Phase-transition failure in aged skeletal muscle regeneration.

Aged skeletal muscle is impaired at every phase of post-injury repair that has been examined, with myeloid recruitment delayed and skewed in composition, debris degradation lagging behind uptake, and muscle stem cell (MuSC) activation following a conserved trajectory at delayed kinetics. Deficits inside a phase may be differences of degree that a longer window absorbs, whereas the transition between phases offers no comparable slack. Each transition is triggered by a defined switch in signal, either the fall in damage input after debris degradation, the TNF/TGF-β balance that permits fibro-adipogenic progenitor (FAP) apoptosis, or the Ly6Chigh→Ly6Clow monocyte conversion. Because positive feedback operates beyond each switch, a compartment arriving late meets a microenvironment already committed to a self-maintaining alternative state that its later output appears unable to reverse. Retained mitochondrial lesions in postmitotic myofibers are one proposed input holding the first switch open. MuSCs face pool contraction, skewed fate allocation, and cell-autonomous defects uncorrected by a young host. FAPs resist clearance past their support phase while a stiffening matrix keeps them fibrogenic, and aged myeloid cells reach the pro-repair switch late and with attenuated output. None of these lesions need be primary for the sequence to fail. Interventions should instead be judged on whether inflammation declines, matrix remodeling closes, myogenic output yields mature fibers, and reserve survives repeated injury. Aging may therefore be read as a loss of temporal coordination, in which sub-threshold delays accumulate between compartments that must act in sequence, until a failed transition settles the tissue into an inflammatory-fibrotic endpoint.