Time-restricted feeding (TRF) is a dietary strategy that limits food intake to a specific daily window, aligning feeding behavior with circadian rhythms without reducing total caloric intake. Unlike caloric restriction, TRF has been shown to promote weight loss, improve metabolic health, and delay age-related diseases. Emerging evidence suggests TRF can reshape brain epigenetics, particularly DNA methylation, and that such modifications may be heritable. To investigate this, we conducted a controlled study using C57BL/6J mice assigned to either ad libitum (AL) or TRF groups. After four months, mating produced offspring stratified by parental feeding regimen. All F1 offspring were maintained on a standard AL diet to isolate inherited effects. Body weights and blood panels were tracked, and glucose tolerance tests (GTT) were performed. Cortical tissue and sperm were collected for molecular analysis, including whole-genome bisulfite sequencing (WGBS), RNA sequencing, and proteomics.
WGBS revealed extensive differentially methylated regions (DMRs) in TRF-fed parental mice, enriched in genes linked to neural function and sensory perception, particularly olfactory and auditory signaling. Multi-omics analysis confirmed coordinated changes in gene expression and protein abundance in these pathways. Notably, F1 offspring from TRF-fed parents exhibited persistent DMRs in the same sensory pathways, despite AL feeding, along with corresponding transcriptomic and proteomic shifts. These offspring also showed improved glucose tolerance and reduced body weight, suggesting inherited epigenetic changes may confer metabolic benefits.
Our findings demonstrate that TRF induces targeted epigenetic remodeling in the brain and germline, with heritable consequences. The consistent modulation of sensory pathways suggests they may serve as a key interface between environmental cues and epigenetic programming. This study highlights TRF as a promising non-pharmacological intervention to promote long-term health and cognitive resilience across generations.