NAD+ Promotes Stem Cell Renewal and Regenerates MitochondriaPrint
NAD+ is shown to renew existing stem cells, repair broken DNA and extend lifespan. Life Extension® receives many inquiries about stem cell infusion therapies offered in the United States and other countries. Our current view from small human trials is that there may be a benefit to infusions of exosomes that are naturally secreted from healthy stem cells. Stem cell exosomes have regenerative properties that help restore functional cells needed to maintain tissue and organ viability.
Overlooked when considering exosome treatments is the ability to rejuvenate existing stem cell pools utilizing approaches many of you already follow. This includes activating AMPK and restoring youthful levels of sirtuins and NAD+. Increasing NAD+ is a promising way to self-renew existing stem cells in order to extend lifespan and prevent disease.1-12 A study published in June 2019 shows how a NAD+ boosting supplement called nicotinamide riboside increased stem cell colonies by 75% in the gut of aging mice.13 Other studies point to the role of NAD+ in restoring circadian rhythms needed for restorative sleep.14
Age-related sleep deterioration and digestive disorders adversely impact quality of life and accelerate degenerative processes in older individuals. The most critical role of NAD+ is DNA repair. Each day, our DNA sustains numerous breaks that are repaired by NAD+-dependent enzymes. With age, NAD+ levels plummet. Another study published in 2019 showed that a modest dose of nicotinamide riboside boosted NAD+ levels by 51% in overweight humans.15 We advise holding off on most stem cell infusions until more is known about safety and efficacy. New data reveal how NAD+ improves functionality of existing stem cells and replenishes mitochondria in cells throughout the body.
What is NAD+?
Nicotinamide adenine dinucleotide (NAD+) is a compound found in every living cell. It is critical for cell energy production. Recent research shows NAD+ does much more.6,8-11,16,17
Hundreds of different proteins in each cell require NAD+ to work properly.17 The most important proteins are the sirtuins, cellular guardians that protect against DNA damage that leads to many age-related ailments.18,19 Sirtuins are an important target for anti-aging interventions.10,11,20-22 Multiple animal studies have demonstrated that increasing sirtuin activity leads to longer life and reduction in age-related loss of function.12,23,24
As NAD+ levels decline with aging, there is reduced sirtuin activity. Boosting NAD+ helps ramp up sirtuin activity. Increasing NAD+ levels can bring additional benefits tied to healthy longevity including:20,25
- Promoting AMPK activity, an enzyme that improves metabolism and helps protect against obesity and diabetes,
- Modulating p53, a tumor suppressor gene that repairs damaged DNA and protects against cancer initiation,
- Inhibiting NF-kB (nuclear factor-kappa B), a protein that induces the chronic inflammation tied to many diseases and premature aging, and
- Inhibiting mTOR, a molecular complex whose abnormal activation contributes to many chronic diseases of aging.
WE RETAIN STEM CELLS AS WE AGE
- Stem cells are capable of self-renewal.
- Stem cells differentiate into functional (somatic) tissue cells.
- The number of stem cells may not greatly decrease with age.
- Aging reduces regenerative potential of stem cells.
- Stem cell senescence contributes to age-related conditions.
Khorraminejad-Shirazi M, et al. Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving efficacy in stem cell therapy. Hematol Oncol Stem Cell Ther (2017).
HOW OLD STEM CELLS MAY BE REJUVENATED
- Boost cellular AMPK
- AMPK lowers excess mTORC1
- Replenish NAD+ cell levels
- Activate sirtuins (with resveratrol)
Khorraminejad-Shirazi M, et al. Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving efficacy in stem cell therapy.Hematol Oncol Stem Cell Ther (2017).
Nicotinamide Riboside Boosts NAD+
Higher levels of NAD+ correlate with improved health and a lower occurrence of age-related disorders.
Lower NAD+ levels contribute to many diseases of older age, including sleep disturbances, metabolic disorders, diabetes, cardiovascular disease, and cognitive decline.7,9-11,14,26
An easy way to boost NAD+ levels is with nicotinamide riboside, which converts to NAD+ in your body.
In human subjects, a 300 mg dose of nicotinamide riboside increased red blood cell NAD+ levels by 51%.15
Nicotinamide riboside is highly absorbable, or bioavailable, when taken orally.27
NICOTINAMIDE RIBOSIDE AND RESVERATROL: A POWERFUL ANTI-AGING DUO
Resveratrol is a plant compound found in red grapes, red wine, and other darkly colored fruits.
Among its many benefits, it activates sirtuins, the key defender proteins linked to longer, healthier life.47-49
But resveratrol can’t do this if cells are low in NAD+.That’s because NAD+ 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 promoting sirtuin activity with resveratrol. This combination ensures that the enhanced sirtuin activity can have its maximum beneficial effect on health and aging.
Remarkable New Findings
Recent studies of NAD+ and nicotinamide riboside have shown two primary ways in which they improve health.
1. Replacing Old Mitochondria and Improving Mitochondrial Function
Mitochondria are the power suppliers of every cell, breaking down nutrients like sugars and fats into energy the cell can use to do work. When mitochondria age, they become dysfunctional, contributing to many illnesses.
Evidence indicates that sirtuins perform cellular housekeeping that includes replacing old and damaged mitochondria with healthy, new ones.28 This process rejuvenates cells and improves their metabolism while maintaining their optimal function.
Because sirtuin activity is dependent on NAD+ (which plummets with age), supplementation with nicotinamide riboside can help preserve cellular functions.
Replenishing NAD+ levels with nicotinamide riboside resulted in enhanced mitochondrial function that:
- Rejuvenated aging bone marrow cells, helping to maintain immune function and prevent bone marrow failure and related diseases,29,30
- Improved muscle function and reduced muscle pathology in an animal model of muscular dystrophy,31 and
- Lessened liver inflammation and induced mitochondrial biogenesis, the formation of new mitochondria, in mice liver cells.32
2. Rejuvenating Stem Cells
Healthy stem cells in tissues are needed to replace dead or dying functional cells with new ones. But stem cells age and become dysfunctional over time, causing tissues to deteriorate and increasing risk for disease.33
Nicotinamide riboside intake can help prevent this. In a study on elderly mice, nicotinamide riboside replenished NAD+ levels, which improved mitochondria function that rejuvenated stem cells in muscles. It also prevented the deterioration of muscle, skin, and brain stem cells.24
This prolonged the lifespan of old mice by approximately 5%. Though this number may not seem huge, the supplementation only began when the mice were already two years old, the equivalent of about 80 years in humans.34
A more significant effect may occur if NAD+ is boosted earlier in life, and combined with interventions like resveratrol that prompts cells to express sirtuin proteins that NAD+ then activates.
New studies corroborate a beneficial impact of NAD+ on other stem cells.13,29 In one study, researchers looked at adult mice gut stem cells, which typically dwindle in older age.13 Injuries to the gut of these older animals have a difficult time healing.
Nicotinamide riboside increased these digestive tract stem cell colonies by approximately 75%, improving the ability to recover from injury. This finding has favorable implications for older individuals suffering from digestive tract discomforts.
WHAT YOU NEED TO KNOW
NAD+ for Healthy Longevity
- NAD+ (nicotinamide adenine dinucleotide) is an essential cofactor for hundreds of cellular processes.
- Sirtuins, cellular defenders linked to longer life and protection from disease, require optimal NAD+ levels to function.
- Levels of NAD+ drop with age, accelerating aging. Nicotinamide riboside helps replenish NAD+ levels.
- Boosting NAD+ has been tied to improved mitochondrial function, healthier stem cells that rejuvenate tissues, and increased longevity.
- Maximizing NAD+ also protects tissues from the effects of age and may reduce risk for age-related diseases such as cognitive decline, cardiovascular disease, and metabolic disease.
Wide-Ranging Benefits of NAD+
Boosting NAD+ levels can have a positive impact on multiple areas of health.
Studying the effect of a supplement on human longevity is difficult, because of the long average lifespan of humans. But many studies show that increasing NAD+ prolongs the life of a variety of organisms.12,23,24,35 In yeast, a single-cell organism with a short lifespan, nicotinamide riboside increased lifespan as demonstrated by improved cell replicative capacity.23
Studies of worms show that nicotinamide riboside can prolong their life by at least 10%.35 These effects extend to mammals as well.12,24
In a recent study of older men, levels of NADH, the reduced form of NAD+ were significantly increased by 59% only two hours after taking one dose of nicotinamide riboside, while markers of oxidative stress were decreased.15 The men in this study had an 8% improvement in peak isometric muscle torque (a measure of muscle force) and a 15% improvement in fatigue associated with exercise.
Studies of mouse models of Alzheimer’s disease have shown improvements with nicotinamide riboside supplementation.36,37 In the most recent study, it reversed the cognitive deficits in mice, improving memory.37 The pathology observed in the brains of Alzheimer’s disease patients, amyloid plaques, was also reduced in the brains of these animals. A previous study had similar findings.36
Obesity and Metabolic Disorders
Sirtuins improve metabolism and can be helpful guardians against weight gain, metabolic syndrome, and type II diabetes.38-43 By boosting sirtuin activity, nicotinamide riboside enhanced metabolism and prevented excessive weight gain in mice.44
In animal models of type II diabetes, this improved metabolism helped control blood sugar levels and shield against the damage done by high blood glucose.42
Improved metabolism and lower body weight help to reduce risk for cardiovascular disease. But nicotinamide riboside does even more to protect the cardiovascular system. One recent study focused on mice with heart disease that had a 30% reduction in NAD+ levels.45 Untreated, they typically developed heart failure. But nicotinamide riboside attenuated the decline in cardiac function.
People aged 50 have about 40% less NAD+ whereas 80-year-old people can have 90%-98% lower levels of NAD+ compared to 21-year-olds. Heart failure risk increases as people grow older. Recent studies show that nicotinamide riboside protects the organs of the cardiovascular system and protects other tissues from the effects of cardiovascular disease.
Normally, if blood flow to a tissue is compromised due to disease, the tissue dies, as happens in a myocardial infarction or a stroke. Preclinical studies show that nicotinamide riboside improves the response of tissues to this type of injury, reducing damage and encouraging recovery of the tissue.5,46
NAD+ PROTECTS STEM CELLS IN AGING MICE
- Enhanced muscle function
- Extended lifespan
- Protection of muscle, neural, and melanocyte stem cells
NAD+ repletion improves mitochondrial and stem cell function and enhances lifespan in mice. Science. 2016 Jun 17;352(6292):1436-43.
How NAD+ Improves Sleep
It’s no secret that sleep patterns become disrupted with age. Much of this problem is due to a disruption in circadian rhythms that govern our sleep/wake cycle. NAD+ has shown the ability to rebalance circadian rhythms through its stimulation of a vital cell protein called SIRT1. In an animal study, mice deficient in SIRT1 experienced decreased quality of sleep.14 Increasing NAD+ levels can help increase SIRT1 and other sirtuins, helping to restore normal sleep/wake cycles.
UNIFIED THEORY OF STEM CELL REJUVENATION
- Adult stem cells lose ability to repopulate tissues with functional cells.
- Systemic deterioration occurs as functional cells degenerate/die.
- How your stem cells may be renewed:
- Boost cellular AMPK
- Suppress excess mTORC1
- Replenish NAD+ cell levels
- Activate sirtuin proteins
Khorraminejad-Shirazi M, et al. Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving efficacy in stem cell therapy. Hematol Oncol Stem Cell Ther(2017).
NAD+ is a critical component of a healthy aging program. Every cell requires it for hundreds of processes. These include activity of sirtuins, cellular guardians linked to prolonged lifespan and healthspan. NAD+ levels and sirtuin expression diminish with advancing age, accelerating aging processes and degenerative disease risk. Nicotinamide riboside is a compound that increases cellular NAD+ levels, enhancing sirtuin activity. New research has found that maintaining more youthful NAD+ levels can slow certain aspects of biological aging.
NAD+ also improves the health of stem cells that can replace dead and dying cells and keep vital tissues functioning. This not only extends lifespan, but also helps reduce the risk for metabolic disease, obesity, cardiovascular disease, cognitive dysfunction, and more.
(Author: Susan Goldschein)
- Braidy N, Berg J, Clement J, et al. Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes. Antioxid Redox Signal. 2019 Jan 10;30(2):251-94.
- Hosseini L, Vafaee MS, Mahmoudi J, et al. Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Biogerontology. 2019 Aug;20(4):381-95.
- Yaku K, Okabe K, Nakagawa T. NAD metabolism: Implications in aging and longevity. Ageing Res Rev. 2018 Nov;47:1-17.
- Yoshino J, Baur JA, Imai SI. NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018 Mar 6;27(3):513-28.
- Matasic DS, Brenner C, London B. Emerging potential benefits of modulating NAD(+) metabolism in cardiovascular disease. Am J Physiol Heart Circ Physiol. 2018 Apr 1;314(4):H839-H52.
- Verdin E. NAD(+) in aging, metabolism, and neurodegeneration. Science. 2015 Dec 4;350(6265):1208-13.
- Aman Y, Qiu Y, Tao J, et al. Therapeutic potential of boosting NAD+ in aging and age-related diseases. Translational Medicine of Aging. 2018;2:30-7.
- Garrido A, Djouder N. NAD(+) Deficits in Age-Related Diseases and Cancer. Trends Cancer. 2017 Aug;3(8):593-610.
- Mouchiroud L, Houtkooper RH, Auwerx J. NAD(+) metabolism: a therapeutic target for age-related metabolic disease. Crit Rev Biochem Mol Biol. 2013 Jul-Aug;48(4):397-408.
- Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014 Aug;24(8):464-71.
- Johnson S, Imai SI. NAD (+) biosynthesis, aging, and disease. F1000Res. 2018;7:132.
- 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.
- Igarashi M, Miura M, Williams E, et al. NAD(+) supplementation rejuvenates aged gut adult stem cells. Aging Cell. 2019 Jun;18(3):e12935.
- Satoh A, Imai SI, Guarente L. The brain, sirtuins, and ageing. Nat Rev Neurosci. 2017 May 18;18(6):362-74.
- Dolopikou CF, Kourtzidis IA, Margaritelis NV, et al. Acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study. Eur J Nutr 2019 Feb 6.
- Kulikova VA, Gromyko DV, Nikiforov AA. The Regulatory Role of NAD in Human and Animal Cells. Biochemistry (Mosc). 2018 Jul;83(7):800-12.
- Ansari HR, Raghava GP. Identification of NAD interacting residues in proteins. BMC Bioinformatics. 2010 Mar 30;11:160.
- Choi JE, Mostoslavsky R. Sirtuins, metabolism, and DNA repair. Curr Opin Genet Dev. 2014 Jun;26:24-32.
- Lee SH, Lee JH, Lee HY, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019 Jan;52(1):24-34.
- Grabowska W, Sikora E, Bielak-Zmijewska A. Sirtuins, a promising target in slowing down the ageing process. Biogerontology. 2017 Aug;18(4):447-76.
- 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.
- Watroba M, Dudek I, Skoda M, et al. Sirtuins, epigenetics and longevity. Ageing Res Rev. 2017 Nov;40:11-9.
- 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.
- 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.
- Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018;64(2):127-34.
- Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95.
- Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016 Oct 10;7:12948.
- Sack MN, Finkel T. Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harb Perspect Biol. 2012 Dec 1;4(12).
- 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.
- Vannini N, Campos V, Girotra M, et al. The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Cell Stem Cell. 2019 Mar 7;24(3):405-18 e7.
- Ryu D, Zhang H, Ropelle ER, et al. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci Transl Med. 2016 Oct 19;8(361):361ra139.
- Lee HJ, Yang SJ. Nicotinamide riboside regulates inflammation and mitochondrial markers in AML12 hepatocytes. Nutr Res Pract. 2019 Feb;13(1):3-10.
- Ahmed AS, Sheng MH, Wasnik S, et al. Effect of aging on stem cells. World J Exp Med. 2017 Feb 20;7(1):1-10.
- Dutta S, Sengupta P. Men and mice: Relating their ages. Life Sci. 2016 May 1;152:244-8.
- 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.
- Hou Y, Lautrup S, Cordonnier S, et al. NAD(+) supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci USA. 2018 Feb 20;115(8):E1876-E85.
- 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.
- Bai P, Canto C, Oudart H, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 2011 Apr 6;13(4):461-8.
- Barbosa MT, Soares SM, Novak CM, et al. The enzyme CD38 (a NAD glycohydrolase, EC 18.104.22.168) is necessary for the development of diet-induced obesity. FASEB J. 2007 Nov;21(13):3629-39.
- 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.
- Kraus D, Yang Q, Kong D, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014 Apr 10;508(7495):258-62.
- 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.
- Yoshino J, Mills KF, Yoon MJ, et al. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011 Oct 5;14(4):528-36.
- Crisol BM, Veiga CB, Lenhare L, et al. Nicotinamide riboside induces a thermogenic response in lean mice. Life Sci. 2018 Oct 15;211:1-7.
- Diguet N, Trammell SAJ, Tannous C, et al. Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy. Circulation. 2018 May 22;137(21):2256-73.
- Toropova YG, Pechnikova NA, Zelinskaya IA, et al. Nicotinamide riboside has protective effects in a rat model of mesenteric ischaemia-reperfusion. Int J Exp Pathol.2018 Dec;99(6):304-11.
- 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.
- 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.
- 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.