Hypothesis: Ketone‑Body Signaling Reprograms Senescent Fibroblast SASP to Promote Regenerative Wound Healing

Core Idea

Transient senescent fibroblasts in early wound healing secrete a developmental SASP rich in PDGF‑AA, Wnt5a and low‑level TGF‑β1 that drives fibroblast activation and matrix deposition without triggering chronic inflammation. We propose that elevated β‑hydroxybutyrate (βHB) from fasting or ketosis selectively suppresses the NF‑κB arm of the SASP while preserving—or even enhancing—this developmental program via HDAC inhibition and HCAR2‑mediated signaling.

Mechanistic Reasoning

1. βHB as an epigenetic modulator – βHB inhibits class I HDACs, leading to increased acetylation of histones at promoters of regenerative SASP genes (e.g., Pdgfa, Wnt5a) and decreased acetylation at NF‑κB‑dependent inflammatory loci (e.g., Il6, Ccl2) [5].
2. HCAR2 receptor signaling – Senescent fibroblasts express HCAR2; βHB binding activates Gi pathways that reduce cAMP/PKA activity, thereby limiting IKK activation and NF‑κB nuclear translocation [6].
3. SASP isoform switch – The result is a shift from a canonical inflammatory SASP (high IL‑6, IL‑8, MMPs) to a transient, pro‑regenerative SASP that maintains PDGF‑AA secretion and gains Wnt5a expression, both known to stimulate fibroblast‑to‑myofibroblast transition and angiogenesis [1][3].
4. Feedback loop – Wnt5a autocrine signaling further stabilizes the senescent state via ROR2, ensuring the SASP remains active only until matrix deposition reaches a threshold, after which βHB levels fall and immune clearance proceeds via NKG2D ligands [2].

Testable Predictions

• In vivo: Aged mice subjected to alternate‑day fasting (raising plasma βHB to ~1‑2 mM) will show accelerated wound closure, increased p16+/p21+ fibroblasts with high PDGF‑AA/Wnt5a and low IL‑6/IL‑8 SASP, and reduced fibrosis compared with ad libitum controls. Pharmacologic blockade of HCAR2 (with specific antagonist) will abolish these benefits.
• In vitro: Human fibroblasts irradiated to induce senescence will exhibit, upon βHB (5 mM) treatment, decreased NF‑κB p65 nuclear translocation, increased H3K27ac at Pdgfa and Wnt5a promoters, and a secretory shift measurable by multiplex ELISA (IL‑6 ↓ 40 %, PDGF‑AA ↑ 2‑fold, Wnt5a ↑ 1.8‑fold). HDAC inhibition mimic (TSA) will replicate the βHB effect, while HCAR2 knockdown will block it.
• Falsification: If βHB fails to alter the SASP profile or does not improve healing in aged mice despite achieving ketosis, the hypothesis is refuted.

Implications

This reframes senolytic timing: rather than blanket removal, modulating senescent cell metabolism to favor a regenerative SASP could harness their hostage‑negotiator function without triggering the pathological fallout of chronic senescence.