Overview
Nicotinamide Mononucleotide (NMN) is a molecule that occurs naturally in the body and plays a key role within cells. The primary way by which NMN can affect our health is by serving as a precursor to NAD+ (nicotinamide adenine dinucleotide). Boosting NAD+ to youthful levels has many positive impacts to our health. The cellular mechanisms as to how this works can be somewhat complicated, so it can be helpful to break it down into three broad categories: DNA Stability, Epigenetic Alteration, and Mitochondrial Function. If these categories look familiar, it is because these are 3 of the Hallmarks of Aging.
NAD+ Declines with Age
NAD+ is involved in over 400 different cellular processes in the body. As we age, our NAD+ levels decline. As seen in the image below, there is a statistically significant decline in NAD+ levels with age. In fact, NAD+ levels can essentially be cut in half over time. NAD+ levels can fall due to dysregulation of circadian rhythm, and NAD+ is also consumed by enzymes such as PARP, CD38, and sirtuins.
NAD+ concentrations decreased significantly with age in post-pubescent females (p = 0.01; n = 22).
(Massudi, H. et al., 2012)
DNA Stability
PARP, full name Poly(ADP-ribose) polymerase, is an enzyme that plays a key role in DNA repair. PARP is activated in response to DNA damage and helps to recruit other proteins to the site of damage to repair it.
Relationship between PARP activity and Maximum Lifespan for different mammalian species. (Grube K, Burkle A, 1992)
As seen in the image above, PARP activity is strongly correlated to maximum lifespan across mammals. This can be seen in the correlation coefficient, r=.84. The closer the correlation coefficient is to 1, the stronger the relationship.
One theory as to why PARP activity is so strongly related to maximum longevity is the DNA Damage Theory of Aging, which states that aging is a consequence of unrepaired DNA damage that naturally occurs over time. DNA damage can occur due to both internal and external factors, such as exposure to radiation, oxidative stress, as well as errors in DNA replication and repair mechanisms. NAD+ is a coenzyme for PARP, meaning that NAD+ is needed for PARP to function. Therefore, supplementing with NMN leads to higher levels of NAD+, which in turn lead to an increased activity for PARP, which means more DNA damage is repaired.
Epigenetic Alteration
Epigenetics is the study of changes in organisms caused by modifications of gene expression rather than alteration of the genetic code itself. Epigenetic changes can switch genes on or off and determine which proteins are transcribed. There are 3 types of epigenetic changes: DNA methylation, histone modification, and non-coding RNAs. NMN can affect histone modification, due to its interaction with a group of enzymes called sirtuins.
Sirtuins are a family of enzymes that are involved in various cellular processes, including metabolism, DNA repair, and gene expression. They are particularly known for their role in regulating aging and longevity and are commonly known as "the guardians of the genome". In humans, there are seven known sirtuins, which are referred to as SIRT1 to SIRT7.
Sirtuins work by removing acetyl groups from proteins through a process called deacetylation. One group of proteins that is deacetylated by sirtuins are called histones. Histones are proteins found within the nucleus that help package DNA. They essentially act as spools, which the DNA wraps around. Tightly wrapped DNA is associated with inactive DNA, because the enzymes needed for transcription cannot get access. Loosely wound DNA is active, meaning it can be transcribed into RNA and later translated into protein. Sirtuin activity can thus lead to changes in gene expression by deacetylating histones. Since NAD+ is a coenzyme for sirtuins, NAD+ levels affect the extent of epigenetic alteration that takes place. Tightly wound DNA is also better protected than loosely wound DNA, so in this sense, it also impacts DNA stability.
Mitochondrial Function
Mitochondrial function can be characterized by ATP generation via oxidative phosphorylation. ATP is the energy currency of cells, and it is created in the membranes of mitochondria via a complex of proteins known as the electron transport chain. NAD plays an important role in this system, toggling between its oxidized or reduced forms: NAD+ and NADH (NADH simply being the electron-carrying form of NAD+). A decline in NAD+ as we age can reduce the performance of mitochondria. Mitochondrial biogenesis, or creation of new mitochondria, can be downregulated by age-induced inactivation of the sirtuin SIRT1. Mitophagy, or clearing of damaged mitochondria is regulated by SIRT3.
Summary
NMN supplementation offers a range of potential benefits for healthy aging that can be classified under the Hallmarks of Aging: DNA stability, Epigenetic Alteration, and Mitochondrial Function. NMN acts as a precursor to boost NAD+ levels. NAD+ levels impact DNA stability by acting as a coenzyme for PARP, which helps signal enzymes for DNA repair. Also, NAD+ is important to mitochondrial function via its activity in the electron transport chain, shuttling electrons between enzymes to help generate ATP. Further, NAD+ is also a coenzyme for "the guardians of the genome", the sirtuins. The sirtuins act as deacetylases, which can remove acetyl groups from histones to modify gene expression. This is known as epigenetic alteration. Supplementing with NMN can boost NAD+ levels, which naturally decline with age. While there is still a lot more to learn about longevity and how we age, it is clear that NAD+ affects many processes involved in aging.
References
Massudi, H. et al. (2012) Age-associated changes in oxidative stress and NAD+ metabolism in human tissue, PloS one. U.S. National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407129/.
Grube K, Bürkle A. (1992) Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proc Natl Acad Sci U S A. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC50636/
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