The cross-talk between neurodegeneration and metabolic disorders

Despite substantial advances extending human lifespan, the gap between healthspan(definition) and lifespan continues to widen, with neurodegenerative diseases (NDDs) and metabolic disorders representing major contributors to this disparity. Growing epidemiological and genetic evidence indicates a bidirectional relationship between NDDs and metabolic disorders, suggesting shared pathophysiological mechanisms that transcend organ-specific boundaries. In this narrative review, we sought to explore the interconnections between neurodegeneration and metabolic dysfunction through the lens of the twelve established telomere(definition) attrition, cellular senescence(definition))." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">hallmarks of aging(definition). We conducted a comprehensive literature search across multiple databases (PubMed, Google Scholar, Scopus, ScienceDirect) from January 2013 to April 2025, focusing on studies examining aging hallmarks in both NDDs (particularly Alzheimer’s disease and Parkinson’s disease) and metabolic disorders (obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease). Our analysis reveals that all twelve hallmarks - i.e., genome instability, telomere attrition, epigenetic alterations, loss of proteostasis(definition), impaired autophagy(definition), dysregulated nutrient sensing, mitochondrial dysfunction(definition), cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis - may serve as convergence points linking these seemingly disparate conditions. These findings support an integrated pathophysiological model wherein aging-related processes simultaneously promote neurodegeneration and metabolic dysfunction through shared molecular pathways. Understanding these mechanistic intersections offers promising opportunities for developing therapeutic interventions that could simultaneously target both neurodegenerative and metabolic diseases, potentially helping to close the healthspan-lifespan gap.