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Effects of fumarate and Alzheimer's disease on the metabolic reprogramming of aging T-cells associated with rescue of the T-cell anti-tumor functions

ABSTRACT: Changes in mitochondrial bioenergetics in aging T-cells play a key role in the decrease in T-cell function and tumor resistance with aging. The bioactive sphingolipid ceramide, induced by aging stress, is a major player in these changes, as its accumulation at the mitochondrial membranes of both mouse and human aging T-cells induces ceramide-dependent mitophagy, which decreases T-cell viability, cytokine secretion, and anti-tumor activity. Besides lipid signaling, our findings show a general depletion of tricarboxylic acid cycle (TCA) metabolites in aging T-cells, with pools of fumarate, malate, and argininosuccinate significantly decreasing in both mouse and human aging T-cells. In vivo supplementation of fumarate to mouse T-cells seemed to correct some of the functional defects observed in aging, with a protection of T-cell viability, cytokine production, and tumor killing capacity in co-cultures with tumor cells. The fumarate supplementation also led to a decrease in ceramide-dependent mitophagy in the aging T-cells, indicating an interplay between ceramide-dependent mitophagy and fumarate metabolism. Interestingly, T-cells from aging mice with Alzheimer's disease are protected against the aging-induce increase in mitophagy, and their fumarate pools are also protected. Here, the NanoString data shows the changes in metabolic and immune markers in aging T-cells with/out fumarate supplementation, as well as in T-cells from Alzheimer's mice, associated with a significant increase in different metabolic enzymes.

ORGANISM(S): Mus musculus

PROVIDER: GSE248924 | GEO | 2025/06/09

REPOSITORIES: GEO

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Effects of fumarate on the metabolic reprogramming of aging T-cells associated with rescue of the T-cell anti-tumor functions

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