Fight Aging!

It has been going on eight years since I last speculated on the order of arrival of the first rejuvenation therapies. Tempus fugit, and time for an updated version! Eight years is a long enough span of time for the first of those rejuvenation therapies to now exist, albeit in a prototypical form, arguably proven in principle but not concretely. The world progresses but my biases remain much the same: the first rejuvenation therapies to work well enough to merit the name will be based on the SENS vision, that aging is at root caused by a few classes of accumulated cell and tissue damage, and biotechnologies that either repair that damage or render it irrelevant will as a result produce rejuvenation. The number of groups aiming to produce these therapies has grown considerably. A longevity industry now exists, scores of biotech and pharmaceutical companies where eight years ago there were only a handful. We are eight years further into the grand transition across decades that is taking place in the medical life sciences, in which the treatment of aging will grow to become the majority of medicine.

Age-related diseases are age-related precisely because they are caused by the same processes of damage that cause aging. The only distinctions between aging and disease are the names given to various collections of symptoms. All of frailty, disease, weakness, pain, and suffering in aging is the result of accumulated damage and consequent dysfunction at the level of cells and protein machinery inside those cells. Once the medical community becomes firmly set on the goal of repairing that damage, humanity will be well on its way to controlling and managing aging as a chronic condition, preventing it from causing harm to the patient by periodically repairing and removing the causes of aging before they rise to the level of producing symptoms and dysfunction. The therapies of the increasingly near future will be very different from those of the past. The full rejuvenation toolkit of the next few decades will consist of a range of different treatments, each targeting a different type of molecular damage in cells and tissues. What follows is a list of potential (and existing!) rejuvenation therapies in a speculative order of arrival.

1) Clearance of Senescent Cells

A good number of companies are presently developing a wide range of senolytic approaches to selectively destroying senescent cells, thereby removing their contribution to degenerative aging. A wide range of small molecules provoke apoptosis in senescent cells in a wide range of different ways, while other approaches train the immune system to better destroy lingering senescent cells. Studies in mice continue to demonstrate rapid, sizable reversal of aspects of aging and many different age-related diseases following the use of senolytic therapies. The most advanced of the first generation senolytic therapies are in phase 2 clinical trials. Given another decade there will be multiple novel senolytic drugs approved for use in the clinic, and no doubt increasingly used off-label by older individuals.

I'll make the argument that the first effective senolytic therapy to be tested in animals, the dasatinib and quercetin combination, is both legitimately a rejuvenation therapy and also readily available to anyone who wants to undergo the treatment. The use of dasatinib and quercetin in combination has been demonstrated to clear senescent cells from some human tissues to a similar degree as it does in mice. It is prescribed off-label by more adventurous physicians and anti-aging practices. It will likely be decades before we know the degree to which any senolytic affects human life expectancy - no-one seems much incentivized to run the sort of long-term human trial that would be required. Nonetheless, the burden of senescent cells is in principle a component of aging, supported by a great deal of animal data. Dasatinib and quercetin removes some of that burden, and this is rejuvenation to my eyes, even if broader benefits to health remain to be demonstrated comprehensively in human trials.

2) Restoration of a Youthful Gut Microbiome

The gut microbiome ages in the sense that the distribution of microbial populations changes in harmful ways: more pro-inflammatory microbes and fewer microbes capable of generating beneficial metabolites. Animal studies suggest that the state of the gut microbiome is at least as consequential to long-term health as diet and exercise. As is the case for senolytics, proven ways to reverse age-related changes in gut microbiome exist, but are not widely used, and it will most likely remain unclear for decades to come as to exactly how much of an effect such a rejuvenation has on human long-term health and life span.

The most obvious and cost-effective intervention for rejuvenation of the aged gut microbiome, the results demonstrated in animal studies and a few small human trials, is fecal microbiota transplant from a young individual. This produces a lasting reset of the gut microbe, and can be readily carried out by anyone willing to put in the work. There are even services that sell screened fecal material from young donors. A second approach is immunization with flagellin to encourage the immune system to clear unwanted microbes, those equipped with flagellae. These microbes are largely harmful, causing chronic inflammation, as well as diminishing the populate size of beneficial species by outcompeting them.

Unlike senolytics, there is no rush to commercialize forms of fecal microbiota transplant for the treatment of age-related conditions. There is one FDA-approved fecal microbiota transplantation therapy, for a condition in which the intestine is overrun with pathological bacteria, but that is about it. Thus it seems unlikely that concrete data will emerge any time soon on the degree to which gut microbime rejuvenation improves health and life span. While we can say that it is evidently rejuvenation, and animal data supports that assertion, whether it is rejuvenation to a practical degree in humans remains to be proven.

3) Clearance of the First Few Types of Amyloid

There are about twenty different types of amyloid in the human body, misfolded proteins that form solid deposits. Not all are robustly associated with age-related dysfunction, but of those that are, some progress has been made towards effective therapies based on either direct clearance or interfering in the pace of creation of altered proteins. In the matter of the amyloid-β associated with Alzheimer's disease, there are now several immunotherapies that have demonstrated effective clearance of amyloid-β from the brain. The side-effect profile leaves much to be desired, and it has become clear that late stage Alzheimer's is past the point at which clearing amyloid-β helps all that much. It may well be a useful preventative strategy, however, assuming that the treatments for clearance can be made more benign.

Transthyretin amyloid is associated with heart disease, and is thought to be the primary cause of death in supercentenarians. There are now FDA-approved therapies based on interfering in the creation of altered transthyretin. Some are applicable to the wild-type rather than genetic condition of transthyretin amyloidosis. Arguably every older person should be using these intermittently, assuming a mild side-effect profile, but it will take some time for costs to fall to the point at which this is practical.

This sentiment applies to any therapy targeting forms of amyloid - and there are many more forms to be addressed. To the degree that these treatments are effective and safe, everyone much over the age of 40 should be undergoing a course of treatment every few years. Should we expect more such treatments to emerge over the next decade? Perhaps. More attention is being given to the amyloid called medin, for example, drawing attention to its contributions to the pathology of degenerative aging. It may be that developers will turn their attention to this and other amyloids, but it is hard to predict how fashion and happenstance steers the choice of investment into specific avenues of medical development.

4) A Robust Cure for Cancer

If asked a decade ago, a universal cure for cancer looked fairly distant. There was clearly work on telomeres and telomerase relevant to cancer, but it didn't have the look of programs ready to make the leap to the clinic. All cancers depend absolutely on the ability to continually lengthen telomeres, and so avoid the Hayflick limit on cell replication. Telomere lengthening occurs through the activity of telomerase or the less well understood alternative lengthening of telomeres (ALT) mechanisms. If telomerase and ALT can both be blocked, temporarily and either globally throughout the body or selectively in cancerous tissue, then cancer will wither and become controllable. This is too fundamental a part of cellular biochemistry for the rapid mutational evolution of cancer cells to work around. Stem cell populations will suffer while telomerase activity is blocked, as they require telomere lengthening for self-renewal, but that is a lesser problem when compared to cancer and one that the stem cell research community will become increasingly able to address in the years ahead.

So a decade ago the fundamental research was progressing, but not all that rapidly. Still, all it takes is one innovative approach to produce good enough animal data, and a clinical program will rapidly arise. At present the drug called THIO is in clinical trials after an accelerated program of development at Maia Biotechnology. THIO is metabolized and utilized by telomerase, then incorporated into telomeres to cause disruptive consequences leading to cell death. Since near all cancer cells aggressively utilize telomerase, these are the cells that die when THIO is introduced. It should work for the 90% of cancers that do not evolve to make use of ALT, and will be widely used off-label following clinical approval for any one type of cancer. From this starting point, we might expect a great deal more effort in the decades to come to focus on telomere lengthening as a primary target in cancer - and at some point a group with a novel approach will swoop in to deal with the remaining ALT part of the problem.

5) Thymic Rejuvenation to Increase the Supply of Immune Cells

Another possible approach to partially restore lost function in the aging immune system is to increase the pace at which new immune cells are created. This is a very slow pace indeed in older people, due in large part to the age-related decline of the thymus. The thymus acts as a nursery for the maturation of T cells, and its atrophy thus restricts the rate at which new cells enter circulation. Over the 2010s, there was some progress towards engineering of replacement active thymus tissue, as well as methods of providing signal proteins that instruct the old thymus to regenerate and begin to act in a more youthful manner. Transplants of young thymus organs into old mice demonstrated that this class of approach can produce a meaningful improvement in immune function, and thereby extend healthy life.

A decade ago, this was one of a number of regenerative approaches that were on the verge, just waiting for someone to join the final two dots together, found a biotech company, and get moving. That now seems to be happening. The approach of providing signal proteins has proven to be hard, but there are now a few biotech companies, some quite well funded and connected, focused on either (a) cell therapies using cell types that naturally home to the thymus, such as Thymmune Therapeutics, or (b) looking for small molecules that cleverly interfere in the regulation of thymus growth while avoiding the pitfalls associated with past efforts, such as Thymofox.

Further, Intervene Immune has run clinical trials of a growth hormone approach, producing data to suggest a modest degree of thymic regrowth over a year or more of treatment; interestingly data from the CALERIE trial of calorie restriction indicates a similar gain from a few years of slight calorie restriction, implying thymic involution to be perhaps a more dynamic process than suspected. Meanwhile, some interesting advances are taking place in the research community, such as the possibility of gene therapy delivery system that can in fact effectively target the thymus following intravenous delivery. Exciting times! The state of the field looks promising for some form of effective thymus rejuvenation strategy to emerge in the decade ahead.

6) Mitochondrial Repair

Mitochondria, the power plants of the cell, are herds of bacteria-like organelles that bear their own DNA. This DNA becomes damaged in the course of normal cellular processes, and certain forms of mitochondrial DNA damage - to the thirteen genes needed for oxidative phosphorylation - produce malfunctioning mitochondria that can overtake their cells. Further, epigenetic changes characteristic of aging disrupt the dynamics of mitochondria, disrupting the quality control process of mitophagy. This also allows poorly functioning mitochondria to replicate and prosper, but occurs in cells throughout the body.

There are numerous possible approaches to the problem of dysfunctional mitochondrial in aged tissues: upregulation of existing repair mechanisms of mitophagy; delivery of replacement mitochondrial DNA or whole mitochondria; partial reprogramming of cells to restore normal gene expression relating to mitochondrial dynamics and mitophagy; and so forth. Of these, the closest to the clinic are mitochondrial transfusion therapies and the various approaches to adjusting repair and propagation of damaged states in mitochondria, trying to tilt the balance to favor better function. The development of partial reprogramming therapies has enormous funding at present, but arguably much larger challenges must be solved before it can be broadly applied to tissues across the body. It remains hard to say how effective these approaches will be relevative to one another. How long will they last before fading in an aged tissue environment? Also unknown.

In the case of mitochondrial transfusion, two companies (cellvie and Mitrix Bio) are working towards clinical programs. Their challenge is near entirely the development of the processes by which enough mitochondria for human use can be manufactured. From the present starting point that is a tough scaling problem. In the case of altering mitochondrial dynamics or the regulation of mitophagy, there are range of possibilities already sold in the supplement market, such as SkQ1 and MitoQ, none of which are all that impressive when compared to the effects of exercise. Will companies like Stealth Bio do any better than this? That remains to be seen. There is a market for small molecule and supplement-like products that are not as good as exercise, but it is probably not a market that should interest us.

The SENS approach is somewhat more radical, involving gene therapy to introduce copies of the thirteen genes into the cell nucleus, altered to ensure that the proteins produced can migrate back to the mitochondria where they are needed. Mitochondria will thus have the necessary protein machinery for correct function regardless of the state of their DNA. This has been demonstrated for three of the thirteen genes of interest, numbers two and three in 2016, and getting that far took the better part of ten years at a low level of funding. A company, Gensight Biologics has championed this approach in clinical trials for one of the genes, in the treatment of a rare genetic disorder, but little further or broader development has taken place outside of academia. Will it be useful to have therapies that fix half the problem, moving six or seven genes to the cell nucleus? Will that reduce the impact on aging by half? It is hard to say until that is possible and demonstrated in mice. A decade ago, it seemed plausible that researchers would get there by now - but this has not happened. There is still too little funding and support for this approach, and one might well argue that backing mitochondrial transfusion seems a better wager at this point, even given the unknowns.

7) Reversing Stem Cell Aging

The stem cell industry remains massively funded, and is ultimately on a collision course with stem cell aging. Most of the conditions that one would want to use stem cell therapies to treat are age-related conditions. Researchers must thus work towards ensuring that the altered cellular environment, the damage of aging, doesn't prevent these treatments from working - that pristine cells can integrate and work well, not immediately die or decline in response to an age-damaged stem cell niche. Despite some progress over the past decade, particularly around the question of whether cellular senescence is degrading cell therapy outcomes, it is fair to say that the research community isn't engaging aggressively with this goal, however. Possible reasons for this include the fact that most stem cell treatments, even without addressing issues of the aged tissue environment, represent a considerable improvement in the scope of what is possible to achieve through modern medicine. So the incentive to go further is perhaps not as strong as it might otherwise be.

Stem cell populations become damaged by age, falling into quiescence or declining in overall numbers. They should be replaced with new populations, but while simple in concept, and even achieved for some cell types, such as the blood stem cells that produce immune cells, this is easier said than done for the body as a whole. Every tissue type is its own special case. There are hundreds of types of cell in the body. Each supporting stem cell population has so far required specific methodologies to be developed, and specific behaviors and biochemistry to be laboriously mapped. It isn't even entirely clear that researchers have found all of the stem cell or stem-like cell populations of interest. There is an enormous amount of work to be done here, and at the moment the field is still largely in the phase of getting the basics, the maps, and the reliable therapeutic methods sorted out for a few of the better understood tissue types, bone marrow and muscles in particular. All in all this has the look of a long-term, incremental prospect, despite the high levels of funding for this line of medical research and development.

Are there ways other than complete replacement of cell populations that might enable reinvigoration of aged stem cell populations? It seems that there might be, though we can argue about the degree to which these approaches are in any way affecting aging per se. There are ways to adjust the regulation of stem cell behavior that improve tissue function even given that one is working with aged stem cell populations. To pick one example, Ship of Theseus develops an approach based on Hox family transcription factors that appears to provoke greater muscle stem cell activity. As another example, look at the work of Mogling Bio, building on demonstrations showing CASIN to improve stem cell function in a number of populations, particularly the hematopoietic stem cells of the bone marrow. These and other, analogous approaches will find their way to clinic long before replacement of stem cell populations is a going concern.

8) Clearance of Cross-Links, Glucosepane-Based and Others

Clearance of cross-links in the extracellular matrix of tissues is, like senescent cell destruction, one of the most exciting of early rejuvenation therapies. It is a single target that influences a great many aspects of aging: if we look at just the cross-link-induced loss of elasticity in blood vessels alone, that has a major influence on mortality through hypertension and consequent impact on cardiovascular health. It is also a single target in the sense that near all persistent cross-links important to aging in humans so far appear to be based on one compound, glucosepane. Thus all that is needed is one drug candidate.

The attention given to glucosepane cross-link clearance remains anemic, despite considerable efforts to create a toolkit and unblock the research community conducted by the SENS Research Foundation and their allies in the research community, including a method of cheaply and reliably synthesizing glucosepane. Work in the mid-2010s conducted in the Spiegel Lab, as well as other parallel lines of research, led to the formation of Revel Pharmaceuticals to commercialize glucosepane cross-link breakers. Unfortunately, little further progress has occurred - while still being a sizable step forward over the state of the field a decade ago, this remains a narrow effort pioneered by few researchers.

A small number of other narrow programs have emerged focused on the lens of the eye, where different forms of cross-linking are involved in stiffening the lens to the point at which muscle strength is inadequate to focus correctly. A lipoic acid choline ester approach looked promising, but failed in Phase 2 trials. Another company, Lento Bio, is now in the early stages of working on another approach to the cross-links that stiffen the lens. Again, there are few groups in this space, and more are needed to ensure a good chance of progress towards the clinic in the near future.

9) Partial Reprogramming

Ten years ago, one could mount a good argument for the epigenetic change characteristic of aging to be distant from the root causes of aging, a downstream effect. Since then, evidence has mounted for some of this epigenetic change to be a direct result of forms of DNA damage and repair, tying it directly to one of the root causes of aging, the stochastic DNA damage that takes place constantly in all cells. At the same time, researchers have demonstrated that the reprogramming techniques based on exposure to Yamanaka factors, initially used in efforts to produce induced pluripotent stem cells for research and cell therapy development, reversed epigenetic aging long before they started to change cell fate. Short-term exposure to reprogramming, now known as partial reprogramming, is potentially a way to reset the epigenetic changes characteristic of aging and restore many forms of cell function. Clearly partial reprgramming cannot help with existing mutational damage to nuclear DNA, nor with the presence of persistent molecules that even youthful cells cannot effectively break down. But it is demonstrated to restore lost mitochondrial function, to pick one example.

When might we expect the first therapies based on partial reprogramming to reach the clinic? This part of the field has become enormously well funded in recent years. Given the the $3 billion investment in Altos Labs alone, never mind the other few biotech startup companies with more than $100M in initial funding each, such as Retro Biosciences and NewLimit, there will be no shortage of effort put into preclinical and clinical development. Nonetheless, the challenges are sizable. Different cell types and tissues require different exposures and balances of reprogramming factors for best effect. Too much reprogramming produces cancer via induced pluripotency. Too much reprogramming in the liver and intestines seems very detrimental to health in animal studies. The most likely path to near term therapies is to restrict them to isolated organs, such as the retina and optic nerve. Another possibility is for the groups working on small molecules capable of triggering expression of reprogramming factors to land on something that is more useful for systemic delivery than the gene therapy approaches, but development of small molecule reprogramming is still in the very early stages.

So it remains to be seen as to how matters will unfold in the years ahead. The advent of reprogramming as the leading, widely recognized approach to rejuvenation, and the degree to which funding poured into this project, caught a lot of people by surprise. It seems likely that the surprises will continue, given that we are only a few years into the development of this part of the field.

10) Immune System Destruction and Restoration

The destruction and recreation of the immune system is not a widespread technique, but it has been demonstrated successfully in human clinical trials and animal studies in a variety of contexts over the past twenty years. Researchers and clinicians have used chemotherapy to destroy immune cells and the hematopoietic cells that create them, followed by hematopoietic stem cell transplant (HSCT) to reconstruct the immune system. This approach has resulted in effective cures for multiple sclerosis patients, and has been attempted with varying degrees of success for a number of other autoimmune conditions. The catch here is that chemotherapy and HSCT are not trivial undertakings. The costs and risks are significant, both immediately and in terms of impact on later health and life expectancy. It only makes sense for people who are otherwise on their way to an early death or disability, as is the case for multiple sclerosis patients. However, there are a number of approaches on the way to practical realization that will make chemotherapy obsolete for the selective destruction of immune cells and stem cells - approaches with minimal or no side-effects. See a combined approach targeting c-kit and CD47, for example. Sophisticated cell targeting systems such as the gene therapy approach developed for senescent cell clearance by Oisin Biotechnologies could also be turned to stem cell or immune cell destruction, given suitable markers of cell chemistry. There are quite a few of these, any one of which would be good enough.

Replacing the taxing procedures of chemotherapy and HSCT with a safe, side-effect-free treatment would mean that the field of immune system restoration could immediately expand to assess its merits as a treatment for immunosenescence, the age-related failure of the immune system. This decay is in part a problem of configuration: a lifetime of exposure to persistent pathogens such as herpesviruses leaves too much of the immune system uselessly devoted to specific targets that it cannot effectively clear from the body, and too little left ready to fight new threats and destroy malfunctioning cells. Then there are various forms of autoimmunity that become prevalent in older people, not all of which are in any way fully understood - consider the comparatively recent discovery of type 4 diabetes, for example. Clearing out the entire immune system, all of its memory and quirks, and restarting it fresh with a new supply of stem cells is a good approach to many of the issues in the aged immune system. Not all of them, but many of them, and considering the broad influence immune function has over many other aspects of health and tissue function, it seems a worthwhile goal.

That said, has there been much meaningful progress in this part of the field over the past ten years? Not really. Some research has moved forward incrementally, such as on the topic of age-associated B cells and their depletion, or clearance of microglia in the brain. In the broader field, good number of immunomodulatory approaches to therapy are under development at various stages, some even explicitly aimed at restoring better immune function in the old, but very few target clearance of immune cell populations. The only one that springs to mind is related to the aforementioned clearance of microglia in the brain, since there are existing drugs and a simple mechanism - CSF1R inhibition - by which this can be achieved. The early stage venture Glionics would like to use this clearance and recovery as a way to delivery drugs throughout the brain, rather than specifically to achieve benefits resulting from clearance.

11) Clearance of Other Amyloids, Aggregates, and Sundry Lysosomal Garbage

A good portion of aging is driven by the accumulation of waste products, either because they are hard for our biochemistry to break down, is the case for glucosepane cross-links and many of the components of lipofuscin that degrade lysosomal function in long-lived cells, or because clearance systems fail over time, as appears likely to be the case for the amyloid-β involved in Alzheimer's disease. There are a lot of these compounds: a score of amyloids, any number of lipofuscin constituents, the altered tau that shows up in tauopathies, and so on and so forth. In many cases there isn't even a good defensible link between a specific waste compound and specific age-related diseases: the waste is one contribution buried in many contributions, and the research community won't start putting numbers to relative importance until it is possible to clear out these contributions one by one and observe the results.

A range of research groups are picking away at individual forms of waste, some with large amounts of funding, some with very little funding, but this is a similar situation to that I outlined above for stem cell aging. There is a huge amount of work to accomplish because there are many targets to address, and with few exceptions, such as amyloid-β, it is unclear which of the targets are the most important. They will all have to be addressed, in some order, but there are only so many researchers and only so much funding. We can hope that as the first effective therapies spread into wider clinical use, treatments for the clearance of forms of amyloid, there will be a growing enthusiasm for work on ways to remove other types of metabolic waste.