R01AG077770

Pro-Youthful Role of GPLD1 on Regenerative and Cognitive Function in the Aged Brain - Project Summary/Abstract

Identifying novel therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing elderly population.

Exercise has been shown to rejuvenate regenerative capacity and cognition in the aged brain in animal models. Moreover, exercise has been shown to improve learning and memory in Alzheimer's disease patients. Excitingly, our lab recently demonstrated that systemic administration of blood plasma derived from exercised mice reverses age-related impairments in adult neurogenesis and cognition in aged mice.

We identify glycosylphosphatidylinositol specific phospholipase D1 (GPLD1) as a liver-derived exercise blood factor - the plasma levels of which correlate with improved cognitive function in aged mice, and the levels of which are increased in active healthy elderly humans. Functionally, we show that increasing liver-derived systemic GPLD1 in aged mice ameliorates age-related regenerative and cognitive impairments.

These data raise fundamental questions as to the function of liver-derived systemic GPLD1: how long lasting are the rejuvenating effects of systemic GPLD1 on the aged brain? What is the role of systemic GPLD1 in mediating the rejuvenating effects of exercise on the aged brain? What molecular mechanisms underlie the rejuvenating effects of systemic GPLD1 in the aged brain?

The purpose of the proposed study is to investigate the rejuvenating effects of systemic GPLD1 on the aged brain. Specifically, our hypothesis is that exercise-induced liver-derived systemic GPLD1 elicits long-lasting rejuvenation of regenerative and cognitive functions in the aged hippocampus. We will test this theory with three specific aims:

1. Characterize the kinetics of brain rejuvenation following increased liver-derived systemic GPLD1.
2. Investigate the necessity of exercise-induced systemic GPLD1 in mediating the rejuvenating effects of exercise on the aged brain.
3. Determine molecular mechanisms underlying the rejuvenating effects of liver-derived systemic GPLD1 in the aged brain.

Successful completion of these studies will have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate age-related neurodegenerative diseases such as Alzheimer's disease.

San Francisco Regents Of The University Of California

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 400% from $630,950 to $3,156,953.