Senescent cells are not static; their functional output hinges on intracellular metabolic state. In young tissue, a subset of senescent fibroblasts activates peroxisome proliferator‑activated receptor alpha (PPARα), driving fatty acid oxidation (FAO) and promoting a SASP enriched in PDGF‑AA that stimulates myofibroblast differentiation and wound closure. When PPARα signaling is attenuated, these cells shift toward glycolysis and secrete a pro‑inflammatory SASP dominated by IL‑6 and TGF‑β, which impedes repair and fuels fibrosis. This metabolic switch explains why senolytics administered too early disrupt healing, while chronic senescent accumulations in aged wounds reflect a failure to engage the PPARα‑FAO program.

Hypothesis: Pharmacological activation of PPARα in senescent cells during acute injury will sustain a transient, PDGF‑AA‑rich SASP, accelerate wound closure, and prevent the emergence of chronic, fibrosis‑promoting senescent phenotypes. Conversely, genetic or pharmacological inhibition of PPARα in senescent cells will convert a normally reparative senescent response into a persistent, fibrotic SASP, delaying healing and increasing collagen deposition.

Testable predictions:

1. In mouse full‑thickness excisional wounds, topical administration of a PPARα agonist (e.g., fenofibrate) to wounds treated with a senolytic (to remove baseline senescent cells) will rescue healing kinetics to levels seen in untreated wounds, as measured by wound area over time and histological re‑epithelialization.
2. Senescent fibroblasts isolated from agonist‑treated wounds will show elevated CPT1A expression (FAO marker), increased oxygen consumption rate, and a SASP profile with high PDGF‑AA/low IL‑6 ratios compared with senescent fibroblasts from vehicle‑treated wounds.
3. Conditional knockout of PPARα specifically in p16^INK4a^‑positive senescent cells (using p16‑3MR; PPARα^fl/fl^ mice) will result in prolonged wound closure, increased hydroxyproline content, and sustained expression of TGF‑β1 and COL1A1 despite normal immune cell infiltration.
4. Metabolomic profiling of wound tissue will reveal a shift from acyl‑carnitines (indicative of FAO) to lactate accumulation in PPARα‑deficient senescent cells, correlating with SASP composition changes.

Mechanistic rationale: PPARα activation enhances NAD^+ levels through increased FAO, promoting SIRT1‑mediated deacetylation of p53 and NF‑κB, which skews transcriptional programs toward PDGF‑AA secretion and away from IL‑6/TGF‑β. This creates a feedback loop where PDGF‑AA‑driven myofibroblast activity remodels the extracellular matrix, releasing latent TGF‑β that is normally kept in check by MMPs secreted by the same senescent cells. When PPARα is inhibited, reduced NAD^+ diminishes SIRT1 activity, leading to hyperacetylated p53/NF‑κB, a shift to glycolytic metabolism, and a SASP that favors fibroblast activation and collagen deposition without sufficient MMP counterbalance.

Falsification: If PPARα agonism fails to improve healing in senocyte‑depleted wounds, or if PPARα loss does not exacerbate fibrosis, the hypothesis would be refuted, suggesting that metabolic reprogramming is not the primary determinant of senescent cell functional polarity in tissue repair.