Rethinking insulin resistance in aging: A reserve-oriented clinical framework

Ageing represents one of the strongest non-modifiable determinants of insulin resistance (IR), a condition that extends well beyond impaired glucose handling and underling a broad spectrum of metabolic, cardiovascular, and neuropsychiatric disorders. In older adults, IR emerges from the progressive loss of physiological reserve across multiple organ systems rather than from isolated defects in insulin signalling. This narrative review examines the metabolic, inflammatory, and hormonal mechanisms linking ageing to insulin resistance, with a specific focus on skeletal muscle deterioration, adipose tissue remodelling, mitochondrial dysfunction, chronic low-grade inflammation, and cellular senescence. Age-related sarcopenia and myosteatosis compromise peripheral glucose disposal, while visceral adipose tissue expansion and adipocyte senescence promote a pro-inflammatory and insulin-desensitizing milieu. These peripheral alterations are amplified by inflammageing, mitochondrial–endoplasmic reticulum dysfunction, and endocrine dysregulation involving growth hormone, sex steroids, and adipokines. Importantly, insulin resistance in ageing is increasingly recognized as a systemic condition affecting brain metabolism, thereby contributing to cognitive decline, depression, and frailty. Understanding insulin resistance as a multisystem failure of metabolic resilience provides a conceptual framework for integrated preventive and therapeutic strategies in older adults, combining lifestyle interventions, targeted pharmacological approaches, and emerging geroscience-based therapies. • Insulin resistance in aging is a multisystem phenomenon reflecting declining metabolic adaptability rather than a simple glucose disorder. • Age-related insulin resistance arises from interconnected mechanisms, including inflammaging, cellular senescence, and mitochondrial dysfunction. • Muscle metabolic quality, rather than adiposity alone, emerges as a key determinant of insulin sensitivity in older adults. • Targeting metabolic resilience may offer a more effective strategy than glucose-centered approaches for promoting healthy aging.