There is a point in the life of a young biotech company at which one traditionally appoints an established figure from industry as the CEO. Running a company that is in the public eye due to clinical trials and heading in the direction of an IPO requires a whole different set of skills than were needed for early growth and technical success in development programs. It also tends to be a sign of the changing balance of influence between founders, investors, and industry partners as development programs progress. This happened earlier in the year for Navitor Pharmaceuticals, one of a number of companies working on mTOR inhibitor therapies capable of modestly slowing the aging process.

Talking up one's position is a part of the duties of an industry CEO: a good CEO is an advocate for the company, for the technology, for the industry. That is expected. I point out this commentary from the new Navitor CEO not for the expected content, but rather as an example of our present slow movement though an important tipping point in the great, many-threaded cultural conversation about aging and the prospects for treating aging as a medical condition. The message of the life science community, that aging can be slowed and reversed, is being taken up by industry and media. It is spreading broadly, and more rapidly than in past years.

In short, the goal of bringing aging under medical control is increasingly being taken seriously, finally, after more than twenty years of earnest advocacy and hard-fought, incremental progress in obtaining research funding. Now, the battle must turn to one of steering funding towards the better rather than the worse options for development. When people agree that the goal must be reached, it becomes very important to settle on the best possible strategy.

On that note, I don't think that therapies that function via inhibition of mTOR, based as they are on modulation of dysfunctional metabolism without doing much to address the causes of that dysfunction, have anywhere near as large an upside, considered in terms of additional healthy years of life, as is the case for the SENS approaches to aging. SENS rejuvenation therapies are intended to repair the underlying damage that causes aging, while mTOR inhibition and similar approaches largely adjust harmful reactions to that damage. They are beneficial to some degree, particularly now that it is possible to separate the desirable and undesirable components of the early mTOR inhibitors such as rapamycin. Still, while modest gains are better than nothing, we should be aiming for large gains.

Targeting Aging Comes Of Age

We finally are beginning to understand the biological basis of aging and age-related diseases, making the discovery of new therapies actionable for the first time. Aging and its underlying biological mechanisms are becoming recognized as a catalyst, if not the central catalyst, for a wide range of poorly treated prevalent diseases. This is a promising new area in science providing actionable insights with potential for tremendous impact on human healthspan.

I have been following the field of the biology of aging since the beginning of my career in science, more than thirty years, while working in targeted ways to find and advance new therapies in the areas of metabolic and cardiovascular disease. Recently, I became the CEO of a biotechnology company, Navitor Pharmaceuticals, that is squarely in this space and focused on leveraging new discoveries to target the activity of mTOR (mechanistic target of rapamycin). In many ways, the progress in the field has reached a tipping point and has prompted me to reflect on the advancements.

Chronic conditions of aging are the major cost drivers for healthcare. There are some shocking statistics to be found regarding the cost of chronic conditions affecting our healthcare system. The multiple chronic conditions chartbook published in 2010 by the Agency for Healthcare Research and Quality is a short and fascinating read. Almost half of all people aged 45-64, and 80% of those 65 and over, have multiple chronic conditions. 71 cents of every US healthcare dollar go to treating people with multiple chronic conditions. Just take a moment to think about that. First off, this is a huge portion of our healthcare budget. It's not cancer. It's not rare diseases. It's not cosmetic or elective procedures. It's chronic illnesses, primarily associated with aging.

Id you have one disorder that is commonly associated with aging, chances are you have another or will develop another one. Basically, it's tough to get old. We all know that. But, now science is leading us to harness some fundamental mechanisms of aging. Two core aging mechanisms appear to have emerged as being accessible to new pharmacological intervention - the mechanistic target of rapamycin, or mTOR, and cellular senescence (which is wrapped up in mTOR as well). Drug development approaches using cellular senescence are emerging, and they are fascinating and worthy of attention. It's an exciting time in the aging space, and hopefully one that yields important new medications capable of reducing the personal, societal, and financial burdens of chronic diseases.

Mitochondria are the power plants of the cell, responsible for generating adenosine triphosphate (ATP), a chemical energy store molecule used to power cellular operations. The inner workings of each mitochondrion are energetic and complicated, consisting of a number of interacting protein complexes that collectively perform the work needed to manufacture ATP molecules. Mitochondrial function occupies a central position in the interaction between metabolism and aging for a number of reasons. Firstly, they generate reactive oxygen species (ROS) as a side effect of ATP production, and the flux of ROS is both damaging and a signal to the cell to step up its efforts to repair damage. A little more ROS than usual can be beneficial. Too much ROS is harmful. Secondly, some of the critical proteins in mitochondrial complexes are produced from DNA inside the mitochondria rather than in the cell nucleus, and that DNA is vulnerable to damage. Some forms of mitochondrial DNA damage can produce damaged mitochondria that cause great harm to the cell and surrounding tissue. Thirdly, cells need ATP, and reductions in ATP production have detrimental consequences over time.

There are many ways in which mitochondrial function can be altered through the removal or reduced production of a specific subunit of one of the mitochondrial protein complexes. Some such changes are disastrous, some are beneficial. Why that is the case is a complicated topic. It has a great deal to do with the balance between production of ROS and production of ATP, the needs of cells, and the reactions of cells, particularly the activation of repair and maintenance mechanisms. That balance is different in each case, and it is a slow and expensive process to run through the protein biochemistry needed to gain insight into what exactly is going on under the hood. The paper here is an example of the sort of work that takes place in this part of the field.

Mitochondria play an essential role in many important physiological processes, including aging. Mitochondrial function has been thought to gradually decline with age, while oxidative damage and mitochondrial DNA mutations accumulate. Although complete disruption of mitochondrial function is detrimental or even lethal for many eukaryotes, including humans, accumulating evidence has revealed that partial inhibition of mitochondrial function tends to increase lifespan. In C. elegans, mutations in various mitochondrial electron transport chain (ETC) genes can greatly extend lifespan; these include mutations in isp-1 and clk-1. In addition, RNAi knockdown of various mitochondrial ETC genes prolongs lifespan in yeast, worms, and fruit flies.

The effects of mitochondrial ETC genes on modulating lifespan appear to be complex. Inhibition of some ETC genes increases lifespan, whereas inhibition of others decreases or does not alter lifespan in C. elegans and Drosophila. For example, mutations in mev-1, which encodes a subunit of complex II, causes a short lifespan in worms. In addition, the underlying causes for lifespan regulation by ETC genes remain incompletely understood. For example, the roles of reactive oxygen species (ROS) production and mitochondrial function in aging and lifespan of ETC mutants can be opposite ways. One model interpreting these opposite effects is that moderate mitochondrial impairments increase lifespan until a threshold is reached, beyond which animals display wide-spread damage, shortened lifespan, or even death. Nevertheless, how mitochondrial genes modulate lifespan and whether they function in modulating lifespan in other species remain incompletely elucidated.

ATP synthase, also known as complex V of the mitochondrial respiratory chain, is the primary cellular energy-generating machinery. In mammals, ATP synthase deficiency is one of the rarer mitochondrial oxidative phosphorylation deficiencies. ATP synthase is also intimately linked to aging. In worms, genetic inhibition of the atp-2 gene, which encodes a subunit in complex V, leads to developmental delay and increased lifespan. Additionally, a genome-wide RNAi screen revealed that RNAi knockdown of subunits atp-3, atp-5, or asb-2 prolongs worm lifespan. However, the underlying mechanism for lifespan extension due to inhibition of these subunits in the ATP synthase remains unclear. As ATP synthase is highly conserved throughout evolution, understanding the role of the ATP synthase in lifespan regulation can lead to untangling of the complexity of mitochondrial ETC genes in modulating lifespan.

Link: https://doi.org/10.1038/s41598-018-32025-w

The practice of calorie restriction reliably slows aging and extends life span in most species tested to date. The degree to which this happens is much reduced in longer-lived species, but a detailed understanding of why this is the case is yet to be assembled. It makes sense from an evolutionary perspective: extended health and life in response to famine helps to raise the odds of successful reproduction. Famines tend to be seasonal, and a season is a large fraction of a mouse life span, but only a tiny faction of a human life span. Thus only short-lived species evolve a sizable gain in life span in response to reduced calorie intake, even though the short-term benefits to health appear quite similar in both short-lived and long-lived mammals.

From a biochemical perspective, cellular metabolism is so complex, and calorie restriction changes so much of it, that it remains a major undertaking to try to put everything in order to understand how exactly calorie restriction works. It is clearly an adaptive response, a shift of the whole of metabolism from one state into another, a change of great complexity. Deciphering all of the details is a fascinating scientific endeavor, but one that will come to be of increasingly little relevance to the future of human longevity. Calorie restriction mimetic therapies that modestly slow aging are hard to construct, while rejuvenation therapies based on repair of the damage that causes aging will deliver far greater benefits with far lower expense.

In 1989, the anti-aging and prolongevity actions of calorie restriction (CR) were explained from the evolutionary viewpoint of organisms having evolved adaptive response systems to maximize survival during periods of food shortage. On the basis of this evolutionary viewpoint, we divided the beneficial actions of CR into two systems; "systems activated under sufficient energy resource conditions" and "systems activated under insufficient energy resource conditions". The former is activated under natural environmental conditions that grant animals free use of energy by providing a plentiful food supply. In other words, when there is grace for free use of energy, animals grow well, reproduce more, and store excess energy as triglyceride in white adipose tissue for later use, but not to such an extent that they become obese. The latter is activated under natural environmental conditions that do not permit free use of energy because of food shortages.

In other words, when there is no grace for free use of energy, animals suppress growth and reproduction and shift energy use from growth and reproduction to maintenance of biological function, but not to such an extent that they become severely starved. Adaptation to natural environmental changes is a top priority for survival in animals. On the basis of the adaptive response hypothesis, we propose a suite of mechanisms for the beneficial actions of CR. Since experimental CR conditions can mimic insufficient energy conditions, we hypothesized that CR suppresses "systems activated under sufficient energy conditions" and activates "systems activated under insufficient energy conditions", and additively induces anti-aging and prolongevity actions. The first set of systems involves GH/IGF1, FOXO, mTOR, adiponectin and BMAL1 signaling, and CR appears to suppress these anabolic reactions. The second set of systems involves SREBP-1c/mitochondria redox, SIRT and NPY signaling, and it is likely that CR activates these reactions to make optimal use of insufficient energy resources.

Studies using monkeys suggest that the beneficial actions of CR may occur in humans as well as other mammals. Ongoing CR research focuses on two themes, i.e. elucidation of the molecular mechanisms of CR, and development of CR mimetic medicines. We consider development of novel CR mimetic medicines to be difficult without an understanding of the molecular mechanisms of CR. To develop CR mimetic medicines that are applicable to humans, further studies are therefore required on the molecular mechanisms of CR, particularly in non-human primates. In this report, we propose that the molecular mechanisms of beneficial actions of CR should be classified and discussed according to whether they operate under rich or insufficient energy resource conditions. Future studies of the molecular mechanisms of the beneficial actions of CR should also consider the extent to which the signals/factors involved contribute to the anti-oxidative, anti-inflammatory, anti-tumor and other CR actions in each tissue or organ, and thereby lead to anti-aging and prolongevity.

Link: https://doi.org/10.18632/aging.101557

Our community year end fundraiser for 2018 will soon be underway to support scientific programs for the development of rejuvenation therapies carried out at the non-profit SENS Research Foundation. As was the case last year, once again Fight Aging! and a few fellow travelers will assemble a challenge fund to encourage new SENS Patrons to set up subscriptions to make monthly or yearly recurring donations to the SENS Research Foundation. The first year of any such new donations will be matched dollar for dollar from the challenge fund.

We think that recurring donations are important: the more that our community supports the SENS programs by providing a regular supply of funding, the easier it becomes for the SENS Research Foundation staff to plan ahead and commit to long-term projects. In past years this initiative has been a success: our matching fund was met last year, and the new monthly donors largely stick around for the long term to continue to support SENS rejuvenation research. This year regular donor Josh Triplett is going above and beyond to put up $36,000 to encourage new SENS Patrons to make the leap. I myself will put in $6,000. We are looking for other challenge fund donors to join us in this initiative. Do you want to make a sizable difference to the future of human health and longevity? This is how it is done.

The SENS Research Foundation uses our donations to fund a range of scientific work on the foundations of rejuvenation therapies, focused on those areas that are furthest behind or that most need unblocking in order to achieve meaningful progress. These are all programs that achieve rejuvenation through repair: validating the list of cell and tissue damage that lies at the roots of aging, and then reversing these forms of damage, one by one. It is in large part thanks to the advocacy, networking, and funding provided by the SENS Research Foundation, and by the Methuselah Foundation before it, that rejuvenation research is as far ahead as it is. When the SENS programs started, popular culture and the scientific community were opposed to any initiative aiming to produce rejuvenation via targeting the molecular damage that causes aging, despite decades of evidence to strongly support this strategy.

In recent years the naysayers have been proven clearly and categorically wrong. Clearance of senescent cells through the use of senolytic therapies has been shown to produce rejuvenation in mice. The first such treatments are in human trials, in development by multiple biotech companies, and being used by a growing number of self-experimenters worldwide. That today there is a new and rapidly growing senolytics industry, poised to deploy rejuvenation therapies that can remove some of the burden of senescent cells in older individuals, is due in large part to the network of advocacy, science, and funding centered on the SENS Research Foundation and Methuselah Foundation. Clearance of senescence cells was in the SENS proposals, front and center, from the very start. Back then, at the turn of the century, the goal of rejuvenation was widely ridiculed. Nonetheless, with persistence, persuasion, and the support of our community of everyday philanthropists, here we are today, embarking upon the construction of an industry that aims to reverse aging.

Senolytics are just the start. They are only a part of the story, and only a narrow slice of the complete human rejuvenation that remains only a possibility, rather than a certainty. Scores of other equally important and beneficial projects under the SENS umbrella of repair therapies are still comparatively neglected, or blocked by the lack of tools, or blocked by the lack of funding, or lacking strong champions in the research community. We can help to change this. We did a great deal to make that change come about for senescent cell clearance, and we can do the same for mitochondrial DNA repair, for breaking the cross-links that stiffen tissues, for clearing amyloids and other harmful metabolic wastes, and more. We shine the light that shows the way, and, given time and resources, we are successful.

Give some thought to joining us. A future in which being old does not mean being sick and diminished is a future worth bringing into existence. We can all help in some way to make this vision a reality.

I think it is entirely appropriate to greet the advent of senolytics with enthusiasm. These treatments are the first legitimate rejuvenation therapies to successfully target one of the root causes of aging, the accumulation of lingering senescent cells in old tissues. The first human trial data is approaching publication, but even before it arrives, the evidence to date strongly suggests that meaningful levels of rejuvenation can be achieved in old people at a very low cost. The first senolytic drugs (such as dasatinib and navitoclax) and plant extracts (such as fisetin and piperlongumine) cost very little, and remove only some senescent cells, no more than half in some tissues, and far fewer than that in others. Nonetheless, in mouse studies they reliably reduce chronic inflammation, reverse the progression of numerous conditions ranging from arthritis to Alzheimer's disease, and extend healthy life span even when applied a limited number of times in very late life.

As we get older, more and more of our the cells in our bodies become dysfunctional and enter into a state known as senescence. These senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are known as the senescence-associated secretory phenotype (SASP). Dr. Judith Campisi from the Buck Institute for Research on Aging, along with her research team, identified that senescent cells secreted the various harmful chemicals that characterize the SASP in 2008, which was when interest in senescent cells really began.

The SASP is a real problem: it increases inflammation, harms tissue repair and function, causes the immune system to malfunction, and raises the risk of developing age-related diseases such as cancer. Even worse, the SASP also encourages nearby healthy cells to become senescent, so even a very small number of senescent cells can cause big problems. Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis or are cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and the senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.

With these experiments, the biotechnology industry had initial proof that targeting one of the aging processes directly could improve health by delaying aging in mice; this began the search to develop therapies that target and destroy these harmful cells. This was the birth of a new class of drugs and therapies that would become known as senolytics. So far, there have been a number of drugs and naturally occurring compounds with senolytic potential and multiple mouse experiments demonstrating that the clearance of these cells can delay the onset of diseases such as cancer, heart disease, osteoporosis, arthritis, and Alzheimer's.

Interest in senolytics has seen a meteoric rise in the last couple of years, with investment money pouring in as confidence in the approach has reached new heights. There are also a number of companies developing therapies to destroy senescent cells, and it is likely that more will join them in the coming years. Leading the charge is Unity Biotechnology, which was founded in 2011 and has raised over $385 million in funding since then. Other companies are hot on its heels developing ways to seek and destroy these harmful cells. Oisin Biotechnologies, based in Seattle, is one such company. Founded in 2016, it has raised around $4 million to date and is developing a unique lipid nanoparticle-based system to deliver senolytic and cancer therapies. Cleara Biotech, based in the Netherlands, and Spain-based Senolytic Therapeutics are also busy developing senolytic therapies.

Link: https://www.leafscience.org/senolytics-target-aging/

Naturally grown tissues are intricately structured, and the physical properties of tissue derive from the patterning of cells and their behavior in generating a supporting extracellular matrix. This natural complexity ensures that there is still a great deal of work to be accomplished when it comes to the 3-D bioprinting of functional tissue structures; not all tissues can be produced using the current state of the art systems, or at least not in a useful state. The work here is an example of the sort of incremental advance needed to produce tissues that are closer in form and function to those growing naturally inside bodies.

The 3-D-printing method, which took two years to research, involves taking stem cells from the patient's own body fat and printing them on a layer of hydrogel to form a tendon or ligament which would later grow in vitro in a culture before being implanted. But it's an extremely complicated process because that kind of connective tissue is made up of different cells in complex patterns. For example, cells that make up the tendon or ligament must then gradually shift to bone cells so the tissue can attach to the bone. "This technique is used in a very controlled manner to create a pattern and organizations of cells that you couldn't create with previous technologies. It allows us to very specifically put cells where we want them."

To do that, the team used a 3-D printer typically used to print antibodies for cancer screening applications. The researchers developed a special printhead for the printer that can lay down human cells in the controlled manner they require. To prove the concept, the team printed out genetically-modified cells that glow a fluorescent color so they can visualize the final product. The technology is initially designed for creating ligaments, tendons and spinal discs, but in the future it could be adapted to any type of tissue engineering application, such as the 3-D printing of whole organs, an idea researchers have been studying for years.

Link: https://unews.utah.edu/the-fine-print/

Salivary glands are one of many small organs that we give little thought to until they fail, and then it becomes difficult to think of anything else. Just like every other tissue in the aging body, that failure becomes more likely with each passing year, with the accumulation of molecular damage and its consequences. One of the potential approaches to this general category of gradual organ failure is the generation of new organs or new functional tissue for transplantation, building tissues in bioreactors from the starting point of cells. This can in principle fix damage that is internal to an organ by replacing that organ entirely, or augment function of a failing organ with the use of tissue patches. The aged environment and its harmful influence on organ function through signaling will remain a challenge, however, until more general rejuvenation therapies are widely deployed.

Japanese researchers have been working on the tissue engineering of functional salivary glands for some years now, and the paper noted below reports on their latest success. Like most groups in the field, they are focused on discovering the necessary signals and environment that can direct cells to build a specific tissue in the same way that occurs during embryonic development. This is quite different on a tissue by tissue basis, but nonetheless progress is being made. The researchers here can build organoids, small sections of functional salivary gland tissue that are limited in size because they lack a capillary network. An important demonstration of functionality is to implant organoids into an animal and show that they integrate and perform the tasks expected of the naturally grown organ. That rarely implies complete success, as the assessed function usually isn't exactly the same, but nonetheless, it may indicate that the research program has progressed far enough to start thinking about use in human medicine.

Researchers create a functional salivary gland organoid

Salivary glands develop from an early structure called the oral ectoderm, but the actual process is not fully understood. It is known that organ development takes place through a complex process of chemical signaling and changes in gene expression, so the scientists began to unravel what the important changes were. They identified two transcription factors - Sox9 and Foxc1 - as being key to the differentiation of stem cells into salivary gland tissue, and also identified a pair of signaling chemicals - FGF7 and FGF10 - which induced cells expressing those transcription factors to differentiate into salivary gland tissue.

To create an organoid, researchers used a cocktail of chemicals that allowed the formation of the oral ectoderm. They used this cocktail to induce embryonic stem cells to form the ectoderm, and then used viral vectors to get the cells to express both Sox9 and Foxc1. Adding the two chemicals to the mix induced the cells to form tissue that genetic analysis revealed was very similar to actual developing salivary glands in the embryo.

The final step was to see if the organoid would actually function in a real animal. They implanted the organoids into actual mice without saliva glands and tested them by feeding them citric acid. When the organoids were transplanted along with mesenchymal tissue -another embryonic tissue that is important as it forms the connecting tissue that allows the glands to attach to other tissues - the implanted tissues were found to be properly connected to the nerve tissue, and in response to the stimulation secreted a substance that was remarkably similar to real saliva.

Generation of orthotopically functional salivary gland from embryonic stem cells

Organoids generated from pluripotent stem cells are used in the development of organ replacement regenerative therapy by recapitulating the process of organogenesis. These processes are strictly regulated by morphogen signalling and transcriptional networks. However, the precise transcription factors involved in the organogenesis of exocrine glands, including salivary glands, remain unknown. Here, we identify a specific combination of two transcription factors (Sox9 and Foxc1) responsible for the differentiation of mouse embryonic stem cell-derived oral ectoderm into the salivary gland rudiment in an organoid culture system.

Following orthotopic transplantation into mice whose salivary glands had been removed, the induced salivary gland rudiment not only showed a similar morphology and gene expression profile to those of the embryonic salivary gland rudiment of normal mice but also exhibited characteristics of mature salivary glands, including saliva secretion. This study suggests that exocrine glands can be induced from pluripotent stem cells for organ replacement regenerative therapy.

That females live longer than males in numerous species is a topic of some interest to evolutionary theorists and other researchers in the life sciences. There are any number of possible explanations, but that this phenomenon exists in many different species tends to favor evolutionary arguments. Something fundamental to gender as it exists in most higher species is closely tied to aging, and the result is near always females that age more slowly than males. In the research noted here, scientists report on an experiment in fly populations that suggests this longevity difference will arise quite naturally from the differing mating strategies of male and female genders, each under selection pressure to maximize their success in reproduction.

Differences in aging and the length of life between males and females are common in the animal realm. Males often have shorter lifespans than females. Researchers used fruit flies, Drosophila melanogaster, to investigate whether sexual selection lies behind sex differences in aging. They wanted to determine whether the two sexes are affected differently when they are in poorer physical condition, in other words, when they have poorer access to nutrients and energy. In particular, they were interested in the ability of the flies to reproduce, and how this ability changes when the flies age, in a process known as "reproductive aging".

Researchers had manipulated the genetic material of some of the flies, such that they had many small harmful mutations in their genes. These mutations had a negative influence throughout life, meaning that an individual with such mutations converted food to useful energy slightly less efficiently. Thus, even though all of the flies had access to the same food and could eat equal amounts, the manipulated flies were in poorer physical condition.

In order to mate with available females, the aging males were compelled to compete with young males. It turned out, as expected, that males in good physical condition were better at this than those who were in poorer condition, independently of how old they were. The reproductive aging of males, however, decreased at the same rate, independently of whether they were in good or poor physical form. Things were different for females. Early in life, there was no difference between the number of offspring produced by females in good condition, who could use the available resources better, and the number produced by mutated females, who were in poorer condition. The two groups, however, aged at different rates. As the females became older, those who were in good physical form had more offspring than their less fortunate sisters.

"The results show that sexual selection contributes to the differences between the sexes in reproductive aging. This is probably because females in good condition, with good access to nutrients, invest the extra resources into maintaining their bodies, such that they can continue to reproduce to a more advanced age. Males, in contrast, seem to invest a great deal of their resources, independent of their condition, into trying to ensure that they achieve successful mating here and now."

Link: https://liu.se/en/news-item/darfor-aldras-honor-langsammare

Bill Cherman and I, cofounders of Repair Biotechnologies, were recently interviewed on the topic of the Longevity Investor Network, an initiative organized by the Life Extension Advocacy Foundation volunteers. The Network is a group of angel investors and venture capitalists of varying backgrounds, all of whom are interested in the rapidly growing longevity industry. Some want to speed the advent of therapies capable of turning back aging, some are long-time fellow travelers from our broader advocacy community, some are newly arrived, just starting to learn about the science and the potential scale of this market. It is a real mix of views and motivations.

Every month a few aging-focused startup companies are presented to the network, and the gatherings are a chance to make connections and put names to faces. To an outsider it might sometimes seem that all of the behind the scenes communication in the venture community just happens automatically, with no need for effort. Nothing could be further from the truth; communication is hard, and building professional networks is an essential part of growing any industry. This is a very helpful initiative for a period in which we are striving to connect promising lines of research to commercial development groups and venture capital.

Why, generally, do you invest in longevity companies?

Reason: It is an effective means of advancing the state of rejuvenation biotechnologies that are at a certain stage of maturity. It is at least ten times easier to raise investment funding than it is to raise philanthropic funding, but there is very little difference in the use such money is put to when comparing late-stage lab work with early-stage startup work.

Venture capital and its angel community cousin like to present themselves as bold and risk-taking, but there is nonetheless an awful lot of herd behavior taking place. Investors follow for preference. A great deal can be accomplished in terms of steering money to sensible destinations by stepping out in front of the crowd and presenting a solid rationale for investment choices, by being the first to put some money down and explaining in detail why you choose to do that. It works at the level of small angel investments, and it works at the level of Jim Mellon's Juvenescence venture.

Bill: There are mission and financial motivations. Mission-wise, no industry can have a more positive impact on humanity than the longevity industry; after all, life is man's fundamental value, and all others require it. Biotech startup investing has historically delivered distinctive results to investors; if longevity startups succeed in extending healthspan, even larger financial outcomes will follow, I believe. I particularly like early-stage preclinical companies, which are often valued in the 7-, low-8-digit range and can IPO and reach unicorn status in as early as 2-3 years.

Why do you see value in having a network of investors who share and collaborate on deals?

Reason: Rare is the deal in which a network of investors was not in some way involved in bringing it about. The present ad hoc assembly of happenstance meetings, persuasion, and passage of information is an essential part of setting up companies, even if the investment is ultimately made by just a few of those participants. Formalizing the networks helps greatly in lowering the barriers to entry for entrepreneurs (there are never enough entrepreneurs) and to finding good investment opportunities on the part of investors. AngelList, I think, has proven this quite comprehensively. The same applies at any level of investment.

Ultimately, however, this is a little different from your run-of-the-mill investment where, at the end of the day, the point is to obtain more of those funny little tokens called money. Here, the goal is more life and the medical control of aging, and, at some point, the funny little tokens become a little less important than getting the job done. That dynamic is still shaking itself out, but I think we need communities whose members recognize that doing no more than aiming at increments of net worth to enable an ever-more luxurious tomb marker at some increasingly near point in the future is obsolete thinking when it comes to life science investment.

Bill: I would note there is value to investors and entrepreneurs. Investors get a more curated deal flow and a more thorough due diligence process, while entrepreneurs, many of whom lack business experience (to their benefit, many times), get access to several people who they can bounce ideas with and who can give them some guidance on fundraising, communicating with stakeholders, etc.

What do you hope the Longevity Investor Network can grow into?

Reason: A much bigger group of investors who largely understand that the point of this exercise is to generate a world in which aging can be controlled and that funding and profit are just means to an end. In a world in which money can truly buy additional health in late life, buy time spent vigorously alive, then money is somewhat less the central focus that it is today. The point becomes living, and, in this, we all win together or we all lose together. Senolytics show the way: high-tech development at the core, and a surrounding halo of cheap, highly beneficial treatments, something that will benefit the entire world as a result of early investments in the field.

Bill: Ideally, a one-stop shop for longevity startups to quickly raise money from smart and helpful investors, so they don't have to burn months of energy with fundraising and can go back to the science as soon as possible.

Link: https://www.leafscience.org/investing-in-longevity/

Being obese or overweight is, for the overwhelming majority of such individuals, a choice. There is plenty of ink spilled over how hard or easy the choice of body weight is to make, but it is nonetheless a choice. Want to weigh less? Then persist in eating fewer calories in the context of a sanely balanced diet. It really is as simple as that. The only way to fail is to fail to eat fewer calories. That this is eternally a challenge, and that obesity is increasingly prevalent in an environment of cheap calories, tells us more about human nature than it does about our biology.

The present consensus on the effects of excess visceral fat tissue is that it increases incidence of near all age-related disease, shortens life expectancy, and raises overall lifetime medical expenditure. Raised levels of chronic inflammation produced by fat tissue are an important mediating mechanism in this outcome, regardless of whether they are produced by greater numbers of senescent cells in fat, immune cells infiltrating fat tissue, inappropriate interactions with cell debris, inflammatory signaling from adipose cells, or other fat-associated mechanisms.

This is a graded effect. Even more modest levels of excess fat tissue, additional weight that in this age of obesity wouldn't merit a second glance when seen on the street, produce significant increases in the risk of age-related disease and later life mortality. The more fat tissue, and the longer that fat tissue is retained, the worse the prognosis. Fat accelerates the damage and dysfunction of aging. On this topic, the publicity materials here note a couple of recent papers that reinforce the message: early life obesity leads to a shorter life expectancy, and fat tissue greatly increases chronic inflammation, exacerbating the serious downstream consequences that inflammation causes.

Being overweight or obese in your 20's will take years off your life, according to a new report

Young adults classified as obese in Australia can expect to lose up to 10 years in life expectancy, according to a new study. The model used by the researchers calculates the expected amount of weight that adults put on every year depending on their age, sex, and current weight. It also takes into account current life expectancy in Australia and higher mortality of people with excess weight. The model predicted remaining life expectancy for people in their 20s, 30s, 40, 50s and 60s in healthy, overweight, obese and severely obese weight categories. It also calculated the number of years lost over the lifetime for people with excess weight in each age group, compared to those with a healthy weight.

On average, healthy weight men and women in their 20s can expect to live another 57 and 60 years, respectively. But, if they are already in an obese weight category in early adulthood, women will lose 6 of these years and men will lose 8. If they are in a severely obese weight category, women will lose 8 years and men will lose 10. The risks of early death associated with excess weight were apparent at every age group but decreased with age. Obese women in their 40s will experience a reduction of 4.1 years, whilst obese men stand to lose 5.1 years. For individuals in their 60s, this reduction in life expectancy is estimated at 2.3 years for women and 2.7 years for men.

New study finds that inflammatory proteins in the colon increase incrementally with weight

Studies in mice have demonstrated that obesity-induced inflammation contributes to the risk of colorectal cancer, but evidence in humans has been scarce. A new study shows that two inflammatory proteins in the colon increase in parallel with increasing weight in humans. An incremental rise in these pro-inflammatory proteins (called cytokines) was observed along the entire spectrum of subjects' weights, which extended from lean to obese individuals. In participants with obesity, there was evidence that two pre-cancerous cellular pathways known to be triggered by these cytokines were also activated.

Sixteen research participants were lean, with a BMI between 18.1 and 24.9, while 26 participants with obesity had a BMI ranging from 30.0 to 45.7. The participants were between the ages of 45 and 70 years of age and were undergoing routine screening colonoscopies. Using blood samples and colonic biopsies, the researchers determined that the concentrations of two major cytokines rose in parallel with BMI. Cytokines are proteins that mediate and regulate immunity and inflammation, among other things. In addition to evidence that they can promote cancer risk in certain tissues, pro-inflammatory cytokines have been identified as actors in insulin resistance and diabetes, as well as inflammatory disorders such as arthritis.

In an effort to identify potential confounding factors, the research team determined that thirteen of the 42 study participants were also regular users of NSAIDs, such as aspirin and ibuprofen. The research team discovered that participants who took NSAIDs at least once per week, compared to those who did not, had lower levels of pro-inflammatory proteins in the colon. This pattern was consistent across the two BMI groups.

Cancer is an age-related condition in large part because the immune system declines with age. One of the many important tasks undertaken by the immune system is suppression of cancer. This is achieved by destroying cancerous and potentially cancerous cells quickly, before they can establish a tumor that will go on to subvert the immune system's normal responses to errant cells. This process of cancer eradication (and tumor development when eradication fails) is enormously complex in detail, but straightforward enough to understand at the high level. How does this interaction between aging, the immune system, and cancer risk work in practice when we are talking about a cancer of the immune system, however? The evidence suggests that persistent viral infection plays a larger direct role here than is the case in most other forms of cancer, which is intriguing given that these viral infections are also likely a major cause of adaptive immune system decline with age.

Immunosenescence is a peculiar remodeling of the immune system, caused by aging, associated with a wide variety of alterations of immune functions. It is has been implicated in pathophysiology of dementia, frailty, cardiovascular diseases, and it is the cause of increased susceptibility to infectious disease, autoimmunity, and cancer. Indeed, about 55% of tumors affect subjects who are over 65 years of age. It is well known that both the innate and the adaptive immune system protect the host against carcinogenesis by a process called "immunosurveillance". By means of this process, the immune cells identify and eliminate cancerous cells before a tumor develops.

The current available data focuses on B cell Non Hodgkin Lymphomas (NHL), which represent more than 90% of lymphoid neoplasms worldwide. Between lymphoma and aging, a complex interplay can be described. B cell NHLs develop by a multistep process closely related to normal B cell counterpart that can be favored with aging. As with all other cancer types, chronological ageing is associated with the accumulation of DNA damage particularly in stem cells. Also, epigenetic abnormalities that have a role in lymphoma and leukemia development can accumulate with aging.

In addition to abnormal genetic events, also age-related impairment in cancer protection is expected to promote B cell lymphomagenesis. The phenotype called "immunosenescence" is associated with a complex dysfunction that increases sensitivity to infections. Chronic infection with Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) in the elderly caused by restricted T cell response can alter the B cell immune repertoire, leading to infection-linked diseases as well as some types of lymphoma. Also, a causal relationship between Hepatitis C Virus (HCV) and NHL has been demonstrated and the most plausible molecular mechanism is lymphoma development by continuous antigenic stimulation.

Link: https://doi.org/10.1186/s12979-018-0130-y

Researchers here report on a gene variant associated with reduced incidence of metabolic disease, type 2 diabetes, and heart disease. The mechanism of action is a reduced uptake of glucose (and thus calories) in the gut. The estimated effect size over decades of life based on the short term data gathered is large: a reduction of a third in mortality risk. That is sizable enough for me to think that the study needs replication before taking it at face value, but it is thought-provoking nonetheless.

One thing to consider while reading this paper is that gene variants of this nature may help to pin down the plausible scope of benefits that could result from beneficial alterations to gut microbial populations. Differences in these microbial populations is a more commonplace way in which glucose uptake and many other aspects of the interaction between diet and health can differ between individuals. It is an area of increasing research interest, though of course the potential benefits pale beside those that can be realized through rejuvenation biotechnologies after the SENS model.

After ingestion, complex carbohydrates are enzymatically broken down to produce monosaccharides (glucose, galactose, and fructose), which are absorbed in the small intestine and used as substrate for the body's metabolically active tissues. The sodium/glucose co-transporter (SGLT)-1 protein is a rate-limiting factor for absorption of glucose and galactose in the small intestine, and it uses transmembrane sodium gradients to drive the cellular uptake of these molecules. Loss-of-function mutations, including missense, nonsense, and frameshift mutations, of the SGLT1 gene result in impaired cellular glucose transport and cause glucose-galactose malabsorption (GGM), a severe genetic disorder.

Functional gene variants in SGLT1 associated with altered glucose metabolism in the general population have not been described. However, in the process of identifying causal mutations for GGM, SGLT1 gene variants that are associated with subtle abnormalities of glucose absorption in vivo have been identified; the importance of these variants, which do not result in GGM, is unknown. We hypothesized that rare or low-frequency variants in SGLT1 that are predicted to be damaging, but still preserve some of the protein's function, result in lower postprandial blood glucose levels by decreasing glucose uptake in the small intestine and thereby reduce overall caloric absorption.

Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%) had lower blood glucose and odds of impaired glucose tolerance than noncarriers. The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects and an external European-Finnish population sample of 6,784 subjects. Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in blood glucose via SGLT1 inhibition would be reduced prevalent obesity (odds ratio 0.43), incident diabetes (hazard ratio 0.58), heart failure (hazard ratio 0.53), and death (hazard ratio: 0.66).

Link: http://dx.doi.org/10.1016/j.jacc.2018.07.061

Today I'll point out a view of the divide between theories of programmed aging and non-programmed aging, written by one of the more prominent programmed aging theorists in our community. I think it matters deeply as to whether we are guided by the theory that aging is caused by accumulated damage, or whether we are guided by the theory that aging is caused by an evolved program that is actively selected for. Is aging a matter of damage causing epigenetic change and cell dysfunction or a matter of epigenetic change causing damage and cell dysfunction?

This is an important division in the research community. The strategies for treating aging that must be proposed, agreed upon, and funded in well in advance of any evidence of effectiveness are very different in either case, and there is no reason to believe that the strategies of the wrong camp will prove to be useful. This is because addressing root causes is a powerful way to produce sizable gains, removing many downstream problems. Addressing downstream problems, on the other hand, has very limited utility: it is much harder, the benefits are much smaller, and the root causes will continue to cause a range of other harms. One side of this debate is wrong, and their proposed therapies will largely be a waste of time and energy, producing only marginal benefits at the end of the day.

Why can't we just determine who is right and who is wrong from an inspection of what is known of aging to date? Well, arguably we can, or at least form strong opinions about it, but there is nonetheless sufficient room for debate. The majority consensus is that programmed aging is an incorrect interpretation of the evidence, but the programming aging community is thriving nonetheless. Aging is complex and poorly understood in the details of its progression, and this is because cellular metabolism is complex and poorly understood. There is a great deal of latitude to argue about which correlated metrics in aging are cause and which are effect when it comes to the inner details of cell behavior, molecular damage, tissue function, and so forth. So given the very same data and evidence as a starting point, for much of aging it is still possible for programmed aging theorists to argue that epigenetic changes are the root cause, and for the rest of the field to argue that epigenetic changes are reactions to underlying molecular damage.

This is somewhat threatening from my point of view. While most researchers don't agree with programmed aging, they do undertake research that is more in accordance with programmed aging than with the view of aging as damage. The strategy doesn't match to the vision of aging, for reasons that have a lot to do with the way in which clinical development is regulated. This is a huge problem, and it is why progress is slow and will continue to be slow. Most researchers believe that all that can be done to intervene in aging is to adjust the operation of metabolism into more resilient states - such as by mimicking the calorie restriction response, adjusting the epigenetics of cells in old tissues. They fully understand that the potential upside here is very limited. The programmed aging advocates think that this is great and exactly what we should be doing, and in that the presence of their faction is an additional hindrance. A battle must be fought into order to steer the research community towards effective strategies, those based on repair of damage, and this is already a tall order.

Where a therapy is newly demonstrated to be effective, the side that didn't predict it will adjust their theoretical framework to contain it. That is happening at the moment for senescent cell clearance, predicted by the damage repair advocates of the SENS rejuvenation research community. Programmed aging theorists will now argue that rising levels of senescent cells are a part of the aging program, in some way a consequence of changing epigenetics. Alternatively, both sides might agree that senescent cell accumulation has a lot to do with immune system aging, and then disagree entirely about why it is that the immune system fails with age. Based on progress to date, I'm not optimistic that this debate will be conclusively resolved any time soon, even as we enter the golden age of therapies based on repair of molecular damage, informed by the theoretical view that aging is at root caused by that damage.

Aubrey and Me

I've been in the field of aging research from the late 1990s, just the time when Aubrey de Grey was getting his start. Before others, Aubrey had the vision to realize that cancer, heart disease, and Alzheimer's would never be conquered without addressing their biggest risk factor: aging. From the beginning, I admired Aubrey's successes in communicating with scholars and the public, and I reached out to him. He has always been gracious and supportive of me personally, appreciating the large common ground that we share.

There is, however, one foundational issue on which we disagreed from the start. Aubrey regards aging as an accumulation of damage. Evolution has permitted the damage to accumulate at late ages because (as Medawar theorized in 1952) there is little or no selection against it, since almost no animals live long enough in the wild to die of old age. Aubrey's program is called SENS, where the E stands for "engineering." The idea is to engineer fixes to the 7 major areas where things fall apart with age.

I regard aging as a programmed process, rooted in gene expression. Just as we express growth genes when we are in the womb and ramp up the sex hormones when we reach puberty, so the process continues to a phase of self-destruction. In later life, we over-express genes for inflammation and cell suicide; we under-express genes for antioxidants, autophagy (recycling), and repair of biomolecules. I believe in an approach to anti-aging that works through the body's signaling environment. If we can shift the molecular signals in an old person to look like the profile of a young person, then the person will become young. The body is perfectly capable of doing its own repair, and needs no engineering from us.

Over the years, research findings have accumulated, and both Aubrey and I have learned a thing or two. I'm happy to say that our favored strategies are converging, even as our philosophical underpinnings continue to differ.

Aubrey now finds optimism in the existence of what he calls "cross-talk". If we engineer a fix for one kind of damage, the body may sometimes regain the ability to repair other, seemingly unrelated kinds of damage. Hence, we may not have to engineer solutions to everything-some will come for free. A dramatic example is in the benefit of senolytics. Cells become senescent over time. I see this as a programmed consequence of short telomeres; Aubrey sees it as a response to damage in the cells. But both of us were surprised and delighted to learn, a few years ago, that elimination of senescent cells in mice had 20-30% benefits for lifespan in mice. Even though only a tiny fraction of all cells become senescent, they are a major source of cytokines (signal molecules) that promote inflammation and can cause nearby cells to become senescent in a vicious circle; this apparently accounts for the great benefit that comes from eliminating them. If we find appropriately selective senolytic agents that can eliminate senescent cells without collateral damage, then the signals that up-regulate inflammation will be cut way back, and a great deal of the work needed to repair inflammatory damage is obviated.

The Life Extension Advocacy Foundation volunteers here note an open access paper from earlier this year. The authors characterize a small, problematic population of the immune cells known as monocytes as being senescent cells, having the same character of inflammatory signaling and disruptive behavior as other types of senescent cell. This finding is one of many discoveries emerging from the great expansion of funding and interest in cellular senescence that has taken place in recent years. The accumulation of senescent cells is an important cause of aging and age-related disease, but broad recognition of this point has required a great deal of time and hard work. Now that research in this field has picked up, the consensus on a range of cell types and behaviors, those observed in age-related disease and known to be harmful, is likely to be revised in the direction of the involvement of cellular senescence.

Monocytes are immune cells that can differentiate into macrophages and are involved in the processes of both innate and adaptive immunity. There are three known types of monocytes: classical, intermediate, and nonclassical. The nonclassical ones are the most pro-inflammatory even though they express high levels of miR-146a, a microRNA that is known to limit inflammatory responses. This apparent contradiction is what led the authors of this study to discover if there is more to miR-146a than meets the eye.

Cellular senescence is a phenomenon by which normal cells stop dividing and begin secreting a highly inflammatory cocktail of chemicals known as the senescence associated secretory phenotype (SASP). In modest amounts, senescent cells have beneficial roles; however, they tend to accumulate as we age, which results in a constant, low-grade inflammation as well as a higher susceptibility to a range of age-related diseases, cancer included, in the elderly. Given that the elevated pro-inflammatory activity of nonclassical monocytes is rather reminiscent of the SASP and that they display such high levels of miR-146a, the scientists reasoned that nonclassical monocytes may well undergo senescence.

Scientists found that elderly patients display an accumulation of these cells compared to younger people. They collected samples from 30 healthy volunteers between the ages of 22 and 35 years and 30 healthy elderly people aged 55 and older. While there was no significant difference in the total percentage of any of the three monocyte types between the two groups, the researchers found out that the elderly had a higher monocyte count per volume of blood, especially nonclassical monocytes. Accordingly, the level of inflammatory cytokines in the blood of the elderly was significantly higher. This led the scientists to conclude that senescent monocytes do indeed accumulate in the blood of the elderly and may well contribute to inflammaging, which is the chronic, low-grade inflammation that is typical among older people.

The researchers suggest that nonclassical monocytes might be a viable target for treating age-related and chronic inflammatory conditions, even non-age-related ones. It may be possible to reduce the SASP secreted by nonclassical monocytes or reduce the number of circulating nonclassical monocytes.

Link: https://www.leafscience.org/type-of-human-monocytes-found-to-undergo-senescence/

The consensus on neurodegenerative diseases, particularly Alzheimer's disease, is coming to be that these varied age-related conditions have deep roots. People on the road to developing Alzheimer's most likely have a biochemistry that is distinguishable from their peers ten or twenty years prior to the emergence of evident symptoms, and perhaps even earlier. The open access paper noted here discusses some of the evidence that supports this viewpoint.

Along these lines, I think that we will see a sizable growth in efforts to find early biomarkers that predict later development of neurodegeneration, building on the work of recent years in which the first few comparatively non-invasive approaches have appeared in the literature. It remains unclear at this time as to the degree to which lifestyle choices matter in these considerations. While there are certainly arguments for Alzheimer's risk to be increased by being sedentary and overweight, one of the biggest questions regarding Alzheimer's is why only some people with these risk factors go on to develop the condition rather than the majority one might expect in the case of a strong causal relationship.

Alzheimer's disease (AD) accounts for around 60-80% of dementia cases, and its symptoms are projected to affect greater numbers of people every year. Insidious and irreversible memory decline is the most recognized feature of AD, beginning with initial short-term memory deficits that make learning new information difficult, but other areas of cognition such as word-finding and executive function can also decline. As a patient progresses through mild, moderate, and severe stages of AD, greater memory deficits, increased confusion, and personality and behavioral changes, among other symptoms, are frequently observed and lead to round-the-clock assistance needs with everyday activities.

The precise brain mechanism affected by neural degeneration in the earliest stages of AD is still largely hypothesized. Recent evidence suggests that various subcortical brain nuclei may show the first AD-related pathology. The transentorhinal region is thought to be the first affected site in the cerebral cortex, and in later stages of the disease, atrophy spreads throughout cerebral cortex association areas. The question of when and in what ways healthy aging diverges from the incipient AD remains poorly understood and the focus of active research, with very recent research suggesting that this divergence may be observed as early as midlife. The identification of pathological aging in midlife could be transformational. The brain is thought to be modifiable in neural and cognitive ways, so early detection and intervention could lead to improved treatment and, ultimately, prevention of Alzheimer's dementia.

Before dementia's symptoms occur, an intermediate stage of mild cognitive impairment (MCI) may occur. MCI can be a transitional stage between normal aging and dementia, but not all people who experience it will develop dementia. MCI is characterized by observable cognitive deficits that resemble, but are less severe than, those typical of different dementias. Particularly in AD, pathophysiological processes leading to the disorder may have already begun an irreversible trajectory of neurodegeneration by the stage of MCI, as several studies suggest that dementia's pathology may be present years or even decades before its clinical diagnosis. Intervention prior to the development of MCI thus may be necessary to significantly reduce dementia incidence. However, the early divergence of healthy and pathological aging remains elusive.

Associations have been found between higher risk for AD and greater midlife decline in episodic memory and executive function. Other evidence may suggest, however, that trends in visuospatial ability deficits more strongly differentiate healthy vs. pathological aging in midlife. Other cognitive domains such as attention and language abilities have not yet displayed substantial differences in middle-aged individuals of varying dementia risk.

In addition to cognitive markers, structural neuroimaging has shown diverging trends in gray matter reduction and loss of white matter integrity in healthy vs. pathological aging. Healthy aging is more strongly associated with decline in frontal regions, while middle-aged individuals more likely to develop AD have shown greater gray matter reductions and loss of white matter integrity. Additionally, midlife volumetric reductions in the fronto-striatal executive network seem to be a normal part of aging, while reductions in the medial temporo-parietal episodic memory network seem to indicate pathological aging. Finally, entorhinal cortex and hippocampal atrophy rates appear to diverge in healthy and pathological brain aging, but it is not yet known if this divergence is relevant to midlife.

Link: https://doi.org/10.3389/fnagi.2018.00275