Supporting Evidence for the Hypothesis that NAD+ Upregulation Increases Cancer Risk

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NAD+ levels in the mitochondria decline with age, and this is a proximate cause of reduced mitochondrial function. Approaches to increasing levels of NAD+ in aging cells have been shown to improve metabolism and mitochondrial function in mice, but the evidence is mixed in humans for there to be any meaningful effect on age-related conditions. The common approaches to NAD+ upregulation, meaning supplementation with derivatives of vitamin B3, such as nicotinamide riboside, are about as effective as structured exercise programs in increasing NAD+ levels.

There is the suspicion that taking this shortcut - without adding all of the other metabolic effects of exercise - could increase the harms done by problem cells in the aging body, such as senescent cells and cancerous cells, by allowing them greater activity. The evidence is sparse for this to be the case, but it is a concern amongst researchers. The research noted here adds a little more weight to the concern side of the scales.

In the 1920s, German chemist Otto Warburg discovered that cancer cells don't metabolize sugar the same way that healthy cells usually do. Since then, scientists have tried to figure out why cancer cells use this alternative pathway, which is much less efficient. Researchers have now found a possible answer to this longstanding question. They showed that this metabolic pathway, known as fermentation, helps cells to regenerate large quantities of a molecule called NAD+, which they need to synthesize DNA and other important molecules. Their findings also account for why other types of rapidly proliferating cells, such as immune cells, switch over to fermentation.

Fermentation is one way that cells can convert the energy found in sugar to ATP, a chemical that cells use to store energy for all of their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which yields much more ATP. Cells typically switch over to fermentation only when they don't have enough oxygen available to perform aerobic respiration. Warburg originally proposed that cancer cells' mitochondria, where aerobic respiration occurs, might be damaged, but this turned out not to be the case. Other explanations have focused on the possible benefits of producing ATP in a different way, but none of these theories have gained widespread support.

Researchers treated cancer cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway. They saw that blocking fermentation slows down cancer cells' growth. Then, they tried to figure out how to restore the cells' ability to proliferate, while still blocking fermentation. One approach was to stimulate the cells to produce NAD+, a molecule that helps cells to dispose of the extra electrons that are stripped out when cells make molecules such as DNA and proteins. When the researchers treated the cells with a drug that stimulates NAD+ production, they found that the cells started rapidly proliferating again, even though they still couldn't perform fermentation.

This led the researchers to theorize that when cells are growing rapidly, they need NAD+ more than they need ATP. During aerobic respiration, cells produce a great deal of ATP and some NAD+. If cells accumulate more ATP than they can use, respiration slows and production of NAD+ also slows. Therefore, switching to a less efficient method of producing ATP, which allows the cells to generate more NAD+, actually helps them to grow faster. "Not all proliferating cells have to do this. It's really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they're burning, that's when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed."

Link: https://news.mit.edu/2021/cancer-cells-waste-energy-0115

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source https://www.fightaging.org/archives/2021/01/supporting-evidence-for-the-hypothesis-that-nad-upregulation-increases-cancer-risk/