Telomere Length in Metabolic Syndrome: Mechanisms, Epidemiology and Clinical Implications: A Narrative Review

Metabolic syndrome (MetS) is a major and growing global public health challenge, affecting a substantial proportion of adults worldwide and contributing markedly to the rising burden of type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, and premature mortality. Despite its high prevalence and systemic consequences, the biological mechanisms linking chronic metabolic stress to cellular ageing remain incompletely resolved. Telomere length (TL), particularly leukocyte telomere length (LTL), has emerged as a candidate integrative biomarker of biological ageing, cumulative metabolic injury, and disease risk; however, the field remains limited by heterogeneous study designs, inconsistent measurement approaches, conflicting genetic data, and uncertainty regarding whether TL is merely a correlate of metabolic dysfunction or a clinically informative biomarker and mechanistic mediator. This narrative review synthesizes evidence on the epidemiology, mechanistic basis, and clinical implications of TL variation in obesity and MetS, with emphasis on human population studies. It specifically addresses the current gap between observational associations and biological interpretation by integrating epidemiological, longitudinal, mechanistic, and Mendelian randomization data within a unified framework. Across large cohorts and meta-analyses, MetS and several of its component traits are generally associated with shorter LTL. Shorter LTL in MetS appears to identify individuals at higher risk of adverse outcomes, including all-cause and cardiovascular mortality. Mechanistically, oxidative stress, chronic low-grade inflammation, mitochondrial dysfunction, hormonal perturbation, and genetic and epigenetic regulation of telomere-maintenance pathways emerge as interconnected drivers of accelerated telomere attrition and cellular senescence. Mendelian randomization studies indicate a more complex architecture, in which adiposity-related traits may causally shorten LTL, whereas genetically longer LTL may associate with selected adverse metabolic phenotypes, consistent with pleiotropy, tissue specificity, and pathway-dependent effects. This review collates the current evidence, highlights major research gaps, and outlines the methodological and biological advances needed to determine whether TL can serve as a clinically actionable biomarker or therapeutic target in MetS.