Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Frailty reflects declining physiological reserve across multiple organ systems with aging, yet the underlying biological mechanisms contributing to frailty remain poorly understood. We tested whether somatic mutations in the blood were associated with incident frailty and faster progression in 730,088 participants from UK Biobank, All of Us, BioVU and the Women’s Health Initiative. We found that clonal hematopoiesis of indeterminate potential (CHIP) and autosomal mosaic chromosomal alterations showed strong associations with frailty, whereas mosaic loss of chromosome X or Y did not. Findings were consistent across survey-based, directly measured and clinically assessed frailty, as well as healthspan phenotypes. A Tet2 mouse model demonstrated multisystem frailty-like functional decline and T-cell remodeling. In humans, T-cell activation-related proteins directly mediated the association between clonal hematopoiesis and frailty. Collectively, these findings support a model in which clonal hematopoiesis accelerates biological aging through immunosenescence.
Source: medRxiv
Authors: Kun Zhao, Candice Quin, Yash Pershad, Liying Xue, Weizhi Cao, Grace I Bowman, Caitlyn Vlasschaert, Robert W Corty, J. Brett Heimlich, Erica N DeJong, Caitlin Lee, Zil Patel, Marco M. Buttigieg, Chris P Verschoor, Calum A Bane, Amy J.M. McNaughton, Dawn M.E. Bowdish, George A Kuchel, Eric A Whitsel, Aladdin H Shadyab, Charles Kooperberg, Andrea Z LaCroix, Alexander P Reiner, Michael J Rauh, Luke M Evans, Alexander G Bick
Institutions: Vanderbilt University, Vanderbilt University Medical Center, University of Aberdeen, Victoria University of Wellington, University of Colorado Boulder, Queen's University, St. Joseph’s Healthcare Hamilton, McMaster University, Health Sciences North, NOSM University, University of Connecticut, UConn Health, University of North Carolina at Chapel Hill, University of California San Diego, Fred Hutch Cancer Center, University of Washington
Language: English
Topic: Frailty in Older Adults
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1211708387, G3013029168, G3068951427, Targeting Clonal Hematopoiesis of Indeterminate Potential using Human Genetics, Immune Response to High-Dose vs. Standard Dose Influenza Vaccine, G3827278403, G444077766, G4499735890, G554960330, G5777902738, Colorado Adoption Project/Twin Study of Lifespan behavioral development & cognitive aging [CATSLife2], G6374953548, G6894818919, G7159829730, G7821233859, G8517869190, G8566225511, Establishing the dynamics of lymphoid clonal hematopoiesis and its aging-related disease consequences, Clonal Hematopoiesis in the Women's Health Initiative
OpenAlex ID: W7215064806