Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence

Nady Braidy, Anne Poljak, Ross Grant, Tharusha Jayasena, Hussein Mansour, Tailoi Chan-Ling, Gilles J. Guillemin, George Smythe, Perminder Sachdev*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Over the last decade, the importance of NAD+ has expanded beyond its role as an essential cofactor for energy metabolism. NAD+ has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or CD38, and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD+ levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD+ metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD+ metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of H2AX levels was also observed together with increased PARP-1 and PARP-2 expression, and CD38 activity, concomitantly with reduced NAD+ and ATP levels and SIRT1 function in the cortex, brainstem, hippocampus and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD+ catabolism, our discovery of CD38 as the major regulator of cellular NAD+ levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases.

Original languageEnglish
Pages (from-to)177-198
Number of pages22
JournalBiogerontology
Volume15
Issue number2
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

Keywords

  • Ageing
  • DNA damage
  • Oxidative stress
  • PARP

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