Homoharringtonine exhibits senotherapeutic activity that mitigates diet- and age-associated obesity and insulin resistance and extends lifespan in mice
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.
Authors
- Eok-Cheon Kim
- Hye-Na Cha
- Nathaniel Vo (ORCID: https://orcid.org/0000-0001-6264-8652)
- Youlim Son (ORCID: https://orcid.org/0000-0003-0381-6534)
- Hoon‐Ki Sung (ORCID: https://orcid.org/0000-0001-6677-9385)
- Suryun Jung (ORCID: https://orcid.org/0000-0002-9645-4204)
- Lauren Pickel (ORCID: https://orcid.org/0000-0001-6025-0915)
- Kafi N. Ealey (ORCID: https://orcid.org/0000-0002-0068-5391)
- Il‐Kug Kim (ORCID: https://orcid.org/0000-0002-2428-8403)
- Jacques Togo (ORCID: https://orcid.org/0000-0003-0188-2968)
- Sunjin Moon (ORCID: https://orcid.org/0000-0002-3803-6354)
- Soyoung Park (ORCID: https://orcid.org/0000-0001-7855-1302)
- Minah Choi
- Hyejin Yoon (ORCID: https://orcid.org/0000-0002-5268-0736)
- Yuna Ha
- Min-Gyeong Shin
- Ju Hee Lee
- Qiwei Zhang
- Seungju Lee
- Jee-Young Lee
- Jielin Yang
- Yu-kyoung Park
- Annie Yew
- Yash Patel
- Soyoung Park
- Jae-Ryong Kim
- Bruno Rodrigues de Oliveira
- Han-Byul Jung
Institutions
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- SickKids Foundation (CA)
- Yeungnam University Medical Center (KR)
- Daegu-Gyeongbuk Medical Innovation Foundation (KR)
- Yeungnam University (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1038/s41467-026-70475-3
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Diabetes Canada
- National Research Foundation
- University of Toronto
- National Research Foundation of Korea
- Ministry of Science and ICT, South Korea
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Banting and Best Diabetes Centre, University of Toronto