Mini review argues immunosenescence framework may unify frailty and multimorbidity in later lifeA new framework for aging immunity offers fresh hope for older adults

Frailty and multimorbidity are closely intertwined syndromes of later life, yet they are still commonly interpreted through parallel clinical frameworks rather than a shared biological mechanism. In this mini review, we propose that immunosenescence provides a unifying axis linking the transition from frailty to multimorbidity. Rather than representing a simple decline in immune function, immunosenescence is better understood as a maladaptive remodeling process characterized by constrained adaptive immune renewal, repertoire narrowing, chronic low-grade inflammation, impaired immune surveillance, and defective resolution and repair. We argue that these changes erode physiological reserve through convergent effects on skeletal muscle maintenance and regeneration, metabolic flexibility, neuroendocrine stress adaptation, and recovery after physiological perturbation, thereby promoting the emergence of frailty. The same immune alterations may then lower the threshold for parallel tissue-specific injury across cardiovascular, metabolic, neural, skeletal, and other systems, favoring non-random disease clustering and the development of multimorbidity. Once multimorbidity is established, disease-derived inflammatory and metabolic stressors may further accelerate immune dysregulation, creating a self-reinforcing cycle of vulnerability. We also highlight translational implications of this framework, including the need to move beyond single inflammatory markers toward integrated immune-ageing signatures and to test pathway-aligned interventions such as lifestyle optimization, vaccination strategies, immune tuning, and selected senescence-targeting approaches. A mechanistically grounded immunosenescence framework may help reorient late-life care toward preserving resilience and slowing chronic disease accumulation.