Since he was a child, James Peyer has been obsessed with stopping aging. Now he has a fund — and a plan.

Delaying death remains the stuff of science fiction, but James Peyer, cofounder of Apollo Ventures, is convinced that it won’t be fantasy for much longer. He started the venture capital firm more than two years ago — when he was only 29 — to back early stage companies that he hopes someday will have the potential to slow aging. So far, it has invested $2 million to $5 million each in four companies, two of which remain in stealth mode. Apollo’s scope includes nine different areas of research with anti-aging potential, including rejuvenating stem cells, reversing problems with cellular energy, and manipulating telomeres, the caps at the ends of chromosomes that shorten with age.

Peyer, who trained as a stem cell biologist, is mindful of regulatory and commercial realities. Aging is not a disease, so the US Food and Drug Administration has never approved a drug to combat it. Peyer plans to support startups that begin by tackling a disease such as muscle wasting or diabetes. Once that succeeds, these companies can broaden their reach to slow or stop aging. But we still don’t know what causes aging, or have clear ways to measure whether it’s slowing down or speeding up, so proving that an anti-aging pill actually works will be another major challenge. Unlike some of the more exuberant investors in the anti-aging space, Peyer is clear-eyed about how hard that will be. Nonetheless, he’s optimistic about combating aging, a problem he’s been obsessed with since childhood. NEO.LIFE’s Karen Weintraub spoke to Peyer earlier this month over coffee at WeWork in Cambridge, Massachussetts. What follows is an edited, condensed version of their conversation.

What turned you on to the field of anti-aging biology?

I became a scientist because I felt like we were treating the diseases of aging the wrong way. We were waiting for people to get cancer or Alzheimer’s disease or something and then trying to do something about it, which felt totally backwards to me. By the time the diseases rear their heads they’re at such a level of complexity that biologically, walking them backwards is an enormous — and maybe in many cases insurmountable — challenge.

We still don’t know much about aging and how to stop it. Is it premature to start investing?

I think definitely not. Are we ready to administer new medicines to healthy people and help them live longer and prevent disease? The short answer is we’re not there.

But are new medicines that may eventually be able to do that ready to undergo clinical development for other diseases? Absolutely yes. And that’s exclusively what Apollo works on.

What is your vision for Apollo?

Creating a portfolio approach to aging. There’s not going to be one single pill that eliminates cancer, Alzheimer’s disease, and [every other disease of aging]. The vision I have is three [or more] things that we could eventually take the way we take vitamins or statins, that really, really make an impact on the risk of these diseases later on.

So one drug won’t be a cure-all?

Diseases of aging aren’t caused by just one type of damage, so in the long run to make us all healthier, we’re going to have to use multiple medicines targeted at the different types of damage. For example, in Alzheimer’s disease we may need to both break down unwanted aggregates [from misfolded proteins] and also regulate glucose levels to really beat the disease. Cancer might need increased immune surveillance and also better DNA damage repair. For this reason, I think we’ll see the serious benefits to healthy lifespan once we start combining multiple safe and effective therapeutics.

One of the companies you funded, Aeonian Pharma, deals with the so-called mTOR pathway. Can you explain a bit about that?

There’s a drug, rapamycin, that extends lifespan in mice by about 15 percent, with lower cancer, lower muscle loss. It’s like a healthspan increase. But the drug’s not safe. It’s an immunosuppressant, among other things. The first company we backed made a version of rapamycin that doesn’t have the side effects. But we’re not going to launch it in an aging trial first, because there happens to be a disease called tuberous sclerosis that has overactivation of this mTOR pathway. We’ll [try] it in that disease first. If it’s safe and effective, let’s talk about using this for muscle loss or neurodegenerative diseases.

Do you have a favorite path of research among the nine you’re pursuing, or do you think it’ll take a combination of the nine?

I don’t have a favorite since all types of aging damage can eventually accumulate enough to cause a disease and kill people. However, there are a few lower hanging fruits where scientists have made the most progress: in senescent cell biology [cells that stop reproducing, as well as cells that can’t regulate themselves] and nutrient sensing pathways. I expect that one of these is where the first human breakthroughs will come.

If you develop a drug for a rare disease, it will be very expensive. So if it also works as an anti-aging therapy, will it only be affordable to the rich?

Drug prices can always come down to match a market. Let’s say our drug starts out as chronic treatment for an orphan disease [one that is very rare]. Our next trial would be to prevent Alzheimer’s or early stage Parkinson’s or something like this, in which you give it chronically to a large number of healthy or nearly healthy people. If it succeeds, the price point for that drug will have to drop really sharply to match the market.

And theoretically, a drug that helps people live longer and healthier will reduce medical costs and save our health system lots of money, right?

Something that can increase the median healthy lifespan of a population, even if it’s just for a year or two years, already approaches the value of a miracle cure for cancer. Even if it’s a quarter of a cure for cancer, it’s still a massive deal. I get relatively excited about that possibility, even though I think that’s still a ways off.

Any thoughts about whether or when will people routinely live to 100 without chronic disease?

This is always a hard question to answer. Living to a healthy 100 will likely require a combination of good preventative therapeutics, and it’s too early to tell how easy or hard that will be. Hopefully as we see the enormous societal gains from adding a decade or so of healthy life from these drugs, it will lead to a sort of “longevity space race” to prevent chronic disease. The major thing holding us back right now is the question, “Can this work?,” and our industry is trying to show the world that indeed it can.

“Hopefully as we see the enormous societal gains, it will lead to a sort of ‘longevity space race’ to prevent chronic disease.”

Are there side effect concerns with anti-aging therapies, such as a fear that by helping cells live longer, for example, we could trigger cancer?

This is going to be a major challenge. Some approaches to slowing the damage of aging have very few unwanted side effects in mice, such as enhancing autophagy [cellular recycling] and routinely clearing senescent cells. When we start talking about stem cells, DNA repair, and telomeres, however, we have to get more careful. Part of the reason that those systems decline as we age was an evolved mechanism to protect us from cancer, so that means we have to be very thoughtful about how we target these things to promote regeneration but avoid increasing the risk of cancer.

What can a firm like Apollo do to advance this field?

With a few million of investment, which my small fund is able to do, we can get a drug ready for phase 1 clinical trial in just a couple of years. A standard oncology drug, by comparison, takes $20 to $40 million. I think there’s a very real argument to be made saying that even leaving aside the anti-aging potential of these drugs, these companies are undervalued. The science is quite far along.

Anything that keeps you up at night when you think about anti-aging treatments?

We’re all affected by the diseases of aging. Because there’s so much emotional appeal in this space, it has been easy to raise money for companies by just appealing to “this is going to reverse aging.” I’m worried about this, because whenever it’s too easy to raise money, you get situations where ideas that shouldn’t be seeing the light of day receive too much hype, too much money and then can create large-scale failures that set back the field as a whole.

Is that happening?

We’re not necessarily at that stage just yet, but I really don’t want to see it go in that direction.

“Whenever it’s too easy to raise money, you get situations where ideas that shouldn’t be seeing the light of day receive too much hype.“

You’re 31. Do you do anything to improve your own odds of living longer?

I take metformin. There’s a lot of circumstantial evidence suggesting that metformin can slightly shift back risks of Alzheimer’s and cancer in addition to diabetes [for which it is an approved treatment].

I take NAD [a coenzyme used in energy production and DNA repair]. We’ve looked pretty deeply into the NAD space. There is clearly some benefit to augmenting production of NAD, especially later in life. The degree of that benefit is still to be determined.

And I take spermidine, a component of sperm. This is one of the under-reported life-extending supplements. When you dose mice with it, they live a lot longer. You have comparable results to rapamycin with almost no side effects.

Don’t you get nervous about taking combinations of drugs that haven’t even been tested separately in humans?

The effect sizes and doses are pretty small. They’re pretty gentle. I certainly wouldn’t advocate for every 35- or 40-year-old to get on all these things right now. Some will. I think that’s okay, too.

What about the basics? Do you get enough sleep?

Not enough good sleep and too much time on airplanes shifting time zones. The circadian rhythm data is quite compelling in a way that makes me very worried, because my circadian rhythm is never adjusted. I remember seeing this sleep disruption data for mice — and holy crap did those mice fall apart! So I get a little worried there.

This Scientist-Turned-VC Wants to Extend Life was originally published in proto.life on Medium, where people are continuing the conversation by highlighting and responding to this story.

Research on aging treatments keeps turning up profound variations in how male and female subjects respond.

There’s a drug that makes mice live 8 percent longer — but only if they’re male. Female mice get roughly that amount of benefit from a totally different treatment, which does nothing for males.

These aren’t just one-off quirks in longevity research. A growing body of scientific research suggests that getting older plays out very differently in males and females. To make significant progress in fighting the diseases associated with aging, researchers will have to better understand and address these sex disparities.

“Males and females are more different organisms than we had originally appreciated, especially when it comes to longevity,” says David Sinclair, a geneticist and co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging at Harvard Medical School.

Life expectancy for women is generally longer than for men. In the United States, a girl born in 2014 could expect to live past age 81, while a boy was likely to survive five years less, to 76.5. The same is true in other higher-order primates, including monkeys and apes, research shows, although the pattern is not consistent across other mammal species.

But early anti-aging research, like most scientific investigations, focused just on male animals. Even when their experiments were in Petri dishes, scientists generally used cells from males.

“For years, people just didn’t really think there was going to be any difference,” says Derek Huffman, an associate professor of molecular pharmacology and medicine at the Albert Einstein College of Medicine in New York. “I think we’re finding out that that is a very dangerous assumption to make.”

In the early 1990s, the U.S. National Institutes of Health began requiring sex balance in the clinical trials it funded. But in 2014, the institutes realized that basic research was still largely biased toward male animals. Francis Collins, the head of the NIH, demanded more balance. “We’re now at a point where you can’t do a serious study without including females,” says Sinclair, who adds that this has essentially doubled the cost of research.

Once they began looking, longevity researchers realized that male and female animals responded very differently to medications intended to promote healthy aging. For instance, male mice live about 8 percent longer if given the equivalent of a low-dose aspirin a day; female mice see no such benefit. Likewise, a weak form of estrogen called 17α-Estradiol has been shown to extend the life span of male mice and do nothing for females.

“There doesn’t seem to be any rhyme or reason to it.”

Female mice, on the other hand, live 14 percent longer than expected when given rapamycin, which is used to prevent organ rejection after kidney transplants, while males get a 9 percent boost. And in a study published in June in Nature Communications, Huffman showed that the growth hormone IGF-1 extends the healthy life span of female mice by 9 percent, while doing little for male mice.

“There doesn’t seem to be any rhyme or reason to it,” Sinclair says.

The disparities seem to exist in people, too, says Brian Kennedy, director of the center for healthy aging at the National University of Singapore and a professor at the Buck Institute for Research on Aging in Novato, California. “My guess is there will be correspondence between what we see in mice and humans,” he says.

There’s a lot of speculation about why this is so, but no hard evidence.

The immediate assumption is that the difference has to do with hormones. Males are exposed to a lifetime of testosterone; females to estrogen. Studies show that men who have been castrated live longer than men who haven’t been, suggesting that testosterone may shorten life span.

The immune system also seems to play a crucial — and sex-dependent — role in aging. Male immune systems apparently weaken faster than their female counterparts, says Huffman. And drugs that address inflammation seem to provide more longevity benefit to males than females — at least in mice.

“We’re now at a point where you can’t do a serious study without including females.”

One particularly odd thing in humans is that though women live longer, they are nonetheless more prone to miserable but non-deadly ailments such as arthritis, Huffman says. Lethal illnesses such as heart disease and cancer strike men more often. (Although Alzheimer’s strikes women more than men, for unknown reasons.)

There’s no clear explanation for this paradox, Huffman says. “That’s a story still to be told.”

Ultra-personalized longevity

To complicate this picture further, the gender differences don’t always crop up. In a study published Monday in Nature Medicine, mice of both sexes got the same increase in healthy life span from drugs that cleared out so-called “senescent cells” — ones that are too old or damaged to reproduce.

Why might that be? James Kirkland, the paper’s senior author and director of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic, says it’s possibly because senescence is such a fundamental biological process that it affects both sexes equally. But he really doesn’t know. (Kirkland says he wouldn’t recommend that people take “senolytic” drugs to clear out these senescent cells because the side effects remain largely unexplored.)

Kennedy has been wondering whether sex differences in aging can be explained by the activity of genes on the Y chromosome. (Men have an X and a Y chromosome; women have two X’s). He’s now tinkering with the sex chromosome of mice — making some males with XX, for instance, to see if the difference disappears.

Sex differences should also serve as a reminder, Kennedy says, that researchers need to be looking at variations by ethnicity and other factors, too. If he’s right, treating aging will be just like most areas of medicine: it will have to be personalized by many things. Longevity won’t be as easy to achieve as simply handing everyone the same pill.

This story was updated on July 16 to correct the description of Kirkland’s reason for caution about senolytic drugs.

His Longevity Pill Won’t Work For Her was originally published in proto.life on Medium, where people are continuing the conversation by highlighting and responding to this story.

A new study helps the case for a supplement known as NR, but it’s not yet a slam dunk.

There hasn’t been much evidence that taking a form of vitamin B known as NR, or nicotinamide riboside, makes you healthier. NR boosts the levels of a molecule called NAD, which plays a key role in cellular health, but it’s been unclear exactly what higher levels of NAD will do for you — and not just for a mouse.

Even so, NR is popular, and sales have been growing. People shell out $40 to $60 a month for supplies of NR pills that go by such brand names as Tru Niagen and Basis. Two companies that have both a rich scientific pedigree and the backing of billionaires, ChromaDex and Elysium Health, have been brawling in court over rights to sell the supposed wonder supplement. Both companies imply it’s an anti-aging pill; ChromaDex’s president calls NR a “once-in-two-lifetimes ingredient.”

That might prove to be true someday, but research published Thursday doesn’t make NR look revolutionary yet.

The study, published in Nature Communications, found that NR is safe to take in high doses for six weeks. It also helped reduce systolic blood pressure — the higher of the two numbers in a reading — by 10 points among participants who had somewhat elevated levels. It did not lower blood pressure for people who already had normal readings.

But the study was small — only 24 people completed it—in addition to being brief. So the finding did not reach statistical significance.

Nonetheless, both ChromaDex’s chief scientific officer and the lead scientist on the study say the new research confirms the supplement’s promise. “It’s very exciting,” says Charles Brenner, the company’s chief scientific adviser, who conducted early research on NR but was not directly involved in this study.

The 24 study participants took 1,000 milligrams a day of Niagen, four times what’s recommended on the bottle. “It’s like taking a bottle per week rather than per month,” Brenner says. But he adds that many customers are already taking more than what’s recommended. “Almost certainly, therapeutic doses will be higher than 250 milligrams per day,” he said in a follow-up email.

Although sometimes in medicine less is more, the dose used in the study was based on amounts shown most effective in lab mice, says Christopher Martens, who led the research at the University of Colorado.

Stress test

In the body, NR is converted into nicotinamide adenine dinucleotide (NAD), which Brenner describes as “the central regulator of metabolism.”

NAD levels fall naturally with age, and many other factors can knock your NAD levels out of whack, including heart failure, brain diseases, alcohol, and even changing time zones, says Brenner, who is also the head of biochemistry and co-director of the Obesity Research and Education Initiative at the University of Iowa.

In his lab research, Brenner has found that NR reverses those negative effects in mice. “If you can give the animal that’s under this metabolic stress nicotinamide riboside, it’s going to allow the stressed tissues to restore their NAD level and improve their function,” he says.

The new study was the third published analysis of NR in people. Together the studies show that the supplement increases levels of NAD in the body. The link that’s yet to be confirmed is whether that extra NAD does anything good, and for whom.

“It’s pointing in the right direction, but here it’s not significant so we can’t draw any conclusions as good scientists,” says David Sinclair, a Harvard Medical School geneticist who works on similar research and has ties to Elysium.

“We need to conduct much larger-scale studies before I can recommend it to the masses.”

Sinclair, who also co-directs the Paul F. Glenn Center for the Biology of Aging at Harvard, published his own research last week in the journal Cell, showing that he could reverse the aging of blood vessels in mice. The loss of a protein called sirtuin 1, which can be triggered by the age-related decline of NAD, damages the vessels, the study found. Sinclair and his colleagues used an NAD precursor called nicotinamide mononucleotide, or NMN, to spur the reversal. (One of Martens’ co-authors has also studied supplementation with NMN and found similar benefits in mice.)

Martens, now an assistant professor at the University of Delaware, says caloric restriction, which is known to extend life span in animals, works the same way — boosting NAD levels to improve cellular health and extend life. But caloric restriction is also known to trigger bone loss and reduce immune function. Martens, Brenner, and Sinclair all say that boosting NAD seems to have fewer side effects than restricting calories.

“Our study provides very promising evidence that NR may have some physiological benefits, but I don’t think that by themselves our data are the definitive measure of safety by any means,” says Martens. He received supplies of Niagen and some funding from ChromaDex for the recent study, but he developed the research plan and protocol independent of the company.

He says the suggestion from his study that Niagen might reduce blood pressure and blood vessel stiffness should be used to direct future research, rather than as evidence of Niagen’s effectiveness. There are 10 active clinical trials involving nicotinamide riboside, looking at whether the supplement affects brain function, muscle metabolism, kidney injuries, metabolic health, the immune system, and the heart.

“We need to conduct much larger-scale studies in hundreds of people to confirm its safety,” Martens says, “before I can recommend it to the masses.”

This story was updated on March 31, 2018, to correct that Brenner is ChromaDex’s chief scientific adviser, not chief scientific officer, and to clarify the description of the study’s findings in people with normal blood pressure.

More on the Supposed Youth Pill was originally published in proto.life on Medium, where people are continuing the conversation by highlighting and responding to this story.

Stem cells are overhyped as a cure for everything. But they‘re finally showing promise in making elderly people stronger.

Phillip George golfs regularly, works out on a treadmill, and lifts a few weights — “not body building, just toning,” he says. Now in his 70s, the retired plastic surgeon used to get achy if he overdid it at the gym or the golf course, and often popped a few Advil or Tylenol.

But George cut way back on the painkillers two years ago, after becoming one of the first patients to try a new tactic to slow aging. As part of a clinical trial led by University of Miami cardiologist Joshua Hare, George got an infusion of millions of someone else’s stem cells, the kind of multi-purpose cells that can form other types of cells. “The pain diminished dramatically,” George says.

There are a lot of doctors who promise cures from stem cells. Hare isn’t one of them. At least not yet.

Nevertheless, after spending his career investigating what stem cells can do for the body, Hare thinks he’s hit upon a way to reduce frailty, boost the immune system and heart, and maybe even fight off Alzheimer’s: by giving patients large doses of a certain kind of stem cell.

His approach hasn’t been proven to work yet, but a review of clinical trials and discussions with scientists suggest that Hare is closer than anyone else to using stem cells to address problems caused by aging.

Although stem cells are considered an incredibly promising area of research, the procedures that have been definitively shown to work are ones that have existed for decades, such as bone marrow transplants and similar interventions for cancer and some blood diseases. No new treatments using the cells have been proven to be medically effective.

It’s not for a lack of trying: the National Library of Medicine lists about 1,700 ongoing studies involving stem cell treatments. But companies that sell treatments for everything from knee pain to autism and heart disease to Parkinson’s disease do not yet have scientific proof in humans.

On top of that, stem cell therapy can be risky when sloppily delivered. Three older women were blinded by a treatment intended to reverse their vision loss, according to a report last year in the New England Journal of Medicine. Many others, including professional athletes and celebrities, have spent tens of thousands of dollars for treatments that have not been shown to be any more effective than placebo. In stepping up its enforcement against unscrupulous clinics last year, the U.S. Food and Drug Administration warned consumers to avoid stem cell therapies that are not FDA-approved, unless they are part of a registered research trial.

“You can really consider them to be these miniature drug-delivery factories.”

That was the case when Phillip George got his infusion two years ago. He was in the first clinical trial to test these cells as a treatment for aging-related frailty. He says the infusion wasn’t painful, and he doesn’t think he took any kind of a risk, even though the procedure had been tried on only about 100 people before him. George also had known Hare for 11 years, since he was on the hiring team that brought the younger doctor to Miami.

So far, so good, George says: “Two years into the process, I don’t see or recognize any negatives from it.”

Regeneration

Your supply of stem cells naturally falls with age. This makes it harder for the body to repair damage, and can lead to inflammation. Inflammation, in turn, undergirds many of the problems we associate with old age, including frailty, heart disease, immune weakness, and Alzheimer’s, says Anthony Oliva, senior scientist at Longeveron, the privately held Miami company that Hare started to bring his ideas to market.

Longeveron uses mesenchymal stem cells, which come from bone marrow. They are known to be involved in regulating and sometimes reducing inflammation, as well as in helping to boost repair mechanisms for blood vessels. They may also prompt the body’s own stem cells to get more active in beneficial ways. There are currently 817 studies worldwide investigating the use of mesenchymal stem cells in people, for everything from knee injuries to ulcerative colitis, according to the federal government’s ClinicalTrials.gov. Mesenchymal stem cells are being tested in cats to see if they can reduce feline inflammation.

“You can really consider them to be these miniature drug-delivery factories,” Oliva says, describing mesenchymal stem cells as almost miraculous. “They can last for many months inside the recipient. They’re homing to the site of inflammation and damage. They are decreasing inflammation. They’re promoting improvement of the vasculature. They’re stimulating intrinsic stem cells to repair and regenerate over months.”

Hare’s research has cataloged how an objective measure of inflammation, the cell-signaling protein TNF-alpha, falls after an infusion of mesenchymal stem cells. In both animals and people, Hare says, the protein level remains lower for six to 12 months.

The cells also appear to be safe. “Working in medicine 30 years, I’ve never seen anything this well tolerated,” Hare says.

The immune system doesn’t react to these donor stem cells because it essentially doesn’t see them, Oliva says. Most cells in the body express a protein called MHC class II on their surface. The protein acts like a flag to alert the body to something foreign. In an organ transplant, the patient’s MHC class II has to match the donor’s to reduce chances of rejection. But mesenchymal stem cells don’t have these flags.

Longeveron uses cells from young donors, who are paid a small stipend and have been screened three times for diseases like HIV, hepatitis, and Zika, Oliva says. Their mesenchymal stem cells are extracted in a far less painful way than you might imagine, with just local anesthesia, a single needle stick, and a Band-Aid to cover the spot.

Longeveron then cultures the cells—putting them in a fluid to make them proliferate—before infusing them into a patient. For now, one donor can supply tens of patients, but Hare hopes to improve the culturing process so that one donor can provide enough cells for several hundred doses. If the company’s trials persuade regulators to approve the therapy, “we’re going to have a very large market and a very significant need,” he says.

A mysterious result

For its frailty research, Longeveron is now running a phase 2b trial — roughly the midpoint of the clinical trial process. It has tested its cells in about 20 out of 120 patients so far, says Suzanne Page, the chief operating officer.

Longeveron also has an early trial comparing the donor cells versus a placebo in a small number of patients with Alzheimer’s disease; another trial looking at frail patients’ resistance to the flu virus after receiving the donor cells compared to placebo; and a fourth looking at metabolic syndrome. Hare is also conducting a study checking back with patients who received stem cell treatments years ago for heart conditions.

To treat organ damage, like a heart attack that leaves a scar in the heart muscle, stem cells probably have to be injected directly into the organ, Hare says. But for a systemic, aging-related condition like frailty, the cells can be infused into the bloodstream because they tend to “traffic to inflamed areas,” he says.

If further trials confirm Longeveron’s approach, “we’re going to have a very large market,” Hare says.

Longeveron’s first published study on frailty showed that patients such as George, who received 100 million mesenchymal stem cells, showed “remarkable improvements in physical performance measures and inflammatory biomarkers.” The average age of the patients was 75.5.

Oddly, the patients who received a double dose of 200 million donor cells did not see any benefit at all. And that result fuels the concerns that molecular biologist Andrew Mendelsohn has about the research.

Mesenchymal stem cells have been the subject of hundreds of clinical trials, notes Mendelsohn, who wrote a commentary about Longeveron’s experiment in the journal Rejuvenation Research. Some studies show improvements, some don’t. When the studies are repeated, their results are inconsistent.

“If you do the experiment in mice, you see all kinds of great results. When you get to people you get all kinds of mixed results,” says Mendelsohn, director of molecular biology for the Panorama Research Institute, a privately owned biomedical research and development holding company in Sunnyvale, California.

Mendelsohn says he thinks Hare’s research has promise. But he won’t be convinced, he says, until he sees clear evidence in repeated clinical trials. “I have a strong belief that eventually it can be engineered to work out, even if it’s not nearly as effective as we might like it to be,” Mendelsohn says.

Paul Knoepfler, a biologist and stem cell scientist at the UC Davis School of Medicine, says he too is troubled by the inconsistent results of stem cell studies, and by the therapy’s relatively modest benefits.

Other research suggests to him that donor mesenchymal stem cells don’t stay in the body for very long, contrary to what Oliva says about how they last for months. Knoepfler is not sure how patients could have a long-term benefit if the body clears out the cells within a week or so.

Furthermore, frailty and other age-related processes are complicated. They’re not caused by one trigger and they probably can’t be fixed by one type of treatment, Knoepfler says.

Even so, he considers Hare’s work worthwhile and says it’s being conducted responsibly. “I don’t see any red flags,” Knoepfler says. “It’s just sort of early days.”

Phillip George acknowledges that the benefits he saw might have been caused by a placebo effect. But he’s still signed up to get a second infusion of the cells, part of a test of whether it can be given multiple times without harm.

“I’m not a Pollyanna. I’m not jumping at the first of everything,” George says. But if he has the opportunity to benefit from a potentially exciting new treatment, if there’s no apparent downside, and if he can benefit science in the process, then why not try?

The Life Extension Death Match

This Anti-Aging Injection Might Actually Work was originally published in proto.life on Medium, where people are continuing the conversation by highlighting and responding to this story.

Nobel laureates and billionaires fight to sell you what they hope is a longevity pill.

“Live healthier for longer through extraordinary science.”

That’s the promise offered by a supplement company called Elysium Health, whose advertisements commonly pop up in social media feeds and in science-related publications. Its founder is an MIT professor and its advisory board includes seven Nobel Prize winners. Do an Internet search for the key ingredients in Elysium’s sole product, Basis, and you’ll come up with reams of scientific research. Customers shell out $40 to $60 a month for a bottle.

But there’s a lot here that isn’t what it seems.

First, the science is still in mice. There’s no evidence that Basis has helped a person live healthier for longer. At least not yet.

Second, Elysium doesn’t make what it sells. Like many supplement marketers, Elysium gets its product from a supplier.

Elysium used to buy its ingredients from an 18-year-old natural products company called ChromaDex. But earlier this year, ChromaDex began to focus on reaching consumers itself. It sold off part of its business and accepted cash infusions totaling nearly $50 million to market its own version of one of the two active ingredients in Basis. The ingredient is nicotinamide riboside, which ChromaDex sells to suppliers as Niagen and to consumers as Tru Niagen, at $45 a bottle or $33.75 a month for an annual subscription. The business opportunity is huge, says ChromaDex president Robert Fried, who calls nicotinamide riboside, or NR, a “once-in-two-lifetimes ingredient.”

Then this fall, ChromaDex sued Elysium for $200 million, essentially accusing its former customer of trying to reap the benefit of its years of work.

Now both companies are fighting to be the dominant provider of NR — and betting that the science behind it will continue to get more compelling.

To your corners

Nearly three years ago, when Elysium began selling Basis, few in the general public had heard of NR, a form of vitamin B3 that is naturally found in milk.

But the scientific world was buzzing about the life-extending potential of a molecule called NAD, which is involved in basic cellular activities like energy production and DNA repair. Harvard anti-aging researcher David Sinclair had shown in mice that reversing the natural decline in NAD that comes with aging can improve metabolism and overall health, and essentially slow the hands of time. Other research showed that NR could boost the levels of NAD in the body.

ChromaDex’s CEO says he had been following work on NAD since 2006, and beginning in 2011, licensed patents from Dartmouth, Cornell, and Washington universities, covering the manufacturing, composition, and use of NR. Around the time Sinclair’s paper was published, ChromaDex developed a reliable way of making NR and began selling it to several supplement providers.

Elysium launched the following year and started selling Basis subscriptions online in early 2015. In Basis, it combined NR with pterostilbene, a compound from grapes and berries that resembles resveratrol, the red wine component that has been shown to turn on genes believed to be involved with longevity.

The company, co-founded by Leonard Guarente, who runs a center on the biology of aging at MIT, promised to upend the supplement industry. Instead of selling questionable products sourced from even-more-questionable suppliers, Guarente pledged that Elysium’s ingredients would be well vetted and pure. The company would plow a large portion of its profits into top-notch scientific research, the kind rarely seen in the world of nutritional supplements.

His vision for a new type of supplement company intrigued prominent scientists, many of whom were frustrated that companies could legally make essentially empty promises, encouraging people to spend billions on products that had no scientific support. Elysium attracted seven Nobel laureates to its scientific advisory board along with over a dozen more researchers, although most of them have expertise in areas other than the biology of aging.

Elysium is a private company, so it’s not clear how well Basis has been selling. But it was enough for Elysium to put in an order in June 2016 that was three times bigger than normal, eventually agreeing to pay nearly $3 million for it, according to ChromaDex’s lawsuit against Elysium. ChromaDex also agreed to stop selling the combination of NR and pterostilbene to anyone other than Elysium.

Then, both sides say, the relationship soured. Two top ChromaDex executives, the vice president of sales and director of scientific affairs, both quit and went to work for Elysium. And Elysium refused to pay for the ingredients it ordered that June, accusing ChromaDex of violating the terms of their contract.

In the first half of this year, ChromaDex stopped supplying Elysium with ingredients. Elysium has since found another supplier, which it has not disclosed.

But the battle over NR rages on. In August ChromaDex filed what’s known as a citizen’s petition with the Food and Drug Administration, claiming it tested Basis made by Elysium’s new supplier and found that it had been “contaminated with toluene.” The petition, signed by ChromaDex’s CEO, called for Basis to be removed from the market until its safety can be checked.

Elysium responded that ChromaDex was abusing the citizen’s petition process, pointing out to the FDA that toluene is commonly used in pharmaceutical processing—including in ChromaDex’s own manufacturing specifications—and that ChromaDex allegedly found it at levels far below what would be dangerous for human health. “ChromaDex’s sole purpose for submitting the petition to FDA was not to raise any safety issue, which does not exist, but to harm Elysium, with which it is engaged in litigation and against whom it is preparing to compete,” the company said in a statement to NEO.LIFE. Elysium is suing ChromaDex over the petition.

And overall, Elysium says, its new version of NR is better than ever, thanks to a new supply chain that “has allowed us to take an exceptional product and make it even purer,” the company’s statement said.

The two companies have been ordered into mediation, but the parties haven’t met yet, and it’s too soon to know whether that will resolve the battle.

The big prize

Clearly, a lot of people think there’s money to be made on nicotinamide riboside.

ChromaDex in April announced a $25 million investment led by Hong Kong billionaire La Ka-Shing, who owns a chain of health and beauty stores, mainly in China. The company recently raised another $23 million, including $7 million from ICONIQ Capital, a California investment group that has invested for Mark Zuckerberg, Sheryl Sandberg, and other wealthy people in Silicon Valley. Pharmaceutical entrepreneur Phillip Frost owns a chunk of the company as well.

They’ve been rewarded by ChromaDex’s sales of Tru Niagen to consumers. In the last financial quarter, revenue jumped 55 percent from the year before. The stock price has tripled since April.

Elysium won’t release financial details but says it has seen strong sales growth as well. The company has raised a total of about $26 million in two fundraising series, the last of which was in 2016. Its investors include Gerald Chan, of Morningside Partners, whose family gave a naming donation to the Harvard School of Public Health in 2014 in honor of their father, T.H. Chan.

These big bets on NR seem premature to Jeffrey Flier, the former dean of Harvard Medical School and an expert in cellular metabolism. There is no scientific evidence that NR does what both companies suggest—that it provides more energy, boosts cellular health, and extends life, he said in a recent interview in his office, high above the medical school’s quad.

ChromaDex’s president says NR could be a “once-in-two-lifetimes ingredient.”

Flier said a high-profile Boston businessman whom he declined to name came to see him after he wrote a Boston Globe op-ed in March criticizing Elysium for using prominent researchers and the veneer of science to promote its product. “I don’t have anything against Elysium,” Flier said he told the man. “It’s just that I like good science.” The man kept pushing, Flier said, insisting that Basis had made him feel much better, and leaving a bottle behind for Flier to sample.

Flier, who later threw out the pills, said he told the man that his own experience and the testimonials of others were proof of nothing. Evidence can only be found in the type of large-scale human research that hasn’t yet been done on NR.

To win approval to sell a drug, a company must show that a product safely and effectively fights disease. It’s virtually impossible to prove that a product extends the human lifespan, because such a study would take decades and be prohibitively expensive. Selling a nutritional supplement is easier and cheaper. All a company has to do is avoid making specific claims — like life extension — that it can’t prove. That’s why bottles of Basis offer “cellular health and optimization” rather than longevity. The longevity benefits are instead implied by Elysium’s corporate “vision,” for life that is “healthier and longer through extraordinary science.”

What researchers have shown so far is that taking NR increases NAD in the blood of both mice and humans. In a new placebo-controlled study of 120 healthy older adults, funded by Elysium, people who took the normal dose of Basis for a month saw a 40 percent jump in their NAD blood levels. Those who took a double dose saw a 90 percent boost. The study was published this fall but was conducted in 2016, while ChromaDex was still Elysium’s supplier.

There’s also good evidence that NAD has the potential to affect aging and its related diseases — in mice.

Charles Brenner, ChromaDex’s new chief scientific adviser and a long-time leader in NAD research, said the molecule is a central regulator of metabolism in every type of tissue. “NAD underlies everything that is important,” he told me after giving a talk last month at Harvard. NAD helps convert fuel into energy, power muscles, circulate blood, and repair DNA.

Brenner, now at the University of Iowa, has spent more than a dozen years tracking the pathways the body uses to create NAD — and he discovered that NR offers the most efficient route. “We found a pathway that stressed cells really depend on,” he said. “The more metabolically stressed an animal is, the more it benefits from NR. We think that in the coming months and years, data will emerge from human clinical testing that will strongly justify particular human populations taking it.”

“This is the type of thing that might yield some bad news that will hurt all of us.”

Rudy Tanzi, an Alzheimer’s researcher at Harvard, said he joined ChromaDex’s scientific advisory board this year because he believes that a shortfall in cellular energy plays a key role in Alzheimer’s — and that boosting NAD might jumpstart cellular energy. He’s tried NR on mice bred to have an Alzheimer’s-like condition and saw a benefit. Another researcher reported similar results last week.

“I don’t want to say anybody should take Niagen to prevent Alzheimer’s, but my goal is to investigate: can Niagen help in Alzheimer’s?” Tanzi said. He takes the supplement himself most days, along with his multi-vitamins, even though he says he’s not sure if it’s doing him any good.

The reason Tanzi can’t be sure is that there still isn’t any research showing that the higher levels of NAD in the human body have the benefits that have been seen in mice.

It’s extremely common for promising results in mice to fail to carry over to people. That’s happened countless times in research on aging, cancer, and particularly Alzheimer’s. And even though research might someday show a benefit for people, it’s not clear how much of an NAD boost would be required. The 90 percent increase that apparently comes from a double dose of Basis might not be enough. Or it could be too much.

NAD expert Eric Verdin, who’s not connected to either company but has collaborated with Brenner on research and is a friend of Guarente’s, said he’s also enthusiastic about what he considers early research on NAD. “The loss of NAD that occurs during aging, I predict will end up being a major pathway in our fight to delay aging and the diseases associated with it. The data is really there,” said Verdin, president of the Buck Institute for Research on Aging in Novato, California.

But what’s much less certain, he said, is whether a supplement can correct this age-related decline. “That’s completely unclear, even though a lot of people are buying these supplements. There’s no evidence they are correcting the problem in older people,” he said.

Verdin said he is also worried that boosting NAD levels might in rare cases spur cancer — and that if something does go wrong with the supplement, it could tarnish his whole area of scientific research. “I have some concern about the field of aging jumping ahead of itself and embracing unproven treatments,” he said. “As a physician and scientist in the field of aging, I’m a little worried this is the type of thing that might yield some bad news that will hurt all of us.”

Overall, he added, NAD supplementation has “become a story about money more than about science and medicine.”

This story was updated on December 15, 2017, to clarify that NR is a form of vitamin B3 and that ChromaDex specifies how NR should be manufactured but does not necessarily manufacture it itself.

The Anti-Aging Habits of Longevity Experts

The Life Extension Death Match was originally published in proto.life on Medium, where people are continuing the conversation by highlighting and responding to this story.

W e all know what we should do to live long, healthy lives — exercise regularly, sleep well, avoid overindulgences — but aren’t there any magic pills or supplements that improve your chances even further? For some insight, I asked a number of scientists who are deep in anti-aging research what they take.

There’s no consensus. Some use the products of their research, popping pills or getting scans that they’ve started companies to develop. Others say we don’t know enough yet to risk swallowing something that might also cause harm. Someday, they all hope, science will help them and everyone else stay healthier and live longer. In the meantime, keep exercising.

Here’s what four scientists do in their own lives:

Aubrey de Grey insists that he never thinks about his own aging (he’s 53) and takes no steps to affect it because “the overwhelming message from research is that they will do very little good.” He adds: “I actually don’t take any such measures, other than the most important one of all, namely to try all I can to hasten the development of new therapies that will keep me and everyone else youthful in old age.” In his day job, as chief science officer and co-founder of the anti-aging non-profit SENS Research Foundation, de Grey works on an “engineering” approach to aging: repairing damage as it occurs, to keep levels low enough that disease won’t result. His devotion to that strategy probably comes at the expense of his own aging rate, de Grey says, “mostly in the sense that I don’t get nearly enough sleep.”

Judith Campisi, who is in her 60s, also denies thinking much about her own fate. “I’m too busy,” says Campisi, who studies the molecular basis of aging at the Buck Institute for Research on Aging outside San Francisco. She is also a cofounder of Unity Biotechnology, a company that aims to counter aging by eliminating cells that have stopped dividing and may be leading to disease.

Only slightly tongue-in-cheek, she says the main steps she takes to keep herself young and energetic are drinking wine and worrying. That’s right: rather than avoiding stress, Campisi says she embraces it. Challenging the brain with stress keeps it young, she says. She’s quick to note that she’s talking about the kind of pressure inherent in the life of a busy scientist, not the life-or-death stress of, say, a Syrian refugee.

She last took a vacation in 2009. “I just don’t have any great desire or need to go away for two weeks and sit on a beach. I’d be bored to death.” She enjoys a glass of good wine whenever she can. “I just love wine. I hang out with winemakers, things like that,” Campisi says. Not only has moderate wine drinking been associated with longevity, but having passions is healthy, she says.

J. Craig Venter, 70, says his science has already saved his life twice. The first time was when he sequenced his own genome. (He was the first person to ever get his own genetic code completely mapped.) That revealed he was at high risk for developing deadly skin cancer, so he became a careful observer of his skin. A few years later he detected a dangerous growth before it could spread. More recently, a workup from a company he co-founded, Health Nucleus, revealed that he had early-stage prostate cancer that was likely to become aggressive. Venter had his prostate surgically removed and has had no repercussions.

He also stays very active. His trainer comes three times a week, he plays tennis regularly, and a few days after our conversation, he was headed to the Arizona desert for a weekend of off-road motorcycle and dune buggy racing. “You can avoid a lot of significant joy in life by doing nothing,” he notes. He rides ensconced in full protective gear, including a helmet and a device that rapidly inflates into a protective bubble in an accident.

Venter has lost more than 50 pounds in recent years, mainly by more careful eating. He’s been on baby aspirin and statins for more than 20 years, because of a family history of heart disease. (His father died at age 59 of sudden cardiac death, less than two weeks after his cardiologist told him he was in fantastic shape.) He takes no vitamins or pills explicitly to extend life. However, he is on the diabetes drug metformin, which is being studied for its possible longevity benefits, since tests detected changes in his insulin sensitivity.

“I’m trying to use the best of scientific knowledge to be as healthy as I can for as long as I can,” he says. “I totally expect to die, without some radical change, some time before I’m 100 years old.”

We all know people who look older or younger than their age. In 2011, Harvard geneticist David Sinclair was helping to start a company called InsideTracker, which aims to measure someone’s biological rather than chronological age. At the time, Sinclair was in his early 40s, but the test said he had the body of a 57-year-old. “I said, I’m going to die young.”

Instead, he aggressively stepped up his anti-aging efforts. Sinclair was among the scientists who first pegged resveratrol, a natural compound found in red wine, as a possible anti-aging supplement. It hasn’t lived up to that hype, but just in case, he’s been taking a concentrated form of it for more than a decade.

In the last year, he added a compound called NMN (Nicotinamide mononucleotide), which his own research in mice suggested had anti-aging effects. The benefits were dramatic, says Sinclair, who is trying to develop the compound into a drug. He quickly lost 15 pounds without significantly changing his lifestyle, bringing him back to his college weight. Sinclair is now 47, but he says InsideTracker measures him at a youthful 31.

The Anti-Aging Habits of Longevity Experts was originally published in proto.life on Medium, where people are continuing the conversation by highlighting and responding to this story.