https://www.fightaging.org/newsletter/

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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Contents

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 https://www.fightaging.org/archives/2019/02/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
https://www.fightaging.org/archives/2019/02/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 https://www.fightaging.org/archives/2019/02/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 https://www.fightaging.org/archives/2019/02/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 https://www.fightaging.org/archives/2019/02/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.


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