Chemicals Reversed Cellular Aging

Harvard’s David Sinclair and his research team have identified six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age.

Rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.

Molecules that reverse cellular aging and rejuvenate human cells without altering the genome. Sinclair and his team developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay.

In 2006, Takahashi and Yamanaka demonstrated that the expression of four transcription factors, OCT4, SOX2, KLF4, and c-MYC (collectively known as “OSKM”), reprograms the developmental potential of adult cells, enabling them to be converted into various cell types. These findings initiated the field of cell reprogramming, with a string of publications in the 2000s showing that the identity of many different types of adult cells from different species could be erased to become induced pluripotent stem cells, commonly known as “iPSCs”.

Reversing Cellular Age Without Triggering Cancer

The ability of the Yamanaka factors to erase cellular identity raised a key question: is it possible to reverse cellular aging in vivo without causing uncontrolled cell growth and tumorigenesis? Initially, it didn’t seem so, as mice died within two days of expressing OSKM. But work by the Belmonte lab, our lab, and others have confirmed that it is possible to safely improve the function of tissues in vivo by pulsing OSKM expression or by continuously expressing only OSK, leaving out the oncogene c-MYC.

Using Gene Therapies to Reverse Cellular Age

Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases, rely on the delivery of genetic material to target tissues. This is achieved through methods like adeno-associated viral (AAV) delivery of DNA and lipid nanoparticle-mediated delivery of RNA. These approaches face potential barriers to them being used widely, including high costs and safety concerns associated with the introduction of genetic material into the body.

Chemicals aka Drugs Can Be Cheaper and Faster to Develop

Developing a chemical alternative to mimic OSK’s rejuvenating effects could lower costs and shorten timelines in regenerative medicine development. This advancement might enable the treatment of various medical conditions and potentially even facilitate whole-body rejuvenation.

In this study, they developed and utilized novel screening methods including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells. They identify a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression. Thus, it is possible to reverse aspects of aging without erasing cell identity using chemical rather than genetic means.

In this study, the provide evidence, based on protein compartmentalization and gene expression patterns in young and senescent cells, that small molecules can reverse the transcriptomic age of cells without erasing cell identity or inducing iPSC-like states. They refer to this approach as the EPOCH method.

The effectiveness of the NCC system as an apparent surrogate biomarker for biological age reversal, with young, old, senescent, HGPS, and OSK-treated cell lines serving as controls, should set the stage for larger, more expansive screens for rejuvenation factors. Follow-up studies are underway to elucidate the cellular machinery that mediates these rejuvenative effects, with an emphasis on the mechanisms by which cells apparently write then later read a “backup copy” of earlier epigenetic information to reset chromatin structures and reestablish youthful gene expression patterns.

Future work will be directed to understanding how long the effects of these and other EPOCH treatments last in vivo and whether they reverse aspects of aging and extend lifespan in mice, paralleling treatment with AAV-OSK. The assays developed in this study, combined with robotics and the increasing power of artificial intelligence, will facilitate increasingly larger screens for genes, biologics, and small molecules that safely reverse mammalian aging, and, given that aging is the single greatest contributor to human disease and suffering, these advances cannot come soon enough.

16 thoughts on “Chemicals Reversed Cellular Aging”

  1. Immortal critters probably wouldn’t be great in the wild as it might slow or prevent evolution in the species. This probably isn’t a player for humans. Not least of which is because we are probably about to take over our own evolution.

    Side note: If we had thousands of races to study as they reached this point of technological capability, and most of them did engage in “intelligent redesign, we would probably have to conclude that this is a natural process (not an “unnatural” one) and that the creatures are not playing God. Whatever natural is. Digressing further, if God didn’t want us rewriting our genetic code, he probably would not have made it open source.

    Also, the human body does produce immortal cells. Our sex cells are kept constantly and scrupulously repaired (and culled) because, if they were not, our children would all be born old. Unfortunately, the metabolic cost of this is sufficiently high that our bodies only do it for the sex cells. In the cold equations of existence, the rest of us is cheaper to just replace every so often. Double unfortunately, this encompasses everything that makes us. Meaning we are disposable by design. On the other hand, we have plenty of food nowadays so metabolic cost is no longer important. Perhaps this suggests a method to make all of it impervious to age and entropy.

    Most of us avoid going anywhere we are not top of the food chain, and there is no clear evidence that bored long-lifers would tend to be especially drawn to suicide or extreme sports after the age of 400, so the half-life of such a population would probably be about a thousand years. If people want to have more children after the first few decades, they will probably have to use a lab to obtain them, which should be easy. However, it doesn’t seem likely that birth rates would skyrocket, even so.

    Also, given that it is difficult to imagine a radical longevity regime that is not at least as expensive as a daily caffeinated beverage at Starbucks, it is unlikely the vast majority of the human race will have the resources to afford it any time soon.

    • > If people want to have more children after the first few decades, they will probably have to use a lab to obtain them

      Part of rejuvenation is rejuvenating the reproductive system. You’re already using medical services to rejuvenate everything else, so may as well.

    • Harold Katchers appears to have found much the same thing, and he says the chemicals are not expensive. NOTE, he is not patenting the chemicals but the process to separate them. So they might not be patentable, and the cost could be low.

  2. Wonder what that cocktail is?

    Speaking of Rejuvant (see what I did there? I’m not sure I do.) Brian wrote it about it last year. It’s a supplement that comes with a lab test for biological age, and then a second, follow up test after you have been using it for six months.

    I did this. The first test told me I was about 2.9 years younger than my biological age (which is not quite eligible for Social Security yet). The second test told me I was 6.3 years younger than by biological age. Do I trust the test to be indicative of something?

    I’m not sure. My knees have given me some pain whenever I go down stairs for several years. That’s gone. There are some other seeming improvements, too, but none of them constitute, by themselves, a smoking gun. I’m going to stay on it I guess, although I do wish that instead of those two horse pills, they had made 4 smaller ones.

    Should be interesting. My finance spreadsheets that I made tell me that, even if I live like a king and never work another second, I should reach a billion dollars in 2023 dollars in the year 2100, long before I’m even halfway to 200. If that comes to pass I’ll have to invite Brian over for cake and ice cream (with enough candles on the cake to make the Canadian forest fires look wimpy by comparison).

    • Are you relying upon them to analyze the test results? Because obviously they could just tell you what you want to hear, to keep you as a customer. Might be useful to take some extra tests, to see if they give similarly positive results.

      • The lab testing outfit is a different company, although, since Rejuvant is the one they are contracted to, anything is possible.

        But I couldn’t even be sure another lab would be using the same testing criteria so getting a second opinion is probably not an option unless you got tests from both at the start and then again after six months.

    • I take pro-Health Calcium AKG Longevity 1,000 mg (and a host of other supplements). Seems to be cheaper than Rejuvant, don’t know if there are differences in the encapsulation as far as its dispersal in your system. As an odd coincidence I two have an excel spreadsheet where I have made similar projections to yours about how soon before I would get to 1 billion dollars (in todays money); and I also tap out at on or before 2100 being the magic dates.

  3. The gold standard, of course, is whether the animal in question actually lives longer, rather than dying shortly after with nice biomarkers..

    It would be very convenient if it were possible to reset the epigenetic program to a younger state, globally, without taking cells that are already specialized by epigenetic settings, and wiping at least some important settings in some of them. Ideally with a small molecule, of course, that wasn’t particularly toxic.

    I tend to think that, if defeating aging were that easy, evolution would already have done it. We don’t age because there are evolutionary advantages to aging, after all, we do it because the cost/benefit ratio for achieving longer lifespans isn’t there so far as Darwin is concerned.

    Logically, were it easy to defeat aging, the cost benefit ratio for an extended opportunity to reproduce, (If only in males, mammalian females run up against other limits.) would be more favorable. But, who knows? Maybe I’ll be pleasantly surprised.

    And, anyway, right now we just need a few more decades, to find harder, more effective solutions.

    • It could be that there is no great upside to longevity from an evolutionary point of view. Better to roll the dice again with new participants (i.e. offspring) than keeping the current ones in the game.

      Look at lions, tigers, wolves, deer, dogs.. Most animals – roughly our size – live something like 10 years, even though nature could have given them human life length, i.e. several decades.

      Most likely, nature could have given us 200 years+ plus lifespans with no adverse effects, just that it’s not beneficial for spreading the genes. Plus, it may be that high levels of danger (from predators etc) would have made such longevity moot. It does not matter if you can live to 200, if you are statistically killed a few times in this time span.

      • Good point.

        The other animals you mentioned can be quite clever but probably not to the point where an extra decade or 2 of lived experience would significantly increase reproductive success. That could be a limiting factor for palaeolithic humans. A few decades is worth the trade off but a few centuries isn’t.

      • Look at the species that do have extraordinarily long lifespans. Tortoise, for example.

        The unifying factor is that they all live in environments where, once you achieve adulthood, you are almost certain not to die of accident, disease, or predation. So every added year of life is an added year of reproductive opportunity, 1 for 1. That’s a good evolutionary case for evolving a long lifespan! Darwin doesn’t care about the downside for the species as a whole, he operates on the level of individuals.

        Now, take a species that lives in a dangerous environment. A mutation occurs that doubles potential lifespan. Is it selected for?

        Nope, because you’re unlikely to realize that potential. You only get, what, 5% of the gain? The other 95% of the time you get eaten before you benefit from it.

        OTOH, a mutation that gives you a few percent better chance of reproducing before you get eaten, at the cost of falling apart a decade after that meal? A clear evolutionary win, ’cause you hardly ever pay the price. And that’s why species evolve to fall apart a while after the median age they survive to in the wild, instead of just living on and on: They’re buying higher performance during the time they’re alive, at the cost of downsides they usually don’t live long enough to experience.

        Only humans moved from that dangerous environment to the safe one, and we now live long enough for the downsides to bite, and to exploit reproductive opportunities in old age. (I had my first kid at 50!) So, we’re evolving longer lifespans, it’s just that it’s going to take a very long time to happen naturally.

        But if there were a really cheap and easy way of greatly increasing lifespan, without serious downside, I think we’d have evolved it by now. So, I don’t think the small molecule approach has much hope of major success.

        But I’d be delighted to be proven wrong.

        • This is a rare occasion where I think your premises are in conflict. I’m not following why not evolving longer lifespans (and this comment is spot on about evolution conserving advantages to reproduction) has any bearing on developing a chemical approach to removing the effects of aging.

          After all evolution conserved Sickle Cell Anemia in malaria prone populations; we now avoid and cure malaria through sanitary engineering and chemical treatments. Plus have the burden of dealing with the downside of Nature’s remedy.

          • It just strikes me that a systematically applied small molecule has to be doing something easy enough that it would likely have evolved on its own, even though the evolutionary pressure for longer lives wasn’t there until recently.

            But, yeah, I guess you’re right that there’s some tension there.

    • “The gold standard, of course, is whether the animal in question actually lives longer, rather than dying shortly after with nice biomarkers..”

      And that is the thing…when Sinclair and his groups market their drug “cocktail” it would be sold as improving said “biomarkers”. It might be years/decades before the customers know whether it actually extends lives or even healthy span (besides improving the aforementioned “biomarkers”)

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