Jennifer Ihuoma ¹ Sharon Negri ¹ Amanda Morato Do Canto ² Anika M. Hartz ³ Aditi Deshpande ^4* Stefano Tarantini ^5*

• ¹ Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma, United States
• ² Faculty of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil
• ³ University of Kentucky, Lexington, United States, Lexington, United States
• ⁴ BioAge Labs, Richmond, United States
• ⁵ University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States

The brain, as the most metabolically active organ in the human body, consumes approximately 20% of the body's energy supply at rest. This high energy demand is fulfilled by processes like neurovascular coupling (NVC), which ensures that areas of the brain requiring more energy receive increased blood flow to supply oxygen and glucose. Neurovascular coupling is coordinated by the neurovascular unit (NVU), composed of neurons, glia, endothelial cells, and smooth muscle cells. This unit also maintains the integrity of the blood-brain barrier (BBB), which regulates the exchange of molecules between the bloodstream and the brain. During brain development, the NVC is formed and ensures that energy requirements of the developing brain are met for fundamental processes such as synaptogenesis and neural plasticity. As we age, there is neurovascular and neurometabolic uncoupling and loss of BBB integrity, which leads to insufficient blood flow, impaired waste clearance, and bioenergetic deficits. Such disruptions have been linked to cognitive decline and neurodegenerative diseases such as Alzheimer's disease (AD), vascular cognitive impairment and dementia (VCID), and multiple sclerosis (MS) as well as metabolic conditions like hypercholesterolemia and insulin resistance. The goal of this research topic is to present cutting-edge basic and translational studies that shed light on the mechanisms driving NVU dysfunction and metabolic imbalance in the aging brain, as well as identify potential therapeutic strategies for preventing or mitigating cognitive decline and neurodegenerative disea se In conclusion, the research presented here highlights the complex interplay between neurovascular health, BBB integrity, and metabolic regulation, all of which are essential for maintaining brain homeostasis throughout life. As the brain ages, impairments in these systems contribute to cognitive decline and neurodegenerative disease. Each study uniquely identifies mechanisms that provide a better understanding of how disruptions in the NVU and metabolic processes accelerate neurodegeneration. Collectively, the studies underscore the importance of targeting both cerebrovascular and metabolic pathways to preserve brain function, from mitochondrial regulators like SIRT3 to pericytes, PVMs, and novel biomarkers such as NGFR. As the field advances, the integration of these molecular and cellular insights will be crucial for developing interventions that protect the aging brain from the ravages of neurovascular uncoupling and metabolic imbalance.