Clonal Hematopoiesis Accelerates Frailty and Functional Decline
- 1Vanderbilt University Medical Center
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 Womens 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.
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BibTeX
@misc{zhao2026clonal,
title = {{Clonal Hematopoiesis Accelerates Frailty and Functional Decline}},
author = {K. Zhao and C. Quin and Y. Pershad and L. Xue and W. Cao and G. I. Bowman and C. Vlasschaert and R. W. Corty and J. B. Heimlich and E. N. DeJong and C. Lee and Z. Patel and M. M. Buttigieg and C. P. Verschoor and C. A. Bane and A. J. M. McNaughton and D. M. E. Bowdish and G. A. Kuchel and E. A. Whitsel and A. H. Shadyab and C. Kooperberg and A. Z. LaCroix and A. P. Reiner and M. J. Rauh and A. G. Bick},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.26363888},
url = {https://www.medrxiv.org/content/10.64898/2026.09.24.26363888v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Clonal Hematopoiesis Accelerates Frailty and Functional Decline
AU - K. Zhao
AU - C. Quin
AU - Y. Pershad
AU - L. Xue
AU - W. Cao
AU - G. I. Bowman
AU - C. Vlasschaert
AU - R. W. Corty
AU - J. B. Heimlich
AU - E. N. DeJong
AU - C. Lee
AU - Z. Patel
AU - M. M. Buttigieg
AU - C. P. Verschoor
AU - C. A. Bane
AU - A. J. M. McNaughton
AU - D. M. E. Bowdish
AU - G. A. Kuchel
AU - E. A. Whitsel
AU - A. H. Shadyab
AU - C. Kooperberg
AU - A. Z. LaCroix
AU - A. P. Reiner
AU - M. J. Rauh
AU - A. G. Bick
PY - 2026
DA - 2026/09/24
PB - medRxiv
DO - 10.64898/2026.09.24.26363888
UR - https://www.medrxiv.org/content/10.64898/2026.09.24.26363888v1
AB - 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 Womens 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.
ER -