Extracellular NAD+ Declines with Age

Current enthusiasm for the development of means to boost levels of NAD+ in older people is driven in part by research such as the open access paper noted here, in which the authors show a clear decline with age in NAD+ outside cells. Inside cells, NAD+ is an important component in the machinery that allows mitochondria to generate chemical energy store molecules to power all cellular functions. Importantly, there is evidence that comparatively straightforward approaches to increase NAD+ levels can produce beneficial effects, such as improved mitochondrial function leading to lowered blood pressure via reduced dysfunction of smooth muscle cells in blood vessels, reducing blood vessel stiffness.

None of this is damage repair, rather a matter of putting damaged cells back to work, overriding one of the less helpful evolved responses to rising levels of molecular damage present in old tissues. The size of benefits is thus necessarily limited in comparison to approaches that can successfully repair the underlying damage that leads to reduced NAD+ levels and many other consequences. If the costs are low enough, then even limited benefits are worth chasing, however. It remains to be seen whether the cost-benefit considerations work out favorably in this case.

In the last decade, there has been growing interest in the role of redox active nucleotides in the metabolism. Nicotinamide adenine dinucleotide (NAD+) represents one of the most important coenzymes in the hydride transfer reactions. NAD+ is the precursor of the pyridine nucleotide family, including NADH, NADP+, and NADPH, and is the end product of tryptophan metabolism via the kynurenine pathway. It has been well established that NAD+ is a substrate for major dehydrogenase enzymes involved in nutrient catabolism. As well, NADH, which is the reduced form of NAD+, preferentially provides electrons to power mitochondrial oxidative phosphorylation. Apart from its roles in fuel utilization, NAD+ also serves as an exclusive substrate for nuclear repair enzymes.

NAD+ has also been shown to be the sole substrate for a new class of NAD-dependent histone deacetylase (HDAC) enzymes known as sirtuins. Increasing histone acetylation is associated with age-related pathologies, whereas gene silencing by upregulation of sirtuins has been shown to extend lifespan in yeast and small organisms. HDACs are also being found to interact with a variety of nonhistone proteins and to thereby change their function, activity, and stability by post-translational modifications. Accurate determination of the NAD+ metabolome is of major interest due to its potential association with cognitive decline, including AIDS dementia complex, cancer, aging, and a plethora of age-related disorders.

While it is thought that NAD+ is predominantly an intracellular nucleotide, emerging evidence suggests that extracellular NAD+ crosses the plasma membrane and replenishes intracellular NAD+. Accurate monitoring of the plasma NAD+ metabolome is necessary and may provide valuable information regarding the effect of various lifestyle and dietary factors, pharmacological and nutraceutical supplementation of NAD+ and/or its metabolites. We quantified changes in the NAD+ metabolome in plasma samples collected from healthy human subjects across a wide age range (20-87 years) using liquid chromatography coupled to tandem mass spectrometry. Our data show a significant decline in the plasma levels of NAD+, NADP+, and other important metabolites such as nicotinic acid adenine dinucleotide (NAAD) with age. Our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD+ metabolome.

Link: https://doi.org/10.1089/rej.2018.2077


Metabolism in the broad and basic sense is obviously and necessarily that which underlies any and all of the 'damage' associated with aging...

It is unfortunate that such a sales job for the phony concept of 'damage repair' as an allegedly superior and more basice approach, and its proposed industry of specialized repair of a style similar to dependently overhauling automobiles periodically in the garage, is pushed with mindless sophistry in these pages...

The baseless bias is far too obvious, and merely defeats what would be the value of a more reasonable and well-balanced appraisal of the situation...

Posted by: Vladimir at November 12th, 2018 9:42 AM

Hello everyone. I read the original article. But I'm struggling to find on which graph exactly the decline of NAD with age is represented. There are so many graphs that makes it little bit confusing and messy. Can anyone help ?


Posted by: Alek Ales at November 12th, 2018 11:14 AM

@alex you can clearly see that at the first graph in the results section

Posted by: Moses at November 12th, 2018 12:58 PM


You could have conveyed the same information in 6 words.

Posted by: Christopher Carr at November 13th, 2018 7:44 AM

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