The decline of NAD+ levels with age

15 January 2025
Dr Fahd Al Qureshah
The decline of NAD+ levels with age

Introduction

The study investigates how age influences blood metabolite levels using nontargeted quantitative metabolomics with liquid chromatography-mass spectrometry (LC-MS). By analyzing 30 individuals divided into young (29 ± 4 years) and elderly (81 ± 7 years) groups, the research identifies metabolites that significantly differ with age, particularly emphasizing those involved in redox balance, including NAD and its phosphorylated form, NADP.


Key Findings

Age-Related Decline in NAD and NADP:

  • Both NAD+ and NADP+, critical redox cofactors, showed a significant decline in the elderly group:
  • NAD+: Lower in elderly individuals (P = 0.046).
  • NADP+: Also decreased significantly with age (P = 0.022).
  • These findings suggest diminished redox metabolism in aging RBCs, which may compromise their antioxidant defense and energy metabolism.
  • NAD+ plays a pivotal role in energy production (via glycolysis and oxidative phosphorylation) and repair processes such as DNA damage response. Its decline might indicate reduced metabolic efficiency and increased vulnerability to oxidative stress in the elderly.

Redox Imbalance and Antioxidant Decline:

  • Alongside NAD+, other antioxidants like carnosine (P = 0.0027) and ophthalmic acid (P = 0.0087) also showed reduced levels in elderly participants.
  • This collective decline in redox-active compounds highlights the increased oxidative stress and reduced repair capacity typically associated with aging.


NAD-Related Pathways and Correlations:

  • Age-related metabolites displayed strong interconnections:
  • NAD+ levels correlated with other RBC-enriched metabolites, such as acetyl-carnosine and carnosine, both involved in cellular maintenance and redox activity.
  • These correlations suggest that the reduction in NAD+ is part of a broader metabolic shift in aging, affecting multiple pathways reliant on efficient redox and energy metabolism.

Coefficients of Variation (CVs) Highlight Tight Regulation of NAD:

  • NAD+ exhibited a relatively low coefficient of variation (CV30 = 0.24), indicating that its levels are tightly regulated across individuals despite age-related differences.
  • This tight regulation underscores NAD+'s critical role in maintaining physiological homeostasis, making it a potential candidate for monitoring metabolic health and aging.

NAD as a Marker of Aging:

  • Given its central role in energy production, redox balance, and cellular repair, NAD+ is increasingly recognized as a biomarker of aging. Its significant decline in this study reinforces its potential use in assessing aging-related metabolic health and as a target for therapeutic interventions aimed at mitigating age-related decline.

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Broader Context of Aging Metabolism

Metabolites with Age-Specific Patterns:

  • The study identified 14 metabolites significantly associated with age:
  • Decreases with age: Leucine (P = 0.0017), isoleucine (P = 0.012), carnosine (P = 0.0027), and 1,5-anhydroglucitol (P = 0.00039).
  • Increases with age: Citrulline (P = 0.00089), N-acetyl-arginine (P = 0.0004), and dimethyl-guanosine (P = 0.0081).

RBC-Enriched Metabolites:

  • Six of the age-related metabolites, including NAD+, were enriched in RBCs, emphasizing the importance of RBC metabolomics in aging research.

Metabolite Variability:

  • The study reported novel CVs for 51 blood metabolites, highlighting the regulatory stability of essential compounds like NAD+ and ATP (CV30 = 0.17), contrasted with the high variability of lifestyle-influenced metabolites.


Implications

Therapeutic Targeting of NAD:

  • The decline in NAD+ with age suggests it could be a therapeutic target for interventions aimed at improving metabolic health and mitigating oxidative stress.
  • NAD+ boosters, such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), are potential strategies to restore redox balance and enhance mitochondrial function in the elderly.

Biomarker Potential:

  • NAD+ and other tightly regulated metabolites like ATP and glutathione could serve as robust biomarkers for aging and age-related diseases, aiding in early diagnosis and monitoring therapeutic outcomes.

RBC Metabolomics in Aging:

  • By focusing on RBC-enriched metabolites like NAD+, the study underscores the potential of RBC metabolomics to reveal subtle yet impactful physiological changes in aging.


Conclusion

This study highlights the critical role of NAD+ as a marker of aging-related metabolic decline, emphasizing its tight regulation and centrality in energy and redox metabolism. Alongside other age-related metabolites, NAD+ provides insights into the biochemical underpinnings of aging, offering avenues for future research and therapeutic interventions targeting metabolic health in older populations.


For full details, refer to the original article: https://pmc.ncbi.nlm.nih.gov/articles/PMC8404239/