Human immune aging clock identifies RUNX1 as a decelerator of T cell senescence.

Area of Science:

• Immunology
• Gerontology
• Computational Biology

Background:

• Immunosenescence, the aging of the immune system, is a major driver of organismal aging.
• Quantifying the heterogeneity of immunosenescence is crucial for identifying therapeutic targets.
• Existing methods lack the precision to map immune aging comprehensively.

Purpose of the Study:

• To construct a quantitative framework for assessing human immune aging.
• To identify key regulators of immunosenescence and potential targets for rejuvenation.
• To map the landscape of immune cell aging at single-cell resolution.

Main Methods:

• Single-cell multi-omics analysis of nearly 1.2 million peripheral blood mononuclear cells from 230 individuals.
• Development of a human immune aging clock based on T cell transcriptomes.
• Functional validation of the transcription factor RUNX1 in T cell senescence.

Main Results:

• A precise map of immune aging was constructed, highlighting naive T cell loss and clonal contraction.
• The transcription factor RUNX1 was identified as a central regulator, with its expression declining in aged T cells.
• RUNX1 deletion induced senescence in young T cells, while its restoration rejuvenated aged CD8+ T cells in vitro and in vivo.

Conclusions:

• The developed immune aging clock provides a quantitative tool for assessing immunosenescence.
• RUNX1 is a critical regulator of T cell aging and a promising target for immune rejuvenation therapies.
• Targeting RUNX1 may offer a strategy to combat age-related decline in immune function.