On Oxidative Stress and NAD+ Metabolism in Aging
NAD+ is featured in the energy generation cycle that takes place in mitochondria within cells, as well as many other roles. Its levels appear to influence and be influenced by all sorts of mechanisms related to longevity and aging. "Nicotinamide adenine dinucleotide (NAD+) is an essential electron transporter in mitochondrial respiration and oxidative phosphorylation. In genomic DNA, NAD+ also represents the sole substrate for the nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP) and the sirtuin family of NAD-dependent histone deacetylases. Age associated increases in oxidative nuclear damage have been associated with PARP-mediated NAD+ depletion and loss of SIRT1 activity in rodents. In this study, we further investigated whether these same associations were present in aging human tissue. Human pelvic skin samples were obtained from consenting patients aged between 15-77 and newborn babies (0-1 year old) ... DNA damage correlated strongly with age in both males and females whereas lipid oxidation (MDA) levels increased with age in males but not females. PARP activity significantly increased with age in males and inversely correlated with tissue NAD+ levels. These associations were less evident in females. A strong negative correlation was observed between NAD+ levels and age in both males and females. SIRT1 activity also negatively correlated with age in males but not in females. Strong positive correlations were also observed between lipid peroxidation and DNA damage, and PARP activity and NAD+ levels in post pubescent males. This study provides 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 signalling."