Researchers from Washington University School of Medicine in St. Louis have discovered a way to delay aging in mice with a protein that is abundant in the blood of young mice but declines with age.
eNAMPT and the NAD salvage pathway
That protein is extracellular nicotinamide phosphoribosyltransferase (eNAMPT), and it plays a key role in the process that cells use to create nicotinamide adenine dinucleotide (NAD), a crucial component that they need for energy production. NAD is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.
In metabolism, NAD facilitates redox reactions, carrying electrons from one reaction to another. This means that NAD is found in two forms in the cell: NAD+ is an oxidizing agent that takes electrons from other molecules in order to become its reduced form, NADH. NADH can then become a reducing agent that donates the electrons it carries.
The transfer of electrons is one of the main functions of NAD, though it also performs other cellular processes, including acting as a substrate for enzymes that add or remove chemical groups from proteins in post-translational modifications, performing cellular signaling, regulating metabolism, facilitating DNA repair, and engaging in many other functions within the cell. Quite simply, without NAD and its supporting precursor proteins, life would be impossible.
You can see in the bottom right of this diagram how NAMPT is part of a recycling mechanism known as the NAD salvage pathway.
The salvage pathway constantly recycles the molecules from NAM into NMN and then into NAD+. Once the NAD+ is used up and becomes regular NAD, the cycle begins again.
Unfortunately, during murine and human aging, the levels of NAD fall, which is thought to contribute to aging and the increasing incidence of age-related diseases, particularly insulin resistance, weight gain, and cognitive decline. The levels of eNAMPT also decline, and this has prompted researchers to see if they could restore NAD levels in aged animals using the eNAMPT protein.
Boosting eNAMPT to delay aging
The new study saw researchers led by senior author Shin-ichiro Imai, MD, Ph.D., a professor of developmental biology, giving aged mice eNAMPT proteins obtained from younger mice, which appears to slow down the age-related decline of health as well as increasing their lifespan by around 16 percent .
The researchers observed that administering eNAMPT and increasing the presence of the protein in the blood had far-reaching effects, such as improved insulin production, improved cognitive function and memory, improved visual function, and better sleep quality. The old mice also improved their physical endurance and were able to run on an exercise wheel for longer periods of time.
Imai’s research team has previously tested other ways of increasing NAD levels, including using the NAD precursor nicotinamide mononucleotide (NMN), also part of the NAD salvage pathway, but this new approach with eNAMPT is unique.
The researchers believe that the body has lots of different pathways for maintaining NAD levels because of the critical importance of the molecule. The eNAMPT approach is yet another way in which NAD levels can be influenced. Given we know that NAD levels decline with age in multiple species, including worms, fruit flies, mice, and humans, this opens the door for interventions that prevent or delay this decline.
In this study, the researchers show that the level of eNAMPT present in blood correlates strongly with lifespan; the more eNAMPT, the longer a mouse typically lives, the less eNAMPT, the shorter its lifespan. This makes sense and goes hand in hand with the loss of NAD, which cells need to function properly.
The mice given eNAMPT saw increased lifespan, living around 16 percent longer than the control mice. The study also found that there was a difference between the sexes in levels of eNAMPT, with female mice consistently showing higher levels of the enzyme.
The hypothalamus is a control center for systemic aging
Imai’s past research has shown that the hypothalamus acts as a control center for aging and is regulated to a large degree by the presence of eNAMPT. The hypothalamus controls processes such as hormones and their release, body temperature, thirst, circadian rhythm, and sleep.
Its youthful function relies on the availability of eNAMPT and a specialized population of neurons that reside in the organ and gradually die off as we age, a problem that other researchers are working on resolving with replacement neurons. Imai and his team have shown that the hypothalamus uses eNAMPT to create NAD and that eNAMPT is released by certain kinds of fat tissue and enters the bloodstream.
They have also shown that eNAMPT travels through the bloodstream within extracellular vesicles, which are bubble-like structures that contain protein complexes that act as messengers between cells. Ultimately, as the hypothalamus sees a decline of eNAMPT in the blood supply, it gradually becomes dysfunctional; this, in turn, drives aging and decreases lifespan.
Lastly, the researchers found that they could accurately predict how long mice would live based on the levels of eNAMPT in the blood. It is not yet clear if this same association applies to people, but if it does, then this makes serum eNAMPT a candidate aging biomarker and a way to monitor changes in biological age when interventions against aging are tested.
Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD + availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD + levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD + biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD + biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans.
This is an interesting study that, once again, highlights the importance of NAD in the biology of aging. If NAD levels can be increased without harmfully influencing other processes, this may prove useful. However, in biology, nothing works in isolation, so separating benefit from adverse effects may prove a challenge given how NAD+ and cellular senescence pathways interact. That said, if they can achieve this, the technique has the potential to fight against age-related diseases.
If you are interested in learning more about NAD and aging, check out our NAD World article, which takes a deeper look at this fascinating molecule that is so central to aging.
 Yoshida, M., Satoh, A., Lin, J. B., Mills, K. F., Sasaki, Y., Rensing, N., … & Imai, S. I. (2019). Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice. Cell Metabolism.