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The health promises of boosting an important metabolic molecule may be clouded by its possible role in promoting cancer-cell growth
As the world’s aging population grows rapidly, so has its appetite for health tips, tricks and products that could help guard against the ravages of time. Among countless dietary supplements—vitamins, minerals and other products—some people have pinned their hopes on a molecule called nicotinamide adenine dinucleotide (NAD), a key player in the cellular production of energy. Often written as NAD+, the name of its oxidized form, the molecule participates in a host of metabolic pathways and is involved in other important processes, such as DNA repair. NAD+ levels naturally decline as people and animals age, and this loss has been proposed as contributing to the underlying physiology of aging.
Studies show that boosting NAD+ levels can extend life span in yeast, worms and mice. Animal research also indicates NAD+’s promise for improving several aspects of health. Raising levels of the molecule in old mice appears to rejuvenate mitochondria—the cell’s energy factories, which falter over time. Other mouse studies have demonstrated benefits such as improved cardiovascular function, enhanced muscle regeneration and better glucose metabolism with NAD+ supplementation.
Banking on such results, multiple companies currently sell dietary supplements containing NAD+ precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). NR supplements, in particular, have attracted buzz for the scientific star power associated with two major suppliers, ChromaDex and Elysium Health. The companies’ research advisers hail from institutions such as Stanford, Harvard and Columbia University. Elysium’s scientific advisory board currently boasts eight Nobel laureates.
But the NR business and some scientists involved have attracted their share of criticism as well. Unlike drugs, dietary supplements are lightly regulated by U.S. authorities, allowing them to be sold before research confirms their safety and effectiveness in humans. Recent clinical trials funded by ChromaDex and Elysium show that adults taking NR-containing supplements for six to eight weeks experience increased levels of NAD+ in their blood without serious side effects. But researchers are still working to prove that NR can actually improve human health—a sticking point for critics and an issue acknowledged by the companies themselves.
“Not everything that works in mice works in humans, which is why it’s critical to do the rigorous human trials,” says Leonard Guarente, a co-founder of Elysium and its chief scientist. The company is studying the effectiveness of its NR-containing supplement for a number of conditions in people, including kidney injury and fatty liver. Early this year, Elysium published a small trial showing that its product could potentially slow the neurodegenerative disease amyotrophic lateral sclerosis. ChromaDex’s NR supplement is also the subject of many clinical trials, with the company recently sponsoring a study of its effects on cognitive function, mood and sleep in people older than 55.
For very different reasons, NAD+ has also attracted a wave of attention from cancer researchers. Recent studies suggest that cancer cells of many types depend on NAD+ to sustain their rapid growth and that cutting off the NAD+ supply could be an effective strategy for killing certain cancers. The data from these studies paint a more complicated picture of NAD+ and raise new questions about the diverse ways taking an NAD+-boosting supplement might influence health. “It might still slow down the aging part, but it might fuel the cancer part,” says Versha Banerji, a clinician-scientist at the University of Manitoba. “We just need to figure out more about the biology of both of those processes, to figure out how we can make people age well and also not get cancer.”
In a Nature Cell Biology study in February scientists reported a newly discovered role for NAD+ metabolism at the intersection of cellular aging and cancer—specifically, in a process called cellular senescence. Senescence occurs when aging, damaged cells stop dividing. The process can help suppress cancer, but it leads cells to produce inflammatory molecules that can also promote cancer growth under certain conditions. In the Nature Cell Biology study, Rugang Zhang of the Wistar Institute, and his colleagues found that in cells entering senescence, rising levels of NAMPT (a major NAD+-producing enzyme in mammals) encourage the release of inflammatory and potentially protumor molecules. Consistent with those findings, mice genetically predisposed toward pancreatic cancer developed more precancerous and cancerous growths when they consumed the NAD+ precursor NMN. Zhang says more research is needed to fully understand the role of NAD+ in cancer, but he adds that “we should be cautious and bear in mind the potential downside of NAD+ supplementation as a dietary approach for antiaging.”
Zhang’s work is part of a growing body of research that has drawn attention to NAD+ metabolism in cancer, particularly involving NAMPT. Compared with healthy tissues, elevated NAMPT levels have been reported in several human cancers including colorectal, ovarian, breast and prostate cancers. In studies in animals and cells, drugs that inhibit NAMPT have shown promise in killing cancer cells or enhancing the effectiveness of other cancer therapies.
In 2016 researchers at Washington University School of Medicine in St. Louis found that among people with glioblastoma—an aggressive form of brain cancer—tumors with higher NAMPT levels correlated with shorter survival times. When human glioblastoma cells were implanted in mice, the cells proliferated and established new tumors. But when researchers suppressed NAMPT in these cells before implantation, they later saw reduced brain-tumor formation and increased survival in the mice—suggesting that glioblastoma cells depend on NAMPT and NAD+ to thrive.
What might this result say about NAD+-boosting supplements? “There’s a lot of buzz about taking NAD+ precursors for their antiaging effects, which is based on a lot of great science,” said Albert Kim, senior author of the 2016 study, in a School of Medicine press release “I don’t know if taking NAD+ precursors makes existing tumors grow faster, but one implication of our work is that we don’t yet fully understand all of the consequences of enhancing NAD+ levels.”
These emerging questions are not ruffling makers of NR supplements. “I’m not losing sleep over this,” says Charles Brenner, chief scientific advisor for ChromaDex. Reports of higher-than-normal NAMPT levels in many cancers do not prove that high NAD+ levels actually promote cancer growth, he notes. He contends that studies that kill cancer cells by suppressing the NAD+-producing enzyme also do not properly address the issue. “Whether low NAD+ would block cancer and whether high NAD+ would promote cancer are two separate questions,” he says.
Indeed, Zhang’s study is one of the first to directly show that providing supplemental NAD+, via the precursor NMN, was associated with increased cancerous growths in mice. But Elysium’s Guarente is skeptical of the data, arguing that Zhang’s study showed a small effect in a small number of animals and that it has yet to be replicated by other groups. “I don’t think the evidence is there at all to say that raising NAD+ levels would favor cancer,” Guarente says.
At the moment, the idea that elevating NAD+ levels could fuel cancer growth remains a hypothesis, but it is one that has attracted considerable attention. Cancer cells have high metabolic needs, including processes requiring NAD+. And many types of cancer cells boost NAD+-making enzymes and then die when those enzymes are blocked by drugs. “We know that they like NAD+, but it’s too early to say, if you add NAD+, whether they will grow really fast,” says Shashi Gujar, a cancer immunologist at Dalhousie University. “Many labs are working to figure that out.”
The answer may not be a single or straightforward one. NAD+ is a ubiquitous and fundamental molecule, involved in many biological pathways and cellular operations. Its ingestion could lead to a mix of positive and negative outcomes, the balance of which might depend on context. NAD+ precursors, consumed orally, may be taken up by some tissues more than others. And different cell types are known to employ distinct metabolic programs, which could lead to tissue-specific responses to NAD+.
Like the tissues from which they arise, cancers are diverse in their cellular ways—and at least some run counter to the “cancer fuel” hypothesis of NAD+. A 2014 study, for instance, reported that in a mouse model of liver cancer, inhibiting NAD+ production was a key step by which an errant gene caused DNA damage and tumor formation. In this case, feeding NR to the mice actually helped protect against these harmful effects.
Together these findings do not necessarily point to ready answers for consumers interested in NR or NMN supplements, so much as they highlight questions for scientists to address in the coming years. “I would say that given that many people are taking these supplements for health benefits, a study of what these do to cancer risk or existing cancer biology is warranted,” says Matthew Vander Heiden, a clinician-scientist at the Massachusetts Institute of Technology’s Koch Institute for Integrative Cancer Research.
The need for more evidence is a sentiment that is shared by others. “There is tremendous interest in the NAD+ field right now,” Gujar says. “And I’m pretty sure sooner or later, we will have the evidence to answer this.”
Helen Shen is a science writer based in Sunnyvale, Calif. She has contributed to Nature, Science and the Boston Globe. Follow Helen Shen on Twitter
Megan Scudellari and Nature magazine
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