Sex-Specific Diet-Microbiota Interactions in Ageing: Implications for Healthy Longevity

Background/Objectives: Diet-microbiota interactions shape ageing; however, their sex-specific dimensions remain poorly defined. Human studies rarely stratify analyses by sex, while most evidence of sex-dependent microbial and metabolic responses comes from preclinical models. This review synthesizes current findings on the sex-specific pathways linking diet, microbiota, and healthy ageing. Methods: A narrative review was conducted by integrating human observational studies, randomized controlled trials, and mechanistic animal research. Evidence was organized into four domains: (1) age-related changes in gut microbial composition; (2) microbiota-derived metabolites; (3) dietary patterns and functional nutrients; and (4) sex-specific endocrine and immunometabolism interactions influenced by the gut microbiota. Results: Ageing is characterized by dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, expansion of Proteobacteria, and reduced production of key metabolites including butyrate, indoles, and polyamines. Dietary fiber, polyphenols, omega-3 fatty acids, and plant-based proteins help restore these pathways and mitigate inflammaging. Sex differences persist into later life: women show reduced estrobolome activity and SCFA decline after menopause, whereas men display higher levels of pro-atherogenic metabolites such as trimethylamine N-oxide (TMAO). Nutritional interventions, probiotics, and microbial metabolites exhibit sex-dependent responses in both human and animal studies. Conclusions: Diet-microbiota interactions shape ageing outcomes through sex-specific metabolic, hormonal, and immunological pathways. Incorporating sex as a biological variable is essential for developing personalized, nutrition-based strategies to support healthy ageing.