Highlights

·   UV radiation triggers the enzymes NAMPT and PARP — which produce and consume NAD+, respectively — in a tug of war between cell survival and dysfunction.
·   Inhibiting NAMPT allows PARP to exhaust the NAD+ supply, which hinders the response from skin cells to UV damage and cell proliferation.
·   NAD+ precursor supplementation overrides NAMPT inhibition in UV-damaged skin cells to promote cell energy production and proliferation, providing a potential skin aging treatment.

Our cells depend on nicotinamide adenine dinucleotide (NAD+) to function and survive. Drops in NAD+ levels caused by aging are linked to diseases like metabolic disorders, cancer, and neurodegenerative conditions. Similar to aging, harmful UV rays from the sun can also trigger NAD+ depletion. Understanding how these NAD+ depleting phenomena work and can be prevented or reversed has become a hot topic in research. 

Tsuji-Naito and colleagues from the DHC Corporation Laboratories in Japan published a study in the Journal of Photochemistry and Photobiology showing that UV damage activates NAD+ synthesis and NAD+ consuming enzymes in a balancing act that determines survival or dysfunction for human skin cells. They show that, in a tug of war, UV radiation activates nicotinamide phosphoribosyltransferase (NAMPT) to produce the NAD+ precursor NMN and also activates the NAD+ consuming enzyme poly ADP-ribose polymerase (PARP). If NAD+ synthesis falters during this balancing act, PARP will severely deplete NAD+ levels, which can trigger skin cell proliferation arrest and dysfunction. Interestingly, blocking NAMPT’s NAD+ production lets PARP drain NAD+, but supplementing with the NAD+ precursors NMN (100 µM) or nicotinamide riboside (NR; 50 µM) restores the cells’ abilities to recover from UV damage.

“Since the skin is continuously exposed to UVA/B irradiation, understanding the protective role of NAMPT in UV stress will help prevent and treat skin photoaging,” said Tsuji-Naito and colleagues.

NAMPT Generates NAD+ to Promote Cell Energy Production and Viability

Since NAMPT generates NAD+’s precursor NMN, Tsuji-Naito and colleagues wanted to test whether this NMN-producing enzyme restores UV-induced NAD+ depletion. They applied the NAMPT inhibitor FK866 to UV-irradiated cells and found that it led to severe NAD+ deficiencies. Moreover, getting rid of NAMPT activity eliminates the recovery of NAD+ levels after UV damage, indicating that NAMPT plays a crucial role in maintaining NAD+ levels to counteract PARP.

Tsuji-Naito and colleagues then tested the effects of UV rays on NAMPT activity, finding that irradiation of skin cells drove NAMPT enzyme function up to almost three times its original activity eight hours after UV damage. The stimulation of NAMPT activity affected cell health by promoting energy production in the face of UV damage. However, blocking NAMPT function during UV radiation diminished cell viability by about 35%, indicating that NAMPT acts to maintain cell health and survival after UV damage.

(Katayoshi et al., 2021 | Journal of Photochemistry and Photobiology) UV radiation induces NAD+-producing NAMPT activation. The graph on the left shows that UV radiation significantly reduces NAD+ levels at one hour after UV radiation exposure but that NAD+ levels recover with time. Treatment with the NAMPT inhibitor FK866 impedes this recovery, showing that NAMPT is responsible for the recovery of NAD+ levels. The middle graph illustrates that UV radiation induces NAMPT activation. The graph on the right shows how blocking NAMPT with FK866 significantly hampers cell viability after UV radiation-induced cell damage. These findings show that UV damage induces NAD+-producing NAMPT activity, which promotes cell health and survival.

UV Damage Triggers NAD+ Consuming Enzymes

Another enzyme involved in NAD+ metabolism is PARP. The PARP enzyme is critical to DNA repair and therefore promotes cell health and survival but consumes large quantities of NAD+ in the process. It can also be stimulated by UV rays, likely from UV-induced DNA damage. But the link between UV rays, PARP, and NAD+ levels has not been closely examined.

This led Tsuji-Naito and colleagues to test if PARP activation explains the reductions in NAD+ levels observed in UV ray-exposed skin cells. They found that UV radiation substantially depleted NAD+ levels, but when they blocked PARP activity with a molecule called 3-AB, NAD+ concentrations were restored. These findings indicate that PARP activation plays a key role in UV radiation-induced drops in NAD+ levels.

(Katayoshi et al., 2021 | Journal of Photochemistry and Photobiology) UV radiation induces NAD+-consuming enzyme PARP activation. The top row of images show PARP activation in green, and the middle row images have cell centers (nuclei) labeled blue. The bottom row has merged images and shows that PARP activation increases substantially at ten minutes following UV radiation exposure but then wanes during the first hour. The graph depicts about a 60% reduction in NAD+ levels following UV radiation exposure but a much less pronounced reduction when the PARP inhibitor molecule 3-AB is administered to skin cells. These findings illustrate that PARP enzymes account for substantial UV radiation-induced NAD+ level depletion.

NAMPT Helps Orchestrate Balanced NAD+ Levels

These results point to a balancing act between NAD+-consuming PARP activation and NAD+-producing NAMPT stimulation with UV damage. With age, the NAD+ level balance dissipates, which can predispose people to age-related diseases. Interestingly, supplementing UV-damaged skin cells with NMN or NR during NAMPT inhibition restores cell energy production and proliferation. These results indicate that the NAD+-boosting molecules may help to maintain balanced NAD+ levels during UV damage and skin aging.

(Katayoshi et al., 2021 | Journal of Photochemistry and Photobiology) The mechanism by which NAMPT protects against UV radiation-induced cell damage in human skin cells. UV radiation stimulates the NAD+-consuming enzyme PARP along with NAD+-producing NAMPT. NAMPT drives SIRT1 enzyme activity that removes molecular tags (acetyl groups) from the protein p53 to inhibit its cell proliferation arrest capabilities. The interplay between PARP and NAMPT activities plays a major role in the balance of NAD+ levels.

“Our findings not only provide a conclusive explanation for the involvement of NAMPT in skin protection against daily UVA/B exposure but also identifies novel candidate molecules, NMN and NR, as potential therapeutic and preventive agents for age-associated skin disorders and functional decline,” said Tsuji-Naito and colleagues.

The study shows the intricate dynamics of NAD+ level balance as we get older. For example, if NAMPT enzyme levels become depleted, PARP enzyme consumption can lead to drastically diminished NAD+ levels, especially in the face of UV skin damage. The study also supports that boosting NAD+ levels with supplements like NMN or NR can promote skin cell health during aging. Shedding light on this pathway may also lead to the discovery of new ways to prevent age-related skin damage.