The 3 Ways NMN May Reverse the Signs of Aging

The various signs and symptoms of aging manifest internally and externally. Although growing older chronologically is unavoidable, it is possible to reduce your biological age, which is the age that your cells and organs function at. 

Having a lower biological age than your chronological age means that your body could feel 30 years old even if your birth certificate states you’re 70, for example. As humans live longer and longer, our healthspans — the number of years we live healthfully and disease-free — are not correlating with our lifespans; most individuals experience one or more chronic diseases as they age.

Recent research has touted the benefits of increasing longevity and reducing the effects of these age-related declines through boosting levels of NAD+ (nicotinamide adenine dinucleotide). One of the ways to do this is through supplementing with NMN, also known as nicotinamide mononucleotide. 

From dysfunctioning metabolisms to declining memory to vision loss, a reduction in NAD+ is related to all of these signs of aging, and NMN has the potential to prevent or reverse these symptoms. 

What is NMN? 

NMN is a precursor to NAD+, an enzyme that every cell in our bodies needs to function properly. However, NAD+ levels are known to decline with age, and this decline is thought to be a driving factor in the development of chronic diseases and the progression of aging. 

NMN is a relative of niacin (vitamin B3); another member of the family is NR (nicotinamide riboside). It was previously thought that NMN needed to be first converted into NR before entering cells and converting into NAD+. However, a recent discovery found a specific NMN transporter which allows for NMN to enter cells directly and boost NAD+ levels, without using NR as an intermediary.

How Does NMN Reverse Signs of Aging?

Although aging is a natural process, it is argued that biological aging the way we know it doesn't have to be inevitable and can be prevented. One of the proposed methods of fighting the aging process is through supplementing with NMN, which is able to mitigate the age-related decline in NAD+ that is seen throughout the body. 

The hallmarks of aging, as described in a June 2013 review published in Cell, are characterized by nine physiological changes: shortening of telomeres, cellular senescence, genetic mutations, accumulated DNA damage, diminished communication between cells, stem cell exhaustion, unregulated nutrient sensing, degradation of cellular proteins, and impaired mitochondrial functioning. NMN has been studied for its effects on many of these hallmarks of aging, which, in turn, reduces the risk of developing chronic diseases.

1. NMN Increases Lifespan in Animals

The most-researched aspect of NMN aims to answer whether or not it can increase lifespan in humans. Although there are some animal studies that provide evidence for this, there has been no long-term research performed with humans and longevity. 

Increasing NAD+ levels has been shown to increase lifespan in yeast, flies, worms, and mice. The mechanisms behind how NMN promotes longevity are based on the fact that NMN boosts NAD+ levels. 

Restoring NAD+ levels prevents or reverses signs of aging through its ability to rejuvenate mitochondrial function, reduce oxidative stress and DNA damage, and slow down cellular senescence.

Maintaining elevated NAD+ levels also increases the activation of sirtuins. Sirtuins are a family of seven proteins that are dependent on NAD+ and play an active role in regulating longevity and cellular health. 

Supplementation with NMN can upregulate sirtuins; a study published in Cell Metabolism in September 2013 found that increasing one of the sirtuins (SIRT1) extended lifespan in mice.

2. NMN Improves Biomarkers of Aging 

In addition to studying lifespan, there are several biomarkers of aging that are used as representations of health and longevity. 

Mitochondria, which are the powerhouses of the cell that provide energy, experience an age-related functional decline similar to the decline that is seen with NAD+.

This mitochondrial dysfunction is a driver of aging and metabolic disorders. In an April 2020 study published in GeroScience, aging mice, who supplemented with NMN, had an increased expression of genes involved in mitochondrial rejuvenation. 

Another biomarker of aging is the length of your telomeres, which are the endcaps to DNA strands that protect chromosomes from deterioration with age. Telomere length is considered a proxy for biological age; shortened telomeres are linked to premature aging and disease. 

In a study published in June 2019 in the journal Cell Metabolism, supplementing mice with NMN stabilized telomere length, reduced DNA damage, and improved mitochondrial functioning, all of which can prevent the signs of aging.

Lastly, elevated NAD+ levels have been shown to mitigate cellular senescence, which is when cells stop dividing and lose function, thus accelerating the aging process and increasing the risk of developing diseases. 

3. NMN Improves Age-Related Physiological Decline

Some of the primary symptoms of aging involve dysfunction of the brain, metabolism, and eyesight. 

The development of cognitive decline or neurodegenerative diseases have many roots; however, mitochondrial dysfunction is a leading cause of these signs of aging in the brain. 

In a March 2015 study published in BMC Neurology, mice with genetic profiles for Alzheimer’s disease had improvements in neuronal mitochondrial function after supplementation with NMN.  

Another cause of neurodegenerative diseases is a reduction in blood flow to the brain. Aging mice who received NMN supplementation had improvements in neurovascular blood flow, which correlated with improved memory and gait coordination. 

Additionally, metabolic dysfunction can manifest as obesity or age-related adiposity, insulin resistance, or a reduction in physical energy. In an October 2016 study published in Cell Metabolism, NMN-supplemented mice had reductions in the typical age-associated gain of body weight and adiposity, increased energy metabolism, and improved insulin sensitivity. 

Metabolic dysfunction also increases the risk of cognitive decline. In a recent study published in May 2020 in the International Journal of Molecular Sciences, diabetic mice who supplemented with NMN had increases in brain NAD+ levels, which activated the SIRT1 pathway and preserved neuronal function and cognition. 

Lastly, NMN has been shown to reverse vision loss. In a study of mice with retinal dysfunction, NMN was able to restore NAD+ levels in the retina and repair vision loss. Maintaining NAD+ levels through NMN may have a therapeutic effect on age-related vision loss or eye disease, affecting approximately one out of every three adults over age 65. 

Key Takeaway:

• NMN is a precursor to NAD+, an enzyme whose levels play a crucial role in aging, disease, and longevity. 
• Supplementing with NMN will boost NAD+ levels, which has been shown to increase lifespan in animals and improve mitochondrial functioning and other biomarkers of aging.
• In animal studies, NMN supplementation has also been linked to improvements in vision, neurodegenerative diseases, and metabolic disorders.
• Although studies in humans are needed, the results from animal research are promising for NMN’s potential to prevent or reverse the common signs of aging and age-related diseases. 

References:

Amano H, Chaudhury A, Rodriguez-Aguayo C, et al. Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease. Cell Metab. 2019;29(6):1274‐1290.e9. doi:10.1016/j.cmet.2019.03.001

Chandrasekaran K, Choi J, Arvas MI, et al. Nicotinamide Mononucleotide Administration Prevents Experimental Diabetes-Induced Cognitive Impairment and Loss of Hippocampal Neurons. Int J Mol Sci. 2020;21(11):E3756. Published 2020 May 26. doi:10.3390/ijms21113756

Fang EF, Kassahun H, Croteau DL, et al. NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metab. 2016;24(4):566‐581. doi:10.1016/j.cmet.2016.09.004

Kiss T, Nyúl-Tóth Á, Balasubramanian P, et al. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. Geroscience. 2020;42(2):527‐546. doi:10.1007/s11357-020-00165-5

Lin JB, Kubota S, Ban N, et al. NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice. Cell Rep. 2016;17(1):69‐85. doi:10.1016/j.celrep.2016.08.073

Long AN, Owens K, Schlappal AE, Kristian T, Fishman PS, Schuh RA. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurol. 2015;15:19. Published 2015 Mar 1. doi:10.1186/s12883-015-0272-x

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194‐1217. doi:10.1016/j.cell.2013.05.039

Mills KF, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016;24(6):795‐806. doi:10.1016/j.cmet.2016.09.013

Mouchiroud L, Houtkooper RH, Moullan N, et al. The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell. 2013;154(2):430‐441. doi:10.1016/j.cell.2013.06.016

Poddar SK, Sifat AE, Haque S, Nahid NA, Chowdhury S, Mehedi I. Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules. 2019;9(1):34. Published 2019 Jan 21. doi:10.3390/biom9010034

Satoh A, Brace CS, Rensing N, et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 2013;18(3):416‐430. doi:10.1016/j.cmet.2013.07.013

Tarantini S, Valcarcel-Ares MN, Toth P, et al. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019;24:101192. doi:10.1016/j.redox.2019.101192

Wiley CD, Campisi J. From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence. Cell Metab. 2016;23(6):1013‐1021. doi:10.1016/j.cmet.2016.05.010

Yoshino J, Baur JA, Imai SI. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018;27(3):513‐528. doi:10.1016/j.cmet.2017.11.002