Curcumin Analogs and Expectations About Natural Senolytics

Senolytic compounds selectively destroy senescent cells to some degree, and thus achieve a narrow form of rejuvenation, as accumulation of senescent cells is one of the root causes of aging. Senolytics produce a reliable reversal of age-related disease and extension of life in mice. As in all such things, quality varies widely: there will be a very large number of marginal senolytics that we should all ignore by the time the first enthusiastic wave of research, exploration, and clinical development is done. Of the senolytic compounds that do have sizable enough effects to care about, and for which there is published data, their effect sizes are at present all in the same ballpark - up to 50% clearance of lingering senescent cells, varying widely tissue by tissue. Another interesting point to consider is that data on senolytic effects in cell cultures is a poor guide as to how well these compounds do in mice. Further, we don't yet know how much variation in effectiveness to expect going from mice to humans.

Fisetin is a supplement that is widely used. Given the recent discovery that fisetin is significantly senolytic in mice - about as good as the dasatinib and quercetin combination - at doses that are ten to twenty times higher than the usual supplement dose used by a great many humans, how should we adjust our expectations regarding the wide range of natural compounds that have been shown in the past to very modestly slow aging or reduce risk of age-related disease in mice? How many of those are in fact senolytic? How many will become meaningfully senolytic if used at much higher doses than is common? These are questions without answers at the present time; the odds are unknown. In the case of curcumin and its analogs, however, I'm much more dubious than I am regarding whether or not fisetin will turn out to be usefully senolytic in humans. Curcumin has a much longer history of widespread use, and it seems unlikely that humanity would have failed to discover that high doses were a reliable treatment for age-related disease, were it as senolytic in humans as fisetin is in mice.

Nonetheless, researchers are now investigating a range of natural compounds and their derivatives that have been claimed to affect aging in mice, even to only very small degrees, and curcumin and its analogs are in that list. This is one of many programs of dubious utility that obtain far too much funding and interest in comparison to the benefits they might plausibly delivery. My suspicion is that this will turn out to be an exercise of largely academic interest, better categorizing a range of marginal ways to influence aging, but until such time as fisetin is rigorously tested in humans, there is always that to point to as a counterargument. Further, since it is much cheaper to develop natural compounds, there will always be those who choose to fish in the shallows just because it is easier to fish in the shallows, regardless of the fact that the rewarding catches are only found further out. This is exactly why we have more research into curcumin than into many of the branches of SENS rejuvenation research. It is a waste in the grand scheme of things, a distraction, but it will nonetheless occupy a great deal of time and resources.

The curcumin analog EF24 is a novel senolytic agent

The mechanisms by which senescent cells (SCs) accumulate with aging have not been fully understood but may be attributable in part to immune senescence that decreases the ability of the body to clear SCs. Although cellular senescence is a tumor-suppressive mechanism, SCs can play a causative role in aging and age-related diseases when they accumulate. This suggestion is supported by the finding that genetic elimination of SCs in naturally aged mice through a transgene can delay various age-dependent deterioration in tissues and organs and extend their lifespan.

This seminal finding stimulates research to identify small molecules termed senolytic agents that can selectively kill SCs as potential therapeutics for age-related diseases. To date, several classes of senolytic agents have been identified, and most of them are natural compounds such as quercetin, fisetin, and piperlongumine. Because natural senolytic compounds have the advantages of low toxicity, they may have a better chance to be translated into clinic to treat age-related diseases or can be used as a lead for the development of more specific and potent senolytic agents.

Curcumin, a natural compound extracted from turmeric, has a broad range of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anti-cancer activities. Numerous studies suggest that curcumin has some health benefits in delaying aging and may be useful in preventing and treating age-related diseases. For example, curcumin was shown to prolong lifespan and extend healthspan in Drosophila melanogaster and Caenorhabditis elegans. To improve the bioavailability and biological activity of curcumin, many curcumin analogs were developed, including EF24, HO-3867, 2-HBA, and dimethoxycurcumin, which have been demonstrated to be more active than curcumin in preventing and treating various diseases and reducing age-dependent deterioration. However, the mechanisms of their anti-aging action have not been fully elucidated.

We hypothesized that curcumin and its analogs may increase healthspan in part by functioning as novel senolytic agents. Therefore, in this study, we examined the senolytic activity of several curcumin analogs and found that EF24 is a novel potent and broad-spectrum senolytic agent in cell culture. We show that EF24 can selectively reduce the viability of human SCs from different tissue origins and induced by different stresses. Its senolytic effect is likely attributable to the induction of apoptosis via proteasome-mediated downregulation of the Bcl-2 anti-apoptotic family proteins such as Bcl-xl. These findings provide new insights into the mechanisms by which curcumin and its analogs function as anti-aging agents and suggest that the curcumin analog EF24 has the potential to be used as a novel senolytic agent for the treatment of age-related diseases.

Comments

> Curcumin has a much longer history of widespread use, and it seems unlikely that humanity would have failed to discover that high doses were a reliable treatment for age-related disease, were it as senolytic in humans as fisetin is in mice.

The ITP did evaluate curcumin - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598361/

> Curcumin and its major metabolite tetrahydrocurcumin (TC) have been shown to extend life span in mice and rats (15,16,34).

> It has been reported that male F344/N rats fed curcumin (2000 ppm in diet) from weaning had a 10% greater probability of survival between 75 and 100 weeks (34). Similarly, it was reported that male C57BL/6NNia mice, fed TC the primary blood metabolite of curcumin, at a concentration of 2000 ppm in diet starting at 13 months, had an 11.7% greater mean life span as compared with mice fed the control diet, with a 6.5% extension of the age at which 90% of the mice had died (16). There was no significant effect of TC in mice in which treatment began at 19 months of age (16).

> In aggregate, these findings were highly suggestive that curcumin would extend life span in our mouse model. The intended concentration of curcumin used in the present study (2000 ppm in the diet) and the method of delivery (in the diet) were the same as those used in previous life-span studies. The actual concentration of curcumin measured in randomly chosen pellets in the present study was reasonably close to 2000 ppm, that is, 1682 ± 126 ppm (data not shown). Moreover, in the present study, curcumin reduced body weights of female mice at all ages. This indicates that at this dose, curcumin has a biological effect, at least in females. Given its reported effects on extending life span in both rats and mice, and the broadly anti-aging effects of curcumin, it is not clear why it had no effect on life span in UM-HET3 mice at any of the three ITP sites.

Another group evaluating curcumin, think the effects could have just been from calorie restriction: https://www.ncbi.nlm.nih.gov/pubmed/23432089

> Published reports of murine life span extension using curcumin or tea components may have resulted from induced caloric restriction. Together, our results do not support the idea that isolated phytonutrient anti-oxidants and anti-inflammatories are potential longevity therapeutics, even though consumption of whole fruits and vegetables is associated with enhanced health span and life span.

Posted by: John at February 8th, 2019 5:19 PM

"Curcumin has a much longer history of widespread use, and it seems unlikely that humanity would have failed to discover that high doses were a reliable treatment for age-related disease" -
Could be caused by the fact that curcumins bioavailability on its own is very low. I've noticed that even some of research on curcumin is done using plain curcumin. Using curcumin with black pepper or some advanced forms of curcumin (micronized, longvida) could have a different result.

Posted by: Märten at February 9th, 2019 4:01 AM

EF24 is $325 for 25mg at Sigma. So not cost effective at present for humans. I wonder if that is because of patent costs.

Posted by: JohnD at February 9th, 2019 10:31 AM

@JohnD
It is expensive because it is a rare substance and high chemical purity. If it really works well for humans, the production will ramp-up and the costs will go down. For mass production every doubling of the volumes on average brings 15% reduction in costs. So if you need to produce that dose for 4 billion persons that would involve 32 times doubling (hence the 4GB limit for 32 bit machines). If i did the numbers right that would mean 87-100 times cheaper than now. And if it was working well, say $1000 per treatment , millions will line up and happily pay the price...

Posted by: cuberat at February 9th, 2019 11:16 AM

> EF24 is $325 for 25mg at Sigma. So not cost effective at present for humans. I wonder if that is because of patent cost

JohnD,

Sigma is a chemical reference supplier, i.e. for standardisation in studies, or to run analysis in comparing the results of doing one's own synth. It is not intended to be a standard supplier of materials for large scale use. It is a common mistake for people to think the cost of production is the cost of what sigma sells something for just because it's high in the google search results or the only result for selling a compound.

Posted by: John at February 9th, 2019 8:32 PM

@john, EF24 does did not show up in my search, for any supplier.. I got the Sigma reference from the Methods and materials section of a prior study. As best as I can tell it is the only EF24 supplier of any kind, at this time.

Posted by: JohnD at February 9th, 2019 8:55 PM

I add some Turmeric/Curcumin to my diet. If I am lucky it will slightly lower odds of cancer but no matter what concurrent setup you use with powder or fresh roots, specially pricey eco powder ordered online, black pepper, five different kinds of pepper, olive oil, various heating times, ethanol from red wine or beer and so and so, even doing that jucky paste with cacao, cinnamon etc. it never seems to have noticeable effect on me.

Certainly no effect that comes even Close to what happes when I eat 10-20mg MitoQ (which will also not help me become a hundred but it certainly brightens my day, hat of to Reason for that tip off in 2014 on FA)

Only robust effect from synthetic curcumin or from high dose diet addition is it seems to remove my libido temporarily....

Posted by: arren brandt at February 11th, 2019 3:20 AM

@arren brandt
Hi man
you can try this combination
I drink turmeric in my green tea with Blackseed Oil + Bacopa+Ashawagandha+Black Pepper with a pinch of Ghee
I feel great while I take this .

Posted by: Salman at February 11th, 2019 11:03 PM

One grammatical failure there bud.

Also the blood levels of human senolytic adventurism by ratio for a rodent, respective time will repair a far less expensive brain and would result in more impressive results for the rodent faster. Id imagine some of the most expensive tissue in complex multicellular lifeforms is nerve based. Benchmarking its efficacy through biopsy. post rat autopsy, or cognitive performance associated with ageing is the window correct? I imagine the value of these substances is greater than you give them credit. But imagine what earths human population density would be, if we all suddenly developed sense.

Posted by: Zachary at July 9th, 2019 3:35 PM

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