ORCID

http://orcid.org/0000-0002-2752-1231

Date of Award

Spring 5-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Aging is a systemic decline in tissue functions that occurs during the course of our life leading to the development of age-associated health deteriorations and ultimately to the expiration of life. Over the past few decades, population aging has become increasingly evident in many parts of the world, leading to increased prevalence of age-related disabilities and diseases. Because age is a major risk factor for many chronic diseases, extensive research effort has been spent to identify common age-associated molecular changes contributing to the pathogenesis and progression of these health issues. One such molecule identified to play a central role in the regulation of aging is nicotinamide adenine dinucleotide (NAD+). NAD+ is a universal energy currency utilized as an essential coenzyme and cosubstrate in a wide variety of biological processes. Many studies over the past decades have demonstrated that NAD+ availability is one of the important factor influencing the health and lifespan in many organisms. Studies from others and ours have demonstrated the enhancement of NAD+ homeostasis and increased activity of NAD-dependent enzymes has beneficial effect against stress, disease, and aging in nearly every single tissue types in the body. In support for the role of NAD+ in aging, NAD+ availability significantly declines with age. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the most utilized NAD+ biosynthetic pathway in mammals. Interestingly, NAMPT has been identified to be secreted out to extracellular space and known to be abundantly present in blood. Given the importance of NAD+ homeostasis in tissue functions and health, we are interested in understanding the role of eNAMPT in aging by characterizing its impact on NAD+ biosynthesis, tissue function, behavior and lifespan. We identified that the modulation of adipose tissue-specific expression of NAMPT alters plasma eNAMPT levels. Increasing or decreasing eNAMPT levels enhance or suppress NAD+ biosynthesis in remote tissue such as hypothalamus. Adaptive response to fasting induces secretion of eNAMPT through its deacetylation by SIRT1, thereby enhancing hypothalamic NAD+ availability. Hypothalamic NAD+ levels regulated by eNAMPT modulate the SIRT1 activity, neural activity and behavior in mice. Furthermore, we identified that adipose-specific NAMPT overexpression offset the age- induced decline in plasma eNAMPT levels, maintaining higher NAD+ availability in hypothalamus, hippocampus, pancreas, and retina. Additionally, we find that eNAMPT levels significantly decline in human in a linear fashion and are strongly correlated with lifespans in mice. Mice with increased eNAMPT levels maintain higher tissue NAD+ levels and functions, shows delay in age-related phenotypes, and significant lifespan extension. Lastly we characterized that eNAMPT circulating in blood is enapsulated within exosome. eNAMPT in the isolated exosome from plasma and adipocyte is internalized by target cells such as hypothalamic neurons and enhance its NAD+ biosynthesis. Finally, administrations of exosomes isolated from young mice improve wheel-running activity of aged mice and significantly extend their lifespan. Our findings revealed exosome as a new mode of regulation for systemic NAD+ biosynthesis and eNAMPT as a key regulatory factor in aging.

Language

English (en)

Chair and Committee

Shin-ichiro Imai

Committee Members

Aaron DiAntonio, Erik Herzog, Sohail Tavazoie, Rajendra Apte,

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