Is NMN Capable of Repairing Damaged DNA?

Damage to our DNA is inevitable, as our cells constantly get exposed to harmful compounds that can cause mutations, misfolded proteins, and mitochondrial dysfunction. While our cells typically work efficiently to repair these bits of broken DNA, this ability declines as we grow older, leading to accelerated aging and disease development. 

A recent study from a research team at Harvard Medical School has uncovered a new method that may be the solution to this age-related DNA-repair dysfunction. 

In this article, we’ll dive into how DNA damage impacts aging, the link between certain proteins that are involved in DNA repair, and the details on this groundbreaking Harvard study. 

DNA Damage and Aging

DNA damage occurs from both exogenous sources — like excess sun on our skin, the polluted air we inhale, or pesticide-laden food we consume — as well as from endogenous sources, such as the accumulation of free radical compounds that cause oxidative stress in the body.

When this damage is left unchecked, aging progresses more rapidly as cellular senescence, telomere shortening, and oxidative stress occur. Senescent cells are ones that have stopped dividing and become dysfunctional, causing inflammation to nearby cells, shortening lifespan, and increasing the risk of neurodegenerative and metabolic diseases. 

Telomere length has a similar association with disease and longevity. Telomeres are the protective end caps to our chromosomes; shortened telomeres are linked to shortened lifespans.  

The Link Between NAD+ and DNA Repair Proteins 

NAD+ (nicotinamide adenine dinucleotide) is an enzyme found in every cell in our bodies; it’s well-established that NAD+ levels decline with age. This reduction is a leading cause of many age-related diseases and dysfunctions, including premature aging. 

One of the ways that maintaining elevated NAD+ levels contributes to longevity is through its activation of sirtuins, which are proteins that regulate cellular metabolism and delay aging. 

Another helpful protein for increasing lifespan is PARP1 (poly[ADP-ribose] polymerase 1), whose primary function is to repair damaged DNA. Both PARP1 and the sirtuin family require NAD+ to function properly. As described in an October 2017 paper published in Nature Reviews Molecular Cell Biology, PARP1 works as a multifunctional enzyme, which can repair single-strand and double-strand breaks in DNA. 

In addition, PARP1 can stabilize DNA replication forks and modify chromatin structures. Chromatin is a compact package of DNA and proteins inside the nucleus; modifying its structure is a way of regulating gene expression. 

Another protein involved in this process is called DBC1, which has a detrimental effect on health and longevity. DBC1 inhibits one of the sirtuins, SIRT1, and it also binds tightly to PARP1. When DBC1 binds to PARP1, it means that PARP1 cannot do its primary job of repairing DNA, leading to an accumulation of damaged DNA, misfolded proteins, and senescent cells. 

However, the researchers at Harvard found a way to overcome this strong bond between PARP1 and DBC1, using the NAD+ precursor, NMN (nicotinamide mononucleotide). NMN is an effective way to boost NAD+ levels, as it quickly enters cells and converts directly into NAD+. 

When NAD+ levels are elevated, the bond between PARP1 and DBC1 is disrupted, as DBC1 also has an affinity to bind to NAD+. Therefore, NAD+ binds to DBC1, leaving PARP1 free. Essentially, the more NAD+ that you have, the better that PARP1 is able to function. This leads to improved DNA repair and fewer damaging compounds that contribute to aging. 

In a typical aging progression, NAD+ levels decline and more DBC1 binds to PARP1, preventing proper DNA repair. However, this process can be ameliorated by boosting NAD+ through supplemental NMN. 

NMN and DNA Repair: Recent Research 

The study from the Harvard Medical School team, which was published in March 2017 in Science, was the first to establish the link between NAD+, PARP1, and DBC1, using human embryonic kidney cells. They confirmed that the PARP1-DBC1 complexes reduce when NAD+ is prevalent.

Next, the researchers aimed to determine if this link could be extrapolated to animals. In older mice, they found that NAD+ levels in the liver were lower than in younger mice, which is to be expected with age. Additionally, they found that the older mice had higher amounts of bound DBC1 and PARP1 complexes, with lower levels of PARP1 activity.

After the mice drank NMN-supplemented water for one week, their NAD+ levels increased and the DBC1-PARP1 complexes were disrupted, in both young and old mice. NMN restored PARP1 activity in the older mice, enabling it to fully function as a DNA-repairing protein.

Another way in which DNA gets damaged is through radiation, which can occur from UV sun exposure, as well as in medical treatments. In an additional experiment in the same paper, older mice were exposed to gamma irradiation, which ordinarily causes severe DNA damage and losses of white and red blood cells. 

However, the mice who received supplemental NMN had a reduction in DNA damage and were protected against the typical radiation-induced cell loss. 

In all, these results indicate that NMN does lead to DNA repair and protection against radiation-induced DNA damage, through the mechanism of boosting NAD+ and PARP1 while reducing the ability of DBC1 to bind to PARP1.

A study published in January 2020 in Nature came up with similar results from cell culture experiments. The researchers used a cell line that expressed XRCC1, which is another protein that is involved in DNA repair.  When DNA damage occurs, PARP1 increases the activity of XRCC1. 

After inducing damage to the cells via laser micro-irradiation, the NAD+ precursors NMN and NR (nicotinamide riboside) were introduced. They found that the presence of NAD+ led to an upregulation of PARP1 and XRCC1 to repair the damaged DNA. 

Although these studies have produced encouraging results, the research thus far has only been done with cell cultures and animals. Therefore, we won’t know for sure if NMN supplementation will also be able to repair damaged DNA in humans until clinical trials are performed. 

Key Takeaway: 

• DNA damage can occur from environmental, dietary, or internal sources; at older ages, the mechanisms to repair this DNA damage deteriorate.
• Researchers have found that supplemental NMN boosts NAD+ levels, which allows for the DNA repair protein PARP1 to be fully functioning. 
• This is important because accumulated damage to DNA and proteins will accelerate the aging process and increase the risk of developing chronic diseases. 

References: 

Li J, Bonkowski MS, Moniot S, et al. A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science. 2017;355(6331):1312-1317. doi:10.1126/science.aad8242

Prieto LI, Graves SI, Baker DJ. Insights from In Vivo Studies of Cellular Senescence. Cells. 2020;9(4):954. Published 2020 Apr 13. doi:10.3390/cells9040954

Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017;18(10):610-621. doi:10.1038/nrm.2017.53

Tiwari V, Wilson DM 3rd. DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging. Am J Hum Genet. 2019;105(2):237-257. doi:10.1016/j.ajhg.2019.06.005

Wilk A, Hayat F, Cunningham R, et al. Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity. Sci Rep. 2020;10(1):651. Published 2020 Jan 20. doi:10.1038/s41598-020-57506-9