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Shelly Albaum

Editor, Science of NAD

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  • Shelly Albaum

Do NAD Levels Decline as You Age?

Updated: Dec 6, 2022

And if so, by how much?


NAD levels decline with age in all organisms, for reasons that are not entirely understood. However, it seems to be a combination of decreased production from metabolic pathways plus increased consumption of NAD by other processes, such as inflammation and cellular repair. In other words, as you get older you need more AND you produce less. That growing gap is what inspires many to replenish NAD using NAD precursors like nicotinamide riboside.



NAD Levels Decline with Age


Scientists are clear that NAD levels decline over time:


It has been well established that NAD+ level decline with age...

-- Aging Cell, March 18, 2021


By middle age, our NAD+ levels have plummeted to half that of our youth.

-- Integrative Medicine, February 1, 2020


Aging is also known to be linked to a decline in NAD+ levels in muscle tissue in lower organisms and mammals...

-- Cell Reports, January 19, 2021


There is also evidence of decreased NAD+ in aged human tissues. Specifically, in vivo NAD+ assays have been used to demonstrate that intracellular NAD+ declines with age in the human brain. Also, NAD+ in post-pubescent males and females negatively correlates with age. Together, these data suggest that there may be a universal age-dependent decrease of cellular NAD+ across species... [emphasis added]

-- Trends in Molecular Medicine, September 9, 2017


...Total NAD+ levels were once considered extremely stable. Recently, however, it has become clear that a steady decline in total NAD+ levels over time is a natural part of life for all species, from yeast to humans. This decline, along with the decreased activity of NAD+ signaling proteins, is believed to be one of the major reasons organisms, including humans, age.

-- Cell Metabolism, March 6, 2018


Some studies suggest that the problem of declining NAD is caused by an enzyme called CD38:


Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction

-- Cell Metabolism, June 14, 2016


By 32 months of age, wild-type mice have about half the NAD+ levels of young mice, whereas CD38 knockout mice maintain their NAD+ levels and are resistant to the negative effects of a high-fat diet (HFD), including liver steatosis and glucose intolerance [emphasis added]

-- Cell Metabolism, March 6, 2018


But other studies note that reduced production also contributes:


Age-related NAD+ decline has partially been attributed to a lower rate of NAD+ biosynthesis. The majority of NAD+ is generated in the salvage pathway and lowered expression levels of NAMPT during aging have been identified as a major factor. The expression of NAMPT at both mRNA and protein levels is reduced in multiple tissues in aged mice. This age-related decline in NAMPT expression leads to a reduction of NAD+ levels in the affected tissues...Another possible mechanism of age-related NAMPT decline is chronic inflammation.

-- Mechanisms of Ageing and Development, October 2, 2021


In humans, NAD decrease varies by tissue, perhaps by 50% in skin, 14% in spinal fluid, 10%-25% in the brain, 30% in the liver,


In humans, NAD+ concentration has been reported to decrease with age in skin samples. Although the precise degree of decline was not calculated, average concentration appeared to decrease at least 50% over the course of adult aging, and to be several fold-lower in adults as compared to newborns. NAD(H) was also reported to decline by approximately 14% in the cerebrospinal fluid of subjects > 45 years of age as compared to those ≤ 45 years. Two MRI-based studies have also provided evidence for NAD+ decline in human brains with age, ranging from ~10% to ~25% between young adulthood and old age...Human liver samples from patients > 60 years of age were found to exhibit an approximately 30% decline in NAD+ concentration compared to samples from patients < 45 years of age...

-- Experimental Gerontology, February 22, 2020


Conclusion


NAD levels drop with age in all organisms tested, including humans. The NAD reductions vary by tissue. The cause seems to be both decreased production through the NAD metabolic pathways, as well as increased consumption of NAD by age-related conditions, most notably an increase in CD38, probably caused by chronic inflammation.

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