Multigenerational daytime-restricted feeding exacerbates irradiation-induced hepatic DNA damage and aging in mice

While feeding timing profoundly impacts hepatic circadian rhythms due to the liver's high sensitivity to dietary signals, its cumulative, intergenerational consequences on vulnerability to environmental stress and stress-induced senescence remain largely unknown. Therefore, this study aimed to investigate the intergenerational effects of multigenerational daytime-restricted feeding (DRF) on the hepatic DNA damage response and liver health in a mouse model.

A multigenerational DRF mouse model was established, where mice from the F0 to F10 generations were subjected to a feeding window restricted to 6 hours during the light phase (Zeitgeber time, ZT2ZT8). Hepatic transcriptional rhythms were analyzed, and mice were exposed to 1 Gy X-ray irradiation to induce DNA damage. DNA damage was subsequently assessed via γH2AX immunofluorescence, and cellular senescence was evaluated by senescence-associated beta-galactosidase (SA-β-gal) staining alongside p21 expression.

Multigenerational DRF disrupted the circadian transcriptional rhythms of key DNA repair genes (e.g., Wrnip1, Nabp2, Fan1), with a trend towards downregulation in F10 livers. Following irradiation, F10 mice exhibited significantly increased γH2AX foci, indicating exacerbated DNA damage. Furthermore, these mice demonstrated elevated p21 expression and a higher number of SA-β-gal-positive senescent cells compared to earlier generations, whereas apoptosis markers (BAX, BCL2) remained unchanged.

Persistent multigenerational DRF impairs the circadian regulation of DNA repair genes and sensitizes the liver to genotoxic stress, leading to increased DNA damage and accelerated cellular senescence. These findings underscore the significant intergenerational impact of dietary timing on the hepatic DNA damage response and highlight the critical importance of meal timing in maintaining liver health and preventing age-related pathologies.