Life Extension Magazine®
Older researcher holding vial while studying NAD+ and lifespan

What Has Scientists Excited About NAD+

Nicotinamide riboside increases cellular NAD+ and extends lifespan by 5% in animal studies.

Scientifically reviewed by: Gary Gonzalez, MD, on May 2021. Written By Jeff Simmons.

There's a reason that researchers have zeroed in on NAD+ as a key factor in a science-based longevity protocol.

Found in every living cell, NAD+ is essential for life-sustaining functions and cellular integrity.

But here's the problem—NAD+ declines with age.1-3

Fortunately, researchers have identified a form of vitamin B3 called nicotinamide riboside that can effectively increase NAD+ in the body toward youthful levels.

There is growing evidence from preclinical studies showing that supplementing with nicotinamide riboside can promote longevity.4-10

One study showed an average 5% increase in the lifespan of old mice–even though supplementation did not begin until the mice were nearing the end of their natural lifespan (24 months).10

That would be the equivalent of gaining nearly an additional four years of life based on today's average human life expectancy of 78.7 years.11

More than 50 clinical trials evaluating the impact of nicotinamide riboside on human health and longevity are listed in the U.S. National Library of Medicine.12

Boosting NAD+ Levels

One of the problems for aging individuals trying to restore NAD+ levels is that it is unstable and is not effective when taken orally.

Researchers have discovered a compound called nicotinamide riboside that is a precursor to NAD+.

This means that taking nicotinamide riboside orally can help jump-start NAD+ production. Cells can then use nicotinamide riboside to produce more NAD+ on their own, effectively boosting levels even into older age.

In both animal and human studies, nicotinamide riboside quickly boosts cellular NAD+ levels and stimulates NAD+ metabolism in cells.13-15

Anti-Aging Benefits of Raising NAD+

Older couple in car enjoying NAD+ benefits

A number of studies confirm that replenishing NAD+ levels can prevent or even reverse many of the changes associated with aging. It also shields against many of the chronic diseases of age.

Various lab and animal studies show that increasing NAD+ levels with nicotinamide riboside:

NAD+ Boosts Sirtuins

In so many ways, NAD+ is essential to the functioning and rejuvenation of the body.

Several important proteins, such as sirtuins, that regulate cellular repair and defenses, require NAD+ to function.

Sirtuins are an important target for anti-aging interventions.1,2,20-22

Sirtuins are dependent on NAD+ to function.

NAD+ levels markedly decline with age, creating an energy deficit that decreases the body's ability to retain youthful function.23

Multiple animal studies have demonstrated that increasing sirtuin activity leads to longer life and reduction in age-related loss of function.4,7,10

Rejuvenating Stem Cells

Researcher studying effects of NAD+ and stem cells

As in humans, NAD+ levels drop in older mice. This leads to a decline in organ function, including in the ovaries.

One of the most recent studies of nicotinamide riboside evaluated its effect in the ovaries of middle-aged mice.24

These older mice suffer from a loss of ovarian follicles (which contain the egg cells released during ovulation), poor egg quality, infertility, and frequent miscarriages or stillbirths.

A similar decline in human reproductive function occurs with age in women.

But when these older mice were given nicotinamide riboside, the health of the ovaries and reproductive function improved.

Ovarian follicles increased in number, and the mice were able to reproduce more easily and with a higher live birth rate. When scientists examined the ovaries, they saw markers of more youthful biology—healthier cells and improved cellular metabolism.

This improvement in organ function may be largely due to rejuvenation of stem cells.

In adult tissues, stem cells are meant to replace old, dysfunctional, and dying cells with healthy young ones. This maintains the health and youthful function of the tissue. But stem cells themselves age and stop working properly, causing the whole organ to fail.

What you need to know

Boost NAD+ For Health and Longevity

  • Nicotinamide adenine dinucleotide (NAD+) is a crucial cofactor for many different enzymes in all cells.
  • NAD+ is required for the activity of sirtuin proteins, which help regulate metabolism and aging.
  • NAD+ levels drop significantly with age, contributing to more accelerated aging, loss of function, and risk for chronic disease.
  • Nicotinamide riboside, a form of vitamin B3, is a NAD+ precursor. Taking it orally has been found to rapidly and safely replenish bodily levels of NAD+.
  • In many studies, nicotinamide riboside reduces markers of aging in tissues, rejuvenates organ function, revitalizes old stem cells, lowers risk for common chronic diseases, and extends lifespan.

Replenishing NAD+ levels with nicotinamide riboside rejuvenated muscle stem cells of aged mice.10

This study showed that boosting NAD+ improved mitochondrial function in muscle stem cells and inhibited stem cell senescence.

The researchers also showed that boosting NAD+ decreased senescence of brain and skin stem cells.

Aged stem cells from diverse tissues have been shown to be made more youthful with increased cellular NAD+ levels.25,26

Longer, Healthier Life

Petri-dish being used in NAD+ research

Studies have consistently shown that increasing NAD+ levels improves overall health and extends lifespan in a range of preclinical models.

Longevity is difficult to study in humans because of our long lives. But boosting NAD+ has been shown to extend life in several other organisms, including yeast, worms, and mice.4,7,10,27

Yeast grown with nicotinamide riboside have an increase in lifespan.4 In worms, this NAD+ precursor extends life by at least 10%.7

In elderly mice the human equivalent of about 70 years of age, nicotinamide riboside extended lifespan by roughly 5% compared to untreated animals.10

In human terms, this is the equivalent of gaining nearly four additional years of life based on today's average human life expectancy of 78.7 years.11

These studies and others show why scientists and doctors are so excited about raising NAD+ levels as one key to anti-aging efforts, and to promoting longevity.

Summary

Older woman standing in car feeling youthful

The compound NAD+ (nicotinamide adenine dinucleotide) plays a critical role in fighting aging and possibly preventing degenerative disease risk.

NAD+ is required for cellular enzymes and proteins to work properly. The sirtuin proteins, which are promising targets for life-extending interventions, need NAD+ to function.

NAD+ levels decline with advancing age.

Nicotinamide riboside, a precursor to NAD+, rapidly increases NAD+ blood levels.

Boosting NAD+ to more youthful levels with nicotinamide riboside has been shown to prolong life and reverse loss of function in animal models.

Nicotinamide Riboside and Resveratrol

Resveratrol is a plant compound found in red grapes, red wine, and other darkly colored fruits.

Among its many benefits, it activates sirtuins, defender proteins linked to longer, healthier life.28-30

But resveratrol can't do this if cells are low in NAD+, which is required for sirtuins to work properly. It would be like pressing the accelerator in your car when your gas tank is empty.

The solution is to increase intake of nicotinamide riboside to boost NAD+ levels at the same time as stimulating sirtuin activity with resveratrol. This combination can promote optimal sirtuin activity, which can translate to better health and greater longevity.

Life Extension® continues to monitor ongoing trials on the impact that nicotinamide riboside could have on human health and longevity.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014 Aug;24(8):464-71.
  2. Johnson S, Imai SI. NAD (+) biosynthesis, aging, and disease. F1000Res. 2018;7:132.
  3. Zhou CC, Yang X, Hua X, et al. Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol. 2016 Aug;173(15):2352-68.
  4. Belenky P, Racette FG, Bogan KL, et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 2007 May 4;129(3):473-84.
  5. Denu JM. Vitamins and aging: pathways to NAD+ synthesis. Cell. 2007 May 4;129(3):453-4.
  6. Lu SP, Kato M, Lin SJ. Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae. J Biol Chem. 2009 Jun 19;284(25):17110-9.
  7. Mouchiroud L, Houtkooper RH, Moullan N, et al. The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell. 2013 Jul 18;154(2):430-41.
  8. Poljsak B, Milisav I. NAD+ as the Link Between Oxidative Stress, Inflammation, Caloric Restriction, Exercise, DNA Repair, Longevity, and Health Span. Rejuvenation Res. 2016 Oct;19(5):406-15.
  9. Tsang F, James C, Kato M, et al. Reduced Ssy1-Ptr3-Ssy5 (SPS) signaling extends replicative life span by enhancing NAD+ homeostasis in Saccharomyces cerevisiae. J Biol Chem. 2015 May 15;290(20):12753-64.
  10. Zhang H, Ryu D, Wu Y, et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016 Jun 17;352(6292):1436-43.
  11. Available at: https://www.cdc.gov/nchs/data/factsheets/factsheet_NVSS.pdf. Accessed December 14, 2020.
  12. Available at: https://www.clinicaltrials.gov/ct2/results?cond=&term=%22nicotinamide+riboside%22&cntry=&state=&city=&dist=. Accessed December 15, 2020.
  13. Airhart SE, Shireman LM, Risler LJ, et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017;12(12):e0186459.
  14. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286.
  15. Trammell SA, Weidemann BJ, Chadda A, et al. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016 May 27;6:26933.
  16. Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 Jun 6;15(6):838-47.
  17. Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging. 2013 Jun;34(6):1581-8.
  18. Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019 Mar;22(3):401-12.
  19. Xie X, Gao Y, Zeng M, et al. Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. Metab Brain Dis. 2019 Feb;34(1):353-66.
  20. Grabowska W, Sikora E, Bielak-Zmijewska A. Sirtuins, a promising target in slowing down the ageing process. Biogerontology. 2017 Aug;18(4):447-76.
  21. Satoh A, Stein L, Imai S. The role of mammalian sirtuins in the regulation of metabolism, aging, and longevity. Handb Exp Pharmacol. 2011;206:125-62.
  22. Watroba M, Dudek I, Skoda M, et al. Sirtuins, epigenetics and longevity. Ageing Res Rev. 2017 Nov;40:11-9.
  23. Imai SI, Guarente L. It takes two to tango: NAD(+) and sirtuins in aging/longevity control. NPJ Aging Mech Dis. 2016;2:16017.
  24. Yang Q, Cong L, Wang Y, et al. Increasing ovarian NAD(+) levels improve mitochondrial functions and reverse ovarian aging. Free Radic Biol Med. 2020 Aug 20;156:1-10.
  25. Igarashi M, Miura M, Williams E, et al. NAD(+) supplementation rejuvenates aged gut adult stem cells. Aging Cell. 2019 Jun;18(3):e12935.
  26. Moon J, Kim HR, Shin MG. Rejuvenating Aged Hematopoietic Stem Cells Through Improvement of Mitochondrial Function. Ann Lab Med. 2018 Sep;38(5):395-401.
  27. Fang EF, Scheibye-Knudsen M, Brace LE, et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014 May 8;157(4):882-96.
  28. Huang JP, Hsu SC, Li DE, et al. Resveratrol Mitigates High-Fat Diet-Induced Vascular Dysfunction by Activating the Akt/eNOS/NO and Sirt1/ER Pathway. J Cardiovasc Pharmacol. 2018 Nov;72(5):231-41.
  29. Gomes BAQ, Silva JPB, Romeiro CFR, et al. Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1. Oxid Med Cell Longev. 2018;2018:8152373.
  30. Kim EN, Lim JH, Kim MY, et al. Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury. Aging (Albany NY). 2018 Jan 11;10(1):83-99.