title: Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats.
abstract: The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our 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. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. 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.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Nady
authors.initials: N
authors.lastname: Braidy
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.forename: Hussein
authors.initials: H
authors.lastname: Mansour
authors.forename: Tailoi
authors.initials: T
authors.lastname: Chan-Ling
authors.forename: Anne
authors.initials: A
authors.lastname: Poljak
authors.forename: Ross
authors.initials: R
authors.lastname: Grant
mesh_terms: D000107:Acetylation; D000375:Aging / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004249:DNA Damage; D004579:Electron Transport; D004789:Enzyme Activation; D005260:Female; D042541:Intracellular Space / Q000378:metabolism; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009928:Organ Specificity; D018384:Oxidative Stress; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D050050:Protein Carbonylation; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D015415:Biomarkers; D016159:Tumor Suppressor Protein p53; D009243:NAD; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C027576:4-hydroxy-2-nonenal