T cells with dysfunctional mitochondria induce multimorbidity and premature senescence

TLDR

Immunometabolism’s impact on age‑associated diseases remains unclear. The study demonstrates that TFAM‑deficient T cells accelerate senescence. Metabolic failure of these T cells triggers a cytokine storm that drives systemic senescence. TFAM‑deficient T cells cause metabolic, cognitive, physical, and cardiovascular decline leading to premature death, and TNF‑α blockade or NAD+ precursors partially mitigate this effect.

Abstract

The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with