Time-restricted feeding (TRF) is a promising dietary strategy for delaying metabolic aging, yet its efficacy in cardioprotection across metabolic stages remains poorly understood. This study demonstrates that a 10-h TRF window significantly mitigates cardiac aging phenotypes including fibrosis, mitochondrial dysfunction, and senescence-associated secretory phenotype in prediabetic mice, whereas these protective effects are largely blunted at the diabetic stage, despite improving systemic metabolism in both prediabetic and diabetic models. Mechanistically, TRF acts as a chronotherapeutic cue that restores the diurnal oscillations of short-chain fatty acid (SCFA)-producing gut microbiota. These rhythmic SCFAs serve as peripheral “metabolic zeitgebers” that resynchronize cardiac diurnal rhythms autophagy. In vitro, SCFAs enhance autophagic flux and preserve mitochondrial integrity in senescent cardiomyocytes. Crucially, the cardioprotective benefits of TRF are largely abolished in p62-deficient mice, identifying p62-dependent autophagy and mitochondrial homeostasis as a key molecular mechanism underlying TRF efficacy. In overt diabetes, the loss of TRF-mediated protection is attributed to a profound “metabolic rigidity” that prevents restoration of autophagic rhythmicity. Overall, our findings reveal that TRF prevents cardiac aging by entraining the gut microbiota–SCFA–cardiac p62 axis during the prediabetic stage, highlighting a critical metabolic window for dietary intervention.
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