Immunosenescence, inflammaging, and metabolic disease: A geroscience perspective on mechanisms and links.

Abstract

Population aging is accompanied by a rising burden of metabolic disorders, including obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular complications. Aging is also associated with broad remodeling of the immune system, characterized by reduced protective capacity together with persistent low-grade inflammatory activity, commonly discussed in terms of immunosenescence and inflammaging. In this narrative review, informed by a structured literature search, we examine links between immune aging and metabolic dysfunction and evaluate inflammaging as a major process at this interface. We first distinguish the related but non-identical concepts of immunosenescence, inflammaging, metaflammation, cellular senescence, and the senescence-associated secretory phenotype (SASP). We then summarize core pathways involving NF-κB, NLRP3, mTOR, AMPK, insulin/IGF-1, and JAK/STAT signaling. Next, we discuss how age-related immune remodeling may contribute to insulin resistance, tissue inflammation, and metabolic impairment across adipose tissue, liver, skeletal muscle, pancreatic islets, vasculature, and the gut barrier, while also considering how hyperglycemia, lipotoxicity, mitochondrial stress, and epigenetic reprogramming may promote selected features of immune aging. We further review emerging biomarker domains, major sources of biological heterogeneity, and candidate therapeutic strategies, including lifestyle interventions, senescence-targeting approaches, and metabolic modulators, with attention to evidence strength, translational limitations, and clinical risk-benefit considerations. The immunometabolic interface thus provides a useful geroscience framework for understanding aging-related metabolic disease, although the direction, reversibility, and modifiability of these relationships in humans remain incompletely resolved.