Aging brings considerable disruption to the vascular system: stiffening of blood vessels; hypertension that damages delicate tissues; a loss of capillary density resulting in reduced delivery of nutrients and oxygen; failure of the blood-brain barrier that keeps unwanted cells and molecules from vulnerable brain tissue; and more. All of this contributes to the onset and progression of neurodegenerative diseases through mechanisms that include increased inflammation in the brain and structural pressure damage to brain tissues.

Impaired cerebrovascular function, a universal feature of aging, is a biomarker for increased risk of Alzheimer’s disease (AD), and is one of the earliest detectable changes in the pathogenesis of AD. Indeed, chronic cerebral hypoperfusion typically develops nearly a decade prior to cognitive decline and precedes the presence of pathological hallmarks of AD, including brain atrophy and accumulation of β-amyloid and pathogenic tau. In accordance with the two-hit vascular hypothesis of AD, these observations suggest that early age-associated cerebrovascular dysfunction may trigger the development of cerebrovascular pathology, driving cognitive impairment and accelerating the pathogenesis of neurological diseases of aging, including AD. Thus, cerebrovascular dysfunction may represent one of the earliest and most therapeutically addressable biological pathways under-lying age-related cognitive impairment and neurological disease.

Research from our lab and others showed that the mechanistic/mammalian target of rapamycin (mTOR) drives several different aspects of cerebrovascular dysfunction in models of AD and vascular cognitive impairment and dementia (VCID), including blood-brain barrier (BBB) breakdown, cerebral hypoperfusion, reduced cerebrovascular reactivity, and impaired neurovascular coupling. We recently established that mTOR drives age-related cerebrovascular dysfunction in 34-month-old aged rats devoid of overt pathology or disease. Cerebral blood flow deficits in aged rats were associated with microvascular rarefaction, synaptic loss, impaired neuronal network activation, and spatial learning and memory impairments. Chronic mTOR attenuation via rapamycin preserved cerebrovascular function and microvascular integrity, improved synaptic integrity and neuronal network activation throughout aging, and negated age-related cognitive decline in aged rats. These recent results indicate that in addition to driving cognitive and cerebrovascular deficits in models of AD and VCID, mTOR underlies the etiology of age-associated cerebrovascular and neuronal dysfunction during normative aging.