A Proposal to Accelerate Progress Towards Human Rejuvenation
Here find the first draft of a proposal regarding the best way forward at the present time to accelerate progress towards the development of diverse, effective rejuvenation therapies. The key is to use philanthropic funding to (a) prove efficacy in low-cost clinical trials, and then (b) market that data to ensure physician adoption of the first working rejuvenation therapies. A PDF version of this draft also exists.
Executive Summary
1. Aging is by far the greatest cause of human morbidity and mortality.
2. Rejuvenation therapies that will greatly reduce unnecessary late life suffering and death are under development, but slowly, and with limited funding.
3. Accelerating the development of rejuvenation therapies is an important goal that, if achieved, will improve quality of life and save many lives in the years ahead.
4. At present there is only limited public support for the goal of human rejuvenation.
5. Faster progress towards rejuvenation therapies will follow greater public and institutional support for rejuvenation therapies. It will mean more funding, more research programs, more biotech companies.
6. A few low-cost rejuvenation therapies exist today, already approved by US regulators for other uses. They can in principle be prescribed off-label in the US, but are not yet widely used.
7. Broad public and institutional support to accelerate the development of rejuvenation therapies will emerge following the widespread use of at least a few rejuvenation therapies.
8. Widespread use of the first rejuvenation therapies requires physician adoption of those therapies, as patients largely follow the options presented by physicians.
9. Physician adoption of an off-label rejuvenation therapy requires a convincing presentation of safety and efficacy in the treatment of common age-related conditions. This can be provided by favorable results from low-cost, few-hundred-patient clinical trials conducted by a reputable organization, and then marketed to physicians and physician organizations.
10. The cost of clinical trials to produce robust, trustworthy data for an existing therapy, already approved by regulators, can be a fraction of that required for clinical trials aimed at regulatory approval of a new treatment.
11. Given this funding, a number of existing organizations are well placed to conduct these trials and publicize the results. All that is needed is the will to act.
Aging is the Greatest Cause of Human Morbidity and Mortality
Age-related disease is by far the greatest cause of human morbidity and mortality. The many different ultimately fatal degenerative conditions of old age result from a much smaller number of underlying mechanisms of aging. These include the accumulation of senescent cells and forms of metabolic waste such as cross-links and amyloids, DNA damage, and more. [1][2]The First Rejuvenation Therapies Exist ...
Historically, treatments for age-related disease have focused on the symptoms rather than the causes, and thus comparatively little headway has been made towards prevention and reversal - towards actual rejuvenation. Even though this remains true today, it is nonetheless the case that the first rejuvenation therapies exist, each capable of reversing to some degree a single contribution to degenerative aging.
For example, the senolytic combination of dasatinib and quercetin has been shown in human clinical trials to significantly reduce the burden of senescent cells in aged tissues following a single course of treatment. [3] Senescent cells grow in number with age, and their inflammatory secretions are disruptive of tissue structure and function, contributing to many of the common fatal age-related diseases. [4] Dasatinib is an FDA-approved drug that can be prescribed off-label at low cost, while quercetin is a supplement, readily available to all at an even lower cost.
As a second example, fecal microbiota transplant (FMT) from young to old individuals has been demonstrated in animal studies to produce a lasting reset of the aged gut microbiome and improved health. [5][6] Restoring the balance of microbial populations in the intestine to a youthful state reduces the harmful effects of an aged gut microbiome on long-term health, including raised inflammation, increased generation of toxic metabolites, and reduced generation of beneficial metabolites. One implementation of this treatment was recently approved by the FDA for treatment of C. difficile infection. [7] This makes it available off-label, in principle at least, and gives support to the community of practitioners that has for years been conducting FMT procedures on an ad hoc basis to treat various forms of dysbiosis.
... But are Not Widely Adopted
Despite the existence of these rejuvenation therapies, and evidence for their benefits in the context of aging, the two treatments noted above are neither widely used nor widely known. The broader public still sees aging as largely set in stone, and treatment of aging as the domain of frauds and snake oil salesmen. The public does not realize that a small number of low-cost medical therapies can, with a single program of treatment, produce a lasting improvement to late life health by addressing one of the contributing causes of aging. Comparatively few physicians are both aware of these therapies and comfortable prescribing them. Comparatively few research groups are working on human clinical trials that would produce further supporting evidence.
If must be noted that clearance of senescent cells and adjustment of the gut microbiome, while supported by evidence to show them to be individually beneficial, are not on their own sufficient for comprehensive rejuvenation of the old. Other contributing causes of aging must also be addressed, such as protein aggregates, cross-linking, stem cell decline, mitochondrial dysfunction, and so forth. [1] A faction within the biotech industry is working on new classes of rejuvenation therapy, and the funding for this effort has risen to a few billion dollars, spread unevenly across a few score companies. [8] This sounds like a lot, but it is an insignificant fraction of the funding devoted to more mainstream medical development; the end to end cost of developing a single therapy was reportedly more than $2 billion in 2013. [9]
If we wish to see rapid progress towards the effective treatment of aging within our lifetimes, a dramatic reduction of age-related disease, an end to frailty and dementia, then initiatives aimed at the production of rejuvenation therapies must greatly expand in size and number, and do so sooner rather than later. At the large scale, public support and understanding is necessary for the biggest, most conservative institutions to choose to put their shoulders to the wheel and advance the field of rejuvenation research. That support and understanding is missing at present, in large part because the first rejuvenation therapies are not widely used, and therefore remain largely unknown and unappreciated.
The problem we face is circular in nature. Little use of existing rejuvenation therapies means little knowledge of those therapies. Little knowledge in turn ensures little use. Presently sparse research and development means a slow pace of transmission of knowledge from the scientific community to thought leaders and the public at large. That lack of broad knowledge ensures that there is comparatively little support for greater funding and an expanded range of initiatives.
A slow process of bootstrapping is the usual way forward when faced with such self-reinforcing roadblocks, years of slow and incremental growth to open up a new field. There are other, faster ways paths ahead, however, enabled by the cost-effective deployment of philanthropic funding.
To Ensure Adoption, Persuade Physicians to Prescribe
The best way to break the cycle described above is to focus on physician adoption, to ensure that physicians and clinicians become comfortable prescribing and providing the few presently available rejuvenation therapies. Most patients only become familiar with the medical technologies presented by their physicians. Ensuring widespread off-label use by the medical community of the few existing, easily implemented, low-cost rejuvenation therapies would lead to a sizable improvement in public knowledge and attitudes regarding human rejuvenation.
A world in which most physicians routinely prescribe beneficial rejuvenation therapies to older patients is a world in which both the public and larger, conservative institutions will come to support further development of this form of medicine, aimed at ever more effective control of aging and age-related disease. Just as importantly, expanding the use of beneficial rejuvenation therapies is a great good in and of itself, a way to alleviate suffering and mortality in the older population.
Clinical Trial Data Persuades Physicians
The best way to convince physicians that a given FDA-approved treatment can be used off-label to treat many diseases of aging, or aging itself, is for reputable organizations to publish favorable results from multiple human clinical trials that employ the treatment. Such trials do not have to be anywhere near as expensive as the formal clinical trials conducted to persuade the FDA to approve a new therapy, as they do not need to be encumbered by the full set of regulatory concerns. They only need to be well run, such that the data produced is of high quality, and run by organizations with a good reputation, to ensure that the message is heard.
Trials of the few existing rejuvenation therapies are taking place, but only to a limited degree, and very slowly. The Mayo Clinic was one of the first groups to run clinical trials using dasastinib and quercetin in kidney disease [10], pulmonary fibrosis [11], and Alzheimer's disease [12], for example. But only for these few age-related conditions, with a limited budget, and at a sedate pace over years. Data has been published for only two of these trials over the last five years. Much more than the work of this single organization is needed to move the needle when it comes to persuading physicians.
It is possible to run a well-managed clinical trial of a low-cost, FDA-approved therapy in as many as two hundred patents for under $1 million, provided that the primary goal is to produce robust data rather than to satisfy regulators. Consider the PEARL trial for rapamycin [13], for example, which was crowdfunded with under $200,000 in charitable donations [14]. Trials for dasatinib and quercetin treatment or fecal microbiota transplantation need not be that much more expensive.
Existing Organizations Can Administer Clinical Trials
Given philanthropic funding for such trials, a number of reputable organizations are well positioned to undertake the task of trial administration. In practice this requires connections to potential principal investigators and clinics capable of performing the work, project management as the work progresses, and analysis and presentation of the results. Again, this is far less onerous for the type of clinical trial envisaged here than is the case for formal clinical trials conducted for regulatory approval of new therapies.
The non-profit Lifespan.io runs crowdfunding campaigns to support research goals, and has collaborated with AgelessRx [15] to fund and organize the PEARL clinical trial for rapamycin. The non-profit Forever Healthy Foundation [16] performs research analysis and holds conferences, is connected to the Kizoo Technology Ventures fund that invests in biotech companies, and could make the transition to organizing small trials. The LongevityTech investment fund [17] is constructing a network of clinics in a number of different locations for the express purpose of running first-in-human clinical trials for new therapies relevant to aging.
Each of these organizations has an existing reputation that can be built upon and expanded by taking on the task of running clinical trials aimed at persuading physicians to make use of the first rejuvenation therapies worthy of the name.
Outreach to Physicians
Given favorable data and reputable trial-running organizations, outreach to physicians is more or less a solved problem. It only requires funding and effort. Organizations that market therapies to physicians and clinical practices exist, while established physician networks and conferences can act as channels for broader discussion and outreach.
In Summary
The first rejuvenation therapies worthy of the name already exist, but are barely used. Ensuring a reasonable proof of efficacy and more widespread use of the first few of these will not just improve late life health, but also change the public perception of the treatment of aging. Physician adoption of these therapies is the key to widespread use, and can be achieved by running multiple, rapid, low-cost clinical trials for the first rejuvenation therapies, followed by marketing favorable results to physicians and physician organizations. Widespread physician-led adoption of the first rejuvenation therapies will produce far greater public and institutional support for progress towards a comprehensive set of rejuvenation therapies, technologies that, together, are capable of producing a dramatic reduction in late life suffering and mortality.
References
[1]: Intro to SENS Research. (2022, December 23) SENS Research Foundation. https://www.sens.org/our-research/intro-to-sens-research/
[2]: López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. In Cell (Vol. 153, Issue 6, pp. 1194-1217). Elsevier BV. https://doi.org/10.1016/j.cell.2013.05.039
[3]: Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., Kellogg, T. A., Khosla, S., Koerber, D. M., Lagnado, A. B., Lawson, D. K., LeBrasseur, N. K., Lerman, L. O., McDonald, K. M., McKenzie, T. J., … Kirkland, J. L. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. In EBioMedicine (Vol. 47, pp. 446-456). Elsevier BV. https://doi.org/10.1016/j.ebiom.2019.08.069
[4]: Di Micco, R., Krizhanovsky, V., Baker, D., & d'Adda di Fagagna, F. (2020). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. In Nature Reviews Molecular Cell Biology (Vol. 22, Issue 2, pp. 75-95). Springer Science and Business Media LLC. https://doi.org/10.1038/s41580-020-00314-w
[5]: Smith, P., Willemsen, D., Popkes, M., Metge, F., Gandiwa, E., Reichard, M., & Valenzano, D. R. (2017). Regulation of life span by the gut microbiota in the short-lived African turquoise killifish. In eLife (Vol. 6). eLife Sciences Publications, Ltd. https://doi.org/10.7554/elife.27014
[6]: Parker, A., Romano, S., Ansorge, R., Aboelnour, A., Le Gall, G., Savva, G. M., Pontifex, M. G., Telatin, A., Baker, D., Jones, E., Vauzour, D., Rudder, S., Blackshaw, L. A., Jeffery, G., & Carding, S. R. (2022). Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. In Microbiome (Vol. 10, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1186/s40168-022-01243-w
[7]: Office of the Commissioner. (2022, November 30). FDA Approves First Fecal Microbiota Product. U.S. Food And Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product
[8]: AgingBiotech.info. (2023, January 05). https://agingbiotech.info/companies/
[9]: DiMasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. In Journal of Health Economics (Vol. 47, pp. 20-33). Elsevier BV. https://doi.org/10.1016/j.jhealeco.2016.01.012
[10]: Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., Kellogg, T. A., Khosla, S., Koerber, D. M., Lagnado, A. B., Lawson, D. K., LeBrasseur, N. K., Lerman, L. O., McDonald, K. M., McKenzie, T. J., … Kirkland, J. L. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. In EBioMedicine (Vol. 47, pp. 446-456). Elsevier BV. https://doi.org/10.1016/j.ebiom.2019.08.069
[11]: Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., & Kirkland, J. L. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. In EBioMedicine (Vol. 40, pp. 554-563). Elsevier BV. https://doi.org/10.1016/j.ebiom.2018.12.052
[12]: Gonzales, M. M., Garbarino, V. R., Marques Zilli, E., Petersen, R. C., Kirkland, J. L., Tchkonia, T., Musi, N., Seshadri, S., Craft, S., & Orr, M. E. (2021). Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial. In The Journal of Prevention of Alzheimer's Disease (pp. 1-8). SERDI. https://doi.org/10.14283/jpad.2021.62
[13]: Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study (PEARL) (2022, October 04) https://clinicaltrials.gov/ct2/show/NCT04488601 ClinicalTrials.gov
[14]: Hill, S. (2021, September 1). PEARL Is Funded, Rapamycin Longevity Clinical Trials Begin. https://www.lifespan.io/news/pearl-is-funded-rapamycin-longevity-clinical-trials-begin/
[15]: AgelessRx. (2022, June 30). PEARL Trial to Prolong Life With Longevity Products. https://agelessrx.com/pearl/
[16]: forever-healthy. (2022, December 23). Forever Healthy - today, tomorrow and far beyond . . . Forever Healthy. https://forever-healthy.org/
[17]: LongevityTech.fund - Home. (2023, January 05). https://www.longevitytech.fund/
Brilliant Reason. Question: Where can we get details about the item 6?
" 6. A few low-cost rejuvenation therapies exist today, already approved by US regulators for other uses. They can in principle be prescribed off-label in the US, but are not yet widely used."
Which approved rejuvenation therapies are those?
Many thanks
@Joe Da Silva: Mentioned further down in the article: the senolytic combination of dasatinib + quercetin, and fecal microbiota transplantation from young to old. There are probably others that would sneak in under a very technical definition of rejuvenation, but those are the definitive two, and the ones I've put the most thought into of late.
Could you provide more information on the dasatinib+quercetin, Reason? I thought I read ( maybe from one of your readers) that d+q could be bad if not done properly. Also, where would you get it?
I recall one of the readers mentioned you could do a fecal transplant in Western Europe ( Germany?)
Thanks
@Robert: One specific implementation of fecal microbiota transplants were recently approved by the FDA. For self-experimenters unconcerned with what the FDA has to say on the matter, there are always services like Human Microbes that provide screened stool samples from donors. As you note, it is no doubt possible to obtain fecal microbiota transplants from a number of sources outside the US.
Dasatinib and quercetin has been used in human trials organized by the Mayo Clinic, and the most conservative approach is to follow the trial dosages and schedules. There are physicians out there who are prescribing it, from what I hear, though not that many of them. It is also possible to obtain dasatinib from many of the usual sources for finding cheaper prescription medications outside the US.
@Reason, thanks for the summary. It's nice to get a succinct overview like this from time to time.
Was there a specific person or target for this proposal?
Thanks Reason,
As I'm a bit over 60 I'd like to do SOMETHING positive besides exercise. So, today's blog ( and your additional comments) is timely. BTW, my birthday is year end, so don't enjoy this time of year.
I'll be honest the biggest issue facing the antiaging movement is the grift and graft that is growing off the funding. We are employing people who are ill suited to do anything but waste money on promotional research debacles. Around 10 years ago when this was a smaller group of people an funding was sparse we had much more focused work on actual issues. Now we have ten times the funding and one half the progress. In fact most of the evidence we point to as why anti aging is a possibility comes from a time when there was far less funding overall.
'The first rejuvenation therapies worthy of the name already exist, but are barely used'
Really? Is the transient lowering of the level of chronic inflammation now equal to rejuvenation in humans?
The use of dasatinib as part of d and q has never enthused me- though it is probably a reasonable approach.
A better approach might be quercetin and fisetin. There is quite a lot of literature on this. Both are available OTC and both are harmless.
Any thoughts ?
@Reason
Regarding Citation 2 The Hallmarks of Aging.
https://forbetterscience.com/2023/01/13/schneider-shorts-13-01-2023-on-a-strictly-confidential-basis/#carlos
https://pubpeer.com/publications/DFFF961B84F01BF3C7D31D80434976
https://pubpeer.com/publications/739249617B87A7F686533529DE6546
I'd really like to hear your opinion on this.
I think there are actually MUCH more powerful therapies available now than the ones you listed. Therapeutic plasma exchange in particular leads to extraordinary epigenetic age reversal, in addition to lots of blood biomarker improvements and incredible rejuvenation in age-related protein levels. My own epigenetic age dropped 9 years in the 9 days after my first TPE session on October 18, which is the biggest drop in epigenetic age I've ever heard of.
I discuss this and two gene therapies in this podcast episode: https://stephenmccain.com/paul-tozour/
Suggestion: rather than trying to convince MDs, esp allopathic MDs, whom have already shown they treat symptoms rather than causes, plus you have to combat not only their traditional medical training, but also state & federal rules, going closer to end-user is likely to be more successful.
The current anti-aging movement, including D+Q, F+Q, Rapa, etc., are due to individual generated demand. Focus on reaching individuals.
Then one step-up, such as chiropractors, whom are generally more health / cause/ results oriented, & because of that, have received wide public support. It is highly likely people in 45 - 65 age group see chiropractors -- the same market anti-aging aims to reach.
While cannabis stores would not work, again because they are all licensed by various regulatory agencies, however, there are many sites, newsletters, publications dealing with CBD, THC, etc., that would probably be open to anti-aging theories, information, products. Essentially, that is what they are already marketing. CBD/THC, as well as Rapamycin go back a million years prior to man's existence.
Even online classes, & in-person continuing education courses on anti-aging would spread info, use, & even financial support. And again, that market is the older age group.
In short, work from the end-user, & go up the chain, rather than trying to work from higher-up existing system, which has proven it does not work.
I think I read somewhere that the real challenge facing senolytic therapies, including those in clinical trials by well funded companies like Unity, is the lack of a simple to administer and read biomarker to measure whether a treatment is sucessfully removing senescent cells.
A million dollar study of 200 patients would be measuring what endpoint exactly? If it is a subjective one such as percieved knee pain then it can be dismissed like earlier stem cell treatments for knee pain.
What is probably needed are intra cellular probes that signal that a cell is senescent without a tissue sample. Perhaps mesure the percent of senescent cells in a patch of skin via a sub curtaneous injection of Oisin's lipid-protein gene therapy vectors that contain a protein or DNA that expresses green flourescence if some internal compents of the cell indicate that it is senescent.
I remember reading about intra cellular "smart" proteins and thinking that someone might be able to combine them with Oisin's nanoparticles into order to create some kind of senescent cell probe:
https://www.ucsf.edu/news/2019/07/415031/limitless-potential-artificial-protein-ushers-new-era-smart-cell-therapies
This probe might be created/researched as a series of grants, or even a prize by the Methuselah foundation. But a million dollars might go a long way to creating a probe.
@jimofoz and how they measure it in the mouse?
LOCKR can already be used to detect multiple cell surface proteins at once and glow green.
https://www.bakerlab.org/2020/08/20/introducing-co-lockr-designed-protein-logic-cell-targeting/
https://www.ipd.uw.edu/2021/01/covid-antibody-lockr-sensors/
Greg Fahy's thymus regeneration would qualify as rejuvenation too. Perhaps it is not super cheap, but the treatment is relatively easy to administer following the protocol of TRIIM-X.
Clinical trials will need two groups : those that get the anti-aging treatment and those that get a placebo.
It will be very difficult to recruit patients for clinical trials. Convincing doctors is not enough,
Senescent , geriatric patients must be convinced , persuaded that anti-aging treatments will work with high percentage of probability.
Widespread usage will happen after those that would be in clinical trials give their personal testimonies, and photos before and after show that they were significantly rejuvenated.
Weren't there other modalities discussed in the Blood Plasma experiments. Things such as Plasma dilution?
I am plagued with dental problems and there has been slip sliding with dental stem cell implants for years. I was shocked when the Japanese announced their gene therapy trials commencing this summer for their approach using gene therapy for dental implants (for children only though.) What happened to Jeremy Mao at Columbia University and the group at the University of London (which said over ten years ago - they anticipated starting therapies within five years.)
It's good thing that the bladder stem cell therapy will finally begin in Germany soon it's for women though. Although the original experiments were successful. I believe that was a decade or so ago.
It's becoming morbid to watch people suffer and die who could be helped, even if only minimally!