Acid–Base Dysregulation Links Aging Metabolism to Frailty

Frailty denotes a state of high vulnerability and, as proposed by Fried and colleagues, arises from "energetic collapse" across multiple physiological systems, in which altered energy metabolism undermines resilience. We suggest that dysregulation of acid-base balance represents a critical yet underappreciated mechanism driving this collapse. With aging, cumulative stress burden diminishes the capacity for intracellular and extracellular acid buffering, renal acid excretion and ventilatory reserve, leading to impaired pH homeostasis, reduced mitochondrial ATP production, and declining cellular and organismal efficiency. Skeletal muscle, bone, liver, and kidney cooperate to mobilize the base reserves and redirect amino acid metabolism to enhance renal acid elimination. But this adaptation occurs at the expense of musculoskeletal integrity-a hallmark of aging. The shrinking iceberg metaphor illustrates frailty progression. Repeated stressors erode the acid buffer and energy reserve. Incorporating acid-base dysregulation into frailty models highlights new therapeutic targets-including diet, exercise and buffering strategies to preserve reserve and delay frailty progression.