Age Related Changes in NAD+ Metabolism Oxidative Stress and Sirt1 Activity in Wistar Rats

By N. Braidy, G. Guillemin, Hussein Mansour, T. Chan-Ling, A. Poljak, R. Grant. PLoS ONE, 2011

606 citations recorded by the source corpus.

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.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/b279756c16e3dd89f3791eb0d2d4eee8bfab5911

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Geriatrics and Gerontology

1. Johan Auwerx
2. D. Sinclair
3. E. Verdin
4. C. Cantó
5. L. Guarente
6. Joseph A. Baur
7. S. Imai
8. R. Houtkooper

In Physiology

1. E. Verdin
2. D. Sinclair
3. Johan Auwerx
4. Joseph A. Baur
5. S. Imai
6. C. Cantó
7. R. Houtkooper
8. Jun Yoshino

Citations in the corpus

• Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2015, background): “Notably, NAD+ declines with age in several tissues (Braidy et al., 2011; Gomes et al., 2013; Stein and Imai, 2014; Yoshino et al., 2011), linking NAD to both senescence and aging.”
• NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “The remarkable reduction of NAD concentration and NAD/NADH ratio in aged rats occurs in parallel with enhanced oxidative stress and diminished antioxidant capacity.(334) NMN addition in isolated aortas elevates the NAD and MnSOD levels, thus enhancing the antioxidant capacity.”
• The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling (2013, positive): “Conversely, reduced levels of NAD+ metabolism were observed in aged rats and mice (Braidy et al., 2011; Yosh- ino et al., 2011), although no mechanistic explanation of this observation was presented.”
• The Role of Sirtuins in Antioxidant and Redox Signaling (2017, background): “GLP-1-(7-34)-amide Inhibits SIRT1 to stimulate pancreatic b-cell mass expansion.”
• Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (2013, background): “Recent studies show that NAD levels are regulated independently in different cell compartments and that overall NAD levels decline during aging (Braidy et al., 2011; Massudi et al., 2012; Yang et al., 2007).”
• NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “Diverse lines of research on worms, rodents, and human cellular models indicate that declining NAD+ levels are a hallmark for senescence (Braidy et al., 2011; Gomes et al., 2013; Khan et al., 2014; Massudi et al., 2012; Mouchiroud et al., 2013; Ramsey et al., 2008; Yoshino et al., 2011).”
• Regulation of SIRT1 and Its Roles in Inflammation (2022, background): “Finally, oxidative stress can be accompanied by a decrease in the NAD level and SIRT1 activity (122).”
• CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism (2016, positive): “Recently, a growing body of evidence indicates that cellular NAD+ levels decrease during the aging process in both rodents and humans (Zhu et al., 2015; Gomes et al., 2013; Braidy et al., 2011; Scheibye-Knudsen et al., 2014, Massudi et al., 2012).”
• NAD+ intermediates: The biology and therapeutic potential of NMN and NR (2017, positive): “It is conceivable that age-associated decline in NAD+ availability (Braidy et al., 2011; Camacho-Pereira et al., 2016; Frederick et al., 2016; Gomes et al., 2013; Massudi et al., 2012; Stein and Imai, 2014; Yoshino et al., 2011) could sensitize aged mice to NAD+ replenishment by NMN administration.”