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.