Resibufogenin as a Senolytic Compound
Researchers continue to search for novel senolytic compounds, those capable of selectively destroying senescent cells while producing a minimal impact on other cells. In youth, senescent cells are rapidly cleared by the immune system, but this clearance falters with age, leading to an accumulating burden of senescence in tissues throughout the body. These lingering senescent cells secrete pro-growth, pro-inflammatory signals that are disruptive to tissue structure and function when sustained over the long term. The lasting presence of senescent cells contributes to the chronic inflammation of aging, as well as to the onset and progression of near all age-related conditions. Animal studies show that clearance of these errant cells can reverse a broad range of age-related conditions, and thus there is considerable interest in the development of senolytic drugs to achieve the same result in humans.
Today's open access paper is illustrative of many similar efforts to discover usefully senolytic compounds that may already exist the vast databases of widely used medicinal products. New discoveries might form the basis for a later clinical development program. Given that every older adult is a potential customer for senolytic drugs, and that these drugs are expected to vary widely in their efficacy from tissue to tissue, there is more than enough room for many different senolytics-focused companies to coexist, and more than enough room for success in many different senolytic clinical programs. We should expect to see a considerable expansion of the set of known senolytic compounds and mechanisms for senolysis in the years ahead.
Senescent cells that accumulate with age have been shown to contribute to age-related diseases and organ dysfunction and have attracted attention as a target for anti-aging therapy. In particular, the use of senescent cell-depleting agents, or senolytics, has been shown to improve the aging phenotype in animal models. Since senescence has been implicated in the skin, particularly in fibroblasts, this study used aged human skin fibroblasts to investigate the effects of resibufogenin.
A component of the traditional Chinese medicine toad venom, resibufogenin was investigated for senolytic and/or senomorphic activity. We found that the compound selectively caused senescent cell death without affecting proliferating cells, with a marked effect on the suppression of the senescence-associated secretory phenotype. We also found that resibufogenin causes senescent cell death by inducing a caspase-3-mediated apoptotic program. Administration of resibufogenin to aging mice resulted in an increase in dermal collagen density and subcutaneous fat, improving the phenotype of aging skin. In other words, resibufogenin ameliorates skin aging through selective induction of senescent cell apoptosis without affecting non-aged cells. This traditional compound may have potential therapeutic benefits in skin aging characterized by senescent cell accumulation.