Nicotinamide Riboside Supplements and Cancer 2024
Does nicotinamide riboside cause cancer?
While previous studies have linked commercial dietary supplements like nicotinamide riboside (NR), a form of vitamin B3, to benefits related to cardiovascular, metabolic and neurological health, a research from the University of Missouri has found NR could actually increase the risk of serious disease, including developing cancer.
The international team of researchers led by Elena Goun, an associate professor of chemistry at MU, discovered high levels of NR could not only increase someone's risk of developing triple-negative breast cancer, but also could cause the cancer to metastasize or spread to the brain. Once the cancer reaches the brain, the results are deadly because no viable treatment options exist at this time, said Goun, who is the corresponding author on the study.
Following the death of her 59-year-old father only three months after being diagnosed with colon cancer, Goun was moved by her father's passing to pursue a better scientific understanding of cancer metabolism, or the energy through which cancer spreads in the body. Since NR is a known supplement for helping increase levels of cellular energy, and cancer cells feed off of that energy with their increased metabolism, Goun wanted to investigate NR's role in the development and spread of cancer.
"Our work is especially important given the wide commercial availability and a large number of ongoing human clinical trials where NR is used to mitigate the side effects of cancer therapy in patients," Goun said.
The researchers used this technology to compare and examine how much NR levels were present in cancer cells, T cells and healthy tissues.
"While NR is already being widely used in people and is being investigated in so many ongoing clinical trials for additional applications, much of how NR works is a black box -; it's not understood," Goun said. "So that inspired us to come up with this novel imaging technique based on ultrasensitive bioluminescent imaging that allows quantification of NR levels in real time in a non-invasive manner. The presence of NR is shown with light, and the brighter the light is, the more NR is present."
Goun said the findings of the study emphasize the importance of having careful investigations of potential side effects for supplements like NR prior to their use in people who may have different types of health conditions. In the future, Goun would like to provide information that could potentially lead to the development of certain inhibitors to help make cancer therapies like chemotherapy more effective in treating cancer. The key to this approach, Goun said, is to look at it from a personalized medicine standpoint.
"Not all cancers are the same in every person, especially from the standpoint of metabolic signatures," Goun said. "Often times cancers can even change their metabolism before or after chemotherapy."
In a Nature Cell Biology study in 2019, 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.”
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.”
The international team of researchers led by Elena Goun, an associate professor of chemistry at MU, discovered high levels of NR could not only increase someone's risk of developing triple-negative breast cancer, but also could cause the cancer to metastasize or spread to the brain. Once the cancer reaches the brain, the results are deadly because no viable treatment options exist at this time, said Goun, who is the corresponding author on the study.
According to Elena Goun, associate professor of chemistry at MU:
"Some people take them [vitamins and supplements] because they automatically assume that vitamins and supplements only have positive health benefits, but very little is known about how they actually work. Because of this lack of knowledge, we were inspired to study the basic questions surrounding how vitamins and supplements work in the body."
"Our work is especially important given the wide commercial availability and a large number of ongoing human clinical trials where NR is used to mitigate the side effects of cancer therapy in patients," Goun said.
The researchers used this technology to compare and examine how much NR levels were present in cancer cells, T cells and healthy tissues.
"While NR is already being widely used in people and is being investigated in so many ongoing clinical trials for additional applications, much of how NR works is a black box -; it's not understood," Goun said. "So that inspired us to come up with this novel imaging technique based on ultrasensitive bioluminescent imaging that allows quantification of NR levels in real time in a non-invasive manner. The presence of NR is shown with light, and the brighter the light is, the more NR is present."
Goun said the findings of the study emphasize the importance of having careful investigations of potential side effects for supplements like NR prior to their use in people who may have different types of health conditions. In the future, Goun would like to provide information that could potentially lead to the development of certain inhibitors to help make cancer therapies like chemotherapy more effective in treating cancer. The key to this approach, Goun said, is to look at it from a personalized medicine standpoint.
"Not all cancers are the same in every person, especially from the standpoint of metabolic signatures," Goun said. "Often times cancers can even change their metabolism before or after chemotherapy."
"A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism" was published in the Journal of Biosensors and Bioelectronics. Funding was provided by grants from the European Research Council (ERC-2019-COG, 866338) and Swiss National Foundation (51NF40_185898), as well as support from NCCR Chemical Biology.
Other Studies
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, a co-founder of Elysium and its chief scientist, says.
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, a co-founder of Elysium and its chief scientist, 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.”
Related: NAD+ Supplements (NR, NMN) and Cancer
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