Homoharringtonine exhibits senotherapeutic activity that mitigates diet- and age-associated obesity and insulin resistance and extends lifespan in mice

Authors
Kim, Eok-Cheon, Jung, Han-Byul, Park, Yu-kyoung, Son, Youlim, Cha, Hye-Na, Patel, Yash, Lee, Ju Hee, Choi, Minah, Park, Soyoung, Kim, Il-Kug, Pickel, Lauren, Lee, Seungju, Ha, Yuna, Shin, Min-Gyeong, Zhang, Qiwei, Yang, Jielin, de Oliveira, Bruno Rodrigues, Vo, Nathaniel, Yew, Annie, Togo, Jacques, Ealey, Kafi N., Jung, Su-Ryun, Moon, Sunjin, Yoon, Hye-Jin, Lee, Jee-Young, Sung, Hoon-Ki, Kim, Jae-Ryong, Park, So-Young


Lab

Journal
Nature Communications

Abstract
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. This study identifies an FDA-approved leukemia drug, Homoharringtonine, that can eliminate aged fat cells, improve metabolic health, reduce inflammation and extend lifespan in mice, revealing a potential approach to treat age- and obesity-related metabolic disease.

Keywords/Topics
Molecular medicine; Obesity; Phenotypic screening; Senescence

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.nature.com/articles/s41467-026-70475-3

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