Cerebrovascular Rejuvenation: Novel Strategies for Prevention of Vascular Cognitive Impairment

Vascular cognitive impairment (VCI) represents the second most common cause of dementia after Alzheimer's disease (AD). Estimates place about 36 million individuals worldwide currently affected by age-related dementia, and this number is expected to reach 150 million by 2050 with a societal cost of nearly $4 trillion. ¹ Our increasingly long lives remain the leading risk factor for a variety of vascular and microvascular pathologies, including but not limited to atherosclerosis, stroke, AD, VCI and dementia, hypertension, and type 2 diabetes. The number of people over the age of 60 has doubled since 1980 and is projected to quadruple by 2050, suggesting that an ever-increasing number of individuals will be affected by the anticipated “dementia epidemic” that will bring diminished cognitive abilities, loss of independence and overall reduced quality of life to millions of elderly individuals worldwide every year. In addition, macro- and microvascular alterations are key contributors to the clinical expression of cognitive dysfunction, and recent studies have shown that decreasing peripheral vascular health is predictive of cognitive decline in the elderly ² and interestingly, evidence from basic research, clinical studies, and epidemiology indicate that age-related accumulation of damage to the cerebral microvascular system is associated with an increased risk for VCI. How aging affects function and phenotype of small blood vessels in the brain and how cerebromicrovascular dysfunction contributes to the pathogenesis of VCI are areas of intense research.

The brain utilizes >20% of the body's energy budget. It relies on the constant supply of oxygen and nutrients as the central nervous system has no storage capacity, and even momentary interruptions in oxygen supply and nutrient delivery rapidly impair neuronal function. To sustain proper brain functioning, moment-to-moment changes in neuronal activity requires a precise spatial and temporal adjustment of oxygen and nutrient delivery as well as effective washout of metabolic waste. This homeostatic challenge is met through a physiological feedforward mechanism present in the brain, termed neurovascular coupling (NVC), which adjusts cerebral blood flow (CBF) to match neural activity to prevent neural ischemic damage, neurodegeneration, and cognitive impairment. It is now well documented that NVC responses significantly decline with age in humans. ^3,4 Experimental studies confirm that age-related functional impairments of cerebral microcirculation compromise NVC responses, which likely contributes to age-related cognitive decline and the development of VCI. ^5,6 Additional microvascular contributions to the pathogenesis of VCI include age-related disruption of the blood–brain barrier and consequential neuroinflammation, ⁷ microvascular rarefaction, and impaired trophic function of the capillary endothelial cells.

To be able rejuvenate the cerebral microcirculation and preserve its functional and structural integrity for prevention of VCI, a lot of research effort has been dedicated to dissecting the mechanisms underlying age-related cerebromicrovascular dysfunction. Growing understanding of shared cellular and molecular mechanisms of aging in model organisms and then in laboratory rodents has allowed researchers to design and evaluate novel strategies aimed to interfere with key aging processes for cerebromicrovascular rejuvenation and prevention of VCI.

In preclinical studies, treatments designed to attenuate ROS production, increase cellular oxidative stress resilience, and/or enhance cellular energetics were shown to successfully reverse aspects of age-related microvascular impairment in the brain. Specifically, there are studies showing that attenuation of mitochondrial oxidative stress (either by the mitochondria-targeted antioxidative peptide SS-31⁵ or mitochondria-specific overexpression of catalase ⁸ ) is associated with significant improvement of NVC responses. Similarly, endothelium-specific delivery of resveratrol, a potent polyphenol with antioxidant properties (including activation of Nrf2-dependent antioxidative defense mechanisms ⁹ ), generated promising results by improving vascular endothelial function and rescuing NVC responses. ¹⁰ In addition, treatments aimed to restore the bioavailability of NAD⁺ thereby increasing activity of the metabolic sensor sirtuins were also equally successful in reversing aging-induced phenotypic changes in the vasculature, restoring endothelium-mediated vasodilation, rescuing NVC responses and improving cognitive outcomes in rodents. ^{11 –14} Recent developments also show an intimate connection between age-related impairment in IGF-1 signaling and cerebromicrovascular and cognitive decline. There is increasing evidence that both circulating and central IGF-1 play a protective role against features of cerebromicrovascular impairment and age-related cognitive decline in mouse models, ^15,16 implicating IGF-1 as an important geroprotective factor in the cerebral circulation.

Future preclinical efforts to rejuvenate the cerebral vasculature, improve cerebral blood flow, protect the blood–brain barrier, and attenuate neuroinflammation should also center on interfering with the other fundamental cellular and molecular processes of aging, including cellular senescence, mitochondrial dysregulation and cellular energetic dysfunction, impaired proteostasis, and reduced cellular stress resistance. Research efforts should persist to understand age-related alteration on the function of multiple cell types within the neurovascular unit and target these changes simultaneously. Although most studies are concerned about the role of functional changes in the arterial circulation, there is also emerging evidence that pathological changes in the cerebral venous circulation also importantly contribute to the pathogenesis of VCI. ¹⁷ It is projected that development of translatable combination strategies for cerebrovascular rejuvenation targeted toward shared biological mechanisms of aging will contribute significantly to the prevention/delay of the pathogenesis of VCI in the aging population.