IF mifepristone (10–25 mg/kg/day, oral gavage, 8 weeks) is administered to 18-month-old C57BL/6 mice of both sexes,

THEN a measurable reduction (≥30%) in senescent cell burden (p16^INK4a^, p21^CIP1^, SA-β-galactosidase) and SASP output (IL-6, IL-8/CXCL1, TNFα protein in plasma and tissue lysates) will be observed in liver, heart, and adipose tissue — quantified by RNAscope for p16/p21, ELISA for secreted SASP factors, and flow cytometry for SA-β-gal in stromal fractions —

BECAUSE the following causal chain operates specifically in aged, RAC3-depleted tissue:

1. RAC3 (Receptor-Associated Coactivator 3), a nuclear receptor coactivator that tonically suppresses early autophagy initiation and prevents p53 nuclear translocation, is progressively downregulated during aging, creating a permissive but disorganised autophagy landscape in aged cells where basal mitophagy is insufficient to clear dysfunctional mitochondria (RAC3 inhibits early autophagy and is downregulated in aging)[https://doi.org/10.1038/cddis.2015.218].

2. Mifepristone, as a potent glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, competes with coactivators including RAC3 at the receptor interface, thereby disrupting the residual RAC3-GR complex that in aged cells partially restrains autophagy flux. By blocking GR-coactivator assembly, mifepristone disinhibits the ULK1/Beclin-1 autophagy initiation complex [SPECULATIVE — direct RAC3-GR-mifepristone biochemistry not yet demonstrated; inferred from RAC3's role as a steroid receptor coactivator and mifepristone's known coactivator-displacing mechanism at GR].

3. Enhanced autophagy flux, specifically directed toward depolarised mitochondria, constitutes mitophagy — mifepristone administration in Drosophila melanogaster extends lifespan of mated females and this effect was associated with mitophagy activation (pathway unspecified in available literature; referenced in the research context document accompanying this evidence set) [SPECULATIVE — pathway identity, i.e., PINK1/Parkin vs. BNIP3/NIX, is not established for mifepristone].

4. In aged cardiomyocytes and other post-mitotic or slow-cycling cells, suppression of autophagy directly induces cellular senescence, meaning that restoring autophagy/mitophagy flux constitutes a repair of the accumulated senescent state rather than mere prevention (suppression of autophagy directly induces senescence in cardiomyocytes)[https://doi.org/10.1101/2024.05.26.595978].

5. Dysfunctional mitochondria that escape mitophagy release mtDNA into the cytosol, activating cGAS-STING, which drives NF-κB-dependent transcription of the core SASP program including IL-6, IL-8, and TNFα — and mitochondria-depleted senescent cells show downregulated SASP mRNAs including IL-8 protein reduction, confirming this is a causal not correlative link (mitochondria-to-nucleus retrograde signalling drives SASP formation and mitochondrial depletion reduces it)[https://doi.org/10...

SENS category: GlycoSENS

Key references: • doi.org/10.1038/cddis.2015.218]. • doi.org/10.1101/2024.05.26.595978]. • doi.org/10.1101/gad.331272.119]. • doi.org/10.1016/j.exger.2014.11.004]; • doi.org/10.1007/s10522-019-09802-9].