Mitochondria‐Associated Membranes as a Convergent Hub of Brain Aging: From Neurodegeneration to Cerebral Ischemia

ABSTRACT Brain aging is the principal risk factor for both neurodegenerative diseases (NDDs) and cerebral ischemic disorders, yet the subcellular mechanisms linking these conditions remain incompletely defined. Mitochondria‐associated membranes (MAMs)—specialized contact sites between the endoplasmic reticulum (ER) and mitochondria—sit at the intersection of two well‐established hallmarks of aging, mitochondrial dysfunction, and loss of proteostasis, making them an attractive mechanistic node for understanding age‐related brain decline. In this review, we propose a MAM‐centered framework that unifies neurodegenerative and ischemic brain pathology under the broader paradigm of brain aging. We first summarize the molecular architecture of MAMs and their core functions in neuronal Ca 2+ transfer, mitochondrial dynamics, lipid metabolism, inflammasome assembly, and autophagic quality control, together with emerging evidence from non‐neuronal brain cells. We then examine how MAM dysfunction intersects with five hallmarks of aging—mitochondrial dysfunction, loss of proteostasis, disabled macroautophagy, chronic inflammation (inflammaging), and altered intercellular communication—drawing on evidence from physiological aging and cellular senescence models. Next, we discuss disease‐specific roles of MAMs in cerebral ischemia and in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. A central theme emerges: Rather than a unidirectional decline of MAMs, brain aging is associated with a loss of MAM homeostasis, in which both insufficient and excessive ER–mitochondria coupling can be pathological and the shared deficit is the failure to maintain contact‐site function within an optimal range. Finally, we consider age‐relevant therapeutic and biomarker strategies targeting MAMs and their potential translation into geriatric neurology. To our knowledge, this is the first review to integrate MAM biology across physiological brain aging, cerebral ischemia, and the four major NDDs within a single homeostatic framework, offering a unified perspective on the mechanisms of age‐related brain decline.