Circulating factors as modifiable therapeutic targets in brain and cerebrovascular aging: Insights from heterochronic parabiosis

Abstract Age-related cognitive decline is a major public health challenge, with vascular contributions to cognitive impairment and dementia increasingly recognized as key drivers of late-life cognitive deterioration. Microvascular and neurovascular dysfunction, including blood–brain barrier (BBB) disruption, impaired neurovascular coupling (NVC), and microvascular rarefaction, play critical roles not only in vascular cognitive impairment and dementia (VCID) but also in the pathogenesis of Alzheimer's disease (AD). While cell-autonomous mechanisms such as mitochondrial dysfunction, genomic instability, and oxidative stress contribute to cerebrovascular and neural aging, accumulating evidence demonstrates that the systemic milieu exerts a profound influence on the aging trajectory of the brain and its vasculature. Heterochronic parabiosis, which surgically joins the circulatory systems of young and old animals, has emerged as a powerful experimental platform for identifying circulating mediators that regulate cerebrovascular aging and represent potential therapeutic targets. Studies show that youthful circulation can restore BBB integrity, improve NVC, enhance microvascular density, and attenuate endothelial senescence in aged brains, whereas aged blood rapidly induces vascular dysfunction in young brains. Mechanistic investigations implicate pro-youthful factors such as growth and angiogenic signals, anti-inflammatory cytokines, and extracellular vesicles, as well as pro-aging mediators including inflammatory cytokines, oxidative stress inducers, angiogenesis inhibitors, and senescence-associated secretory factors. By demonstrating that key features of cerebrovascular aging are dynamic and reversible, insights from heterochronic parabiosis provide a conceptual and experimental roadmap for pharmacological strategies aimed at modulating the systemic milieu. Targeting circulating pathways that influence endothelial function, BBB integrity, and neurovascular coupling may offer novel opportunities for the prevention or pharmacological treatment of age-related cognitive decline and dementia.