Time-restricted feeding improves functional capacity of adipose-derived stem cells with activation of OSK-associated transcriptional programs.

Abstract

Time-restricted feeding (TRF), a circadian-based dietary intervention, has emerged as a promising strategy to counteract metabolic and age-related dysfunctions. However, how TRF can reverse stem cell aging and restore tissue regenerative potential remains unclear. In this study, we investigated the effects of long-term TRF on senescent adipose-derived stem cells (ADSCs) in a high-fat diet (HFD) induced aged mice model. Mice were assigned to standard or HFD diets under ad libitum or TRF (8 h/day) regimens for 7 months. TRF effectively attenuated HFD-induced weight gain and metabolic inflexibility. Functionally, TRF preserved ADSC morphology and mitochondrial integrity, restored proliferation and migration capacity. Restored balanced lineage differentiation and markedly reduced senescence markers, reactive oxygen species, and inflammatory cytokines. TRF was associated with increased expression of Oct4, Sox2, and Klf4 (OSK) in ADSCs. Lentiviral overexpression of OSK partially recapitulated restoration-associated phenotypes in vitro. However, while OSK overexpression was sufficient to induce these changes, the present data do not establish a necessary role for OSK in mediating TRF-induced effects. Analysis of adipose tissue was consistent with the cell assay, confirming that TRF alleviated fibrosis and inflammation in aged adipose tissue. We find TRF as a noninvasive, physiologically safe intervention to restore aged stem cell function and tissue homeostasis during aging.