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

Area of Science:

• Immunology
• Gerontology
• Mitochondrial Biology

Background:

• Aging is linked to chronic inflammation and functional decline, but its cellular origins remain unclear.
• Hematopoietic stem cells (HSCs) initiate trained immunity, a heightened immune state, primarily through myeloid cells.
• SIRT3, a mitochondrial deacetylase, is crucial in HSCs but declines with age.

Purpose of the Study:

• To investigate the role of SIRT3 in HSC aging and its impact on aging-associated inflammation and trained immunity.
• To determine if modulating SIRT3 in HSCs can ameliorate age-related physiological decline.

Main Methods:

• Mice models were used to study SIRT3 expression in HSCs during aging.
• SIRT3 was overexpressed in HSCs to assess its effects on aging phenotypes.
• Immune cell function, inflammation markers, and tissue-specific functions (cognition, motility) were analyzed.

Main Results:

• SIRT3 expression in HSCs decreases with age, correlating with maladaptive trained immunity and inflammation.
• Overexpression of SIRT3 in HSCs reversed age-related HSC decline.
• SIRT3 intervention improved myeloid cell function, reduced inflammation, and attenuated age-related cognitive and motility deficits in mice.

Conclusions:

• HSC aging, driven by reduced SIRT3, is a key source of aging-associated inflammation via maladaptive trained immunity.
• Targeting SIRT3 in HSCs offers a potential therapeutic strategy to combat age-related physiological decline and extend healthspan.