Homoharringtonine as a Senotherapeutic Drug
The extremely high cost of obtaining clinical approval for a new drug incentivizes the research and development communities to focus on finding new uses for existing drugs in place of the rational design of new drugs. This likely contributes to a reduced quality of therapies; we live in a world in which the creation of marginally effective drugs is favored over the search for better drugs because it is cheaper to find marginally effective drugs. One of the few drug repurposing exercises that is producing interesting results is the search for senotherapeutic therapies among drugs approved for the treatment of various cancers, as many of these drugs have positive effects on cancer precisely because they selectively destroy or otherwise suppress the inflammatory signaling of senescent cells, but were developed prior to an understanding of the importance of this mechanism.
The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. 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 male 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). Importantly, we found that HHT treatment delays aging and extends the lifespan in progeroid and aged mice. Our study demonstrates the novel senotherapeutic potential of HHT to mitigate age- and obesity-related metabolic dysfunction and extend longevity in mice.