Homoharringtonine exhibits senotherapeutic activity that mitigates diet- and age-associated obesity and insulin resistance and extends lifespan in mice
- Eok-Cheon Kim
- Han-Byul Jung
- Yu-kyoung Park
- Youlim Son
- Hye-Na Cha
- Yash Patel
- Ju Hee Lee
- Minah Choi
- Soyoung Park
- Il-Kug Kim
- Lauren Pickel
- Seungju Lee
- Yuna Ha
- Min-Gyeong Shin
- Qiwei Zhang
- Jielin Yang
- Bruno Rodrigues de Oliveira
- Nathaniel Vo
- Annie Yew
- Jacques Togo
- Kafi N. Ealey
- Su-Ryun Jung
- Sunjin Moon
- Hye-Jin Yoon
- Jee-Young Lee
- Hoon-Ki Sung
- Jae-Ryong Kim
- So-Young Park
2026-03-31
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 2150 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.