Resumen de Mitochondrial T cell failure induces multimorbidity and agin
With the continuous extension of life expectancy, there is an urgent need to understand the common molecular pathways by which aging results in a progressively higher susceptibility to chronic morbidity, disability, and frailty. Immunometabolism has emerged as a new field to boost immune responses for cancer immunotherapies, and to dampen autoimmune diseases. However, the potential of targeting immunometabolism to modulate aging and age-associated diseases has not been profound studied.
The hypothesis of this thesis is that during aging exist a decline in T cells mitochondrial metabolism. As consequence, T lymphocytes might induce a loss of systemic organism homeostasis leading to aging. We generated a mouse model lacking the transcription factor A (Tfam), specifically in T cells (Tfamfl/flCd4Cre). Tfam depletion induces a severe decreased in mtDNA content leading to a failure to express key components of the electron transport chain. Importantly, we detected loss of metabolic flexibility in T cells from old wild type and young Tfamfl/flCd4Cre mice, causing in both cases that T cells, become proinflammatory, secreting high amounts of Th1 cytokines (IFN-γ and TNF-α). Besides, Tfamfl/flCd4Cre mice at young age are susceptible to viral infections and to develop a premature phenotype of inflammaging.
We observed that Tfamfl/flCd4Cre mice resembled a frail aged appearance and several features associated with aging such as hematological alterations, kyphosis, body weight decline or a reduction in survival. Interestingly, we found that T cells with a metabolic failure act as aging accelerators in mice and instigate multiple age-related features, such as altered cognitive and physical disabilities, and profound cardiovascular alterations. Next, we deepen into the molecular mechanisms driving multimorbidity. We detected the upregulation of senescence markers in multiple tissues. Th1 cytokines could directly mediate senescence induction in distal organs. Finally, we have used our novel mouse model to prevent senescence and delay the multimorbidity phenotype by the blockage of TNF-α signaling or treatment with NAD+ precursor. Our results settle T cells metabolism at the crossroad between inflammation, senescence and aging, suggesting that immunometabolism could be a therapeutic approach to delay aging and aging-associated diseases
