# eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $322,875

## Abstract

TITLE OF PROJECT
eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging
ABSTRACT
In recent years, nicotinamide adenine dinucleotide (NAD+) metabolism has emerged as a central topic in the
field of aging and longevity research. It has been established that NAD+ availability declines over age at a
systemic level, triggering a variety of age-associated pathophysiological changes in diverse model organisms.
In mammalian NAD+ biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme that
converts nicotinamide and 5’-phosphoribosyl-pyrophosphate to nicotinamide mononucleotide (NMN), an
important NAD+ intermediate. Interestingly, there are two distinct forms of NAMPT in mammals: intra- and
extracellular NAMPT (iNAMPT and eNAMPT, respectively). We have previously demonstrated that eNAMPT
mediates a novel intertissue communication system between adipose tissue and the hypothalamus, regulating
hypothalamic NAD+ levels and functions. We have now found that eNAMPT is carried in exosomes through
the circulation in mice and humans. Exosomal eNAMPT is internalized into primary hypothalamic neurons and
enhances NAD+ biosynthesis intracellularly. The genetically engineered mice that can maintain higher levels
of exosomal eNAMPT at old ages exhibit a variety of anti-aging phenotypes and a significant extension of
healthspan. These new findings demonstrate a novel systemic mechanism that regulates the process of aging
and determines healthspan/lifespan, driven by an exosome-mediated delivery of eNAMPT. Thus, we
hypothesize that exosomal eNAMPT is delivered to specific tissues through the interaction with a specific
receptor-like protein and regulates various tissue functions, including the hippocampus-dependent cognitive
functions. The K53R mutant of NAMPT, whose secretion is enhanced, could be used as a genetically
engineered biologic that mitigates age-associated functional decline in mice. We will address this hypothesis
by the following specific aims: 1) To elucidate the mechanism of exosomal eNAMPT targeting, we will examine
the requirement of the NAMPT protein structure and also test a potential receptor candidate for exosomal
eNAMPT to be internalized, 2) to further analyze the effects of supplementing eNAMPT-containing exosomes in
aged mice, we will analyze their effect on the hippocampus-mediated cognitive functions, and 3) to test
eNAMPT as an anti-aging biologic, we will examine the effects of eNAMPT mutants encapsulated into
exosomes on cognitive, behavioral, and other tissue functions in aged mice. Thus, the anticipated outcome of
the proposed research will open a new avenue to understand how systemic NAD+ homeostasis regulates aging
and longevity and develop a novel anti-aging intervention by using exosomal eNAMPT as a biologic.

## Key facts

- **NIH application ID:** 10160728
- **Project number:** 5R01AG047902-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** SHIN-ICHIRO IMAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $322,875
- **Award type:** 5
- **Project period:** 2014-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160728

## Citation

> US National Institutes of Health, RePORTER application 10160728, eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging (5R01AG047902-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10160728. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*