The metabolic-inflammatory axis in aging: A multi-organ framework anchored in Sarcopenia - A review

Inflammaging refers to chronic low‑grade inflammation that develops with age and promotes multiple age‑related diseases. It arises from the close crosstalk between metabolic disturbance and inflammation, yet how this coupling acts across tissues remains poorly understood. As a hallmark of aging, sarcopenia often coincides with metabolic‑inflammatory dysfunction in the gut, liver, and adipose tissue, all tied together by insulin resistance (IR). In this review, we systematically examine the pathophysiological basis of the "metabolic-inflammatory axis" during aging, clarifying its conceptual boundaries with related terms such as "inflammaging," "immunometabolism," and "metabolic inflammation." We delineate the roles of three core molecular modules-nutrient sensing pathways (AMP‑activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)), mitochondrial stress (mitochondrial reactive oxygen species (mtROS)-p53), and epigenetic regulation (acetyl‑Coenzyme A (AcCoA)-histone acetyltransferase (HAT))-in mediating metabolic-inflammatory coupling. Using sarcopenia as a clinical anchor, we construct a tissue-specific atlas of the metabolic-inflammatory axis and elucidate the principles of organ crosstalk-and its mediators-within the gut-liver-adipose-muscle (GLAM) core axis. We then summarize current intervention strategies stratified by evidence level and identify knowledge gaps and future research directions. This review establishes a mechanistic link between molecular pathways and age-related multi-organ dysfunction, supporting a paradigm shift from single-disease management to multi-system healthspan interventions in aging.