Age-Related NAD+ Decline

Research provides evidence of an age-related decline in NAD+ levels, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD+ and changes in the composition of cells or tissues with aging. Research Authors: Melanie R. McReynolds, Karthikeyani Chellappa, Joseph Source: ScienceDirect

Research Highlights:

• NAD+ is an essential metabolite that decreases with age.
• Changes in metabolism and tissue composition may contribute to NAD+ decline.
• Lack of cellular/subcellular resolution is a limitation in most NAD+ studies.
• NAD+ supplementation has proven beneficial in aging rodents.

NAD+ is an Essential Metabolite in the Body

Study Summary
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite reported to decrease in concentration in aged animal tissues. Strategies aimed at increasing NAD+ availability have shown potential in treating various conditions in rodents, including age-related degeneration, spurring interest in the effects of supplements on human health. However, many aspects of NAD+ metabolism remain poorly understood, and human data are limited.

Here, we discuss evidence of age-related NAD+ decline, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD+ and changes in cell or tissue composition with age.
A major challenge in this field is developing better tools to resolve the NAD+ content of specific cells and subcellular compartments, as well as defining threshold levels at which NAD+ depletion causes physiological consequences in different tissues. Understanding how NAD+ metabolism changes with age in humans could eventually enable more targeted strategies for maintaining its availability, such as inhibiting major consumption factors in specific tissues or delivering precursors directly to depleted sites. In the meantime, clinical trials with oral supplements are expected to provide some of the first direct evidence of whether boosting NAD+ can impact human physiology.

Therefore, this is an exciting time for NAD+ research, with much to learn about both its basic biology and its potential therapeutic applications.

Key Points of the Study

NAD+ is Critical for Life
Nicotinamide adenine dinucleotide (NAD+) is an electron (hydride) acceptor critical for life. It is a product of vitamin B3 metabolism, and severe deficiency leads to a condition known as pellagra, characterized by the 4 Ds: dermatitis, dementia, diarrhea, and death. The electron exchange process converts NAD+ to its reduced form, NADH, in a process essential for central carbon metabolism, including glycolysis, the Krebs cycle, and oxidative phosphorylation.

Evidence of Age-Related NAD+ Decline
There is substantial evidence that NAD+ levels decline with age in rodent tissues (Braidy et al., 2011; Camacho-Pereira et al., 2016; Guest et al., 2014; Dall et al., 2019; Mouchiroud et al., 2013; Frederick et al., 2016; Gomes et al., 2013; Zhu et al., 2015; Zhou et al., 2016; Yoshino et al., 2011; Stein and Imai, 2014). (Reviewed in Yoshino et al., 2018). NAD+ decline has been observed during aging in worms (Mouchiroud et al., 2013), rodent tissues, and human samples.

Why Does NAD+ Decline with Age?

Multiple mechanisms may contribute to age-related NAD+ decline. The simplest explanation is increased activity of NAD+-consuming enzymes, which may be linked to inflammation (CD38) or DNA damage (PARPs). However, it remains unclear whether NAD+ synthesis is fully maintained with aging, and more complex changes, such as shifts in cellular composition or the redox state of aged tissues, may also play a role.

How Much NAD+ is Enough for the Body?

Knowing that measured NAD+ levels decrease with age or disease, it is important to understand how much NAD+ is actually required for normal tissue function. Since NAD+ is essential for hundreds of biochemical reactions, including energy production via glycolysis and mitochondria, any changes in its levels could have serious consequences. However, mice with a dramatic (~85%) reduction in skeletal muscle NAD+ surprisingly exhibit only mild effects.

Can NAD+ Supplementation Slow Aging?

There is a wealth of literature demonstrating the health benefits of NAD+ supplementation in rodents, although studies specifically addressing aging are still relatively limited, and human data are often lacking or unremarkable across most metrics. Nicotinamide riboside supplementation from two years of age improved stem cell function in C57BL/6 mice and modestly extended their remaining lifespan (Zhang et al., 2016). Nicotinamide mononucleotide injections, administered between the ages of 5 and 17 months…

Study Conclusion

NAD+ plays a fundamental role in metabolic reactions that are essential for life. Observations that (1) NAD+ levels decrease with age in many tissues, and (2) supplementation with NAD+ precursors benefits aging rodents, have created a compelling narrative that restoring NAD+ levels to youthful concentrations might prevent some of the harmful effects of aging. As such, NAD+ research is garnering interest for developing therapies and/or nutrients aimed at promoting healthier aging. However, much remains to be further researched.

This study was supported by a grant from the National Institutes of Health (DK098656 to J.A.B.). K.C. was supported by a fellowship from the Crohn’s and Colitis Foundation. M.R.M. was supported by the Burroughs Wellcome Fund and Howard Hughes Medical Institute through the PDEP and Hanna H. Gray Fellows Program.

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