#writing 3 10 page papers in the span of 5 days... brain damage.

[didanawisgi]

[CAUTION: This article is unusually complex. Life can be like that.]

There is growing interest in the nucleotide NAD+ (nicotinamide adenine dinucleotide) because of recent research revealing it’s regulation of diverse pathways controlling lifespan.1 A paper by Belensky et al2 in the same issue of Cell as a commentary on it1found that a precursor of NAD+ (nicotinamide riboside) extended yeast life span via activation of pathways that respond to increased NAD+, such as those that depend upon the SIR2 gene. Moreover, the beneficial effects of caloric restriction appear to be NAD+ dependent, as well as mediated by the NAD+-dependent SIRT1/Sir2 activity.3,4

The ratio of NAD+/NADH regulate many aspects of metabolism, including DNA repair, stress resistance, and cell death.4

“Changes in NAD+ metabolism have been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disease, and normal ageing.”4 In fact, the authors of paper #4 suggest that, “NAD+ synthesis through the kynurenine pathway [de novo synthesis of NAD+ from tryptophan] and/or salvage pathway [from nicotinamide] is an attractive target for therapeutic intervention in age-associated degenerative disorders.”

NAD+ is also reported to play a critical role as part of cellular respiration during the process of oxidative phosphorylation and ATP production.4 “Therefore, ATP synthesis and redox potential is directly proportional to intracellular NAD+ concentration.”4 The NAD+/NADH ratio is a measure of the metabolic state because of its importance in regulating intracellular redox state.4

Sirtuins are deacetylases that regulate large numbers of genes by removing acetyl groups from DNA. The function of the longevity gene SIRT1 has been shown to depend on the availability of NAD+. “Not surprisingly, the life-enhancing properties of sirtuins go hand in hand with those of NAD+ metabolism, suggesting a causal relationship where SIRT1 translates alterations of NAD+ levels into transcriptional events.”4 Interestingly, the DNA repair enzyme PARP (poly(ADP-ribose) polymerase) uses large amounts of intracellular NAD+ and is thereby in competition with sirtuins for the limited supply of NAD+. Under conditions of excessive expression of PARP, cellular NAD+ can be depleted, killing the cell. “Hyperactivation of PARP1 following DNA strand breaks can rapidly consume intracellular NAD+ pools, resulting in a loss of ability to synthesize ATP, and the cessation of all energy-dependent functions and consequent cell death.”4

The authors of paper #4 note that over-activation of PARP1 has been reported in the brains of Alzheimer’s disease patients, as well as in those with diabetes, MTPT-caused Parkinson’s disease, shock, and other conditions. It has been suggested that PARPs may play a role in aging by promoting NAD+ depletion. One study5 reported that PARP-1 activity in mononuclear blood cells increases with aging in at least thirteen mammalian species. In another study,5A researchers reported that “[o]ur results suggest that oxidative stress induced NAD+ depletion could play a significant role in the aging process, by compromising energy production, DNA repair and genomic surveillance.” The latter study5A examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female Wistar rats, reporting that “[o]ur results are the first to show a significant decline in intracellular NAD+ levels and NAD/NADH ratio in all organs by middle age (i.e., 12 months) compared to young (i.e., 3 month old) rats … The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.”

The authors of one paper5B write that “… when cells are subjected to oxidative stress by exposure to H2O2 [hydrogen peroxide], PARP-1 is activated and SIRT1 activity is robustly reduced, as PARP-1 activation limits NAD+ bioavailability. Treatment with PARP inhibitors in these circumstances allows the cell to maintain NAD+ levels and SIRT1 activity. … these observations indication that PARP-1 is a gatekeeper for SIRT1 activity by limiting NAD+ availability.”

The authors of paper #4 report that “[p]revious work from our group has shown for the first time that resveratrol induces a dose-dependent increase in activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT1)” but that this is unpublished data.

Interestingly, a very recent paper found that “enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models [of breast cancer], increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model.”6

Mitochondrial Biogenesis Induced by SirT1 Depends on Availability of NAD+

A very recent paper,6A in explaining how exercise or SirT1 activates PGC-1alpha, a master regulator of mitochondrial biogenesis, points out that the activity of SirT1 relies on NAD+ as a necessary coenzyme. The paper6A goes on to describe how, in its study of exercise in mice, chronic contractile activity (exercise) has a robust effect on mitochondrial biogenesis and that resveratrol acted synergistically with exercise to increase mitochondrial content when SirT1 was activated. “[T]he maximal effect of RSV [resveratrol] requires both SirT1 and a condition of energy demand in muscle that would be high in NAD+ and AMP, cofactors which activate SirT1 and AMPK, respectively.” 6A

Precursors That Can Be Taken As Supplements to Increase NAD+

There is (so far) remarkably little information on ways to increase NAD+ with natural products that are commercially available. There are three main physiological precursors: tryptophan, niacin, and niacinamide. It is reported that, “the administration of radiolabeled nicotinamide and nicotinic acid [niacin] has clearly shown that nicotinamide is a better precursor of NAD+ and that nicotinic acid is rapidly cleared by being converted to nicotinamide and excreted as nicotinuric acid.”6B Resveratrol was reported in paper #4 (but only as unpublished data) to dose-dependently increase the activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase. In another paper,7 quercetin was reported to oxidize NADH to NAD+ in rat liver, thus increasing the availability of NAD+. However, as the researchers also explain, “direct measurements of NADH/NAD+ are very difficult to perform.”7 This was as of the paper’s publication in 2005. The researchers inferred the NADH/NAD+ ratio from the ratio of beta-hydroxybutyrate to acetoacetate. Quercetin has also been reported to be a PARP-1 inhibitor.7B Niacinamide is known to be an inhibitor of PARP, thus may prevent the decrease in NAD+ that results from PARP activity. There is a salvage pathway of specific enzymes that converts niacinamide to NAD+.

Niacinamide (NAM) As a PARP Inhibitor May Explain NAM’s Antiviral Effects

Interestingly, PARP is reported to be critical for the integration of foreign DNA, as absence of the PARP enzyme interrupts the HIV life cycle.7C An early study published in 1996 on the effects of niacin reported that a daily niacin (combining niacin and niacinamide) intake in AIDS patients that equaled only 3–4 times the U.S. recommended daily allowance (at that time) of 20 mg/day experienced slower progression and improved survival.7D That was, of course, well before the current multidrug cocktails were developed that enable HIV infected individuals to survive 20 years or more, but still demonstrates the anti-viral effects of the vitamin.

Other natural PARP inhibitors include the flavonoids fisetin and tricetin8 and flavone.9

More About PARP Inhibitors

Keep in mind that PARP is an important enzyme for DNA repair and transcription. Hence, PARP inhibition has to be limited so as to avoid excessive impairment of DNA repair. “Impaired SIRT1 activity due to PARP mediated NAD+ depletion allows increased activity of several apoptotic effectors such as p53, therefore sensitizing cells to apoptosis. Adequate NAD+ levels are therefore critical to maintaining Sirt1 activity which can delay apoptosis and provide vulnerable cells with additional time to repair even after repeated exposure to oxidative stress.”5A

PARP inhibitors are now being incorporated into therapy for diseases such as cancer and diabetes.10–12 This cripples the DNA repair ability of cancer cells, which generally have deficient DNA repair to start with, further limiting their ability to repair DNA and making the cancer cells more vulnerable to apoptosis. In diabetes, moderate PARP inhibition can help maintain cellular NAD+ availability for ATP synthesis. In fact, as mentioned above, overactivation of PARP1 has been reported in diabetes, Alzheimer’s disease, traumatic brain injury, shock, and other conditions.4 A recent paper5C reported that PARP is hyperactivated by oxidative stress induced by beta amyloid; this PARP overactivation (and depletion of NAD+) could be an important source of cell death in Alzheimer’s disease.

Another recent paper “provided quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD+ catabolism in human tissue. The resulting NAD+ depletion may play a major role in the aging process by limiting energy production, DNA repair and genomic signaling.”13 In this paper, the authors note that other investigators have linked PARP1 hyperactivity to diseases such as diabetes, MPTP-induced Parkinson’s disease and injury induced brain disorders. They further reported for the first time, in this study,13 that PARP activity increases with age in human skin, correlating with both age and NAD+ depletion (in males, but not in females). Consistent with the regulation of SIRT1 activity by NAD+ availability, they found a significant decline in SIRT1 activity with age in post-pubescent males but, again, not in females. The authors suggest that one possibility is that females have a greater capacity to recycle NAD+ from the PARP metabolite nicotinamide; however this remains to be determined.

References

1. Denu. Vitamins and aging: pathways to NAD+ synthesis. Cell. 1293):453-4 (May 4, 2007). 2. Belenky et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 129:473-84 (2007). 3. Wolf. Calorie restriction increases life span: a molecular mechanism. Nutr Rev. 64(2):89-92 (2006). 4. Massudi et al. NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns. Redox Rep. 17(1):28-47 (2012). 5. Grube and Burkle. Poly(ADP-ribose) polynerase activity in mononuclear cell lines of 13 mammalian species correlates with species specific lifespan. Proc Natl Acad Sci USA. 89:11759-63 (1992). 5A. Braidy et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in Wistar rats. PLoS One. 6(4):e19194 (Apr. 2011). 5B. Canto and Auwerx. Interference between PARPs and SIRT1: a novel approach to healthy ageing? Aging. 3(5):543-7 (2011). 5C. Abeti and Duchen. Activation of PARP by oxidative stress induced by beta amyloid: implications for Alzheimer’s disease. Neurochem Res. 37:2589-96 (2012). 6. Santidrian et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 123(3):1068-81 (2013). 6A. Menzies et al. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J Biol Chem. 288(10):6968-79 (2013). 6B. Imai. The NAD world: a new systemic regulatory network for metabolism and aging — Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem Biophys. 53:65-74 (2009). 7. Buss et al. The action of quercetin on the mitochondrial NADH to NAD+ ratio in the isolated perfused rat liver. Planta Med. 71:1118-22 (2005). 7B. Milo et al. Inhibition of carcinogen-induced cellular transformation of human fibroblasts by drugs that interact with the poly(ADP-ribose) polymerase system. FEBS J. 179(2):332-6 (1985). 7C. Murray. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis. 36:453-60 (2003) 7D. Tang et al. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. [a study of the Multicenter AIDS Cohort Study] Am J Epidemiol.143:1244-56 (1996) 8. Weseler et al. Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive disease or type 2 diabetes. J Nutr. 139:952-7 (2009). 9. Geraets et al. Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression. Eur J Pharmacol. 573:241-8 (2007). 10. Peralta-Leal et al. PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radic Biol Med. 47:13-26 (2009). 11. Soriano et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res. 89:684-91 (2001). 12. Du et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 112(7):1049-57 (2003). 13. Massudi et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 7(7):e42357 (July 2012).

#NAD+ #nicotinamide adenine dinucleotide #anti-aging #aging #family medicine #regenerative medicine #integrative medicine