The gut as a central hub for multi-organ crosstalk in aging.

The progression from aberrant DNA epigenetic modifications at the molecular level to the functional decline of cells, and subsequently to the deterioration of tissues and organs, represents a central process that shapes organismal health and aging. Aging of individual organs and the diseases associated with this process, including the decline of intestinal, skeletal muscle, cerebral, cardiac, hepatic, pulmonary and renal function, constitute key manifestations of systemic ageing and major contributors to reduced lifespan. The maintenance of organ and whole-body energy metabolism depends fundamentally on the digestion and absorption of nutrients following their entry into the intestinal tract. In recent years, the gut microbiota has emerged as a critical regulator of physiological and pathological communication among the intestine, muscle, brain, heart, liver, lungs and kidneys. It is now recognized as an important determinant of both health maintenance and disease progression. This Review presents the first comprehensive synthesis of the interactions between the gut microbiota and multi-organ ageing. It systematically examines how intestinal ageing and microbiota dysbiosis, acting through inflammatory responses and perturbed epigenetic regulation, contribute to complex networks of communication among multiple organs. Particular emphasis is placed on the mechanisms through which the gut microbiota influences the ageing trajectories of distal organs such as skeletal muscle, the central nervous system, the heart, liver, lungs and kidneys, primarily through the modulation of microbial metabolites and immune responses. Furthermore, we propose emerging intervention strategies targeting the gut or its microbiota that hold promise for mitigating ageing-associated disorders. We also discuss the potential applications of personalized interventions and precision nutrition in delaying ageing and preventing related diseases. By integrating the most recent advances in the field, this review broadens current understanding of the mechanisms underlying gut–organ communication in ageing and provides new conceptual and translational perspectives for future clinical intervention.