Imageomics defines granular morphological changes of human skin with age and reveals a rejuvenating effect of xenografting

Rejuvenating aging human skin is a major therapeutic goal, but objective, quantitative measures of intrinsic aging are limited. We performed a cross-sectional histological study of UV-protected buttock and abdominal skin in adults spanning multiple decades of life to identify features that reliably track age. Epidermal thickness measured between rete ridges was unchanged, but rete ridge size declined linearly with age: ridges became shorter and thinner in both sites, though rete ridge number decreased only in the abdomen. Consistent with these structural changes, proliferative cells (Ki67+) per ridge and expression of integrin β4 (ITGB4), a putative stem-cell marker, were reduced in aged skin. We combined these biomarkers into a predictive model that estimated skin age more accurately than any single marker. To test whether the model detects longitudinal change, we analyzed aged abdominal skin before and after xenografting onto young or aged mice, a procedure previously reported to rejuvenate human skin in young but not aged recipient mice. Both individual biomarkers and the imaging model indicated rejuvenation regardless of host age; however, notably, engraftment efficiency was lower in aged hosts, with surviving grafts showing younger histological phenotypes. These results provide quantitative criteria for assessing intrinsic skin aging and suggest that the process of engraftment itself is sufficient to induce rejuvenation-like changes.