IOWA Alumni Magazine | January 2017
Cellular Power

The Discovery of NR: From Yeast to Human Supplement

UI researchers examine the health potential of nicotinamide riboside, a vitamin uncovered by a University of Iowa professor.

In 2004, Charles Brenner peered into a petri dish in his Dartmouth College lab and noticed something extraordinary. The biochemist watched as a compound managed to sustain the life of yeast cells, remarkably, even after he knocked out a gene required to produce a central regulator of metabolism.

As it turned out, that compound was a new vitamin called nicotinamide riboside, or NR, a form of Vitamin B3 that Brenner found in milk. Its unique ability to safely and efficiently boost that metabolic regulator—nicotinamide adenine dinucleotide, or NAD—has led Brenner and other researchers to continue to investigate its potential.

Over the past decade, Brenner showed that he could extend the lifespan of yeast cells with NR, and scientists elsewhere have demonstrated that NR helps animals resist weight gain, slow the aging of organs, and resist noise-induced hearing loss. These curious observations raised a tantalizing question: How might NR be used to improve human health?

Today, Brenner is the Roy J. Carver head of biochemistry at the University of Iowa, where he's one of many UI researchers working on the answers. What he knows for sure is a healthy NAD supply contributes to just about everything the body's cells and tissues do. Mitochondria rely on it to convert food to energy and maintain a healthy metabolism. NAD also protects the DNA in our genome from damage, preserves nerve function, detoxifies free radicals, and shows promise in its ability to keep our cells and organs resilient.

"We know metabolism slows in aging, and that mental and muscular functions also decline," Brenner says. "NAD is central to all of those processes but declines in aging. If it's possible to safely boost our NAD, we might be able to maintain wellness and stave off some of the diseases and conditions associated with aging."

Brenner recently published the findings of the first-ever clinical trial in humans that demonstrated NR's ability to safely raise levels of NAD. In the journal Nature Communications, Brenner outlined the results: the vitamin reliably increased the NAD metabolism of 12 healthy subjects with no serious side effects.

Thirteen years after his discovery in that Dartmouth lab, Brenner's vitamin is no longer an obscure compound of interest to him and a few colleagues. NR has become a promising and widely sold dietary supplement, with an estimated 200,000 Americans taking the vitamin daily as an over-the-counter supplement after the FDA deemed it "generally regarded as safe," says Brenner.

Brenner also serves on the scientific advisory board for a company called ChromaDex, which developed NR for human use, and he co-founded ProHealthspan, which sells NR to consumers (see sidebar). At UI, Brenner collaborates with colleagues across campus to study NR's use in areas like maternal health, neurodegeneration, athletic performance, diabetes, aging, metabolic rate, and heart function.

Scientists have long known about two other vitamins that generate NAD, but NR is unique, says Brenner, because it performs the task more efficiently and without side-effects. Niacin, for instance, is another NAD precursor, but it can cause uncomfortable flushing of the skin.

Because NAD is involved in many aspects of health, researchers across the campus have tested NR. Justin Grobe, assistant professor of pharmacology, researches its effect on resting metabolism; Amy Sindler, assistant professor of health and human physiology, examines the impact of NR on physical performance; and E. Dale Abel, the John Stokes Chair and director of the Fraternal Order of Eagles Diabetes Research Center and head of internal medicine, studies how NR can protect the ailing heart.

Two additional Iowa City collaborations have uncovered the power of NR to protect damaged nerves in mice. Mark Yorek, associate chief of staff at the Iowa City VA and professor of internal medicine, and Brenner recently demonstrated protection against nerve damage that occurs in diabetes. Meanwhile, Donna Hammond, professor of anesthesiology, worked with the Brenner group to show how NR can prevent and reverse nerve damage that can occur in cancer patients as a side effect of chemotherapy. The results were so striking that Hammond plans to enroll patients at UI Hospitals and Clinics to test whether NR can help protect women undergoing chemotherapy.

Much remains to be discovered about NR, but the research program begun at Dartmouth 13 years ago and continued at the UI continues to make strides. Brenner says it's relatively rare to see a molecule emerge from a laboratory into common use, and the researchers at what he calls "NR world headquarters" are determined to find out more about its promise.

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UI researchers study tiny units for big gains in metabolic health.

He doesn't wear a hardhat, but University of Iowa assistant professor of biochemistry Eric Taylor and his colleagues go to work each day inside a factory. At his lab in the Pappajohn Biomedical Discovery Building in the Carver College of Medicine, Taylor can be found pulling the levers of what he calls our bodies' raw goods refineries—our mitochondria, the tiny fuel-processing dynamos humming away within our cells.

Taylor is among the many UI doctors and scientists working to harness the power of our mitochondria—and the central role they play in cellular metabolism—to boost health, fight disease, and counter the effects of aging. With colleague Stefan Strack of the Department of Pharmacology, Taylor leads the cross-departmental University of Iowa Mitochondrial Interest Group, which collaborates on an array of research.

"It's absolutely clear that mitochondrial function is important to overall health," says Taylor, noting that mitochondrial function declines with aging and contributes to diseases like diabetes, cancer, and neurodegeneration. Mitochondria are also the gatekeepers for the life and death cycle of cells.

These organelles, which link together to create a highly interconnected network of tubes, have an inner and outer membrane that keep their unique contents separate from the rest of the cell. Mitochondria take in oxygen and burn macronutrients—carbohydrates, fats, and proteins—then harvest and release the energy. The result is ATP, the major cellular energy currency essential for sustaining the myriad cellular activities vital for life.

A typical cell houses a couple hundred of the free-floating, membrane-encased mitochondria, though cells that need a lot of energy, like those in our muscles, liver, and heart, can have thousands. The mitochondrial population in a human body is unfathomably large, numbering in the quadrillions, and the organelles can multiply to bolster cells where more energy is needed.

Taylor's mitochondria interest group meets monthly and includes doctors and scientists involved in cardiovascular, diabetes, and cancer research. Group member E. Dale Abel, chairman of the UI Department of Internal Medicine and director of the Fraternal Order of the Eagles Diabetes Research Center, studies mitochondria's impact on heart failure. "A pretty broad swath of individuals are interested in how the breakdown of our mitochondria contributes to disease," says Abel, who is hopeful that therapies targeted toward these energy factories could yield significant benefits to patients.

Taylor's lab, which is part of UI's diabetes research center, investigates how the balance among mitochondrial carbohydrate, protein, and fat utilization affects cellular and whole-body health. This balance is disrupted in many diseases, and modulating it may present unique ways to treat disease. In a recent study, Taylor's team found that mitochondria hold the key to a potential new strategy in treating Type 2 diabetes. By blocking a specific pathway for mitochondrial carbohydrate metabolism in lab mice, Taylor found it forced the liver to use a less-efficient route to create glucose. That resulted in reduced blood sugar levels in mice, which compensated by burning more fat and keeping cholesterol lower—which would all be therapeutically desirable outcomes for diabetes patients.

Terry Wahls, 82MD, 86R, a UI professor of internal medicine and renowned nutritional guru, approaches her research from a different perspective. She evangelizes the power of mitochondria to her students, patients, and the readers of her many books—and for good reason.

A decade ago, Wahls was confined to a tilt-recline wheelchair because of secondary progressive multiple sclerosis, a chronic disease that attacks brain and spinal cord. She underwent chemotherapy, but the disease marched forward. Faced with a bedridden future, Wahls began researching alternatives and honed in on a key target: her mitochondria.

Wahls designed a nutrient-packed food plan tailored to boost her mitochondria and, thus, the overall cellular health of her brain. Her modified Paleolithic diet now known as the Wahls Protocol—eschewing processed foods in favor of the leafy and protein-rich fare of our hunter-gatherer ancestors—put her on track to recovery and has gained her a national following.

Mitochondrial deficiency, explains Wahls, is at the heart of MS and other diseases affecting the brain, including Parkinson's and psychiatric disorders. She says our diet influences whether or not our mitochondria are receiving the nutrients they need to deliver energy at peak efficiency. Her advice is simple: "Get rid of the sugars, get rid of the grains, and replace them with vegetables, meat, and fish. Mitochondria also do well with healthy fats, so I have people eat things like avocados, coconut oil, and olive oil."

Today, Wahls rides her bike to and from work each day, she's written several books detailing her use of "intensive nutrition recovery" to beat MS, and she continues her research at UI. In recent months, she received a $1 million grant from the National Multiple Sclerosis Society to study the effects of diet on MS-related fatigue.

As researchers like Taylor and Abel continue to tinker inside our energy factories, Wahls says people can keep their own power plants humming by feeding them the nutrients needed to thrive. In a talk she gave at a TedX event in Iowa City in 2011 that went viral—it's been viewed 2.6 million times on YouTube to date—she challenged those in the audience to become "ambassadors for their mitochondria."

Says Wahls: "If I can rise up from a tilt-recline wheelchair doing this, imagine what eating for your mitochondria can do for you?"

Putting NR to the Test

The blue bottle of vitamins sat unopened on my desk for a few days before I reached for it one morning in November. Like everyone else in America, I'd been up until the wee hours watching the presidential election unfold, and I was dragging. "Fuels the Body's Energy Engines," read its label.

I'd been acquainting myself with the human body's energy engines—our mitochondria—for this story, and figured today of all days mine could use a boost. I pulled the cotton plug, slugged down two capsules with my coffee, and joked with my co-workers that I'd have a full head of hair again by next week.

* * *

I'd met Charles Brenner, a UI professor of biochemistry and internal medicine, a couple weeks earlier in his fourth-floor office at the labyrinthine Bowen Science Building. He caught me up to speed on the relatively brief history of nicotinamide riboside—from his 2004 discovery of the vitamin to more recent studies in mice showing that it stymies weight gain, improves blood sugar and cholesterol levels, reduces nerve damage, and prolongs lifespans.

Testimonies, anecdotal as they are, abound online about the wonders of NR, which is sold today as an over-the-counter dietary supplement. That includes a product called TruNiagen, which is made by ProHealthspan, a company co-founded by Brenner. Many NR users report improved energy, greater muscle tone, better sleep, and softer skin. Health blogs ask whether NR is "the anti-aging supplement of the future" and speculate about the vitamin's potential to treat age-related diseases, including some forms of cancer and Alzheimer's.

Brenner is reluctant to speculate anything beyond the current research, however. "We're cautious but excited because nicotinamide riboside is a safe compound, which boosts NAD, and people report feeling better," he says.

As the buzz in the supplement world has mounted around NR, Brenner has channeled his expertise to a few enterprises beyond his lab, including serving on the scientific advisory board for ChromaDex, the company that developed NR for human use, as well as co-founding ProHealthspan—positions he's quick to disclose when talking about his research.

The murky world of health supplements is full of miracle pills and secret-of-the-stars promises, of course. But the connection of a respected UI researcher and NR stoked my curiosity. I haven't regularly taken vitamins since my Flintstones chewable days, and I tend to ride out any aches and pains instead of reaching for the Tylenol. Still, I found myself firing off an email to Brenner: "What's the best way to get a batch of NR?"

* * *

I've been taking Brenner's vitamin for a few weeks now—two 125-milligram tablets each morning—and some days I think I feel a difference. Other days, not so much.

Early on I noticed a kind of low-voltage hum, like I've had a cup of coffee, minus the jitters, or that I've just finished chasing my kids around the yard. I've had a few above-average workouts at the gym. Late one night I cleaned the house instead of crashing, leaving little doubt in my wife's mind that I was indeed taking a miracle pill. On the whole, though, there hasn't been much of a change. The perceived upticks could just as easily be a result of being more cognizant of the natural ebbs and flows of my energy levels.

In short, the results of my profoundly unscientific trial are inconclusive. The pros: a sporadically cleaner house. The cons: still no hair.

Still, after talking with Brenner and other researchers, I'm more aware of the intricate power plants at work within my cells—my mighty mitochondria—and the nutrients needed to fuel them. Whether that awareness translates to willpower during our office's next Donut Friday has yet to be rigorously tested.

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