Your Ultimate Guide to NMN and Its Anti-Aging Benefits

What you put into your body affects how you age. While that might not exactly be a head-turning or mind-blowing anti-aging tip (since it’s likely a concept that has many millennia under its belt), right now, we’re learning a lot about how the body ages. And with it, we’re getting clues into the kinds of things we can put into our bodies to support healthy aging.

To do so, researchers have ventured into a new terrain inside cells over the last decade that some call the “NAD World.” This molecular ecosystem sustains a network of vital cell functions, and, some researchers think, it could be at the core of anti-aging. As it turns out, there are ways to dial up the functionality of this system, such as nutraceuticals — consumable substances that support health.

From this scientific exploration, researchers may have exposed an anti-aging secret. One particular atomic node that can shift the “NAD World” tides is called nicotinamide mononucleotide (NMN), which has garnered the attention of many, even the US military. NMN — a compound that gets directly converted to NAD that can be made or taken up by the cell — can support energy metabolism, physical activity, and healthy weight gains, which have been shown to link to healthy aging. With the growing support of these findings in animals and, in some cases, humans, NMN supplementation could be the anti-aging tip we’ve been hunting for.

What’s the “NAD World” and its link to aging?

Aging is the phenomenon of bodily deterioration — what researchers call “physiological decline.” Some researchers think that the functional failing of cells and tissues occurs due to changes at the molecular level linked to a decrease in the activity of enzymes that play a role in maintaining cell health, metabolism, survival, and longevity. So, what’s responsible for controlling the activity of these life-supporting molecular machines?

The “NAD World” is centered around the role of the molecule NAD — short for nicotinamide adenine dinucleotide — in bridging energy metabolism and aging. Many enzymes in these processes depend on NAD to function, leading researchers to speculate that NAD is indispensable for healthy aging. Along these lines, they posit that NAD controls the pace of cellular metabolism and anti-aging enzymes that mediate pathways related to survival and aging in response to NAD availability.

But it turns out that as we age, the levels of NAD begin to decline in various cell types and tissues, explaining the devolving function of vital enzymes. That means that NAD is a critical metabolite in supporting tissue function and integrity in aging animals. We’re not 100% sure how or why this happens, but we know that there are decreases in the production of NAD and increases in the activity of enzymes that depend on NAD to function, likely because they’re trying to help shore up the health of aging cells.

NAD and epigenetics

Biological aging has several hallmarks, including shifts in the preservation of our genetic material, or what’s called genomic stability. Another closely related biological aging hallmark pertains to epigenetics — the modification of DNA molecules and the overall structure of our genome. Our DNA is usually depicted as a two-stranded string, but it’s actually wound up into distinct configurations in each cell to create unique identities.

Since every cell has the same genetic blueprint, different instructions are laid out and read in cells to populate the body with the zoo of cell types that make it go, from light-sensing cells in the eye to light-blocking cells in the skin. To do so, DNA gets coiled and unwound to hide and expose different bits of genetic information; that is epigenetics.

Some enzymes controlled by NAD that play a role in anti-aging are responsible for maintaining genomic and epigenetic integrity. One essential family of enzymes that depends on NAD is called the sirtuins. In experimental model organisms including yeast, worms, and flies, the dosage or the activity of sirtuins determines the length of their life span (reviewed in Imai et al., 2010). Sirtuins also mediate the lifespan-extending effect of caloric restriction — a dietary regimen that retards aging and extends life span in a wide variety of organisms.

The intimate connection between NAD biosynthesis and sirtuin activity suggests that promoting NAD biosynthesis with precursors like NMN could effectively enhance sirtuin activity at a systemic level and maintain better body functionality, particularly the functionality of crucial cell types throughout our entire lives. Such an approach is well-suited to deal with the natural, physiological aspects of aging.

A macroscopic view of the “NAD World”

At a less microscopic level, the “NAD World” concept also suggests that NAD levels depend on feedback loop signals originating from the complex arrangements of cells in different tissues and organs. For example, muscle, fat tissue, the brain, and the pancreas communicate to cells throughout the body to modify their NAD levels and metabolic activity in response to environmental factors like diet, temperature, oxygen levels, humidity, and light cycles (or sleep). 

So, the gradual inability to maintain optimal NAD levels may dampen the robustness of the feedback loop signals required to preserve the proper metabolic functions of all our cells. The loss of NAD levels would cause a breakdown in signals to all sorts of cells necessary to support healthy metabolism and aging, whether those digesting food in our gut, keeping the structure of our bones, or tasked with fighting off intruders at the surface (skin) or within (immune system).

What are the benefits of NMN?

NMN administration can compensate for the deficiency of NAD caused by these NAD-consuming enzymes. What’s more, researchers have shown that administering NMN to supplement NAD production supports healthy aging in mice. Some studies show that NMN supplementation likely supports anti-aging from the level of epigenetics and cell structures to that of organs and the body’s overall physiology.

The efficacy of NMN is currently being assessed for age-associated metabolic alterations in mice. For example, NMN has been reported to improve the cell’s power generators’ (mitochondria) function in various metabolic organs, including skeletal muscle, liver, heart, and eyes (reviewed in Yoshino et al., 2018). NMN supplementation can support the health and function of specific cells, tissues, and organs:

Brain

Brain health is a significant part of aging. For these reasons, researchers think that generating more healthy brain cells (neurogenesis) during adulthood could be a therapeutic strategy in overcoming brain aging.

Essential to neurogenesis are populations of neural stem cells (NSCs) that can self-renew and develop into neural stem/progenitor cells (NSPCs). The NSPCs undergo finite, lineage-restricted cell divisions to differentiate into the major cell types of the brain. Studies have revealed that aging is a negative regulator of NSPC proliferation, whereas NSPCs could be reactivated in the aged brain. Thus, restoring the function of NSPCs could effectively prevent brain aging.

One animal study showed that levels of NAD in the hippocampus — a brain region critical for learning and memory — were declining with age (Stein and Imai 2014). Yet, the long-term NMN administration was able to maintain the NSPC pool. Another animal study reported that NMN could induce NSC replication and promote NSC differentiation (Zhao et al., 2015). Thus, these findings NMN could be a promising agent for maintaining the NSC and NSPC pools to support healthy brain aging. 

In aging animals, NMN has been shown to support healthy cognition by assisting the brain’s blood vessels (Kiss et al., 2019a; Tarantini et al., 2019). Also, NMN can support healthy brain health by reinforcing the survival of cells in the hippocampus and prefrontal cortex — a brain region critical for decision making and many other high-level cognitive functions (Hosseini et al., 2019a).

Eye

We have specialized brain cells crucial for light transduction necessary for vision called photoreceptors, which come in two flavors. Rod and cone photoreceptors mediate dim and precise central vision in ambient light, respectively. The death of photoreceptors results in vision loss. Research has shown that long-term supplementation with NMN supported healthy rods and cones, assisting in detecting light.

The cornea is the transparent outer layer at the front of the eye, helping your eye focus light so you can see clearly. This tissue is highly infiltrated by nerves, which can be affected by aging. A recent study also reported that subconjunctival injection of NMN or other NAD precursors effectively supported corneal health.

Immune System

NMN is likely an excellent candidate to suppress inflammaging — the increase in inflammation associated with aging. For example, long-term NMN administration suppresses age-associated adipose tissue inflammation in mice (Mills et al., 2016).

Blood Vessels (Vascular)

Our organs need blood to get the oxygen and nutrients they need to function. But with age, our blood vessels become stiffer and have a more challenging time dilating, making it harder for these targets to get their vital cargo, especially during stress.

Old mice, just like people, develop this stiffness and altered dilation. But NMN, when given to old mice for eight weeks, supported both blood vessel elasticity and dilation capacity, pointing to this NAD precursor’s anti-aging potential in the vascular system.

Body Weight

Long-term administration of NMN can significantly reduce age-associated body weight gain. This weight loss works dose-dependently, meaning that the more NMN supplemented, the more significant the reduction in weight gain.

NMN-treated mice also maintained higher food and water consumption levels than control mice, which suggested that NMN did not cause severe side effects, such as growth defects and loss of appetite (Mills et al., 2016). These findings indicate that the administration of NMN could be an effective option for maintaining body weight and supporting metabolic health in the face of aging.

Healthy Blood Sugar Levels

The metabolism of NAD plays a crucial role in how we keep our blood sugars levels healthy. What’s more, by ameliorating the deficiency in NAD biosynthesis, NMN was shown to maintain healthy blood sugar levels (Revollo et al., 2007).

Long-term (12 months) NMN administration in mice ameliorated the age-associated decline when cells in your muscles, fat, and liver don't correctly respond to taking up blood sugar (Mills et al., 2016). The same treatment also improved the age-associated decrease in the ability of our cells to use blood glucose effectively, leading to a buildup in blood sugar levels.

Can NMN reverse aging?

With all of the exciting research that’s occurred in animals surrounding NMN, we’re only at the very beginning of understanding what kind of anti-aging potential this NAD precursor has in people. And we’ve gotten to see some of the results.

A recent clinical study reported that administering a single dose of 100 to 500 mg of NMN in healthy adult men was safe and effective with no adverse side effects (Irie et al., 2020). In a clinical study (NCT 03151239), postmenopausal women with prediabetes took 250 mg of NMN daily for ten weeks. Here, NMN administration increased skeletal muscle blood sugar sensing (Yoshino et al., 2021).

In another clinical study (ChiCTR2000035138), 300, 600, and 1200 mg of NMN were taken for six weeks every day (Liao et al., 2021). The improvement of aerobic capacity was dependent on the dosage; the large dosage of NMN with exercise has better effects. This work showed that NMN increases the aerobic capacity of humans during exercise training.  

We all want to know whether the results from mice will translate to you and me. Human studies will help us understand some key questions that need more examination, such as “How much NMN should I take?”, “How long does it take for NMN to start working?”, “What is the best way to take NMN?”.

What we do know is that the levels of NMN in foods — such as vegetables (edamame and broccoli), fruits (avocado and tomato), mushrooms, seafood (shrimp), and meat (raw beef) — is far below what so far is safe in humans through supplements, whether through powder or lozenges, and even IV. 

Nevertheless, human studies so far support the use of NMN as a safe and effective long-term treatment to increase NAD metabolism in humans. More studies are still needed to help us understand NMN and its anti-aging potential.

References:

​​Braidy N, Berg J, Clement J, Khorshidi F, Poljak A, Jayasena T, Grant R, Sachdev P. Antioxid Redox Signal. 2019 Jan 10;30(2):251-294. DOI: 10.1089/ars.2017.7269. Epub 2018 May 11. PMID: 29634344; PMCID: PMC6277084.

Hong W, Mo F, Zhang Z, Huang M, Wei X. Front Cell Dev Biol. 2020 Apr 28;8:246. DOI: 10.3389/fcell.2020.00246. PMID: 32411700; PMCID: PMC7198709.

Hosseini L, Farokhi-Sisakht F, Badalzadeh R, Khabbaz A, Mahmoudi J, Sadigh-Eteghad S. Neuroscience. 2019 Dec 15;423:29-37. DOI: 10.1016/j.neuroscience.2019.09.037. Epub 2019 Oct 31. PMID: 31678348.

Imai S. Pharmacol Res. 2010 Jul;62(1):42-7. DOI: 10.1016/j.phrs.2010.01.006. Epub 2010 Jan 18. PMID: 20085812; PMCID: PMC2873125.

Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H. Endocr J. 2020 Feb 28;67(2):153-160. DOI: 10.1507/endocrj.EJ19-0313. Epub 2019 Nov 2. PMID: 31685720.

Khaidizar FD, Bessho Y, Nakahata Y. Int J Mol Sci. 2021 Apr 2;22(7):3709. DOI: 10.3390/ijms22073709. PMID: 33918226; PMCID: PMC8037941.

Kiss T, Balasubramanian P, Valcarcel-Ares MN, Tarantini S, Yabluchanskiy A, Csipo T, Lipecz A, Reglodi D, Zhang XA, Bari F, Farkas E, Csiszar A, Ungvari Z. Geroscience. 2019 Oct;41(5):619-630. DOI: 10.1007/s11357-019-00074-2. Epub 2019 May 29. PMID: 31144244; PMCID: PMC6885080.

Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. J Int Soc Sports Nutr. 2021 Jul 8;18(1):54. DOI: 10.1186/s12970-021-00442-4. PMID: 34238308; PMCID: PMC8265078.

Mendelsohn AR, Larrick JW. Rejuvenation Res. 2014 Feb;17(1):62-9. DOI: 10.1089/rej.2014.1546. PMID: 24410488.

Revollo JR, Körner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S. Cell Metab. 2007 Nov;6(5):363-75. DOI: 10.1016/j.cmet.2007.09.003. PMID: 17983582; PMCID: PMC2098698.

Shade C. Integr Med (Encinitas). 2020 Feb;19(1):12-14. PMID: 32549859; PMCID: PMC7238909.

Stein LR, Imai S. EMBO J. 2014 Jun 17;33(12):1321-40. DOI: 10.1002/embj.201386917. Epub 2014 May 8. PMID: 24811750; PMCID: PMC4194122.

Abdellatif M, Baur JA. NAD+ metabolism and cardiometabolic health: the human evidence. Cardiovascular Research. 2021;117(9):e106-e109. doi:10.1093/cvr/cvab212 

Yoshino J, Baur JA, Imai SI. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018 Mar 6;27(3):513-528. DOI: 10.1016/j.cmet.2017.11.002. Epub 2017 Dec 14. PMID: 29249689; PMCID: PMC5842119.

Yoshino J, Mills KF, Yoon MJ, Imai S. Cell Metab. 2011 Oct 5;14(4):528-36. DOI: 10.1016/j.cmet.2011.08.014. PMID: 21982712; PMCID: PMC3204926.

Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S. Science. 2021 Jun 11;372(6547):1224-1229. DOI: 10.1126/science.abe9985. Epub 2021 Apr 22. PMID: 33888596.

Zhao Y, Guan YF, Zhou XM, Li GQ, Li ZY, Zhou CC, Wang P, Miao CY. Stroke. 2015 Jul;46(7):1966-74. DOI: 10.1161/STROKEAHA.115.009216. Epub 2015 Jun 9. PMID: 26060246.