Silicon Valley fever dreams of immortality aside, it turns out that most people don’t want to live forever. That’s what one U.S.-based survey found when it queried about 900 respondents and asked if they would pop a pill to extend their lives.

Since 1950, the average lifespan across the planet has increased by 26 years—but subtract nine years for the time spent fighting one disease, disability or another. A 2021 study found that’s how much shorter the average healthspan is than lifespan, and that one-fifth of an individual’s life will be lived with morbidity. Suddenly, the math of a longer life no longer adds up to a net positive.

Rejuvenating the longevity industry

But, in fact, healthy aging is more of a numbers game than one might think. One of the biggest breakthroughs in longevity research in the last decade or so is the discovery that lots of interventions slow aging—at least in things like nematodes and mice.

“That means there are hundreds of different candidate strategies for slowing human aging, and we just have to test them,” noted Brian Kennedy, director of the Center for Healthy Longevity and professor at the National University of Singapore.

Kennedy and colleagues are doing exactly that, investigating everything from promising longevity drugs like rapamycin to natural products like alpha-ketoglutarate (AKG), a molecule in the body that is involved in a number of metabolic and cellular functions, including gene regulation and expression.

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Kennedy is considered a pioneer in geroscience, a field that seeks to understand the genetic, molecular and cellular systems behind aging. His work with colleagues at MIT in the 1990s on a group of so-called immortality genes called sirtuins first brought him to prominence. The former director of the Buck Institute for Research on Aging, Kennedy is also chief science officer at Ponce De Leon Health, a supplement company using the branded ingredient LifeAKG in its flagship product Rejuvant.

In 2020, he and his colleagues published research in the prestigious journal Cell Metabolism that demonstrated LifeAKG, formulated with a proprietary time-release technology, significantly extended lifespan and healthspan in mice. A 2021 follow-up study using LifeAKG in humans is perhaps the first of its kind to show an astonishing eight-year improvement in healthspan based on epigenetic changes in DNA over a seven-month period.

The pluses around NAD+

AKG is one of a number of natural products showing up in more and more dietary supplements specifically formulated for healthy aging, a market that the Nutrition Business Journal projects will hit $700 million by 2025. Ingredients like CoQ10, dehydroepiandrosterone (DHEA) and resveratrol continue to top the list of sales each year, but nearly a third of the category is something of a black box simply labeled “other.”

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Perhaps no “other” ingredients in recent years have generated as much interest as those targeting NAD, or nicotinamide adenine dinucleotide, a coenzyme in cells that is also critical to many metabolic and cellular processes, including mitochondrial health. NAD levels flag as we age, and since the 1990s scientists have studied how different precursors of the oxidized form of NAD, NAD+, might help boost or restore cellular health. But getting older isn’t the only reasons NAD declines. Stress is also a major factor, according to Andrew Shao, PhD, senior vice president of global scientific and regulatory affairs for ChromaDex.

“What we’re seeing, mainly in preclinical but also clinical studies, is that there’s functional decline, starting at the mitochondrial level, that accompanies this disruption in NAD metabolism due to metabolic stress,” he explained. “So, what do we do? Well, if we can maintain those NAD levels, we’re essentially equipping ourselves and our tissues in our body to better cope with those inevitable stresses that happen and accumulate over time. That’s what boosting healthspan is all about.”

Los Angeles-based ChromaDex has devoted its R&D efforts to the NAD+ precursor nicotinamide riboside (NR), which it markets to manufacturers under the brand name Niagen. It also sells its own NR-based product under the Tru Niagen label. While there are many pathways to reach NAD+, Shao said his company believes NR offers the most efficient way to get there.

It’s not just fanciful talk. More than a dozen clinical studies have been conducted on Niagen that demonstrated increases in NAD+ that were associated with a number of health benefits. For instance, a 2022 randomized, double-blind, placebo-controlled study in patients with heart failure showed that those taking NR nearly doubled their whole-blood levels of NAD+, which correlated to a decrease in systemic inflammation.

Making sense of senolytics

The Food and Drug Administration (FDA) just killed the buzz around another NAD+ precursor supplement ingredient, nicotinamide mononucleotide (NMN), because it is also being investigated as a drug. In the United States, at least, NR appears to be the safest bet for products targeting NAD+ for improving healthspan.

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That’s not the only reason that Life Extension chose Niagen for its NAD+ Cell Regenerator, one of several products in the dietary supplement company’s portfolio of longevity-targeted solutions. The main reason is that there are fewer biochemical steps for NR to get into cells compared to NMN, according to Vanessa Pavey, a naturopathic doctor who works as an education scientist for Life Extension.

She said that while there is growing interest in NAD+ products, the company’s top sellers in the healthy aging category remain long-time stalwarts like resveratrol. One formulation combines Niagen and a highly bioavailable form of resveratrol called trans-resveratrol, along with bioavailable-enhanced phytonutrients quercetin and fisetin.

These two latter antioxidant flavonoids are also drawing more scrutiny for their healthy aging effects related to clearing out senescent cells, old cells that have lost their ability to divide but don’t die. These so-called zombie cells accumulate and spew inflammatory compounds associated with age-related diseases.

“In fact, the literature is saying that fisetin is the most potent herbal senolytics identified yet,” Pavey said. “Even more powerful than quercetin, even though that was the first one looked at. So our take is, let’s take them all.” The result is Senolytic Activator, which also includes black tea leaf extract, another senolytic flavonoid, and apigenin, a phytonutrient for tamping down the inflammatory response from senescent cells.

The clock is ticking

One key breakthrough helping keep longevity science alive is the discovery of different biomarkers of aging, such as the DNA methylation clock used in the LifeAKG study, according to Kennedy. “They’re not perfect yet,” he noted, “but they’re really useful, because they give us an endpoint to test whether the interventions are working or not.”

These aging clocks are becoming increasingly more sophisticated thanks to big data and machine learning techniques. A company called Deep Longevity, for instance, has developed a platform dubbed Senoclock that can reportedly predict biological age by analyzing data from clinical blood reports, psychological surveys, microbiomic tests and epigenetics. It then offers recommendations, including dietary supplements, to improve healthspan metrics.

“If we are dealing with a clinical blood test, BloodAge might tell us that a patient would look two years younger if they had 10% lower cholesterol,” explained Fedor Galkin, research director at Deep Longevity. “Now that we have this piece of information, our recommendation engine checks the curated database for any applicable recommendations.”

The ability to slow down aging represents an exciting time in geroscience. But Shao at ChromaDex cautioned that natural product companies have to tread cautiously, rather than get caught up in the hype, especially when it comes to health claims.

“Aging can’t be stopped or reversed,” he said. “What you can do is, you can change that trajectory. We’re all going to decline; our function is going to decline. The question is, at what pace? That’s where we have control. That’s where these products and lifestyle changes … come into play.”

For Kennedy, longevity is still about numbers—the eight billion on Earth. “It’s not about billionaires. It’s about billions,” he said. “There are billions of people who need this. What we’re trying to do, especially in the academic world, is to look at cost-effective interventions and cost-effective biomarkers that we can scale to Singapore and beyond.”