New strategies to reprogram immunosenescence

This thesis explores strategies to rejuvenate immunity by investigating the molecular and cellular mechanisms that drive T cell aging. Immunosenescence, the age-associated decline in immune competence, is marked by the accumulation of senescent cells, impaired adaptive responses, and reduced vaccine efficacy. Central to this process is the dysfunction of CD4⁺ T cells, which lose mitochondrial fitness, fail to maintain telomeres, and accumulate chronic stress signaling complexes. The first part of this work identifies sestrin–MAPK complexes (sMAC) as central mediators of T cell senescence. Pharmacological disruption of sMAC dismantled these complexes, reduced stress signaling, and restored fatty acid oxidation. Rejuvenated T cells regained proliferation, synapse integrity, and responsiveness to stimulation, and importantly, recovered their ability to provide help to B cells, reactivating humoral responses normally impaired in old age. These results demonstrate that T cell senescence is not an irreversible endpoint but a state maintained by specific molecular interactions that can be disrupted. The second part of the thesis links metabolic competence to telomere biology. Senescent T cells lack CPT1A, the rate-limiting enzyme for fatty acid oxidation (FAO), which leads to defective synapse organization and abrogated telomer transfer from antigen-presenting cells. Re-expression of CPT1A reinstated FAO, enabled telomere acquisition, and promoted telomere elongation. Furthermore, telomere transfer triggered FAO-dependent asymmetric division, with unequal distribution of CPT1A during the first cell cycle, supporting the formation of long-lived memory subsets. Finally, systemic experiments showed that adoptive transfer of rejuvenated T cells into aged mice reduced senescence-associated signaling in peripheral organs and extended survival. Together, this thesis demonstrates that dismantling stress-inducing complexes,reprogramming metabolism, restoring telomere dynamics, and reinstating humoral responses can collectively reverse key aspects of immunosenescence. These findings provide a conceptual framework linking molecular signaling, immune cell fate, and organismal survival, and open new perspectives for interventions aimed at sustaining immune competence across the lifespan.