Time-restricted feeding improves metabolic flexibility, promotes beiging, and mitigates fibro-inflammation in the adipose tissue of aged mice

Adipose dysfunction contributes to age-related systemic decline primarily through its adverse effects on energy metabolism, insulin sensitivity, circulating adipokines, and inflammation. Time-restricted feeding (TRF) has emerged as a promising approach to correct adipose and metabolic dysfunction. However, most of these studies were carried out in young animals. Whether TRF could exert similar beneficial effects in the adipose tissue during aging remains unknown. To address this, 18-month-old C57BL/6 mice were placed on either a TRF diet (food intake restricted to a 6-hour time window every day in the dark phase) or an unrestricted diet for 6 months. Young animals on an unrestricted diet acted as additional controls to compare the effects of aging. Here, we demonstrate that a 6-month TRF regimen induces a biphasic pattern in whole-body energy metabolism characterized by a selective increase in energy expenditure and oxygen consumption during the active dark phase, aligning with the feeding schedule. TRF increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) and reverses age-associated whitening of brown adipose tissue (BAT) in aged mice. In addition, TRF selectively enhances mitochondrial metabolism in WAT depots. Furthermore, TRF reduces macrophage infiltration, induces a favorable shift in macrophage polarization (lower M1/M2 ratio), and decreases fibrosis in adipose tissue. Overall, our findings indicate that TRF promotes a metabolically beneficial adipose phenotype characterized by beiging and reduced fibro-inflammation during aging. These results underscore the potential of TRF as a dietary intervention to mitigate adipose dysfunction and promote metabolic health in the aging population.