Stem cell-free therapy for healthy brain aging: Mechanisms, challenges, and prospects

The stem cell secretome, which includes bioactive molecules and extracellular vesicles (EVs), has been reported to have neuroprotective effects in various neurological conditions. Current research indicates that secretome constituents, particularly EVs, can regulate pathways related to aging hallmarks and are therapeutic targets for brain aging. EVs can traverse the blood-brain barrier (BBB) and transfer neuroprotective cargoes such as proteins, peptides, miRNAs, and lipids to aged neural tissue. By acting on inflammation, apoptosis, mitochondrial damage, and cellular senescence, the secretome can restore neural homeostasis and induce neurogenesis and angiogenesis. While stem cell therapy is hindered by the risk of tumorigenicity and immune rejection, secretome and EV-based acellular therapies are safer and possibly more targeted choices. The content and delivery optimization of such vesicles to influence significant regulatory pathways of aging is currently of interest. This review highlights the dual importance of mechanistic insights and translational perspectives and discusses our current understanding of how the secretome, along with EVs, regulates hallmarks of brain aging with practical aspects of clinical application. The present review provides a novel and comprehensive analysis of current knowledge on stem cell-derived secretome and EVs as targeted modulators for healthy brain aging, with a critical evaluation of translational hurdles and clinical implementation.