The world population is aging. Despite our advances in extending lifespan, there is tremendous individuality in age-related morbidity and mortality. It is recognized that the breakdown of the blood-brain barrier (BBB) in hippocampus marks an early event of cognitive impairment in aging. However, how aging affects BBB in the hypothalamus, and its ensuring metabolic consequences is not well understood. The goal of this study is to test whether the age-related decline of tanycyte number contributes to the weakening of the BBB in the hypothalamus and its impact on metabolic impairment and mortality. We will determine if proliferative capacity of tanycytes decreases with age, leading to age-dependent loss of tanycytes. We will explore if inadequate tanycyte proliferation leads to weakened BBB in the mediobasal hypothalamus and its consequences. We will evaluate if aging of the AgRP neurons outside the BBB marks the decline of AgRP neuronal function and metabolic derailment in advanced aging. Lifespan is influenced by both genetic and environmental factors. Given the essential roles of the AgRP neurons in metabolic control and their unique anatomical localization outside the BBB, information obtained from this study will establish the importance of the hypothalamic BBB in metabolic control and longevity in advanced aging.

Public Health Relevance

Lifespan is influenced by both genetic and environmental factors. Advanced aging is associated with impairment of metabolic regulation, which increases the risks for age- related mortality. Experiments outlined in this study will significantly advance our understanding of how the permeability of the blood-brain barrier (BBB) in the mediobasal hypothalamus is regulated with age, and shed light on its role in metabolic control and mortality in advanced aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG063506-02
Application #
9897509
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mackiewicz, Miroslaw
Project Start
2019-04-01
Project End
2024-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118