To determine long-term effects and mechanisms of glycolic-acid (GA) chemical peeling on skin structure, function, and aging pathways in intrinsic aging versus photoaging.

Female SKH-1 hairless mice (n=80) were assigned to intrinsic aging (no UV) or photoaging (daily UVA/UVB). The right torso received 70% GA every two weeks; the left side was the intra-animal control. Follow-up lasted up to 18 months (photoaging irradiated until month 11; final sampling at month 12). At 3-month intervals we assessed histology, EdU proliferation, molecular markers (RT-qPCR for Trp53, Pot1a, telomere length; Western blot for p21, mTOR; ELISA for IL-6, telomerase), barrier/wound repair, and performed single-cell and bulk RNA-seq.

GA increased dermal collagen in both models and, with prolonged treatment, reduced epidermal thickness. In intrinsic aging, GA decreased epidermal but increased dermal proliferation, lowered IL-6 and mTOR, transiently elevated p21, enhanced telomerase, and slowed telomere shortening; barrier recovery and wound healing improved. Under ongoing UV, GA raised cutaneous IL-6 and reduced p21, with time-dependent bidirectional changes in p53/mTOR/telomerase. Single-cell data showed photoaging-associated expansion of basal/spinous and progenitor keratinocytes and emergence of squamous cell carcinoma (SCC) cells; GA partially preserved hair-follicle stem cells, increased fibroblasts, and reduced SCC proportions. Bulk RNA-seq revealed MAPK/inflammatory enrichment in photoaging and cell-cycle programs after GA.

Long-term GA peeling confers anti-aging benefits in intrinsic aging by modulating inflammation and cell-cycle activity and promoting dermal remodeling and repair. Under persistent UV, GA displays biphasic effects with potential late promotion of photocarcinogenesis, underscoring the need for strict photoprotection and caution in precancerous settings.