25-Hydroxycholesterol as a Basis for Senolytic Therapy
25-hydroxycholesterol is an oxidized form of cholesterol, and researchers here demonstrate that it is senolytic to some degree in mice. This may be competitive with existing first generation senolytics; from the paper, it looks like it clears about half of the excess of senescent cells present in old mice, in muscle tissue at least. Like all other senolytics, its effectiveness likely varies widely by tissue type and location in the body. Oxidized cholesterols are largely thought to be harmful in the body, particularly because they can cause macrophages to become dysfunctional and accelerate the progression of atherosclerosis. It is unclear as to whether that could prove to be a blocking issue at the sort of doses and schedules used in senolytic therapy.
Researchers have shown that the endogenous metabolite 25-hydroxycholesterol (25HC) significantly reduced the burden of senescent cells in multiple cell types in both mice and human cell culture, and in live mice, where it showed particular efficacy in skeletal muscle. "Given that 25HC shares no common molecular motifs with other senolytics, it appears that this molecule represents a brand new class of potential interventions."
25HC is a little understood oxidized lipid involved in cholesterol metabolism. The team identified it after discovering that the molecule disrupted cellular senescence in CRYAB, a small heat shock protein which was upregulated upon senescence in nine different cell types from two species, mice and humans. Diseases associated with CRYAB include myopathies, diseases that affect muscles that control voluntary movement in the body.
Working in mouse and human cell cultures researchers isolated specific cell types from skeletal muscle, made them senescent and showed that 25HC could kill them selectively. The team then went on to test 25HC in aged mice; experiments showed 25HC improved their muscle mass. Researchers also determined that 25HC killed senescent cells in mouse dermal fibroblasts, and in primary human cells from the lung, heart, liver, kidney, and articular cartilage. "We are intending to use this molecule in multiple paradigms of aging and we're hoping that other researchers will start testing it as well."