Towards Lipid-Based Senolytics
Senescent cells are poised for self-destruction, but held back by a range of mechanisms that are amenable to sabotage, given suitable small molecules. Much of the first wave of senolytic drug development, treatments that can selectively destroy some fraction of the harmful burden of senescent cells found in aged tissues, exploited ways to force senescent cells into apoptosis. New ways to provoke forms of programmed cell death in senescent cells are being found all the time, and it is interesting to keep an eye on this part of the field. The illustrative work noted here is only conducted in cell culture, so should be taken with a grain of salt until animal data arrives, but is novel for employing ferroptosis as the chosen path to destruction, and in the use of lipids rather than the usual small molecules.
Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice.
Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic polyunsaturated fatty acids (PUFAs) and reactive oxygen species (ROS) levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.
This does have animal data though, right? "...with senolytic properties both in cell culture and in multiple mouse models of aging". Figure 2: "Evaluation of the senolytic effects of α-ESA and α-ESA-me in models of accelerated aging and naturally aged mice" talks about grip strength, etc.
It sounds interesting. It would sure be nice to have an (effective) over-the-counter senolytic. α-ESA is in bitter melon seeds, apparently.
The dosage sounds pretty high, though. 50mg/kg of α-ESA for mice -- not sure how that scales to humans (or to bitter melon extract).
@John that's a good point. If a-ESA goes by allometric scaling (adjusting for larger human BSA), 50 mg/kg a-ESA in mice would actually be 4 mg/kg a-ESA in humans, which would be ~300 mg/day for a 70 kg human - definitely in line with doses of other kinds of OTC supplements.