Imperfect repair in aging: senescent cells and the hepatic fibrotic niche.

Abstract

Aging proceeds in a nonuniform spatiotemporal manner across tissues. While metabolic stress and chronic inflammation are implicated, the underlying mechanisms remain elusive. Here, we propose that imperfect wound healing-a failure of full resolution-creates and sustains pathological niches that drive progressive age-related dysfunction. Using the liver as a model system, we deconstruct this 'imperfect repair'. We posit that it is driven by a pro-fibrotic, non-resolving microenvironment sustained by complex crosstalk between functionally heterogeneous senescent cells and non-senescent scar-associated cell (SAC) populations (including macrophages, endothelial cells (ECs), and hepatic stellate cells (HSCs)). This pathological ecosystem is further shaped by the spatial context of hepatic zonation collapse, and the dysregulation of core signaling hubs, like WNT, Transforming Growth Factor (TGF)-β, and YAP and TAZ (YAP/TAZ). Viewing aging through the lens of imperfect repair provides a unifying framework linking senescence, inflammation, and fibrosis. This perspective shifts the therapeutic paradigm from targeting single senescent cells toward engineering the pathological niche itself, and redirects focus from end-stage disease, to the sub-clinical, spatial origins of tissue vulnerability. [BMB Reports 2026; 59(1): 13-26].