Benefits of NAD+

NMN and NR treatments can improve cognition, motor function, and preserve neuronal functions, and sometimes reverse, neuronal damages.

For more information, see references below:

Park, J.H., Long, A., Owens, K., and Kristian, T. (2016). Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia. Neurobiol. Dis. 95, 102–110.

Wei, C.C., Kong, Y.Y., Li, G.Q., Guan, Y.F., Wang, P., and Miao, C.Y. (2017b). Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway. Sci. Rep. 7, 717.

Gong, B., Pan, Y., Vempati, P., Zhao, W., Knable, L., Ho, L., Wang, J., Sastre, M., Ono, K., Sauve, A.A., and Pasinetti, G.M. (2013). Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-g coactivator 1a regulated b-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol. Aging 34, 1581–1588.

Hou, Y., Lautrup, S., Cordonnier, S., Wang, Y., Croteau, D.L., Zavala, E., Zhang, Y., Moritoh, K., O’Connell, J.F., Baptiste, B.A., et al. (2018). 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. Published online February 5, 2018.

Long, A.N., Owens, K., Schlappal, A.E., Kristian, T., Fishman, P.S., and Schuh, R.A. (2015). Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model. BMC Neurol. 15, 19.

Sorrentino, V., Romani, M., Mouchiroud, L., Beck, J.S., Zhang, H., D’Amico, D., Moullan, N., Potenza, F., Schmid, A.W., Rietsch, S., et al. (2017). Enhancing mitochondrial proteostasis reduces amyloid-b proteotoxicity. Nature 552, 187–193.

Wang, X., Hu, X., Yang, Y., Takata, T., and Sakurai, T. (2016). Nicotinamide mononucleotide protects against b-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 1643, 1–9.

Fang, E.F., Scheibye-Knudsen, M., Brace, L.E., Kassahun, H., SenGupta, T., Nilsen, H., Mitchell, J.R., Croteau, D.L., and Bohr, V.A. (2014). Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157, 882–896.

Brown, K.D., Maqsood, S., Huang, J.Y., Pan, Y., Harkcom, W., Li, W., Sauve, A., Verdin, E., and Jaffrey, S.R. (2014). Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab. 20, 1059–1068.

Dutca, L.M., Stasheff, S.F., Hedberg-Buenz, A., Rudd, D.S., Batra, N., Blodi, F.R., Yorek, M.S., Yin, T., Shankar, M., Herlein, J.A., et al. (2014). Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243. Invest. Ophthalmol. Vis. Sci. 55, 8330–8341.

Hamity, M.V., White, S.R., Walder, R.Y., Schmidt, M.S., Brenner, C., and Hammond, D.L. (2017). Nicotinamide riboside, a form of vitamin B3 and NAD+ precursor, relieves the nociceptive and aversive dimensions of paclitaxel-induced peripheral neuropathy in female rats. Pain 158, 962–972.

Lin, J.B., Kubota, S., Ban, N., Yoshida, M., Santeford, A., Sene, A., Nakamura, R., Zapata, N., Kubota, M., Tsubota, K., et al. (2016). NAMPT-mediated NAD(+) biosynthesis is essential for vision in mice. Cell Rep. 17, 69–85.

Vaur, P., Brugg, B., Mericskay, M., Li, Z., Schmidt, M.S., Vivien, D., Orset, C., Jacotot, E., Brenner, C., and Duplus, E. (2017). Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J. 31, 5440–5452.

Yin, T.C., Britt, J.K., De Jesu´ s-Corte´ s, H., Lu, Y., Genova, R.M., Khan, M.Z., Voorhees, J.R., Shao, J., Katzman, A.C., Huntington, P.J., et al. (2014). P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury. Cell Rep. 8, 1731–1740.

Zhuo, L., Fu, B., Bai, X., Zhang, B., Wu, L., Cui, J., Cui, S., Wei, R., Chen, X., and Cai, G. (2011). NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway. Cell. Physiol. Biochem. 27, 681–690.

NAD+ protects the liver from fat accumulation, hepatitis, high LDL cholesterol levels, and insulin resistance. For more information, see references below:

Mukherjee, S., Chellappa, K., Moffitt, A., Ndungu, J., Dellinger, R.W., Davis, J.G., Agarwal, B., and Baur, J.A. (2017). Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration. Hepatology 65, 616–630.

Gariani, K., Ryu, D., Menzies, K.J., Yi, H.S., Stein, S., Zhang, H., Perino, A., Lemos, V., Katsyuba, E., Jha, P., et al. (2017). Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J. Hepatol. 66, 132–141.

Altschul, R., Hoffer, A., and Stephen, J.D. (1955). Influence of nicotinic acid on serum cholesterol in man. Arch. Biochem. Biophys. 54, 558–559.

Garg, A., Sharma, A., Krishnamoorthy, P., Garg, J., Virmani, D., Sharma, T., Stefanini, G., Kostis, J.B., Mukherjee, D., and Sikorskaya, E. (2017). Role of Niacin in current clinical practice: a systematic review. Am. J. Med. 130, 173–187.

Rivin, A.U. (1962). Hypercholesterolemia. Use of niacin and niacin combinations in therapy. Calif. Med. 96, 267–269.

Gariani, K., Menzies, K.J., Ryu, D., Wegner, C.J., Wang, X., Ropelle, E.R., Moullan, N., Zhang, H., Perino, A., Lemos, V., et al. (2016). Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 63, 1190–1204.

NAD supplementation is a potential approach to increase mobility in the aged-population that suffer from slow wound healing and muscle pain as a result of decreased blood flow. Old mice treated with NMN improved blood flow and endurance.  See below for references:

de Picciotto, N.E., Gano, L.B., Johnson, L.C., Martens, C.R., Sindler, A.L., Mills, K.F., Imai, S., and Seals, D.R. (2016). Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15, 522–530.

Rajman et al., “Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence,” Cell Metabolism 27, March 6, 2018, pg.529 -547

Adequate NAD+ levels are essential for recovery of age-related heart diseases. See below for references:

Ryu, D., Zhang, H., Ropelle, E.R., Sorrentino, V., Ma´ zala, D.A., Mouchiroud, L., Marshall, P.L., Campbell, M.D., Ali, A.S., Knowels, G.M., et al. (2016). NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci. Transl. Med. 8, 361ra139.

Xu, W., Barrientos, T., Mao, L., Rockman, H.A., Sauve, A.A., and Andrews, N.C. (2015). Lethal cardiomyopathy in mice lacking transferrin receptor in the heart. Cell Rep. 13, 533–545.

Chan, P.K., Torres, R., Yandim, C., Law, P.P., Khadayate, S., Mauri, M., Grosan, C., Chapman-Rothe, N., Giunti, P., Pook, M., and Festenstein, R. (2013). Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich’s ataxia can be reduced upon HDAC inhibition by vitamin B3. Hum. Mol. Genet. 22, 2662–2675.

Martin, A.S., Abraham, D.M., Hershberger, K.A., Bhatt, D.P., Mao, L., Cui, H., Liu, J., Liu, X., Muehlbauer, M.J., Grimsrud, P.A., et al. (2017). Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI Insight 2.

NAD supplementation reduces inflammation markers including TNF-alpha and IL-6 in skeletal muscles and shows beneficial effects in autoimmune diseases. See below for references:

Gomes, A.P., Price, N.L., Ling, A.J., Moslehi, J.J., Montgomery, M.K., Rajman, L., White, J.P., Teodoro, J.S., Wrann, C.D., Hubbard, B.P., et al. (2013). Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638.

Kaneko, S., Wang, J., Kaneko, M., Yiu, G., Hurrell, J.M., Chitnis, T., Khoury, S.J., and He, Z. (2006). Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. J. Neurosci. 26, 9794–9804.

In vitro settings, it was shown that coronavirus infection “strikingly depletes cellular NAD+ levels, and boosting NAD+ pharmacologically or with NAD+ precursors increases the enzymatic activity of antiviral [agents] and inhibits coronavirus replication.”

Reference:

Charles Brenner, “Viral Infection as an NAD+ battlefield,” Nature Metabolism 4, 2-3 (2022). 

Decline in NAD+ is associated with loss of oocyte quality. NAD+ supplementation led to restoration of oocyte yield in 14-month-old female mice. 

Reference:

Bertoldo et al., “NAD+ Repletion Rescues Female Fertility during Reproductive Aging,” Cell Rep  2020 Feb 11;30(6):1670-1681.

NAD+ supplementation protects against high-glucose-induced kidney damages and against chemotherapy associated kidney injuries.

References:

Zhuo, L., Fu, B., Bai, X., Zhang, B., Wu, L., Cui, J., Cui, S., Wei, R., Chen, X., and Cai, G. (2011). NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway. Cell. Physiol. Biochem. 27, 681–690.

Guan, Y., Wang, S.R., Huang, X.Z., Xie, Q.H., Xu, Y.Y., Shang, D., and Hao, C.M. (2017). Nicotinamide mononucleotide, an NAD+Precursor, rescues age-associated susceptibility to AKI in a Sirtuin 1-dependent manner. J. Am. Soc. Nephrol. 28, 2337–2352.

NMN plays an important role in controlling pancreatic cells that are responsible for secreting insulin.

Reference:

Revollo et al., “Nampt/PBEF/Visfatin Regulates Insulin Secretion in β Cells as a Systemic NAD Biosynthetic Enzyme,” Cell Metabolism, Vol 6, Issue 5, 7 November 2007, pg. 363-375.

NAD+ supplements improve muscle function by improving mitochondrial function, muscle endurance, running capacity, and capabilities to recover from muscle injury. See below for references:

Gomes, A.P., Price, N.L., Ling, A.J., Moslehi, J.J., Montgomery, M.K., Rajman, L., White, J.P., Teodoro, J.S., Wrann, C.D., Hubbard, B.P., et al. (2013). Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638.

Canto´ , C., Houtkooper, R.H., Pirinen, E., Youn, D.Y., Oosterveer, M.H., Cen, Y., Fernandez-Marcos, P.J., Yamamoto, H., Andreux, P.A., Cettour-Rose, P., et al. (2012). The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847.

Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E.R., Lutolf, M.P., Aebersold, R., et al. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443.

Goody, M.F., Kelly, M.W., Reynolds, C.J., Khalil, A., Crawford, B.D., and Henry, C.A. (2012). NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy. PLoS Biol. 10, e1001409.

Ryu, D., Zhang, H., Ropelle, E.R., Sorrentino, V., Ma´ zala, D.A., Mouchiroud, L., Marshall, P.L., Campbell, M.D., Ali, A.S., Knowels, G.M., et al. (2016). NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci. Transl. Med. 8, 361ra139.   Improves mitochondrial function, recovery from muscle injury, and running capacity in mice (Ryu et al 2016).

NR and NMN can improve the lifespan of various species including yeasts, C. elegans, and mice. In the case of BubR1 mouse, median lifespan was extended by 58% and maximum by 21%.

References:

North, B.J., Rosenberg, M.A., Jeganathan, K.B., Hafner, A.V., Michan, S., Dai, J., Baker, D.J., Cen, Y., Wu, L.E., Sauve, A.A., et al. (2014). SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J. 33, 1438–1453.

Belenky, P., Racette, F.G., Bogan, K.L., McClure, J.M., Smith, J.S., and Brenner, C. (2007). Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell 129, 473–484.

Mouchiroud, L., Houtkooper, R.H., Moullan, N., Katsyuba, E., Ryu, D., Canto´ , C., Mottis, A., Jo, Y.S., Viswanathan, M., Schoonjans, K., et al. (2013). The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441.

Mills, K.F., Yoshida, S., Stein, L.R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Migaud, M.E., Apte, R.S., Uchida, K., et al. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806.