Nature agingJul 16, 2026

Trained immunity connects aging of blood stem cells to inflammation in aging

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 17, 2026

Abstract

SIRT3, a mitochondrial deacetylase, is reduced during aging and is associated with impaired immune response in hematopoietic stem cells.

Aging leads to heightened inflammation and decline in hematopoietic stem cell function.
SIRT3 suppresses the immune response linked to aging and maladaptive trained immunity.
Overexpression of SIRT3 in hematopoietic stem cells ameliorates age-related decline in these cells.
Improved SIRT3 levels enhance tissue function and reduce cognitive and mobility declines in aged mice.
Hematopoietic stem cell aging may drive chronic inflammation and tissue dysfunction related to aging.

Simplified

Trained immunity is a state of heightened immune response that is initiated in hematopoietic stem cells (HSCs) and mediated mainly by their myeloid progeny. Aging-associated inflammation drives many aging-related diseases, yet its biological origin is largely unknown. Here we show that SIRT3, a mitochondrial deacetylase highly expressed in HSCs but reduced during aging, suppresses the HSC response to aging that drives maladaptive trained immunity, chronic inflammation and tissue functional decline in mice. Overexpression of SIRT3 in HSCs not only ameliorates aging-associated HSC decline, but also improves the function of distant tissues, including attenuation of age-related declines in cognition and motility, via myeloid cells with modulated inflammatory programs. These findings reveal that HSC aging is a driver of aging-associated inflammation through maladaptive trained immunity and broaden the possible clinical applications of targeting HSCs from hematological diseases to include countering aging-associated physiological decline and improving healthspan.