Mitochondrial fission drives the phenotypic switch of senescent cells from regenerative to inflammatory, providing a senomorphic target to preserve tissue repair

The beneficial versus harmful actions of senescent cells hinge on a metabolic checkpoint that governs their secretory phenotype. We hypothesize that elevated mitochondrial fission, mediated by Drp1 activation, pushes senescent fibroblasts into a chronic inflammatory SASP state, whereas promoting mitochondrial fusion sustains a transient, regeneration‑supporting SASP. This switch explains why young wound‑derived senescent cells express developmental programs that aid repair [https://doi.org/10.1101/2025.06.08.658533] while accumulated senescent cells in aging secrete factors that impair healing and drive fibrosis [https://doi.org/10.1007/s11357-022-00551-1].

In acute injury, transient senescence attracts immune cells for clearance and remodeling via a SASP rich in chemokines and growth factors [https://pmc.ncbi.nlm.nih.gov/articles/PMC12557303/]. Aging shifts the mitochondrial balance toward fission, increasing ROS production and NF‑κB signaling, which remodels the SASP toward IL‑6, IL‑1β, and TGF‑β dominance, thereby delaying healing and reinforcing paracrine senescence. Supporting this, transferring even a few senescent fibroblasts into young skin raises local senescence burden and impairs subsequent wound closure [https://doi.org/10.1007/s11357-022-00551-1], indicating that not all senescent cells are inherently reparative.

We propose that pharmacological modulation of mitochondrial dynamics can revert harmful senescent cells to a protective phenotype without eliminating them. Specifically, administering a Drp1 inhibitor (e.g., Mdivi‑1) or activating fusion promoters (e.g., MFN2 agonists) in aged mice will reduce fission, lower mitochondrial ROS, and shift the SASP from inflammatory to regenerative signatures. Predicted outcomes include: (1) decreased SASP IL‑6 and TGF‑β levels in wound tissue, (2) increased expression of fibroblast‑growth‑factor‑2 and vascular‑endothelial‑growth‑factor‑A, (3) accelerated re‑epithelialization and collagen remodeling comparable to young wounds, and (4) no reduction in senescent‑cell number as measured by p16^Ink4a^ or SA‑β‑gal staining.

To test this, we will employ a full‑thickness excisional wound model in 24‑month‑old mice. Groups will receive vehicle, a senolytic (navitoclax) as a comparative clearance arm, or a Drp1 inhibitor delivered topically via hydrogel. Wound area will be quantified daily via planimetry. At days 3 and 7 post‑injury, we will harvest peri‑wound tissue for SASP cytokine multiplex, mitochondrial morphology EM imaging, and senescence marker immunostaining. If the hypothesis holds, Drp1 inhibition will improve closure rates to match young controls, while senolytics will reduce senescence but not accelerate healing, and may even impair early inflammatory clearance.

Falsifiable outcomes: If Drp1 inhibition fails to alter SASP composition or wound kinetics, or if senescence burden drops without functional benefit, the mitochondrial fission‑SASP link is refuted. Conversely, a clear rescue of regenerative SASP parameters and accelerated repair would substantiate the idea that targeting the metabolic state of senescent cells offers a senomorphic strategy that preserves their transient, chaperone‑like functions while averting the chronic damage associated with aged senescence.