Study Finds Protecting Skin Cells from UV Damage Depends on NMN Synthesis
According to studies, maintaining adequate NAD+ levels is essential for skin cell survival after UV radiation damage.
Highlights
- UV radiation activates the enzymes NAMPT and PARP — which create and consume NAD+ — in a tug of war between cell survival and death.
- By inhibiting NAMPT, PARP is able to deplete the NAD+ supply, preventing skin cell responses to UV damage and cell proliferation from working.
- NAD+ precursor administration bypasses NAMPT inhibition in UV-damaged skin cells to promote cell energy production and proliferation, and may be a potential skin aging cure.
NAD+
NAD+ is required for cell function and survival. NAD+ levels drop as we age, which has been linked to disorders such as metabolic problems, cancer, and neurodegenerative diseases. Sunburn can also cause low NAD+ levels, similar to aging. Understanding how these NAD+ depleting events operate and how they may be prevented or reversed is a major area of study.
Tsuji-Naito and coworkers from DHC Corporation Laboratories in Japan published a paper in the Journal of Photochemistry and Photobiology demonstrating that UV damage stimulates NAD+ synthesis and NAD+ consumption enzymes in a dynamic dance that determines whether human skin cells survive or die. UV radiation activates nicotinamide phosphoribosyltransferase (NAMPT) in a tug of war, which generates the NAD+ precursor NMN and also the NAD+ consuming enzyme poly ADP-ribose polymerase (PARP), according to their study.
When NAD+ synthesis slows down during this balancing act, PARP will severely reduce NAD+ levels, which can lead to skin cell proliferation arrest and dysfunction. Surprisingly, blocking NAMPT's NAD+ production allows PARP to drain NAD+, but supplementing with the precursor chemicals NMN (100 µM) or nicotinamide riboside (NR; 50 µM) restores cells' ability 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
Tsuji et al. wanted to see whether the NMN-producing enzyme NAMPT restoration restores UV-induced NAD+ depletion, so they exposed NAMPT-deficient cells to FK866. They discovered that FK866 caused severe NAD+ deficiencies in UV-irradiated cells and that eliminating NAMPT function prevents the recovery of NAD+ levels after UV damage, implying that NAMPT is important for ensuring that NAD+ levels remain high enough to counteract PARP.
The researchers from NAMPT's team then studied the effects of UV rays on NAMPT activity, finding that skin cell irradiation increased NAMPT enzyme function by nearly three times its original level 8 hours after UV damage. The activation of NAMPT activity enhanced energy production in the face of UV injury, which was beneficial to cell health and survival. Blocking NAMPT activity, on the other hand, reduced cell viability by around 35%, suggesting that it helps cells maintain their health and survive after UV damage.
UV Damage Triggers NAD+ Consuming Enzymes
The protein PARP plays a role in NAD+ metabolism. The PARP enzyme is essential to DNA repair and, as a result, helps to preserve cell vitality. It also stimulates when exposed to UV radiation, most likely from UV-induced DNA damage. However, the relationship between UV rays, PARP activity, and NAD+ levels has not been thoroughly investigated.
Because of this, Tsuji-Naito and colleagues investigated whether PARP activation was responsible for the declines in NAD+ levels seen in UV ray-exposed skin cells. They discovered that UV radiation substantially decreased NAD+ levels, but when they prevented PARPR activity with a molecule called 3-AB, NAD+ levels were restored. These findings suggest that PARP activation is essential for UV radiation-induced reductions in NAD+ levels.
NAMPT Helps Orchestrate Balanced NAD+ Levels
The findings suggest that, in the presence of UV damage, there is a balance between NAD+-consuming PARP activation and NAD+-producing NAMPT stimulation. The NAD+ level equilibrium deteriorates with age, which puts people at risk for age-related illnesses. Supplementing UV-damaged skin cells with NMN or NR during NAMPT inhibition reestablishes cell energy production and proliferation, according to these results. These findings suggest that the NAD+ boosting molecules could assist in maintaining normal NAD+ levels throughout UV exposure and aging.
“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.
As we age, the study reveals the intricate dynamics of NAD+ levels equilibrium. If NAMPT enzyme levels drop, PARP enzyme activity may cause severely lowered NAD+ concentrations, especially in the presence of UV damage. The research also suggests that increasing NAD+ levels with supplements such as NMN or NR can improve skin cell health as we get older. This pathway could also help us find new ways to prevent skin aging-related damage by shedding light on it.
