Gojo, S.;Chamoto, K.;Teruyama, F.;Taya, T.;Shikuma, A.;Matoba, S.;Numajiri, K.;Umetani, S.;Chen, Y.;Peled, A.;Galun, E.;Assy, N.;Zick, A.;Noiman, S.;Michel, D.;Pelled, D.;Inaba, T.

Mitochondrial dysfunction is a hallmark of cellular aging, but whether age-associated cellular decline can be functionally reversed remains unclear. Here, we applied mitochondrial genome replacement to replicative senescent fibroblasts and aged T cells derived from mice and humans. In senescent fibroblasts, replacement with mitochondria from young cells extended proliferative lifespan, whereas replacement with aged mitochondria accelerated proliferative decline, indicating bidirectional modulation of aging-associated phenotypes. In aged mouse T cells, mitochondrial genome replacement restored proliferative capacity and significantly enhanced antitumor activity following adoptive transfer into tumor-bearing mice. Similarly, mitochondrial genome replacement in aged human T cells enhanced cytokine production and shifted the transcriptomic programs toward a more youthful state. Collectively, these findings identify mitochondrial genetic integrity as a functional regulator of aging-associated cellular states and support the emerging view that mitochondria actively influence cellular aging trajectories.