected tissue. Until now, scientists did not fully understand why repair processes malfunction in fibrotic diseases.

Researchers now been able to decipher a molecular mechanism responsible for the ongoing activation of connective tissue cells. In experimental studies, the researchers targeted the protein PU.1. In normal wound healing, the formation of PU.1 is inhibited by the body so that at the end of the normal healing process the connective tissue cells can return to a resting state. "We were able to show that PU.1 is activated in various connective tissue diseases in the skin, lungs, liver and kidneys. PU.1 binds to the DNA in the connective tissue cells and reprograms them, resulting in a prolonged deposition of tissue components."

PU.1 is not the only factor involved in fibrosis, as factors that are involved in the deposition of scar tissue have already been identified in the past. What has been discovered now, however, is that PU.1 plays a central role in a network of factors controlling this process. "PU.1 is like the conductor in an orchestra. If you take it out, the entire concert collapses." This approach has already been tested using an experimental drug, fuelling the hope that clinical trials on inhibiting PU.1 may soon be able to be launched, aimed at better treating fibrosis.

Arguing for Exercise to be a Useful Treatment for Sarcopenia Because it Affects Mitochondria, Unlike Most Other Attempted Interventions

In this open access paper, the authors argue that exercise (and particularly strength training) remains the best therapy for sarcopenia, the age-related loss of muscle mass and strength, because exercise improves mitochondrial function and other attempted treatments do not. This seems a reasonable position. There are many, many possible contributing causes of sarcopenia, all with accompanying evidence, but the most compelling in my opinion is stem cell dysfunction. Even so, one still needs to offer an explanation as to why exactly stem cell activity in muscle tissue declines with age, a way to link it to the root cause molecular damage of aging listed in the SENS research proposals. Perhaps faltering mitochondrial function is a noteworthy underlying cause.

Resistance exercise continues to be the most effective intervention against sarcopenia. In addition, maintenance of physical activity can delay the progression of sarcopenia. Despite the strong support for maintaining an active lifestyle, adherence to physical activity guidelines remains low. The traditional therapeutic focus of sarcopenia treatment is to target growth-related pathways to increase muscle mass. Here, we discuss the positives of these strategies, but also build a case for targeting mitochondrial bioenergetics as a way to maintain muscle mass and function with age.

The vast majority of adults fail to meet physical activity guidelines. While 60% of adults, both European and American, self-report that they meet guidelines, objectively measured physical activity reveals that fewer than 10% of adults in the United States meet physical activity guidelines. Moreover, sedentary behavior alone increases the risk for sarcopenia. While there are few trials in humans on the effects of lifelong sedentary behavior, studies in mice reveal lifelong sedentary behavior impairs mitochondrial function.

It was thought that resistance exercise training had little or no effect on mitochondrial biogenesis or function. However, recent studies have shown that resistance exercise training increases mitochondrial protein fractional synthesis rates (FSRs) and improves mitochondrial function. Young adults engaged in a resistance exercise program showed increases in mitochondrial enzyme activity and respiration. While the changes in mitochondrial respiration are modest in comparison to endurance exercise, improvements in in vivo phosphocreatine recovery rates and oxidative capacity appear comparable in older adults engaged in either exercise intervention.

Aerobic exercise is generally not appreciated as a stimulator of hypertrophy; however, there is evidence that it can lead to muscle hypertrophy. Nearly half a century ago, it was first documented that aerobic exercise increases mitochondrial content. Since then, research has consistently documented that aerobic exercise improves both mitochondrial content and function. Aerobic exercise increases mitochondrial turnover since it increases both mitochondrial biogenesis (protein synthesis) and mitophagy (mitochondrial-specific autophagy). The improvement in the rate of ATP production from aerobic exercise training suggests that more energy is available to maintain proteostasis. Additionally, improvement in mitochondrial efficiency (reduction in ROS generated per oxygen consumed or ATP generated) suggests that there is less oxidative stress and damage, which would in turn improve the quality of the proteome. In all, aerobic exercise mediated improvements in mitochondrial function likely protects against sarcopenia.

Delivery of Senolytics Can Help Following Acute Kidney Injury, but Tissue Damage and Loss of Function Remains

Researchers here investigate the mechanisms by which senescent cells are created during acute kidney injury (AKI). Senescent cells are usually created as a part of the injury and regeneration process, and then destroyed quickly afterwards, but there is more to it in this case. The senescent cells linger and their signaling causes fibrosis, a form of scarring that further harms the injured kidney. The researchers find that some (but not all) senolytic drugs can clear out these senescent cells, reducing fibrosis. However, introducing this treatment after AKI failed to lead to regeneration of damage to the tubule structures of the kidney. That only some senolytics work for this particular type of senescent cell and tissue is perhaps the most interesting finding here: it reinforces the developing thesis that there are significant differences between senescent cells in different tissues and circumstances, and thus variety is desirable in the development programs for small molecule senolytic drugs.

Tubule repair is a common event after kidney injury, but is frequently associated with interstitial inflammation and maladaptive processes that lead to fibrosis, the hallmark of all forms of kidney disease and a reliable predictor of progression to chronic kidney disease(CKD). Recently, multiple studies identified multipotent mesenchymal stromal progenitor cells (pericytes) as the cell population that is responsible for collagen deposition after injury. Kidney fibrosis has also been correlated with arrest of tubular epithelial cells (TECs), which suggests that the epithelium plays a primary role in the progression of kidney disease. However, the factors that contribute to the cell cycle arrest are not known. Cell cycle arrest is a universal marker of cellular senescence and is evoked by a variety of stressors.

Several studies have reported a correlation between the presence of senescent cells and kidney fibrosis both during the aging process and in the context of disease, but a systematic study of cellular senescence after AKI and its potential contribution to the progression of tubular damage and fibrosis is lacking. Here, we show that in mice TECs commonly become senescent after various types of kidney injury, and that this occurs surprisingly early after injury. We show that senescent TECs express higher levels of proinflammatory factors of the SASP as a result of cell-autonomous control by the TLR/IL-1R-mediated innate immune signaling pathway, and that senescent TECs are a source of the mesenchymal progenitor-activating ligands.

Tubule-specific inhibition of TLR/IL-1R signaling by conditional inactivation of the Myd88 gene prior to senescence not only reduced the levels of epithelial cell-derived proinflammatory cytokines, interstitial infiltration, and fibrosis, but also decreased the accumulation of senescent cells and ameliorated tubular damage. Whereas inactivation soon after injury was equally effective in decreasing the number of senescent TECs, inflammation, and fibrosis, it did not protect from tubular damage. Similarly, eliminating p16+ senescent cells, but not senescent cells by FOXO4-DRI inhibitory peptide, which induces apoptosis of senescent cells by disrupting the interaction between FOXO4 and p53, reduced kidney fibrosis without reducing tubular damage.

Our results indicate that TEC senescence is a common and early event after kidney injury, and that signaling by the TLR/IL-1R pathway within the epithelium controls this phenomenon. Our findings also suggest that early intervention after injury is likely required to reduce organ damage after AKI. Furthermore, this study reveals what we believe is a novel function of the epithelial TLR/IL-R1 signaling in controlling the onset of TEC senescence in a cell-autonomous manner, consistent with the concept that the tubular epithelium triggers kidney disease following injury and also drives its progression.

Arguing that Public Desire for Greater Longevity is Growing

Our community has undertaken years of advocacy for rejuvenation research, with the aim of developing ways to reverse age-related disease and disability, and thus greatly extend healthy life spans. The first concrete results are emerging from the research community, the result of philanthropy and persuasion, then the incremental accretion of funding to programs that showed promising initial data. So now we have senolytics, and I would hope not too many years from now we'll have glucosepane cross-link breakers - and then more thereafter.

But have we persuaded the broader public at all? Have we convinced more than a small number of people of the plausibility of the goal of human rejuvenation? Of the merits of ending aging, of eliminating the enormous scope of suffering and death that is all around us? At the large scale, and over decades, progress requires public support. Aging research as a whole needs the same widespread, overwhelming support enjoyed by HIV or cancer research programs; the history of both of those vast patient advocacy initiatives is well worth studying. We are not there yet. But are we further along than was the case at the turn of the century? You might compare the results of the survey noted here with another survey conducted last year; while it certainly looks like progress, I think it is far from clear as to where exactly things stand.

People generally do not believe in the plausibility of targeting the mechanisms of aging in order to slow down and reverse age-related damage. After so many millennia of fruitless dreams, with so many powerful psychological defenses that protect our state of mind when we face the idea of inevitable death by aging, becoming hopeful is usually too much to ask. This can explain why most people, when asked about their desired lifespan, add only a few years to the life expectancy of their given countries.

However, in the last few years, things have apparently started to change. In 2015, in a study by Donner et al, it was found that given perfect mental and physical health, 797 out of 1000 participants wanted to live to 120 or longer; over half of these 797 people desired unlimited lifespans (around 40% of all participants). A new study by YouGov shows even more impressive results. We at generally stay away from strong statements such as "living forever" or "immortality", because these expressions are hardly scientific and have a religious background. The notion of immortality even seems to scare some people because it seems to limit their freedom and because immortals are pictured by pop culture as criminals, crazy, or morally inferior. Therefore, people often reject the idea of extended life without perfect health.

However, in a new study by YouGov that included around 1200 participants, one in five (19%) people agreed with the statement "I want to live forever" without any promises related to perfect health. 42% of the participants chose "I want to live longer than a normal lifespan, but not forever", while 23% said, "I don't want to live longer than a normal lifespan." People in different age groups reacted to this survey differently; it turns out that the idea of radical life extension was more supported by young people (24%) than by people over 55 (13%), while support for the status quo was the opposite (19% of young people didn't want to live longer than a normal lifespan, while this position was shared by 29% of people aged 55 and older).

The YouGov survey participants were randomly selected, and few of them will be regularly exposed to news about aging and longevity research. However, over 60% explicitly expressed a desire for radical life extension. That is a big jump from the Pew Research study from 2013, where only 38% of the participants expressed the desire to undergo medical treatments to slow aging and live to be 120 or more. Of course, the questions in these surveys were formulated differently, so we cannot directly compare them. However, looking at various, similar studies, it appears that, in the last 5 years, 20% more Americans have become aware that something serious is going on in the rejuvenation biotechnology industry.

Age-Related Diseases are Just the Names we Give to Portions of Aging

Aging is a process of damage accumulation in cells and tissue structures, followed by reactions to that damage, some of which are compensatory and some of which make matters worse, and lastly the consequent failure of biological systems necessary to support health and life. Age-related diseases are names we give to some of the aspects of system failure, but they are not distinct from aging. One cannot draw a line between aging and age-related disease; it is a futile endeavor, and that the medical industry and regulatory bodies are set up to do so is one of the major challenges facing those who want to develop commercial rejuvenation therapies based on clearance of senescent cells or other recent scientific advances.

This point about aging and age-related disease is somewhat reinforced by the genetic analysis noted here, though I'm yet to be convinced of the utility of this sort of research beyond gaining a purely curiosity-driven scientific understanding of how aging progresses in detail. Since we all age for the same reasons, the same underlying damage, and since rejuvenation therapies will repair that damage in the same way in all patients, and since we have a good list of that damage, there are certainly days when it seems to me that anything other than just building the repair therapies and testing their effects is something of a sideline.

"According to Gompertz mortality law, the risk of death from all causes increases exponentially after the age of 40 and doubles approximately every 8 years. By analyzing the dynamics of disease incidence in the clinical data available from the UK Biobank, we observed that the risks of age-related diseases grow exponentially with age and double at a rate compatible with the Gompertz mortality law. This close relation between the most prevalent chronic diseases and mortality suggests that their risks could be driven by the same process, that is aging. This is why healthspan can be used as a natural proxy for investigation of the genetic factors controlling the rate of aging, the 'holy grail' target for anti-aging interventions."

To find genetic factors associated with human healthspan, the researchers studied the genomes of 300,477 British individuals. Overall, 12 genetic loci affecting healthy life expectancy were discovered. To confirm that these results hold true for other ethnicities, they used genetic data of UK Biobank participants with self-reported European, African, South Asian, Chinese and Caribbean ancestry. Of the 12 single nucleotide polymorphisms (SNPs), 11 increased risk both in discovery and in replication groups. Three of the genes affecting healthspan, HLA-DQB, LPA, and CDKN2B, were previously associated with parental longevity, a proxy for overall life expectancy.

At least three genetic loci were associated with risk of multiple diseases and healthspan at the same time and therefore could form the genetic signature of aging. HLA-DQB1 was significantly associated with COPD, diabetes, cancer, and dementia in this study and was demonstrated to be associated with parental survival earlier. The genetic variants near TYR predict death in the prospective UKB cohort and are involved in the earlier onset of macular degeneration. The chromosome 20 locus containing C20orf112 was not associated with the incidence of any of the diseases at the full-genome level, and yet was affecting the healthspan of studied individuals.

Calorie Restriction Reduces Neuroinflammation

Calorie restriction, also known as dietary restriction in the scientific community, is the practice of consuming up to 40% fewer calories than usual, while still obtaining optimal levels of micronutrients. It produces sweeping changes in the operation of cellular metabolism, slows near all measures of aging, and extends life in mice. Thus for any particular aspect of aging, and here the focus is on chronic inflammation in the brain that accelerates progression of age-related neurodegeneration, it is possible to invest a great deal of time and effort into investigating just how calorie restriction slows it down.

This sort of work is of great scientific interest, as it will help researchers to build a comprehensive map of cellular metabolism and the changes that take place over the course of aging. It is not, however, a road to rejuvenation. Calorie restriction, like all approaches involving upregulation of cellular stress responses, has a much smaller effect on life span in humans than in short-lived species such as mice. There isn't a way to conjure a reversal of aging in the elderly from this biochemistry. That requires a completely different strategy, based on identification of root cause damage, and repair of that damage, as outlined in the SENS roadmap for development of rejuvenation therapies.

A growing body of evidence demonstrates that dietary restriction (DR) exerts its beneficial effects on brain aging at multiple levels. Although there is some degree of discrepancy across studies, likely due to the difference in the model organisms and experimental design, DR appears to mitigate all of the morphological and functional alterations in the brain associated with aging. A major hallmark of aging is systemic, low-grade chronic inflammation throughout the body, termed inflammaging. Notably, these inflammatory signs are similar to the ones associated with obesity and metabolic diseases, providing a possible glimpse into why DR exerts anti-inflammatory effects on aging-associated inflammation.

As with other organs, chronic low-grade inflammation is a common feature of the aged brain. Neuroinflammation is a host defense mechanism against harmful stimuli and damage in the brain. However, chronic inflammation can be deleterious in normal aging as well as in pathological aging related to neurodegenerative diseases. The central nervous system (CNS) is composed of heterogeneous cell types, including neurons, microglia, astrocytes, and oligodendrocytes. Although two major glial cell types, astrocytes and microglia, are known to be key players in inflammatory responses in the brain, it is now well recognized that all neural cells participate to some degree in the neuroinflammatory responses.

Neuroinflammation often manifests as astrogliosis, microgliosis, and an increase in secreted inflammatory mediators, such as cytokines, chemokines, and complement proteins. Accumulating evidence from clinical and basic research suggests that neuroinflammation is tightly connected to the decline in brain function during aging. Although the precise mechanisms of DR's neuroprotective functions are not fully elucidated, it has been suggested that DR exerts neuroprotective effects through multiple pathways, such as modulating metabolic rates, reducing oxidative stress, increasing anti-inflammatory responses, regulating insulin sensitivity, and improving synaptic plasticity and neurogenesis. All of the molecular changes induced by DR may directly or indirectly contribute to the regulation of neuroinflammation associated with aging and neurodegenerative diseases. DR may directly mitigate activation of glial cells and modulate expression of inflammatory cytokines and indirectly regulate neuroinflammation by reducing inflammatory stresses, such as accumulation of toxic proteins and oxidative stress.

Considering the MouseAge Project

Here, an update on the MouseAGE project from the popular science press. This initiative aims to produce a viable biomarker of aging based on visual inspection of mouse faces. Since age-related mortality in humans correlates fairly well with apparent age of the face, and since machine learning techniques can be used to assess aging from photographs in an automated fashion, it seems reasonable to think that it might be possible to achieve a similar analysis in mice. If successful, it might by used to speed up the assessment of potential rejuvenation therapies, a faster alternative to running life span studies. Given the low cost of development, it is worth a try as an alternative approach to the epigenetic clock and other biomarkers of aging under development. The project was crowdfunded in 2017 and data collection began last year.

Vadim Gladyshev is asking lab scientists to whip out their smartphones and take photos. Not selfies, exactly, but snapshots of their lab mice. It's a fiddly task, Gladyshev admits: mice move fast, and need to be kept still for the camera. He suggests grabbing them with one hand or taking them by the tail while they use their front paws to hold a rod. The impromptu photo shoots are all part of a crowdsourced effort to develop an algorithm that can help predict the biological age of a mouse from its mug shot - information that could help researchers studying aging understand the connection between a person's biology and how old he or she looks.

Scientists now know, for example, that people who look younger than their years tend to live longer than people whose appearance more closely matches the time they've been alive. People are surprisingly good at predicting biological age when it comes to fellow Homo sapiens. But pinpointing the biological age of mice is far more challenging. Instead, assessing the effect of anti-aging drugs in lab mice often involves taking blood samples and running expensive tests. Biomarkers such as DNA methylation signatures and analyses of metabolites and biochemical measurements consume resources and run up costs. Alternatively, researchers may need to sacrifice mice in order to examine the internal effects of a compound.

The idea for a cheap and less wasteful alternative came to Gladyshev and Alex Zhavoronkov, founder of Insilico Medicine, a company specializing in artificial intelligence (AI) for aging research and drug discovery, a couple of years ago. The pair got to chatting and came up with the idea of using a mouse's appearance as a marker of biological age - just as developers have attempted to do for humans. Mouse photo shoots have already been staged in labs across the US and Europe, and around 500 lab mice are in the catalog. The team plans to release the algorithm publicly a few months from now and allow researchers to use it for free. But the project is still in the image-collection stage, as the more reference images it has, the better the algorithm will perform. The team aims to collect images of 1,000 mice by March, but Gladyshev is planning to continue collecting until the project has sourced at least 10,000. "Future programs would tell whether one group of mice is biologically younger than another, allowing us to more easily test interventions. Instead of waiting for mice to die, they can be quickly assessed for their potential to live longer."

$100 Million Longevity Vision Fund Launches

A new fund to invest in companies working on aging recently launched, the $100 millions Longevity Vision Fund. From what has been said, and what was presented at the Longevity Leaders conference, it sounds very much as though the Longevity Vision Fund principals wish to follow in the footsteps of Juvenescence, with an initial focus on small molecule drug discovery infrastructure. Unlike Juvenescence, it will probably continue to focus on established infrastructure technologies related to age-related disease, such as diagnostics, and fairly safe work with modest benefits, such as stem cell therapies, rather than invest in any of the current attempts to produce rejuvenation therapies. Whether the strategy changes later, to shift to be more in line with the rhetoric on the fund website, remains to be seen. Such a shift looks somewhat unlikely based on what is said in the article here, though the details given at the conference were more nuanced.

Inspired by British billionaire Jim Mellon, chairman of anti-aging upstart biotech venture Juvenescence, Sergey Young unveiled a $100 million fund on Monday to catalyze the development of a comprehensive solution to counteract the damaging consequences of aging. The 47-year-old considers himself a product of Peter Diamandis - the man behind the non-profit XPRIZE and venture capital fund BOLD Capital Partners - and is in charge of all things longevity at both organizations. Like Mellon, who penned Juvenescence: Investing in the Age of Longevity prior to the launch of the company Juvenescence, Young is in the embryonic stage of writing his own book designed to decode the science of aging for the masses. Meanwhile, his $100 million Longevity Vision Fund will back organizations who are working on technology to reverse the aging process and prolong healthy human life.

"We are currently working on 6 deals ... and are looking at all the usual suspects in terms of themes." These areas include early detection of serious diseases using ultrasound technology; early diagnostics for heart, cancer, and neurodegenerative diseases; stem-cell and microbiome-based therapeutics; and big data as well as AI-based applications. Unsurprisingly, Young is in dialogue with Alex Zhavoronkov's AI shop at Insilico Medicine. Zhavoronkov has deep connections in the R&D space - last year he raised funds at the behest of Shanghai high-flyer WuXi AppTec, Singapore's Temasek, Peter Diamandis, and Juvenescence.

For long-time investor and venture capitalist Young, who has insight into the aging research and development effort within the US and to a lesser extent in the UK, China and India's sizable populations pose compelling prospects for deals for his fund. "In the next decade, advancements will allow us to be a lot more predictive and preventative in the most damaging diseases. I'm thinking AI-enabled medicine will empower doctors .. technological advances to improve sleeping and meditation will emerge - and these are an essential part of a healthy, long life, along with a plant-based diet."

An Interview with Sebastian Aguiar of Apollo Ventures

Apollo Ventures is one of the first wave of investor concerns focused on the treatment of aging, and the principals and staff have put a fair amount of work into building a model for finding and commercializing promising research. They also publish the Geroscience popular science site, which is a helpful act of advocacy for the wider cause. As is the case for near all bigger venture funding organizations, they have a senolytics company (Cleara Biotech) in their portfolio, and thus the SENS model for rejuvenation is advanced.

What initially attracted you to aging as a general discipline?

Through multiple, orthogonal, potentially synergistic interventions, we are able to extend the healthy lifespan of model organisms. In mice, the ablation of senescent cells can extend median lifespan by 30%. The augmentation of autophagy and the transient re-activation of telomerase yield similar rejuvenating effects. These interventions should be combined, as they may be synergistic. It is only a matter of time before these interventions are working in the clinic. This kind of evidence was enough for me to commit my career to geroscience because, many years ago, I saw that the 'writing is on the wall' - thanks to advances in molecular biology, healthy life extension is no longer science fiction. This century, geroscience will be a paradigm shift comparable to the antibiotics revolution in the last century.

What is the main challenge you have faced as a longevity investor?

Most geroscientists are not working on translational research. They are basic scientists. Basic science is the bedrock of everything we do, but it's not enough. Pharma has dropped the ball in drug discovery and development, and there is a major gap in the pipeline between academic proof-of-concept and drug development. There is not enough collaboration between biologists, chemists, and drug hunters. The transition through the 'valley of death' of drug development is where company-building venture capital firms such as Apollo Ventures can step in. For example, there are many biologists with data showing that gene X or protein Y, when modulated, has salutary effects. They might even identify a 'hit' molecule, such as a natural product or library compound that modulates the target or mechanism of action, but they usually don't partner with chemists to perform medicinal chemistry optimization, pharm/tox, and validation in multiple animal models of disease.

The other challenge is that, as investors, we don't see many established, aging-focused biotechs that satisfy our investment criteria. The science may be solid, but the team is lacking, or vice versa. There are not many experienced C-level biotech managers out there, and few understand geroscience. This will change once the field has a few clinical successes. Then the floodgates will open.

What can we expect from you and Apollo Ventures in 2019?

We will unveil a few more geroscience companies that are currently in stealth mode. Apollo will continue to build our internal team as well. We are looking for people with talent in both geroscience and biotech business management. Apollo was founded by a partnership of successful entrepreneurs and aging scientists with expertise in the biopharma and management consulting businesses. The depth of scientific expertise and biopharma business acumen within Apollo is unique in the geroscience space. Another distinguishing feature is that Apollo is focused more heavily on company building than other investors who are oriented toward investing in pre-established companies.

Reporting on the Longevity Leaders Conference

Some of the Life Extension Advocacy Foundation folk were at the recent Longevity Leaders conference in London, and wrote up a report on the event. The conference split up into three streams later in the day, one of which is followed here. Being focused on the pensions and life insurance industries as much as biotechnology, there were a lot of people present with minimal exposure to the prospects for rejuvenation and slowing of aging. It was noteworthy to see so many there being newly interested in the topic of treating aging as a medical condition, and motivated to learn more because it is important to their work in other areas of endeavor.

The conference was quite broad in scope and included people from the aging research community, the pharmaceutical industry, general healthcare, and the business and insurance fields. Speaking of insurance companies, it was interesting that the large insurance companies Prudential and Legal & General were both sponsoring the event; Prudential had even produced an interesting booklet for guests with the title "Prepare for 100" boldly on the cover. The book went on to talk about the changes coming to medicine and how people could soon be living longer than ever before thanks to the new medical approaches that are currently being developed.

Dr. Aubrey de Grey was in fine form as usual during the keynote panel discussion at the start of the event, just as he was when, later that day, I had the opportunity to interview him about progress with SENS. While we will be publishing the interview I did with Aubrey later, it's a good time to share the interesting concept of damage crosstalk now. It turns out that Aubrey has become more optimistic about the medical control of age-related damage and has moved his prediction of longevity escape velocity down from 20 years to 18. Quite simply, there is increasing evidence that the different aging processes have a lot more influence and interaction with each other (crosstalk) than previously thought.

Lynne Cox, a biochemist from the University of Oxford, chaired a discussion panel with Brian Delaney, president of the Age Reversal Network and who serves on our Industry Advisory Board, and Tristan Edwards, the CEO of Life Biosciences. The discussion topics were "What's at the cutting edge of aging research and development?" and "How can we accelerate research and development and the advancement of new therapies to address aging and age-related disease?" The panel was in a round table format, and attendees were also able to directly join the discussion, which proved lively and interesting. Lynne Cox, in particular, provided some very informative details about aging research.

There was considerable discussion about senescent cell clearing therapies as well as touching upon the topic of biohacking. The general feeling was that biohacking had the potential to set the field back if people conduct it in an unscientific manner and harm themselves in the process. Indeed, this echoes our sentiment that people who self-test at home should be very careful and apply a science-based approach to what they are doing. The bottom line is that if you are not recording your biomarkers and doing things scientifically, you risk hurting yourself and are taking things on faith rather than evidence; this also has potential to harm the field and set research back, so please hack responsibly.

On a more positive note, the panel was in favor about science doing something about aging and age-related diseases, and discussion of senolytics, senomorphics (therapies that block senescent cell inflammation), and cellular reprogramming were all enthusiastically discussed, especially by the academics present. This is very welcome, and it was great to see so many academics being frank about the potential of medicine to bring aging under medical control in order to prevent age-related diseases, which is in stark contrast to a decade ago, when suggesting the idea could harm your career and get you mocked by your peers. Times have certainly changed, as more and more researchers are now focusing on how we can rise to the challenge that aging presents.


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