MUSCLE HEALTH AND FUNCTIONAL VULNERABILITY: A MULTIDIMENSIONAL APPROACH TO SARCOPENIA ACROSS CLINICAL AND AGING CONTEXTS - SALUTE MUSCOLARE E VULNERABILITA' FUNZIONALE: UN APPROCCIO MULTIDIMENSIONALE ALLA SARCOPENIA NEI CONTESTI CLINICI E DELL'INVECCHIAMENTO

Background: Sarcopenia is a progressive and multifactorial muscle disease traditionally associated with aging. However, growing evidence suggests that it also plays a pivotal prognostic role in several non-geriatric contexts, including chronic diseases, endocrine therapies, and neurodegenerative processes. Its recognition as an independent clinical entity by the ICD-10 system underscores its relevance across medical disciplines. Objectives: This doctoral thesis aims to explore sarcopenia through a multidimensional lens, investigating its pathophysiological mechanisms, clinical correlates, and biomarker profiles across diverse patient populations. The overarching goal is to assess the value of muscle parameters—namely strength, mass, and physical performance—as indicators of systemic vulnerability, predictors of clinical outcomes, and potential therapeutic targets. Methods: The thesis comprises four original studies conducted on distinct clinical cohorts: (1) lung transplant recipients, (2) transgender individuals assigned female at birth undergoing testosterone-based gender-affirming hormone therapy, (3) older adults from a longitudinal population-based cohort with available Alzheimer’s disease blood biomarkers, and (4) geriatric patients with varying degrees of cognitive impairment. Each study employed observational and longitudinal designs, integrating clinical assessments with advanced diagnostic and statistical methods, including dual-energy X-ray absorptiometry (DXA), handgrip strength tests, biomarker profiling, and structural equation modeling. Results: Across all studies, reduced muscle strength and mass were significantly associated with poorer clinical outcomes, including decreased lung function, lower physical performance, and biomarker-based evidence of neurodegeneration. In lung transplant recipients, muscle parameters predicted long-term ventilatory capacity. In transgender individuals, muscle adaptation to hormonal therapy was age-dependent and functionally heterogeneous. In older adults, neurodegeneration biomarkers (NfL, p-tau181, GFAP) were linked to sarcopenia incidence and progression, revealing a possible muscle–brain axis of aging. Conclusions: Sarcopenia emerges as a systemic, dynamic, and modifiable condition that transcends traditional geriatric frameworks. Muscle strength is a cost-effective, clinically valuable tool for identifying at-risk individuals and monitoring disease trajectories across multiple medical contexts. Future directions include biomarker-guided prevention strategies, digital health monitoring, and the integration of geroscience therapeutics targeting the biological mechanisms of aging.