NAD+ Shown to Reverse Aging Biomarkers

As we age, our vitality declines as cells can no longer produce the energy of youth.

An essential co-factor required for cellular energy transfer is NAD+, which plays a critical role in regulating the rate at which we biologically age.

NAD+ is used by every cell in the body. Harvard researchers have shown that increasing NAD+ levels in mammals can reverse several biochemical parameters associated with the aging process.¹

In a recent study,² researchers have shown that NAD+ works in two distinct ways to mitigate aging. First, it increases mitochondrial activity and secondly, it activates specific sirtuins shown to regulate life span.^3-6

The good news is that higher levels of NAD+ can be restored via a unique form of vitamin B3 called nicotinamide riboside. With this advance, it is possible for aging individuals to boost their NAD+ cellular levels.

NAD+: An Essential Component of Life

 

Nicotinamide adenine dinucleotide (NAD+) is found in every cell in the body and is critical for regulating genes that accelerate aging.⁷

NAD+ also plays an important part in the transfer of energy released from fatty acids and glucose to the mitochondria to be converted into cellular energy.^8,9

When NAD+ levels decline, energy transfer in cells breaks down, leading to mitochondrial dysfunction that results in many of the physical symptoms of aging.^1,10,11 Fortunately, by increasing intracellular levels of NAD+, age-related mitochondrial dysfunction can be reversed.¹

NAD+ battles aging by activating key anti-aging enzymes called sirtuins, specifically SIRT1 and SIRT3. Sirtuins contribute to longevity by favorably controlling gene expression.^8,11-15

SIRT1 and SIRT3 modulate multiple biological processes summarized in the table at the end of this article.³

Sirtuins can be activated at any age through caloric restriction. In response to undereating, cellular levels of NAD+ increase.⁸

Studies in yeast have shown that increasing NAD+ levels positively affects the function of sirtuins and significantly extends yeast life span.¹⁸ A study done in worms (C. elegans) showed that older worms had lower levels of NAD+ when compared to younger worms. When NAD+ levels were decreased even further, the worms aged faster. When worms had their NAD+ levels restored, it prevented metabolic changes of aging and increased their life span.⁵

Of course, it is a large step—evolutionarily and biologically—from yeast and worms to mammals. However, studies done in mammals have also shown that NAD+ levels are critical for not only healthy cellular and mitochondrial functioning, but aging itself.

A study done at Harvard has shown that increasing NAD+ levels in mammals can reverse the aging process.¹ This study was done on mice that were bred to have a defect in SIRT1. These mice exhibited multiple signs of accelerated aging, including mitochondrial dysfunction. However, when the levels of NAD+ were increased in these 22-month-old mice, the results were nothing short of amazing: Key markers of aging, including insulin resistance, inflammation, and muscle wasting—all processes commonly associated as a “normal” part of aging—were lowered to that of mice aged 6 months.

Knowing that NAD+ is vital to cellular functioning and that NAD+ levels decrease as we age, many scientists believe a key process in slowing, stopping, or even reversing the aging process is to maintain healthy, youthful NAD+ levels. The interest in finding ways to maintain youthful NAD+ levels has given rise to a form of vitamin B3, nicotinamide riboside, which converts to NAD+ in the body.^19,20

By increasing NAD+ levels, nicotinamide riboside has been shown in multiple studies to positively affect mitochondria. In addition, a recently released study² has shown that nicotinamide riboside can both increase healthy mitochondrial activity and activate specific sirtuins shown to regulate life span.^3-6

Let’s now examine some of the well-studied mammalian sirtuins to better understand the importance of maintaining healthy NAD+ levels in preventing premature aging.

What You Need to Know

The Importance of Optimal NAD+

• Nicotinamide adenine dinucleotide, or NAD+, is a co-factor that plays a crucial role in many biochemical reactions.
• Optimal levels of NAD+ are essential for the proper functioning of mitochondria, the producer of energy for the body, and sirtuins, which are enzymes known to be an integral part of the aging process.
• While NAD+ levels decrease with age, the use of the natural compound nicotinamide riboside can restore NAD+ to healthy, youthful levels.
• Raising levels of NAD+ has been shown to reverse key indicators of aging.

SIRT1 and Longevity

SIRT1 is the most extensively studied mammalian sirtuin. It plays an important part in multiple biological functions, including tumor suppression, apoptosis, metabolic regulation, and the aging process. Several mouse studies have demonstrated the influence of SIRT1 activity on extending life span.^34,35 Delayed bone loss, reductions in the incidence of sarcomas and carcinomas, and improved glucose control and wound healing have been shown in a model of SIRT1 transgenic mice.³⁴ In another transgenic mouse model, increased activity of brain-specific SIRT1 resulted in an approximate 11% increase in median life span.³⁵

An array of research has shown the connection of SIRT1 with premature cellular senescence, a process that contributes to accelerated aging.^36,37 By interacting with biological molecules like p53, SIRT1 regulates cellular senescence, apoptosis, metabolism, and cell cycle.³⁶ A study examining the effects of SIRT1 inhibition in human umbilical vein endothelial cells suggested the role of this enzyme in protecting against endothelial dysfunction, one of the consequences of cellular senescence.³⁶

SIRT1 is emerging as an outstanding housekeeper for the maintenance of stem cells by fighting cellular senescence. This was seen in a study involving human mesenchymal stem cells in which the reduction of SIRT1 activity resulted in accelerated cellular senescence. However, when SIRT1 activity was increased in bone marrow-derived stem cells, it showed that senescence was delayed, leading the authors to conclude that SIRT1 may contribute to the prevention of human mesenchymal stem cell senescence.³⁸

A more recent study discussed the importance of SIRT1 in the maintenance of hematopoietic stem cells’ homeostasis and that loss of SIRT1 in hematopoietic stem cells resulted in DNA damage.³⁹

It is well established that genomic instability and impaired DNA damage repair are some of the contributing factors that result in accelerated aging and cellular senescence.⁴⁰ Exciting findings show that SIRT1 fosters DNA damage repair⁴¹ and that it protects vascular smooth muscle cells against DNA damage and atherosclerosis.⁴² Neurodegenerative disorders and age-related cognitive decline have been linked with defects in DNA repair.

Researchers at MIT determined that SIRT1 activation reduces DNA damage and provides an important therapeutic path in neurodegenerative diseases.⁴³ Together, these findings confirm the protective roles that SIRT1 has not only in maintaining genomic integrity but also against neurodegeneration.

A study in mice found that an increase of SIRT1 activity in the brain increased longevity by an approximate 11%, while at the same time reducing the incidence of cancer.⁴⁵ Yet a more recent study on age-related muscle loss or sarcopenia determined that activation of SIRT1 can improve muscle performance, one of the hallmarks of sarcopenia.⁴⁴ This is clear evidence that SIRT1 can fight premature aging and promote longevity.

SIRT3: A Key Mitochondrial Sirtuin

Primarily located in the mitochondria, SIRT3 plays an important role in the regulation of several mitochondrial processes.⁴⁵ It has been associated with fatty liver, obesity, hyperlipidemia, and insulin resistance in mice lacking SIRT3 and fed high-fat diets.⁴⁶

A recent report found that increased SIRT3 activity improved the regenerative capacity of hematopoietic stem cells.⁴⁷ It is also recognized that this sirtuin is important in neurodegenerative disorders like Huntington’s disease.⁴⁸ Clearly, the impact that SIRT3 has on metabolic regulation, neurodegenerative disorders, and stem cell regeneration plays a crucial role in premature aging when impaired.

Summary

Nicotinamide adenine dinucleotide, or NAD+, is a critically important molecule for multiple biochemical processes in the body.

Numerous studies show that maintaining optimal levels of NAD+ through the use of natural compounds such as nicotinamide riboside are necessary for the health of mitochondria.

Sirtuins, which are enzymes that play a crucial role in the aging process, are dependent upon NAD+ to perform their life-giving functions.

New and groundbreaking studies are showing that maintaining optimal NAD+ levels can positively impact indicators of aging such as insulin resistance, muscle wasting, and inflammation. This gives credence to the hypothesis that aging itself is not only preventable, but reversible.

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. Gomes AP, Price NL, Ling AJ, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624-38.
2. Gariani K, Menzies KJ, Ryu D, et al. Eliciting the mitochondrial unfolded protein response via NAD repletion reverses fatty liver disease. Hepatology. 2015.
3. Ghosh S, Zhou Z. SIRTain regulators of premature senescence and accelerated aging. Protein & Cell. 2015;6(5):322-33.
4. Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006;20(21):2913-21.
5. 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):430-41.
6. Satoh A, Imai S-i. Systemic regulation of mammalian ageing and longevity by brain sirtuins. Nat Commun. 2014;5.
7. Imai S, Armstrong CM, Kaeberlein M, et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771):795-800.
8. Sauve AA. NAD+ and vitamin B3: from metabolism to therapies. J Pharmacol Exp Ther. 2008;324(3):883-93.
9. 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;34(6):1581-8.
10. Prolla TA, Denu JM. NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metab. 2014;19(2):178-80.
11. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-71.
12. Belenky P, Racette FG, Bogan KL, et al. Nicotinamide riboside promotes Sir2 silencing and extends life span via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 2007;129(3):473-84.
13. Hirschey MD, Shimazu T, Huang JY, et al. SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harb Symp Quant Biol. 2011;76:267-77.
14. Chen Y, Fu LL, Wen X, et al. Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis. 2014;5:e1047.
15. Scher MB, Vaquero A, Reinberg D. SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 2007;21(8):920-8.
16. Kim HS, Patel K, Muldoon-Jacobs K, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17(1):41-52.
17. Alhazzazi TY, Kamarajan P, Verdin E, et al. Sirtuin-3 (SIRT3) and the Hallmarks of Cancer. Genes Cancer. 2013;4(3-4):164-71.
18. Imai S. A possibility of nutriceuticals as an anti-aging intervention: activation of sirtuins by promoting mammalian NAD biosynthesis. Pharmacol Res. 2010;62(1):42-7.
19. Khan NA, Auranen M, Paetau I, et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med. 2014;6(6):721-31.
20. Belenky P, Stebbins R, Bogan KL, et al. Nrt1 and Tna1-independent export of NAD+ precursor vitamins promotes NAD+ homeostasis and allows engineering of vitamin production. PLoS One. 2011;6(5):e19710.
21. Sebastian C, Satterstrom FK, Haigis MC, et al. From sirtuin biology to human diseases: an update. J Biol Chem. 2012;287(51):42444-52.
22. Min SW, Sohn PD, Cho SH, et al. Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front Aging Neurosci. 2013;5:53.
23. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95.
24. Oellerich MF, Potente M. FOXOs and sirtuins in vascular growth, maintenance, and aging. Circ Res. 2012;110(9):1238-51.
25. Kemper JK, Choi SE, Kim DH. Sirtuin 1 deacetylase: a key regulator of hepatic lipid metabolism. Vitam Horm. 2013;91:385-404.
26. Schug TT, Li X. Sirtuin 1 in lipid metabolism and obesity. Ann Med. 2011;43(3):198-211.
27. Tao R, Wei D, Gao H, et al. Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. J Biol Chem. 2011;286(16):14681-90.
28. Ahn J, Lee H, Jung CH, et al. MicroRNA-146b promotes adipogenesis by suppressing the SIRT1-FOXO1 cascade. EMBO Mol Med. 2013;5(10):1602-12.
29. Pang W, Wang Y, Wei N, et al. Sirt1 inhibits akt2-mediated porcine adipogenesis potentially by direct protein-protein interaction. PLoS One. 2013;8(8):e71576.
30. Frojdo S, Durand C, Molin L, et al. Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. Mol Cell Endocrinol. 2011;335(2):166-76.
31. Sasaki T, Kim HJ, Kobayashi M, et al. Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide. Endocrinology. 2010;151(6):2556-66.
32. Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008;8(5):347-58.
33. Green MF, Hirschey MD. SIRT3 weighs heavily in the metabolic balance: a new role for SIRT3 in metabolic syndrome. J Gerontol A Biol Sci Med Sci. 2013;68(2):105-7.
34. Herranz D, Munoz-Martin M, Canamero M, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. 2010;1:3.
35. 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):416-30.
36. Ota H, Akishita M, Eto M, et al. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol. 2007;43(5):571-9.
37. Langley E, Pearson M, Faretta M, et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. Embo j. 2002;21(10):2383-96.
38. Yuan HF, Zhai C, Yan XL, et al. SIRT1 is required for long-term growth of human mesenchymal stem cells. J Mol Med (Berl). 2012;90(4):389-400.
39. Rimmele P, Bigarella CL, Liang R, et al. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Reports. 2014;3(1):44-59.
40. Liu B, Wang J, Chan KM, et al. Genomic instability in laminopathy-based premature aging. Nat Med. 2005;11(7):780-5.
41. Jeong J, Juhn K, Lee H, et al. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med. 2007;39(1):8-13.
42. Gorenne I, Kumar S, Gray K, et al. Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation. 2013;127(3):386-96.
43. Dobbin MM, Madabhushi R, Pan L, et al. SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci. 2013;16(8):1008-15.
44. Mohamed JS, Wilson JC, Myers MJ, et al. Dysregulation of SIRT-1 in aging mice increases skeletal muscle fatigue by a PARP-1-dependent mechanism. Aging (Albany NY). 2014;6(10):820-34.
45. Giblin W, Skinner ME, Lombard DB. Sirtuins: guardians of mammalian healthspan. Trends Genet. 2014;30(7):271-86.
46. Hirschey MD, Shimazu T, Jing E, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell. 2011;44(2):177-90.
47. Brown K, Xie S, Qiu X, et al. SIRT3 Reverses aging-associated degeneration. Cell reports. 2013;3(2):319-27.
48. Fu J, Jin J, Cichewicz RH, et al. trans-(-)-epsilon-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease. J Biol Chem. 2012;287(29):24460-72.