The mechanisms and mechanics of aging

Aging tissues paradoxically stiffen while losing mechanical resilience, becoming fragile, poorly regenerative and chronically inflamed. We review evidence that these phenotypes emerge from progressive failure of mechanotransduction across a mechanically integrated axis linking extracellular matrix (ECM) architecture, integrin adhesions, cytoskeletal force transmission and nuclear mechanics. We discuss how matrisome remodeling, glycation-driven crosslinking and reduced ECM turnover alter not only bulk stiffness but also fiber deformability, ligand presentation and matrix remodelability, thereby lowering the fidelity of mechanosensing. We then synthesize how distorted mechanical inputs and age-intrinsic changes in mechanotransduction machinery propagate through focal adhesion signaling, actin-microtubule dynamics, mechanosensitive ion channels and nucleo-cytoskeletal coupling to dysregulate mechanosensitive transcription factors (including YAP/TAZ and MRTF), promote senescence and amplify the senescence-associated secretory phenotype (SASP), which further degrades the ECM. Finally, we highlight premature aging syndromes as causal evidence showing that disruption of either ECM structure or nuclear integrity can collapse mechanotransductive homeostasis and trigger tissue degeneration. Together, these studies support a mechanical drift framework and motivate rejuvenation strategies aimed at resetting the aged mechanochemical niche.