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At the Longevity Investors Conference last October in Switzerland, speakers described breakthrough therapies being developed to manipulate genes for longer lifespans. Swag bags bestowed pill bottles promising super longevity, stirring hopes for centuries of youth.

Then Charles Brenner took the stage. The biochemist from City of Hope National Medical Center, in Los Angeles, addressed these ideas and treatments one by one, picking them apart, explaining that they’re based on faulty research. We can’t stop aging, he told the crowd. We can’t use longevity genes to stay young because getting older is a fundamental property of life.

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Scanning their faces, he saw puzzled expressions. Mission accomplished.

Believing we can rewrite the manual for human lifespan is like believing in the tooth fairy.

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Over the past year, Brenner has been challenging life-extension theories on Twitter, YouTube, and the conference circuit, where he’s been introduced as the “longevity skeptic.” He resembles an eagle—he’s hairless on top with an aquiline nose and penetrating gaze—an appearance that goes well with his astute intellect, tenacity, and willingness to fly solo as one of the most boisterous critics of anti-aging science.

Brenner tells people the reasons for suspicion date back to Herodotus’ made-up account of the Fountain of Youth in 425 B.C. Some things never change, he says, even as the field of aging research has picked up scientific momentum in recent years. Investments in longevity startups are predicted to jump from $40 billion to $600 billion in the next three years. Lured by funding from digital age tycoons such as Jeff Bezos and Peter Thiel, top scientists are aligning with companies to advance their work.

In Body Image
THE GREAT DEBUNKER: Charles Brenner clearly takes pride in his image as a brassy skeptic of extending human lifespan. Photo courtesy of Charles Brenner.

Brenner is critical of several big promises emanating from these companies and researchers, such as claims that cellular reprogramming could halt aging. He dismisses speculation from gerontologist Aubrey de Grey that anti-aging therapies will keep us above ground for multiple centuries. But perhaps no scientist in the field of aging has attracted Brenner’s criticisms more than David Sinclair, the Harvard biologist and bestselling author of Lifespan: Why We Age and Why We Don’t Have To. Sinclair is working on therapies that he says could slow human aging to a crawl, allowing us to live decades longer.

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At best, Brenner says, scientists can develop therapies that maintain the health of older people and help keep them out of the hospital—an increasingly important goal as the average age in the United States and elsewhere keeps climbing. Brenner is tackling this problem as the chief scientific advisor of a bioscience company called ChromaDex, which markets supplements for “healthy aging.” But believing we can rewrite the operating manual for lifespan itself, Brenner told me, is like “believing in the tooth fairy.”

Is Brenner right about the biological limits on lifespan? And should we trust the views of scientists involved with drug and supplement companies? The answer is as nuanced as the science itself.

Twenty years ago, Brenner was immersed in academic research. He had just become an associate professor of genetics and biochemistry and director of the cancer mechanisms program at Dartmouth Medical School. In 2003, he explained, “I was minding my own business, trying to figure out how an enzyme works,” when he made a major discovery about nicotinamide riboside, or NR, a form of vitamin B3 that could support longer health spans: more years of health before death, with fewer age-related, chronic diseases.

What Brenner stumbled upon was the pathway by which NR produces nicotinamide adenine dinucleotide, or NAD. This is the molecule that powers the machinery of our cells and helps build and maintain their structures. But damage to the NAD system is inevitable. We bring some of these injuries upon ourselves—think alcohol or cigarette abuse—while others, such as sunlight, can’t be avoided. Even the oxygen we breathe is a problem, causing chemical reactions that stress out the NAD system as we age, gradually reducing NAD and increasing vulnerability to chronic illness. Brenner realized that taking NR as a pill could increase NAD and help offset damage, allowing for graceful aging.

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In the science of aging, every advance gets announced like it was climbing Mount Everest.

Around the same time, others were thinking about NAD, but in a very different way. In the 1990s, most scientists thought researching lifespan was career suicide. To Leonard Guarente, it was a golden opportunity. When he dedicated his lab at the Massachusetts Institute of Technology to the subject, he said, “We were the only ones who were really doing molecular biology of aging.”

Soon, Guarente and his lab members were making findings about a family of enzymes called the sirtuins, which reside in the cells of most living things and control which parts of our DNA get switched on or off. When the MIT scientists added an extra copy of the gene that controls these enzymes, they found that yeast cells and worms lived longer.1 Guarente formed a theory: The sirtuins had evolved in our ancestors to play a key role in longevity. In times of great stress, when food supply is low, the sirtuins express DNA in ways that increase lifespan—a trick that enables more time to reproduce after the famine, when conditions are better for raising healthy offspring.

In their respective labs, Brenner2 and the MIT researchers3 showed that when NAD levels were raised in yeast, the sirtuins became more active, and this sirtuin uptick led to longer lifespans. The research confirmed, “without a doubt,” Guarente said, that there are longevity genes, and they can be manipulated, potentially helping humans live much longer.

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One of the bright postdocs in Guarente’s lab was Australian-American biologist Sinclair, who worked alongside Guarente for four years before he was hired by Harvard Medical School in 1999. A few years later, he became interested in an antioxidant called resveratrol, which plants produce when they’re stressed. Because resveratrol is found in red wine, researchers wondered if it might explain why the Pinot-loving French have fewer incidents of heart disease. In 2003—the same year that Brenner made his discovery about NR—Sinclair fed resveratrol to yeast cells, and found their lifespans increased by 70 percent.4 It seemed to mimic the effect of restricting calories, without the hunger. When Sinclair tried giving resveratrol to the yeast after he’d removed a sirtuin gene, this lifespan benefit disappeared. Other experiments suggested resveratrol led to key changes that tend to support longer lifespan in mice.5

To Sinclair, this work reinforced the view that sirtuins play an important role in lifespan, and it suggested the fountain of youth was crimson, sweet, and bottled at a store near you. Journalists turned the finding into front-page news, making Sinclair famous and sending sales of red wine through the roof.

In Body Image
THE LONGEVITY ADVOCATE: David Sinclair insists organisms have longevity genes that can extend maximum lifespans. Photo from Wikimedia Commons.

Sinclair’s book, Lifespan, goes on to describe his experience of becoming a media sensation as well as the anticlimactic fallout: He and other scientists realized that the human gut is no match for yeast and mice when it comes to soaking up resveratrol. Today, the scientific consensus is that you won’t become a superager by swilling red wine. Even so, Sinclair’s research was an “important first proof,” he writes in Lifespan, that molecules can delay aging in organisms through the same mechanism as calorie restriction, which inspired a wave of research on other “sirtuin-activating compounds,” including NAD.

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The pages of Sinclair’s book are infused with his enthusiasm for the cause of helping people stay healthy and live many more years than any human before. “What if we could be younger longer?” he writes. “Not years longer but decades longer.”

Sinclair, who is co-director of Harvard’s Paul F. Glenn Center for Biology of Aging Research, thinks the science points clearly to the potential. “At least in animal studies, it looks like [certain NAD precursors] can rejuvenate stem cells,” he told me. “We’ve found longevity genes that control the body’s defenses against aging and thus offer a path to slowing aging through natural, pharmaceutical, and technological interventions,” he wrote in Lifespan, adding that sirtuins are longevity genes “because they have demonstrated the ability to extend both average and maximum lifespans in many organisms.”

After his discovery in 2003, Brenner progressed in his academic career, moving steadily west over the years from Dartmouth to the University of Iowa, where he held an endowed chair and served as head of the biochemistry department, before coming to City of Hope in 2020 as the inaugural chair of a new department. There, he continues to be a pioneer in studying NAD metabolism. “I love doing science, and we find new and important things every month in the laboratory,” he said. Increasingly, though, he has felt compelled to step outside the lab into the public arena to challenge what he sees as the quackery within longevity science.

Brenner wasn’t always so concerned by the views of scientists such as Sinclair. In 2008, he briefly partnered with Sinclair, contributing as a scientific advisor to Sirtris Pharmaceuticals, a company founded by Sinclair and others to develop therapies for age-related diseases.

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But Brenner grew wary of Sinclair’s research findings and his perspectives on both sirtuins and the ability to control lifespan. Brenner left Sirtris following its acquisition by the pharmaceutical giant GSK in 2009; after Lifespan gained widespread acclaim and popularity, he couldn’t hold his tongue anymore. The biochemist took his critique to social media. In 2018, Brenner started a Twitter account and declared it was a “no BS zone.” He attracted nearly 50,000 followers while posting educational material about NAD and critiquing Sinclair’s communications on resveratrol and sirtuins.

Should we trust scientists who have financial interests in drugs that promise to slow aging?

“There’s a massive [research] literature showing that resveratrol isn’t a [sirtuin] activator,” Brenner told me, echoing his comments on social media. He penned a scathing response to Sinclair’s Lifespan book, “A Science-Based Review of the World’s Best-Selling Book on Aging.” The paper, published this past January in The Archives of Gerontology and Geriatrics, accuses Sinclair of “dreamy counterfactuals” that steer people away from “basic facts about aging.”

“The idea that [a yeast gene] anticipated the causes of aging in animals is mind-blowing,” Brenner said. He pointed out that, even in yeast, increasing sirtuin activity leads to longer life in just one out of 5 million cells. If you zoom out to consider the entire group of yeast that was studied, he said, extra sirtuins actually undermined yeast longevity. “The verdict is in,” Brenner said, that sirtuins aren’t dominant longevity genes that were selected and passed down in evolution. What is genetically encoded is the limit on lifespan, he and others have argued.

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Sinclair responded that sirtuins clearly play a role in the aging process. “There are dozens of papers showing the benefits of raising NAD are lost when [sirtuins] are deleted,” he told me. “It’s not just in mice. When you overexpress [sirtuins] in worms, in flies, in yeast, it extends lifespan. And so it seems to be a conserved effect that some of these sirtuins are limiting for lifespan, and that if you give the organism more of them, they’re healthier and live longer.” Guarente, too, said that a large volume of published research links aging and sirtuins, “cementing their role in longevity and health.”

Brenner isn’t backing down. Studies that have connected sirtuins to longevity suffer from several biases, he wrote in 2022. One of those is “framing bias,” when scientists design research questions in ways that lead to the conclusions they prefer, such as when they make assumptions about the role of sirtuins. “Review articles that propagate these biases are so rampant that few investigators have considered how weak the case ever was for sirtuins as longevity genes,” he wrote.

“If I were to endorse the view that sirtuins are longevity genes, and that my 2007 finding that NR extends lifespan in yeast and, therefore, it’s going to extend lifespan in humans, I could have parlayed non-evidence based claims into significant money,” Brenner said.

“Just about every advance in the history of medicine is not really a breakthrough. It’s a slow, cumulative slog.”

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Brenner does have a financial interest in his advisory role for ChromaDex, a public company that sells NR. The market value for supplements that boost NAD is estimated at $250 million in the U.S. alone. In addition to Brenner’s work with ChromaDex, Guarente’s belief in the potential for sirtuins and NAD to support health and possibly lifespan led him to co-found Elysium Health, a private life sciences company that sells NR and another NAD precursor, called nicotinamide mononucleotide, or NMN. The market for these NAD boosters is projected to reach $1 billion by 2030.

Boosting NAD is useful, Brenner explained, because our bodies need loads of it to preserve health as we age. NR supplements crank up enough NAD to power the cells in handling their many tasks, even as our reserves of NAD get drawn down to repair constant damage from oxygen, inflammation, and other stressors.

Brenner has shown that NR, when taken orally, protects against heart failure in mice.6 Recent studies by other researchers have found that doses of NR lead to improvements in age-related problems, such as Alzheimer’s, Parkinson’s disease, high blood pressure, and inflammation. Benefits in people with ALS and non-alcoholic fatty liver disease have been shown by Guarente and other researchers at Elysium, where Guarente is chief scientist. Since Brenner began taking the NR supplement made by ChromaDex, he told me that his cuts and scrapes seem to heal faster, and he feels like he bounces back faster from tough workouts.

Brenner is confident about NR’s superiority over the other NAD booster, NMN. He points to evidence that NR is the biggest piece of NAD that can get into any cell. “NMN doesn’t make sense as a supplement or drug,” he told me.

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Other researchers at the University of Washington—including Shin Imai, who was a postdoc in Guarente’s lab—have published data pointing to the opposite conclusion: very fast uptake of NMN into cells.7 Sinclair said the science points clearly to the potential for NMN’s effectiveness. In 2017, he and Imai co-founded a company called MetroBiotech that is running clinical trials on drug formulations of NMN. The privately owned pharmaceutical could charge more if it’s able to sell NMN as a drug, compared to marketing it as a supplement.

Imai conducted the first clinical trial of NMN in humans, reporting in 2021 in Science that it improved insulin sensitivity in older, pre-diabetic women.8 It’s printed right on the bottle that supplements aren’t intended to treat diseases. Nevertheless, Imai said, “Now we have a series of clinical evidence for the efficacy of treatment in humans.”

But the benefits of NR and NMN supplements for health span, let alone lifespan, are debated. “Every human clinical trial that I’ve seen where people claim some effect from NAD precursors, when you actually dive into the papers, they’ve all got major weaknesses,” said Matt Kaeberlein, also a former postdoc in Guarente’s lab, who went on to become a leading biogerontologist at the University of Washington.

Although the prediabetic women in Imai’s research on NMN did improve their insulin sensitivity, they didn’t get other expected benefits, such as better blood lipids. “It’s some evidence in the right direction, but not compelling evidence that it’s clinically therapeutic,” said Samuel Klein, a professor of medicine and nutritional science at Washington University in St. Louis. Klein was a former partner in MetroBiotech, but he’s given up all relationships with businesses related to NMN and NR. “The research was more important to me than the potential for financial gain,” he said. (Imai, too, has left MetroBiotech.) Klein told me the benefits seen from NAD boosters in some animal studies haven’t translated to people because the dosing isn’t right, or because “humans are simply not rodents.”

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In many ways, Brenner is a much-needed skeptic. “In an area like aging, every advance gets announced like it was climbing Mount Everest,” Arthur Caplan, a bioethicist at New York University, told me. “Just about every advance in the history of medicine is not really a breakthrough. It’s a slow, cumulative slog. I don’t care what study it is—minimally, it has to be confirmed by further research.”

Brenner would agree. But sometimes Brenner’s own assertions seem to verge on hype. When he declares that taking NMN for health doesn’t make sense, without noting the data that support NMN, it can sound like an overstatement. When I brought up the NMN data, though, he told me it’s “deeply flawed”—and referred me to his published paper on the topic, as he so often does.

Unquestionably, Brenner and Sinclair have impressive scientific credentials. They also have financial interests in NAD boosters. Does that mean the public shouldn’t trust their research and perspectives?

Not necessarily, said Josephine Johnston, a bioethicist and research fellow at The Hastings Center, an independent research institute that focuses on health and science. She explained that partnering with companies is an important incentive for scientists across biomedical fields. “We don’t want inventions languishing in academic labs and not actually getting out to the public,” Johnston said. In fact, translation of academic research into commercial products has been a policy goal of the U.S. government for decades. American universities also have robust requirements for scientists to disclose financial relationships.

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Brenner lists his financial interests in his published papers, noting when he’s received research funding from companies such as ChromaDex. Sinclair does the same, disclosing his position at MetroBiotech and several other private sector roles.

It’s tough to declare a winner in the standoff between Brenner and Sinclair. After all, we all have a stake in aging. Caplan said one surefire way the public can identify which scientists to trust is to determine whether they engage in debates. That speaks well for Brenner, who continues to be invited to longevity conferences, despite his “longevity skeptic” status. Another measure of trustworthiness is whether scientists with conflicting findings are willing to collaborate.

A few years ago, for example, the National Institute on Aging and the University of Wisconsin investigated whether caloric restriction extends lifespan in rhesus monkeys. Because it was an important experiment, they partnered to run the same study in parallel at two different sites, ensuring rigor and responsibility. When they got conflicting results, instead of arguing, they worked together to spot differences in their study designs.9 They came to a shared conclusion that caloric restriction does improve the health and survival of the monkeys.

Perhaps Sinclair and Brenner will one day run side-by-side research on sirtuins, or the benefits of NMN compared to NR. Both, at least, agree on the gap in comparative research. “We need studies directly comparing the two, and both may have unique benefits,” Sinclair said. Brenner acknowledged the need for more research in humans. Generally speaking, he said, “I don’t like to get out ahead of my skis or get ahead of where the evidence is in science.”

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There are several examples of such partnerships, sometimes called “adversarial collaborations,” but it’s easy to imagine this one ending badly. Brenner clearly takes pride in his image as the Great Debunker of extending human lifespan, while Sinclair is standing by his reputation as the biologist who said we can. Could they arrive at a shared conclusion?

Whether it’s advanced through disputes or collaboration, science will have the last word on how well and long we can live. “Charles Brenner and David Sinclair are both distinguished scientists,” Klein said. “The fact that they have opinions that are polar opposites reflects the nature of NAD science. Nothing is black and white. There’s a lot of gray.”

Matt Fuchs is a freelance writer covering science and health, and editor-in-chief of Leaps.org. Follow him on Twitter.

Lead image: Tasnuva Elahi, from The Fountain of Youth/Wikimedia and a photo of Brenner from Longevity Investors Conference.

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References

1. Kaeberlein, M., McVey, M., &Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & Development 13, 2570-2580 (1999).

2. Belenky, P., et al. Nicotinamide riboside promotes SIR2 silencing and extends lifespan via NRK and URH1/PNP1/MEU1 pathways to NAD+. Cell 129, 473-484 (2007).

3. Imai, S., Armstrong, C.M., Kaeberlein, M., & Guarente, L. Transcriptional silencing and longevity protein SIR2 is an NAD-dependent histone deacetylase. Nature 403, 795-800 (2000).

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4. Howitz, K., et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191-196 (2003).

5. Baur, J.A., et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337-342 (2006).

6. Digeut, N., et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation 137, 2256-2273 (2018).

7. Grozio, A., et al. SLC12A8 is a nicotinamide mononucleotide transporter. Nature Metabolism 1, 47-57 (2019).

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8. Yoshino, M., et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224-1229 (2021).

9. Mattison, J.A., et al. Caloric restriction improves health and survival of rhesus monkeys. Nature Communication 8, 14063 (2017).

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