Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.

Wei-Chieh Mu, Marine Barthez, Yufan Feng, Yibing Chen, Chih Ling Wang, Jing-Yi Huang, Jie Li, Paul Lanhart, Clair Tsui, Yang Joon Kim, Eric Verdin, Mihai G Netea, Danica Chen

Department of Metabolic Biology and Nutrition, University of California, Berkeley, CA, USA. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that restoring SIRT3 in hematopoietic stem cells can reverse maladaptive trained immunity and improve systemic healthspan in mice. This is relevant because it identifies a root cause of aging-associated inflammation (HSC dysfunction) rather than just treating downstream symptoms, although the findings are currently limited to murine models.

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