Tumor Suppressors Are Longevity Genes: A Conceptual Shift in Cancer Biology

Abstract For decades, tumor suppressor genes have been viewed exclusively through the lens of cancer prevention. Here, we propose a conceptual shift: tumor suppressors are endogenous longevity genes, and their anti‑cancer functions are downstream consequences of a deeper evolutionary role — the preservation of organismal lifespan. We synthesize molecular, evolutionary, and human evidence to support this claim. p53‑null mice die within ~3 months [1–8], traditionally attributed to spontaneous lymphomas; however, wild‑type mice live ~2–2.5 years, revealing that p53 is essential for maintaining the longevity machinery. We integrate p53, PTEN, SIRT6, NRF2, p63, and SIRT3 into a unified conceptual framework showing how tumor suppressors restrain growth, suppress retrotransposons, maintain mitochondrial fitness, and prevent inflammaging [9–15, 16–22, 23–32, 33–38, 39–45, 46–52]. Recent single‑cell analyses of supercentenarians demonstrate an expanded population of cytotoxic T cells exhibiting sustained p53/p63/p73 activity [63–65], providing direct human validation that longevity requires persistent tumor‑suppressor function. This work reframes tumor suppressors as the molecular architecture of healthy ageing.