INTERGENERATIONAL EPIGENETIC REPROGRAMMING OF BRAIN AND SENSORY PATHWAYS BY TIME‑RESTRICTED FEEDING

Time-restricted feeding (TRF), a form of intermittent fasting that confines food intake to a defined daily window without reducing total caloric intake, has emerged as a powerful modulator of metabolic health and aging. Beyond its known benefits, recent evidence suggests that TRF can reshape the brain’s epigenetic landscape, raising the possibility that these molecular changes may be inherited across generations. To examine this, we implemented TRF in C57BL/6J mice for four months and compared them with ad libitum (AL) controls before generating offspring from all parental combinations. All F1 offspring were maintained on AL diets to isolate inherited effects. Multi-omics profiling, including whole-genome bisulfite sequencing, RNA-seq, and quantitative proteomics, revealed extensive TRF-induced differentially methylated regions in parental cortical tissue, enriched in genes governing sensory perception, particularly olfactory and auditory pathways. These epigenetic alterations were accompanied by coordinated transcriptional and proteomic shifts, indicating functional remodeling of neural circuits. Strikingly, F1 offspring exhibited persistent methylation signatures in the same sensory pathways despite never being exposed to TRF, along with parallel transcriptomic and proteomic changes. Offspring of TRF-fed parents also displayed improved glucose tolerance and lower body weight, suggesting that inherited epigenetic modifications may confer metabolic advantages. Together, these findings demonstrate that TRF induces targeted epigenetic reprogramming in the brain and germline with intergenerational transmission, highlighting sensory perception pathways as a potential interface linking dietary timing to neural and metabolic outcomes. This work positions TRF as a promising non-pharmacological strategy capable of shaping health trajectories across generations.