Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment

Project Summary/ Abstract
More than 50 million people aged 65 and above suffer in vascular cognitive impairment and dementia (VCID).
The incidence of VCID is projected to nearly triple by 2050, which will cost more than 2 trillion US dollars in
health and social care expenditures. Yet, there are no interventions to treat or prevent cognitive decline in the
elderly. Microvascular endothelial dysfunction is a critical contributor to age-related VCID. Functional alterations
in the microvascular endothelial cells lead to neurovascular uncoupling responses, the lack of a critical process
of adjustment of cerebral blood flow required to support neuronal activity. Further, structural alterations in
endothelial cells negatively affect the integrity of blood-brain barrier (BBB), which leads to increased capillary
permeability and neuroinflammation. Endothelial dysfunction also contributes to decreased capillary density
leading to a reduction in basal CBF. These pathological changes in the endothelial phenotype precedes the
onset of cognitive decline in aged humans, suggesting that interventions that maintain or restore cerebrovascular
health would be effective for the prevention and treatment of age-related VCID. Adipose tissue plays a pivotal
role in the interplay between metabolism and aging. Emerging evidence links increased thermogenesis in the
adipose tissue with extended longevity. Activation of the thermogenic program results in remodeling of both white
and brown adipose tissue marked by increased fuel utilization and insulin sensitivity. It also results in an overall
improvement in systemic inflammatory milieu and a favorable adipokine profile, which could have beneficial
effects on the aging cerebral microvasculature. Our preliminary studies provide prima facie evidence that
activation of adipose tissue thermogenesis improves cerebromicrovascular function and positively impacts
cognition in aged mice. However, the circulating mediators or the cerebromicrovascular mechanisms behind
thermogenesis-mediated positive cognitive outcome in aging are not known. Our central hypothesis is that
activation of thermogenic program corrects metabolic dysfunction and ameliorates systemic
inflammation, thereby improving microvascular endothelial function and preserving cognitive integrity
in aging. To address this hypothesis the following aims are proposed: Aim 1: Characterize thermogenesis-
induced alterations in metabolic and inflammatory milieu in aging. The thermogenesis mediated alterations
in adipose tissue secretome will have beneficial effects on overall metabolism and systemic inflammation in
aging. Aim 2: Determine the impact of thermogenesis on microvascular endothelial structure and
function in aging. Prolonged activation of thermogenesis can improve cerebrovascular function and structure
in aging and lead to improved cognitive health. The successful completion of the proposed studies will identify
novel strategies to counteract age-related VCID.

Grant Number: 5K01AG073613-05
NIH Institute/Center: NIH
Principal Investigator: Priya Balasubramanian