Fight Aging! Newsletter, October 15th 2018

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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  • The Popular Press in Better Form on Senolytic Research and Development
  • A Biodegradable Device for Electrical Stimulation of Nerve Regrowth
  • Aging as Damage versus Aging as Evolved Program from the Viewpoint of a Programmed Aging Theorist
  • A Few More Reasons Not to Become Overweight and Obese
  • Salivary Gland Organoids Integrate and Generate Saliva When Implanted into Mice
  • Replacement of Aged Microglia Partially Reverses Cognitive Decline in Mice
  • Glycation Damage as a Hub of Aging Pathology
  • Deciding How Much Life is Enough: Another Way to Sabotage Your Future Self
  • Prelamin A May Contribute to Sarcopenia in Normal Aging
  • The Road to Dementia Starts Early
  • A Problem Population of Monocytes are Found to be Senescent Cells
  • A Human SGLT1 Variant Reduces Glucose and Calorie Uptake, thereby Lowering Disease Risk and Mortality
  • Immune System Aging and Risk of Lymphoma
  • Discussing the Longevity Investor Network
  • Evidence for Gender Longevity Differences to Arise from Mating Strategies

The Popular Press in Better Form on Senolytic Research and Development

Research programs and investment in commercial development related to senolytic therapies are growing rapidly, particularly in the last couple of years. As today's article demonstrations, journalists in the popular press are improving when it comes to their ability to report sensibly on these developments. This has taken far too long to come to pass; it wasn't all that long ago that near every article in the media on the prospects for treating aging was some combination of nonsense, scorn, and fear-mongering.

Senolytic treatments are those that selectively destroy senescent cells in aged tissues. The accumulation of senescent cells is one of the root causes of aging; even in small numbers these errant cells cause chronic inflammation and degrade tissue function in numerous ways via the signal molecules they generate. Removing senescent cells is a form of rejuvenation, capable of reversing aspects of aging and age-related disease and extending healthy life span. The data in mice is robust, impressive, and expanding. The first human data will be published over the course of the year ahead.

Clearance of senescent cells as a way to intervene in the aging process has been recognized as a plausible goal for quite some time, and in fact was in the SENS rejuvenation research proposals from their inception around the turn of the century. Unfortunately, aging was not seen as a legitimate target for therapy at that time, and obtaining support for this line of work has required long years of advocacy and philanthropy. In a better world, in which the research community had not relinquished its duty in the matter of aging for the better part of a generation, this all could have happened two decades or more before it finally arrived.

These days there seems a certain eagerness to forget the years in which the SENS program was mocked, researchers dismissed the likely relevance of senescent cells to aging, and the talking heads of the media sneered at the idea of treating aging as a medical condition. It is now said that nothing could have happened any faster than it did, that in fact everyone was doing the right thing just as soon as they could. This is self-serving nonsense. Countless lives have been lost and continue to be lost because of entirely unnecessary delay in the matter of addressing aging and age-related disease as an urgent concern. Senolytics is just one branch of many needed approaches. Most of the others, biotechnologies that could be just as influential on the progression of aging, are still minority concerns, disregarded by the research community, the press, and the public at large. Much work remains to be accomplished.

Want to live for ever? Flush out your zombie cells

Two blown-up images of microscope slides are the same cross-sections of mouse knees from a six-month-old and an 18-month-old animal. The older mouse's image has a splattering of little yellow dots, the younger barely any. That staining indicates the presence of so-called senescent cells - "zombie cells" that are damaged and that, as a defence against cancer, have ceased to divide but are also resistant to dying. They are known to accumulate with age, as the immune system can no longer clear them. They have been identified as a cause of ageing in mice, at least partially responsible for most age-related diseases. Seeing the slides, it makes me worried about my own knees. "Tell us about it," says Pedro Beltran who heads the biology department at Unity Biotechnology, a 90 person-strong company trying to halt, slow or reverse age-associated diseases in humans by killing senescent cells. "We think about it all the time... Wait until you see your brain."

Developing therapies to kill senescent cells is a burgeoning part of the wider quest to defeat ageing and keep people healthier longer. Unity, which was founded in 2011, has received more than 385m in funding to date. Its first drug entered early clinical trials in June, aimed at treating osteoarthritis. Other startups with zombie cells in their sights include Seattle-based Oisín Biotechnologies which was founded in 2016 and has raised around 4m; Senolytic Therapeutics whose scientific development is based in Spain and which was established last September; and Cleara Biotech, formed this June backed by 3m in funding and based in the Netherlands. In addition, Scottish company CellAge, also founded in 2016, has raised about 100,000 to date, partly through a crowdfunding campaign.

"The concept is totally getting the imagination of investors because it isn't about just slowing down the clock but actually turning it back and rejuvenating people," says Aubrey de Grey, who for nearly a decade through his campaigning charity the Strategies for Engineered Negligible Senescence (Sens) Research Foundation has been urging scientists to work towards eliminating ageing and extending healthy lifespan indefinitely. "I've never seen a field grow so quickly," says Laura Niedernhofer, a researcher who studies ageing at the University of Minnesota Medical School, adding that there isn't even as yet any human data. "There is a recognition that there is potential here to go to a root cause of ageing."

To date about a dozen drugs have been reported that can mop up zombie cells. Clearance of the cells in mice has been shown to delay or alleviate everything from frailty to cardiovascular dysfunction to osteoporosis to, most recently, neurological disorders - though whether killing senescent cells extends life is complicated. Most of the benefit seen in mice seems to be in extending healthspan, the time free of frailty or disease, and as a result median lifespan. True longevity - the maximum time the animals remain alive for - remains relatively unchanged, though studies show a 36% extension of remaining lifespan in mice that were treated when they were very old.

Unity's method is based on targeting the biological pathways senescent cells use to resist the normal death of ageing cells. Inhibit the right pathway and death can be "nudged" to occur. The company's approach is to find small molecules (so called "senolytics") that can do this. Oisín is trying to do something more ambitious: killing all a person's zombie cells in one go. The idea is to load the body with nanoparticles that insert a "suicide gene" into every cell. It only triggers if a cell has a lot of a particular protein (p16) that acts as a marker of zombie cells, albeit imperfectly.

Oisín is planning to run what co-founder Gary Hudson calls a "stealth ageing trial" in people with a variety of late-stage cancers next year (there are lots of cancers for which no treatment is available so the regulatory bar to the clinic is lower). That will test a version of its anti-ageing therapeutic modified to target cancer, but it may also be possible to see - by virtue of observable age characteristics - whether the drug has had any effect on senescent cells.

If eliminating senescent cells does improve specific age-related diseases in humans, the next step will be to go broader. That's tough because regulators don't recognise ageing as a treatable condition. On the positive side, if there is an eventual treatment it wouldn't have to be taken every day. Imagine an annual or biennial therapy, starting from middle age, that sweeps away any senescent cells building up. And because you wouldn't chronically be on the drug, the risk of side-effects would be minimised.

A Biodegradable Device for Electrical Stimulation of Nerve Regrowth

Living tissue has an electromagnetic component to its operation, both at the very small scale inside cellular processes, but also at the larger scale of signaling through the nervous system. I would say that beyond a few well established lines of research and development, such as work on pacemakers or direct stimulation of nerves, the manipulation of electromagnetic fields and currents for therapeutic effect is far from being a mature area of the life sciences. If one roves the literature in search of connections between electromagnetism, regeneration, and metabolism, there are many small interesting areas of study, a few papers here and a few papers there, but nothing that approaches the breadth and funding of, say, any given field under the broad umbrella of small molecule drug development. Perhaps this indicates a comparative lack of potential. Alternatively, perhaps it indicates that modern materials science and biotechnologies are a requirement to proceed effectively, and thus the field is by necessity still young.

The most advanced lines of work in this corner of the life science community are those involving forms of direct electrical stimulation of tissues, often in attempts to mimic natural electrical currents in the body. In these places in our physiology comparatively crude approaches can achieve results that are useful enough to build into therapies. Consider pacemakers, for example, or deep brain stimulation. While modern examples are increasingly subtle and reliable, benefits nonetheless result from electrical stimulation in absence of a complete understanding of what that stimulation does to cellular metabolism. The same sort of paradigm operates for research groups working on the electrical stimulation of damaged nerves; the ability to produce benefits for patients is somewhat ahead of the understanding of what exactly is going on under the hood in terms of cellular activity and signaling. It does tend to make progress more a matter of trial and error than it might otherwise be, but progress is progress; it should all be welcomed.

Implantable, biodegradable devices speed nerve regeneration in rats

Researchers have developed an implantable, biodegradable device that delivers regular pulses of electricity to damaged peripheral nerves in rats, helping the animals regrow nerves in their legs and recover their nerve function and muscle strength more quickly. The size of a quarter, the device lasts about two weeks before being completely absorbed into the body. "We know that electrical stimulation during surgery helps, but once the surgery is over, the window for intervening is closed. With this device, we've shown that electrical stimulation given on a scheduled basis can further enhance nerve recovery. This and other platforms represent the first examples of a 'bioresorbable electronic medicine' - engineered systems that provide active, therapeutic function in a programmable, dosed format and then naturally disappear into the body, without a trace."

The researchers studied rats with injured sciatic nerves. This nerve sends signals up and down the legs and controls the hamstrings and muscles of the lower legs and feet. They used the device to provide one hour per day of electrical stimulation to the rats for one, three or six days, or no electrical stimulation at all, and then monitored their recovery for the next 10 weeks. Any electrical stimulation was better than none at all at helping the rats recover muscle mass and muscle strength. In addition, the more days of electrical stimulation the rats received, the more quickly and thoroughly they recovered nerve signaling and muscle strength. "Before we did this study, we weren't sure that longer stimulation would make a difference, and now that we know it does we can start trying to find the ideal time frame to maximize recovery. Had we delivered electrical stimulation for 12 days instead of six, would there have been more therapeutic benefit? Maybe. We're looking into that now."

Wireless bioresorbable electronic system enables sustained nonpharmacological neuroregenerative therapy

Peripheral nerve injuries represent a significant problem in public health, constituting 2-5% of all trauma cases1. For severe nerve injuries, even advanced forms of clinical intervention often lead to incomplete and unsatisfactory motor and/or sensory function. Numerous studies report the potential of pharmacological approaches (for example, growth factors, immunosuppressants) to accelerate and enhance nerve regeneration in rodent models. Unfortunately, few have had a positive impact in clinical practice.

Direct intraoperative electrical stimulation of injured nerve tissue proximal to the site of repair has been demonstrated to enhance and accelerate functional recovery, suggesting a novel nonpharmacological, bioelectric form of therapy that could complement existing surgical approaches. A significant limitation of this technique is that existing protocols are constrained to intraoperative use and limited therapeutic benefits. Herein we introduce (i) a platform for wireless, programmable electrical peripheral nerve stimulation, built with a collection of circuit elements and substrates that are entirely bioresorbable and biocompatible, and (ii) the first reported demonstration of enhanced neuroregeneration and functional recovery in rodent models as a result of multiple episodes of electrical stimulation of injured nervous tissue.

Aging as Damage versus Aging as Evolved Program from the Viewpoint of a Programmed Aging Theorist

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.

A Few More Reasons Not to Become Overweight and Obese

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.

Salivary Gland Organoids Integrate and Generate Saliva When Implanted into Mice

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.

Replacement of Aged Microglia Partially Reverses Cognitive Decline in Mice

Researchers here report on a compelling demonstration that shows the degree to which dysfunctional microglia contribute to age-related neurodegeneration. The scientists use a pharmacological approach to greatly deplete the microglial population and then allow it to recover naturally. The influx of new microglia improves many aspects of brain function, though interestingly this procedure doesn't appear to affect the inflammatory status of brain tissue. Most neurodegenerative conditions are thought to be driven to some degree by inflammation, while the data here suggests that the activities of glial cells that support neuronal function are not to be neglected.

The data also suggests that inflammation is a reaction to the state of brain tissue, rather than something that arises from intrinsic issues within glial cells. That conclusion is contradicted by other recent research in which senescent glial cells are shown to definitively contribute to the pathology of neurodegenerative disease. Perhaps the resolution of this contradiction is that senescent glial cells are resistant to depletion via the methodology used here, but that is pure speculation on my part.

Microglia are the primary immune cells of the central nervous system (CNS), where they act as responders in the event of infection or injury. Microglia "at rest" are highly dynamic cells, constantly extending and retracting their processes to sample the local environment. Beyond immune function, studies implicate microglia in maintaining tissue homeostasis and synaptic connectivity. In neurodegenerative disease or following traumatic brain injury, microglia can assume long-lasting changes in morphology, densities, gene expression, and cytokine/chemokine production. Studies have indicated that these signals, when persistent in the brain, can lead to further harm.

Microglia are critically dependent upon signaling through the colony-stimulating factor 1 receptor (CSF1R) for their survival. We identified several orally bioavailable CSF1R inhibitors that noninvasively cross the blood-brain barrier, leading to brain-wide microglial elimination within days, which continues for as long as CSF1R inhibition is present. In particular, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells, effectively replacing the entire microglial tissue. This process takes approximately 14-21 days to complete; thereafter, the new microglia are virtually indistinguishable from the resident microglia.

With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation-related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age-related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis.

Age-related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age-induced deficits in long-term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

Glycation Damage as a Hub of Aging Pathology

Glycation is a form of chemical reaction in which a sugar bonds to a protein or lipid. There are many forms of sugary molecules floating around in our metabolism, but broadly the role of glycation in aging might be divided into two portions, both of which involved what are known as advanced glycation endproducts (AGEs). In the first, short-lived AGEs produce chronic inflammation and otherwise disrupt cell function through their interaction with cell surface receptors such as RAGE and RANKL. This is a prominent feature of metabolic syndrome, type 2 diabetes, and other pathological states of metabolism. In the second, long-lived AGEs accumulate slowly over time, linking together molecules in the extracellular matrix and as a consequence altering the structural properties of tissue. This may be most important in skin and blood vessels, where it contributes to loss of elasticity, but is also apparent in cartilage and bone, where it causes loss of strength and resilience.

In the first case, the solution is to eat less and lose weight, as this can address near all of the prevalent problems related to metabolic disorders in this modern world of cheap calories and indolence. In the second case new biotechnology is required, however: our biochemistry just isn't capable of dealing with persistent AGEs and the cross-links they produce in the extracellular matrix. The most advanced of present approaches involves mining the bacterial world for species capable of breaking down persistent AGEs and extracting the relevant enzymes as the basis for a therapy. This is by no means a popular area of research, however. When it comes to AGEs, most of the scientific community is far more interested in producing pharmaceutical therapies that tinker with short-term AGE balance and consequences in type 2 diabetes. We can hope that this will change in the years ahead.

Glycation is both a physiological and pathological process which mainly affects proteins, nucleic acids, and lipids. Exogenous and endogenous glycation produces deleterious reactions that take place principally in the extracellular matrix environment or within the cell cytosol and organelles. Advanced glycation end product (AGE) formation begins by the non-enzymatic glycation of free amino groups by sugars and aldehydes which leads to a succession of rearrangements of intermediate compounds and ultimately to irreversibly bound products known as AGEs.

The accumulation of AGEs with aging has been found in many parts of the body, including the blood, blood vessel walls, retina, lens, kidney, brain, peripheral nerves, joints, and skin. The build-up of these products results in significant changes in the metabolism, appearance, and biomechanical properties of these organs. AGEs accumulate over time because kidney function decreases with age regardless of the subject having diabetes. However, aging itself is a condition that favors AGE formation and accumulation due to the age-associated increase in oxidative stress.

In addition, repair processes are less efficient. Basal glycation that occurs over a number of years contributes to aging and can lead to various pathologies by exerting deleterious effects that, while similar to those caused by diabetes, are expressed later and often to a lesser degree. In contrast, it can also be hypothesized that the dietary restriction and qualitative and quantitative changes observed in the elderly diet, may limit their consumption of exogenous AGEs.

The accumulation of AGEs during aging is especially notable in structures that contain collagen. A build-up of glycation products is correlated with increased rigidity in the arteries, tendons, and skin. AGEs play adverse proinflammatory roles in osteoporosis and the serum level of soluble RAGE could therefore have a potential diagnostic role in the monitoring of osteoporosis progression. AGEs also play a role in the aging of skeletal muscle. Muscle mass and strength decrease during the aging process, which can increase the fragility and dependence of the elderly. Glycation and oxidation, especially with respect to lipids, also affect the pathophysiological process of age-related macular degeneration and formation of cataracts, thereby disrupting the quality of vision and the visual field.

Deciding How Much Life is Enough: Another Way to Sabotage Your Future Self

We are adept at sabotaging the person we will be. Time preference is a tyrannical aspect of the human condition; we aggressively and instinctively discount the value of everything in the decades ahead, even our own lives. People let their health run down through lack of maintenance, sabotaging their future selves of two decades hence. Another more subtle manifestation is the decision made on just how much life is enough life. The infrastructure of savings, retirement, life insurance, our peers and our families, our stories, our cultural myths and traditions, all are geared towards a life of a certain shape and length. We are encouraged to plan ahead with a line to be drawn at a given age, a time to wrap it up and shut things down.

In the era in which aging was set in stone, there was a lot to be said for managed expectations. Stoic acceptance of the inevitable requires a little time to work though and put in place firmly enough to carry through to that end. But that is no longer our era. Now that the first rejuvenation therapies exist and can be accessed easily, the extensive infrastructure devoted to a fixed span of life is an impediment. It steers people incorrectly. Numerous biotechnologies of rejuvenation are progressing towards the clinic, and most will be available in some form a few decades from now. Human life is no longer of a certain span - unless you yourself decide it should be by shutting yourself away from what is happening in the labs and the clinics.

When asked how long they want to live, people often say no more than ten years above their country's average lifespan. This, mind you, is in a world where aging is still inevitable; people know that they won't be in top shape during those ten extra years, and yet, perhaps hoping that they might be an exception to that rule, they still wish for that little extra time. Even when told that they will live these extra years in complete health, the most common choice is the current maximum recorded human lifespan, which is roughly 120 years.

If we assume that no rejuvenation therapies are available to extend the time you spend in youthful health, then it is somewhat understandable if you don't feel up for a very long life, because the odds are that its final decades will be increasingly miserable; however, if rejuvenation therapies were available, and you could be fully healthy for an indefinite time, why stop at 120 years? Life extension advocates have probably all had their fair share of conversations with people who insist that 80-odd years will be more than enough for them, health or no health - worse still, some don't care about preserving their health precisely because they think that 80 years is a sufficiently long time to live.

How long one wants to live is only his or her business; just like no one should have the right to force other people to live no longer than the current maximum (an imposition that would indirectly result from a hypothetical ban on life extension therapies), no one should have the right to force anyone else to live longer than 80 years, if that's what he or she wishes for whatever reason. Indeed, it's not the right to die when you see fit that's at issue here; the question is whether people who claim that 80 years are enough have seriously thought the matter through before making their minds up or are simply parroting what others typically say out of social pressure.

Prelamin A May Contribute to Sarcopenia in Normal Aging

Progeria is caused by a mutation in Lamin A (LMNA), a gene that codes for a vital component of cellular structure. The cells of progeria patients are misshaped and dysfunctional, leading to symptoms that appear superficially similar to highly accelerated aging. One of the outcomes of this discovery is a broadening of research into lamin proteins in normal aging; researchers have found low levels of malformed lamins and related proteins in older individuals. Evidence is accumulating for the presence of these proteins to contribute to aspects of aging, but the size of the effect is still very much in question. It may or may not be significant in comparison to, say, the harms caused by the various forms of molecular damage outlined in the SENS rejuvenation research programs. The open access paper here delves into an association between lamins and muscle cells, drawing a potential connection to the loss of muscle mass and strength that occurs with age, a condition called sarcopenia.

Biological aging involves complex dysfunctional cellular processes with unclear underlying mechanisms, including a potential involvement of alterations at the nuclear level in a wide range of tissues. Normal nuclear function requires lamin A, a protein located at the inner nuclear envelope, where it regulates nuclear integrity, architecture, and chromatin organization. Defective processing of lamin A and accumulation of its precursors, progerin and/or prelamin A, occurs during physiological aging and is also responsible for premature aging syndromes. Symptoms include growth impairment, bone and skin abnormalities, joint contractures, and muscle dysfunction. In the present study, we aimed to determine whether and how high levels of prelamin A deteriorate the function of skeletal muscle fibers.

Myofibers contain several hundred peripherally located nuclei. Each of them controls protein synthesis in a defined volume of cytoplasm termed the myonuclear domain (MND). Regular positioning of these nuclei is essential for optimal nuclear cooperation, MND size, and efficient regulation and distribution of gene products. Here, we tested the hypothesis that an accumulation of prelamin A would alter nuclear number and positioning, ultimately disrupting the ability of fibers to generate force. To test this, we used various transgenic mouse models that mimic premature aging syndromes, wherein the composition of nuclear envelope proteins is altered. We isolated and membrane-permeabilized individual muscle fibers, then ran a series of contractile and morphological analyses, including an evaluation of the 3D organization of nuclei.

Our results indicate that, in the presence of prelamin A, the abundance of nuclei and myosin content is markedly reduced within muscle fibers. This leads to a concept by which the remaining myonuclei are very distant from each other and are pushed to function beyond their maximum cytoplasmic capacity, ultimately inducing muscle fiber weakness.

The Road to Dementia Starts Early

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.

A Problem Population of Monocytes are Found to be Senescent Cells

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.

A Human SGLT1 Variant Reduces Glucose and Calorie Uptake, thereby Lowering Disease Risk and Mortality

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).

Immune System Aging and Risk of Lymphoma

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.

Discussing the Longevity Investor Network

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.

Evidence for Gender Longevity Differences to Arise from Mating Strategies

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."


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