Key Points:
- In response to low NAD+ levels, the liver produces an NAD+ precursor called nicotinic acid riboside (NaR).
- The kidney uses NaR to increase body-wide NAD+ levels, a task normally reserved for the liver.
- NaR declines with age, and restoring it through supplementation mitigates age-related kidney decline.
NAD+ is under intense investigation for its potential longevity effects, as its age-dependent decline is associated with exacerbating conditions like heart disease and neurodegenerative disorders. Ever more studies are showing that restoring NAD+ with its precursors leads to the mitigation of these diseases. Now, researchers from UCI have found that our body has a way of maintaining body-wide NAD+ levels despite its depletion in specific organs.
Kidney NAD+ Compensates for Its Low Levels in the Liver
A recent advance showed that the popular NAD+ precursors NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) are metabolized in the liver before elevating NAD+ throughout the body, supporting the pivotal role of the liver in maintaining body-wide NAD+ levels. Surprisingly, UCI researchers found that, despite reducing liver NAD+ levels by 60% in mice, NAD+ levels in the blood and other tissues and organs remained the same.
The researchers reduced liver NAD+ levels by genetically deleting an important enzyme that synthesizes NAD+, called NMNAT, which was specifically deleted from the liver. Even more surprisingly, the mice lacking NMNAT exhibited no obvious metabolic defects and maintained normal weight, body composition, and glucose levels. These findings are unexpected because NAD+ plays an essential role in metabolic health, and its decline has been shown to accelerate metabolic aging.
To determine how such a dramatic reduction in liver NAD+ levels can sustain metabolic health, the UCI researchers looked for elevations in metabolites from the mice lacking NMNAT. They found an unknown molecule that increased a remarkable 30-fold in the liver and was also elevated in the bloodstream. Further testing of this mysterious molecule confirmed that it was NaR (nicotinic acid riboside), which had previously only been detected in single cells and plants.
Additional experiments revealed that, when low on NAD+, the liver produces NaR, which is then utilized by the kidney to produce NAD+. The kidney also utilizes NaR to secrete the NAD+ precursor nicotinamide into circulation. Once nicotinamide is released into the bloodstream, it can be distributed to other organs and tissues to make NAD+. The findings suggest that the kidney generates NAD+ to compensate for a lack of liver NAD+ production.
Restoring NaR Levels Mitigates Age-Related Kidney Decline
Since NAD+ levels decline with age, the UCI researchers checked whether NaR also declines with age. They found that 25-month-old mice, roughly equivalent to 71-year-old humans, had lower circulating NaR levels than 3-month-old mice, roughly equivalent to 22-year-old humans. Moreover, they showed that NaR levels decline with age due to a disruption in NaR synthesis, which is made from the amino acid tryptophan. The authors state that,
“Reduced [liver] NaR production likely contributes to the decreased kidney NAD+ and nicotinamide production in aging.”
Upon finding that NaR declines with age, the researchers sought to determine if supplementing aged mice with NaR can reverse kidney aging. To do so, they placed NaR into the drinking water of 25-month-old mice for two weeks. This restored NAD+ levels in the kidney, liver, heart, and pancreas. Furthermore, NaR supplementation reduced markers of kidney damage, suggesting that NaR can mitigate kidney aging.
Is Nicotinamide the Best NAD+ Precursor?
Niacin, also known as nicotinic acid, is an NAD+ precursor used to raise “good” HDL cholesterol and lower triglyceride levels, according to the Mayo Clinic. The UCI researchers found that oral intake of niacin increased NaR liver production and kidney NAD+ levels in normal mice. Moreover, a recent study showed that NMN and NR also increase liver NaR levels in mice. Importantly, this study additionally demonstrated that NMN, NR, and nicotinamide are converted to niacin in the gut before entering the bloodstream.
To date, there are no studies systematically comparing the effects of NMN, NR, nicotinamide, and niacin on NAD+ levels in live animals. While influencer David Sinclair has stated that niacin won’t raise NAD+ levels as much as NMN, this is not supported by scientific evidence. In contrast, the recent findings that NMN, NR, and nicotinamide are converted to niacin before entering the bloodstream support the idea that all four precursors raise NAD+ levels similarly.
However, when taking into account the costs of NAD+ precursor supplements, NR and NMN tend to be more expensive than niacin and nicotinamide. Moreover, niacin tends to cause flushing, an unwanted side effect for most individuals. Thus, nicotinamide, which probably increases NaR levels, may be the best option when it comes to supplementing with NAD+ precursors. No-flush niacin is also an option, but there is less research on this form of niacin.
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