Loss of Ca²⁺ Signaling Fidelity During Aging: Mitochondrial Dysfunction, Senescence, and Cognitive-Motor Decline

Aging is characterized by a progressive decline in cellular homeostasis that ultimately compromises tissue integrity, regenerative capacity, and organismal function. Among the molecular processes increasingly recognized as central regulators of aging, intracellular Ca²⁺ signaling has emerged as a major determinant of metabolic adaptation, stress responses, inflammation, and cell fate. Ca²⁺ controls essential biological functions in virtually every tissue. Importantly, the remarkable versatility of Ca²⁺ signaling depends on the precise spatial and temporal coordination of channels, pumps, exchangers, buffering proteins, and organelle contact sites that together generate highly organized intracellular Ca²⁺ microdomains. During aging, the quality of this signaling progressively deteriorates. Altered activity of plasma membrane channels, defective endoplasmic reticulum (ER) Ca²⁺ handling, impaired mitochondrial buffering, oxidative stress, and chronic inflammation collectively destabilize intracellular Ca²⁺ homeostasis. These alterations converge on mitochondrial dysfunction, one of the central hallmarks of aging, leading to bioenergetic decline, excessive reactive oxygen species production, cellular senescence, and impaired tissue adaptation. In the nervous system, disrupted Ca²⁺ signaling contributes to synaptic dysfunction, neuroinflammation, and neuronal vulnerability associated with cognitive decline and neurodegenerative disease. In skeletal muscle, defective Ca²⁺ handling impairs excitation-contraction coupling, mitochondrial metabolism, and regenerative capacity, thereby promoting sarcopenia and motor decline. In this review, we discuss how aging remodels the cellular Ca²⁺ signaling toolkit across neuronal and muscular systems, with particular emphasis on mitochondrial dysfunction, senescence and inter-organelle communication. Finally, we examine therapeutic strategies aimed at restoring Ca²⁺ signaling fidelity as potential interventions to preserve tissue function and extend healthspan.