Predicting the Order of Arrival of the First Rejuvenation Therapies

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. Until very recently, no medical technology could achieve this goal, and few research groups were even aiming for that outcome. We are in the midst of a grand transition, however, in which the research and development community is finally turning its attention to the causes of aging, understanding that this is the only way to effectively treat and cure age-related disease. 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 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, we'll be well on the way to controlling and managing aging as a chronic condition - preventing it from causing harm to the patient by periodically repairing and removing its causes before they rise to the level of producing symptoms and dysfunction. The therapies of the future will be very different from the therapies 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. In this post, I'll take a look at the likely order of arrival of some of these therapies, based on what is presently going on in research, funding, and for-profit development. This is an update to a similar post written four years ago, now become somewhat dated given recent advances in the field. Circumstances change, and considerable progress has been made in some lines of research and development.

1) Clearance of Senescent Cells

It didn't take much of a crystal ball four years ago to put senescent cell clearance in first place, the most likely therapy to arrive first. All of the pieces of the puzzle were largely in place at that time: the demonstration of benefits in mice; potential means of clearance; interested research groups. Only comparatively minor details needed filling in. Four years later no crystal ball is required at all, given that Everon Biosciences, Oisin Biotechnologies, SIWA Therapeutics, and UNITY Biotechnology are all forging ahead with various different approaches to the selective destruction of senescent cells. No doubt many groups within established Big Pharma entities are also taking a stab at this, more quietly, and with less press attention. UNITY Biotechnology has raised more than $100 million to date, demonstrating that there is broad enthusiasm for this approach to the treatment of aging and age-related disease.

With the additional attention and funding for this field, more methods of selective cell destruction have been established, and there is now a greater and more detailed understanding of the ways in which senescent cells cause harm, contributing to the aging process. Senolytic drugs that induce apoptosis have been discovered; senescent cells are primed to enter the programmed cell death process of apoptosis, and so a small nudge to all cells via a drug treatment kills many senescent cells but very few normal cells. Researchers have established that senescent cells exist in the immune system, and may be important in immune aging. Similarly, the immune cells involved in the progression of atherosclerosis are also senescent, and removing them slows the progression of that condition. Other research has shown that removing senescent cells from the lungs restores lost tissue elasticity and improves lung function. Beyond these specific details, senescent cells clearly contribute to chronic inflammation in aging, and that drives the progression of near all common age-related conditions. The less inflammation the better. These effects are caused by the signals secreted by senescent cells: that their harm is based on signaling explains how a small number of these cells, perhaps 1% by number in an aged organ, can cause such widespread havoc.

2) Immune System Destruction and Restoration

At the present time it is a challenge to pick second place. A number of fields are all equally close to realization, and happenstance in funding decisions, regulatory matters, or technical details yet to be uncovered will make the difference. The destruction and recreation of the immune system wins out because it is already possible, already demonstrated to be successful, and just missing one component part that would enable it to be used by ordinary, healthy, older people. At present researchers and clinicians use chemotherapy to destroy immune cells and the stem cells that create them. Repopulation of the immune system is carried out via cell transplants that are by now a safe and proven application of stem cell medicine, little different from the many varieties of first generation stem cell therapy. This approach has been used to cure people with multiple sclerosis, and has been attempted with varying degrees of success for a number of other autoimmune conditions for going on fifteen years now: there are researchers with a lot of experience in this type of therapy.

The catch here is that chemotherapy is a damaging experience. The cost of undergoing it is high, both immediately, and in terms of negative impact on later health and life expectancy, similar to that resulting from a life spent smoking. 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 very close 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. A combined approach targeting c-kit and CD47 was demonstrated earlier this year, 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 chemotherapy with a safe, side-effect-free treatment would mean that the established programs for immune system restoration could immediately expand to become a useful, effective treatment for immunosenescence, the age-related failure of the immune system. This 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 just how recently type 4 diabetes was discovered, 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.

3) Clearance of the First Few Types of Amyloid

There are about twenty different types of amyloid, 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 clearance. Last year, a clinical trial of transthyretin amyloid clearance produced good results. This type of amyloid is associated with heart disease, and is thought to be the primary cause of death in supercentenarians. This year researchers finally demonstrated clearance of amyloid-β in humans, after a long series of failures. Amyloid-β is one of the forms of metabolic waste that accumulates in Alzheimer's disease.

So these types of rejuvenation therapy already exist in the sense of prototypes and trial treatments. To the degree that they are effective and safe, everyone much over the age of 40 should be undergoing a course of treatment every few years. In practice, since both of the above mentioned therapies are tied up in the slow-moving edifice of Big Pharma regulatory capture, it will be a long time before they make it to the clinic in any way that is accessible to an ordinary individual. The most likely path to that goal is for other groups outside that system to reverse engineer the basic technology from the scientific publications, implement their own methodologies, and market it in other regulatory regions, making it available via medical tourism. This is how stem cell medicine progressed, and seems likely to be the way that any other very significant field will also move forward.

4) Clearance of Glucosepane Cross-Links

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.

Four years ago, the situation for glucosepane clearance looked pretty bleak. The funding was minimal, and the tools for working with glucosepane in living tissues didn't exist. Researchers avoided the whole topic, as making any progress would require a lot of funding and effort to even get to the point of starting in earnest. The SENS Research Foundation and their allies have since made major inroads into this challenge, however. Last year, a method of cheaply and reliably synthesizing glucosepane was established, and now the road is open to anyone who wants to try their hand at drug discovery. That is now underway in the Spiegel Lab, among others, and I'd hope to see the first potential drug candidates emerge at some point in the next couple of years.

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. There has been 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 has demonstrated that this class of approach can produce a meaningful improvement in immune function, and thereby extend healthy life. This is one of a number of regenerative approaches that is on the verge, just waiting for someone to start a company or join the final two dots together and get moving.

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, either by replicating more readily or being more resistant to quality control mechanisms. Such cells become dysfunctional exporters of harmful signals and oxidized proteins, something that contributes to the progression of atherosclerosis via increased amounts of oxidized lipids in the bloodstream, to pick one example. If we're lucky, a substantial proportion of these cells will become senescent as a result of their mutant mitochondria, and will thus be destroyed by senescent cell clearance therapies. Regardless of whether or not that is true, a method of either repairing or working around this type of damage is needed.

Most of the possible approaches may or may not work well, because of the replication advantage that damaged mitochondria have over normal mitochondria, and are still to be tested in practice rather than theory or demonstration: upregulation of existing repair mechanisms; delivery of extra functional mitochondrial DNA or whole mitochondria; and so forth. 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 just this year, and getting that far has taken the better part of ten years at a low level of funding. It is likely that things will go faster in the future, now that there is a for-profit company, Gensight Biologics working on the problem in addition to non-profit groups, but it is still the case that the bulk of the work remains to be done.

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? Hard to say until it is done and demonstrated in mice. Halfway there is probably a target reached by 2020 or so at the present pace. Mitochondrial function appears from all the evidence to be an important aspect of aging, so it is to my eyes worth trying at the halfway point to see what the outcome is.

7) A Robust Cure for Cancer

Some might find it counterintuitive that a universal cure for cancer is not last in this list. We've all been educated to think of cancer as the greatest challenge for medical science, the problem to be solved last of all. Nonetheless, a more rapid arrival of a generally applicable cure for cancer looks to be the likely course of events, as the basis for a treatment that can in principle put a halt to all cancer at all stages of development is currently in the earliest stages of development. 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: these two are a small set of targets for modern medicine, and researchers are working on the challenge. 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, as they can for many of the standard approaches to cancer treatment at the present time. 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.

8) Reversing Stem Cell Aging

The stem cell industry is massively funded, and is 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 ensure that the altered cellular environment, the damage of aging, doesn't prevent the 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. On the whole, 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. So this seems at the present time like a long-term prospect, despite the high levels of funding for this line of medical research and development.

9) 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 make it into the clinic, most likely for the clearance of forms of amyloid, there will be a growing enthusiasm for work on ways to remove other types of metabolic waste.

Comments

Reason, how do you envision the final defeat of aging? I mean something more permanent and not needing constant new therapies every few decades. Do you think we will be able to change metabolism so it doesn't accumulate damage by the end of this century or do you think the final solution will be replacement of biological body by some more durable substrate?

Also, does partial repair of current 7 categories of damage mean they will evolve into some new currently unpredictable different types of damage and thus needing qualitatively different therapies or will current therapies incrementally improved be able to keep reversing the level of damage many times over?

Posted by: Kepheus at November 23rd, 2016 7:20 PM

@Kephus: Increasingly effective SENS implementations to stay one step ahead of aging until such time as biology can be replaced with more robust machinery. At some point it will become more cost-effective to migrate to a new substrate than to improve the effectiveness of repair on the existing one. If you are going to spend the level of effort required to improve human biology radically, you might as well take that same effort and build with machinery rather than biology to obtain a much more robust shell.

See: http://hplusmagazine.com/2011/08/19/the-million-year-life-span/

Posted by: Reason at November 23rd, 2016 8:16 PM

Excellent piece. Thank you.

Posted by: Peter Christiansen at November 23rd, 2016 9:15 PM

Reason - would you not be worried if you reset your immune system (2) without a re-invigorated thymus (5)? That might result in a naïve (adaptive) immune system, with an impaired ability to be re-educated...

Posted by: Mark at November 24th, 2016 7:26 AM

Three things I am looking forward to in comming years:

1) Senescent cells removal
2) AGE breakers
3) Stem cells rejuvenation (mostly skin, hair and some organs)

These three will already have big impact on rejuvenation and they are coming fairly soon.

Posted by: RS at November 24th, 2016 7:45 AM

@Mark: the degree to which that is a problem is an open question. The existing immune reboots carried out in patients suggest so far that is isn't a major issue, but the situation may well be different for much older individuals.

@Arren Brandt: No. There's a whole bunch of probably marginal items that are mostly not addressing root or close to root causes on the other side of the line drawn for this post.

Posted by: Reason at November 24th, 2016 8:17 AM

As this is Thanksgiving, I want to give thanks to Reason for his blog on reporting the latest in medical rejuv and encouraging donating to the cause. Also, I really appreciate the detailed list of areas of damage and where we stand in regards to this for this particular blog. So, thanks Reason for your involvement and keeping us current on the latest in this very important field.

Posted by: Robert C. at November 24th, 2016 3:09 PM

Does somebody have an opinion on Remofuscin (tetrahydropyridoether) which is mentioned on the lipofuscin Wikipedia page? It seems to work for age-related macular degeneration by simply dumping the lipofuscin out of the cells. As it was a random discovery maybe this pathway could be exploited further with similar molecules? Could this be a method to check off one SENS target with little to no effort? I didn't find an article anywhere on this great blog.

Posted by: Matthias F. at November 24th, 2016 9:21 PM

Hi Matthias,

See here and here.

Posted by: Michael at November 24th, 2016 10:26 PM

While I'm here, let me second Robert's expression of gratitude toward Reason: for FA! as a source of information and inspiration, and for his generous and leveraged support for SENS Research Foundation and rejuvenation research generally.

Posted by: Michael at November 24th, 2016 10:29 PM

I also would like to give my thanks to Reason for providing the community with such consistent and terrific coverage of longevity news and for all the donations they have contributed for so many years.

Posted by: Adam Hruby at November 24th, 2016 10:40 PM

i think we will see clogged arteries being cleared (without surgery), high in the list.

Posted by: Erik at November 25th, 2016 3:55 AM

Cyclodextrins have great potential as Protective Agents of Protein Aggregation. Cyclodextrins and their derivatives are antiaggregant agents in a number of proteins (e.g., amyloid-β, insulin, recombinant human growth hormone, prion protein, transthyretin, and α-synuclein) and some multimeric enzymes. http://onlinelibrary.wiley.com/doi/10.1002/asia.201600259/full
Subcutaneous administration of cyclodextrin significantly improved spatial learning and memory deficits in Alzheimer disease mice model doi:10.1084/jem.20121239.
Because cyclodextrin treatment in humans is safe (FDA approved application of 2 hydroxypropyl-β-cyclodextrin for the treatment of Niemann-Pick disease, type C. Phase I clinical trial) and cyclodextrin beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis http://stm.sciencemag.org/content/8/333/333ra50.

Posted by: Dmitry Dzhagarov at November 25th, 2016 9:56 AM

Dmitry: as the paper itself notes, the most likely mechanism for the ability of hydroxypropyl-β-cyclodextrin to lower Aβ burden in the mouse model is AD finding is by normalizing membrane cholesterol content and reducing the appearance of abnormal cathepsin D-positive lysosomes, leading to reduced beta-secretase cleavage of APP and an upregulation of genes involved in cholesterol trafficking and Aβ clearance. They suggest that the effects on lysosomes are secondary to reduced Aβ accumulation, but I suspect the causation may work in the reverse direction, since they found that HBCD lowered cellular membrane cholesterol, and abnormally high lysosomal membrane cholesterol can impair the acidification and function of lysosomes, which are necessary for clearance of intracellular Aβ. Obviously, it would've been nice if they had tested cholesterol levels in lysosomal rather than just plasma membranes.

Posted by: Michael at November 25th, 2016 1:36 PM

I am 73 years and am in good basic health because of hiking and careful eating. However this life extension article, like just about all of them, ignore the problems of aging.
1. Parts wear out: knees, hips, especially.
2. Parts deteriorate with age: skin, hair, prostate, heart.

The assumption of life extension is that our bodies will remain functional and mobile. I once saw a photo of ten centenarians and only one was standing with the aid of a cane. The nine others were in wheelchairs. I had a colleague whose grandmother was in a nursing home for ten years bedridden. Tired of the visits, my colleague hoped that her grandmother would die.

Chemicals may extend the life worms and rats, but these creatures have brief lives and do not experience that wear and tear of decades of living. Any discussion of life extension should include the quality of life and the overall condition of our bodies.

Posted by: Edward at December 2nd, 2016 10:51 AM

Edward, the goal of rejuvenation and regeneration (which aren't only about chemicals) is precisely to repair and/or replace the worn out parts. It is precisely about extending BOTH the longevity and the quality of life - these go hand in hand.

Posted by: Spede at December 2nd, 2016 12:24 PM

Fantastic post. Reason, I think keeping this post in the sidebar as "The Current State of Life Extension Therapies" or something, with periodic updates, would be a great resource for new readers. I certainly will link friends who ask me about anti-aging therapies to this post.

At the least, would you consider making a post like this annually? Even if some categories don't change, it would be great for getting a big-picture sense of anti-aging progress.

Posted by: James at December 6th, 2016 3:28 PM

For small tech biz (every tech hub in USA wants more of them !), someone with knowledge of "Fight Aging" & SENS rejuvenation research portfolio, and has motivation for a start-up bio, can use the U.S. Congress renewed SBIR Phase I, and respond to NIH.GOV or another agency's RFP, via virtual team with university faculty at the nearest tech hub. Phase I of SBIR is typically $150 K & "Proof of Concept". Question: Suggest some possible sub-topics for such aspiring biotech innovators ?

Posted by: Avi Dey at January 4th, 2017 4:00 AM

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