Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice

Abstract

<title>Abstract</title> Mammalian aging coincides with an accumulation of senescent cells. Depletion of senescent cells shows promise to treat age-related diseases. However, many of the senolytic drugs used to deplete senescent cells cause profound toxic side effects. Here we tested a prodrug form of a pan-cytotoxic drug and demonstrated dramatically reduced side effects in geriatric mice while gaining senolytic selectivity. Specifically, we employ a strategy that takes advantage of the greatly enriched expression of the lysosomal hydrolase β-Galactosidase in senescent cells as a tool to selectively convert the prodrug into the active parent drug. In young, old and geriatric mice this prodrug was well tolerated and proved capable of reducing the burden of senescence in multiple tissues without evident toxicity. Importantly, chronic systemic treatment of geriatric mice resulted in reduced frailty index, improved muscle tissue and stem cell functions, improved cognitive functions and overall improved survival. This work supports future senolytic prodrug designs, based on other metabolic functions characteristic of senescent cells, on different parent drugs and aimed at clinical development. This new class of senolytic prodrugs promises capabilities of targeting selectively and safely specific senescent cell types in multiple tissues to treat age-related diseases in geriatric people.