Homoharringtonine, a novel senotherapeutic, mitigates diet- and age-associated obesity and insulin resistance and extends the lifespan of mice

Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2,150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests senotherapeutic activity in vitro in multiple cell types including human preadipocytes, while inflicting minimal cytotoxicity to non-senescent cells.

HHT treatment prevents diet- or age-induced metabolic abnormalities in mice targeting senescent adipocytes and preadipocytes to improve WAT function and reduce WAT inflammation. Moreover, HHT treatment attenuates age-associated phenotypes of human adipose tissue. Mechanistically, the senotherapeutic effects of HHT are mediated through the direct interaction of HHT with heat shock protein family A member 5 (HSPA5).