Protein post-translational modifications in aging and cancer: Mechanisms and translational implications

Aging is a key risk factor for cancer, with complex, context-dependent processes influencing both tumor initiation and progression. While certain aging-associated processes restrain cellular proliferation, others drive tumor initiation and progression, revealing a context-dependent duality in the role of aging in cancer. Increasing evidence indicates that many of these transitions occur not through genomic alterations, but through reprogramming of protein post-translational modifications (PTMs). Phosphorylation, ubiquitination, acetylation, methylation and an expanding repertoire of acylations collectively regulate protein activity, stability, localization and interactions, translating aging-associated stresses, including metabolic imbalance, microenvironmental remodeling and accumulated damage, into functional cellular outcomes. In this review, we examine how PTMs bridge aging and cancer through three interconnected axes: integration of stress signals, encoding of metabolic states, and modulation of the tissue microenvironment. We discuss how major PTM systems coordinate core cellular processes, such as checkpoint control, proteostasis(definition), chromatin organization and cell–environment communication, and how, through dynamic and combinatorial actions, they establish distinct regulatory states that determine whether tissues sustain homeostasis, progress to dysfunction, or undergo malignant transformation. An in-depth understanding of how PTMs define these states provides valuable insights into disease stratification and offers new avenues for therapeutic interventions.