There are a number of markers, expressed homogeneously across human cells and DNA, which are associated with the physiological process of aging. These markers come in tandem with increases in chronic inflammation, disruptions in immune homeostasis, heightened oxidative stress, and more. A number of specialty ingredients found in dietary supplements and functional foods and beverages are now being marketed as tools to reverse these markers, and, as optimists hope, the hands of the cellular clock.

Hallmarks of Biological Age

“Even though there is still no consensus about whether aging is biologically programmed, almost all gerontologists agree aging is a clinical disease responsible for the vast majority of deaths among the world’s population,” said Marianne McDonagh, vice president of sales for Bioenergy Life Science, Inc.

It remains to be seen whether nutritional interventions can unlock healthy aging directly by reducing phenomena such as DNA methylation, senescence, NAD+ depletion, or telomere shortening, which lead to cascading adverse effects on cells’ ability to function.

DNA methylation, a process in which small molecules called methyl groups are added to DNA, proteins, or other molecules, takes place gradually over the human lifespan and represses gene expression. DNA methylation was discovered many years ago, but it wasn’t until relatively recently that researchers began to widely use DNA methylation as an epigenetic clock.^1-2

According to a 2020 review, a number of nutrients and food groups are associated with DNA methylation rates in healthy populations, including folate, vitamin A, vitamin D, whole grain cereals, fish, legumes, fruits, and vegetables.³

Science has come a long way since Elizabeth Blackburn discovered the enzyme telomerase, which lengthens strands of DNA before the cell copying stage. Since the production of telomerase declines with age, telomere shortening is associated with age-related pathologies, such as homeostatic dysregulation, frailty index, and more. Emerging studies have linked specialty supplements, broad dietary patterns, and exercise to greater telomere length.^4-6

Another phenomenon tied to the aging process is senescence, in which cells are unable to continue multiplying even in optimal conditions. The number of senescent cells in the body increases with age; these cells express pro-inflammatory cytokines and other toxins which impair tissue function.⁷

“All of these hallmarks represent a reason why the aging of our cells can affect our lives significantly. With a longer lifespan, we don’t always experience a longer health span or higher quality of life,” said Shawn Baier, vice president of business development, innovative products division, at TSI Group. “It is important to note that supplementation won’t completely reverse cellular aging, but it can address some of the negative effects connected to it.”

Emerging Nutraceuticals

There are two primary outcomes for ingredients marketed for cellular aging. The first is inducing the death of senescent cells, and the second is improvements in the mechanical integrity of healthy cells, said McDonagh.

A collection of specialty ingredients have been studied for their role in boosting NAD+ (nicotinamide adenine dinucleotide), a coenzyme essential for energy metabolism, DNA repair, and other biological processes. NAD+ levels are estimated to decline by as much as 40-50% as people enter late adulthood.⁸

“Optimizing NAD+ status through precursor supplementation and its impact on age-related conditions will continue to be a topic of intense research interest,” said Dr. Andrew Shao, senior vice president of global scientific and regulatory affairs at ChromaDex. “Of particular importance to NAD+ precursors and other bioactive compounds is that a ‘one size fits all’ approach is not optimal. Recommendations need to be personalized, not just according to one’s genetic background, but also lifestyle habits and goals.”

The most established NAD+ boosters include nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and a select group of plant bioactives.

Nicotinamide riboside (NR), a patented form of vitamin B3 marketed by ChromaDex as Tru Niagen, has been linked in multiple human clinical trials to increases in NAD+ levels. In a study on a small group of 13 overweight or obese men and women, a daily dose of 1,000 mg of NR led to significant elevations in two markers of NAD+ synthesis, and improved skeletal muscle acetyl carnitine metabolism. A safety and metabolism study involving 140 overweight but otherwise healthy men and women found that eight weeks of supplementation with three doses of NR up to 1 gram daily was safe for all subjects, and NAD+ levels increased in a dose-dependent manner ranging from 14% to 114%. Another study showed that a higher dose of 2,000 mg of NR daily also appeared to be safe.^9-11

Through studies supported by ChromaDex’s external research program, lower endogenous NAD+ levels have been linked to a number of age-related conditions, including heart disease, Parkinson’s disease, Ataxia telangiectasia, autoimmune disorders, and more, Shao said. Outside of diseased populations, findings “suggest there is an opportunity to optimize the health of the general population with the proper supplementation program,” he said.

Bioenergy Life Science supplies a portfolio of ingredients centered around its proprietary D-ribose ingredient. “Our work at BLS primarily focuses on an anti-aging philosophy with the development and launch of RiaGev, the only nicotinamide riboside boosters that increase NAD+, ATP (adenosine triphosphate) and oxidative stress (through increasing endogenous glutathione) simultaneously,” said McDonagh. Accomplishing this can help to mediate the loss of homeostasis in cells, which leads to a functional decline in tissues and excessive circulating hormones such as cortisol or estrogens.

D-ribose, which is synthesized in the body from glucose, has also been established by pharmacokinetic studies to boost ATP levels in the human body. ATP provides energy to support many processes in living cells such as muscle contraction, nerve impulse propagation, chemical synthesis, and more.

In a study on 257 patients with chronic fatigue syndrome and fibromyalgia, subjects underwent a 3-week treatment with D-ribose and saw significant improvements in self-reported measures of their conditions, including 61.3% greater energy scores, 37% greater overall wellbeing scores, 29.3% improved scores in sleep, 30% greater mental clarity scores, and a 15.6% decrease in pain, as assessed through the Visual Analog Scale. The early data suggests that D-ribose has potential in the self-reported measures assessed.¹²

Another study conducted on D-ribose demonstrated its applicability in sports nutrition formulas. Pharmacokinetic changes were observed in a group of eight subjects who supplemented with D-ribose or a placebo thrice daily after a week of cycle training that consisted of sprints. While both groups saw similar depletions of muscle ATP after training, muscle ATP was restored to a level close to pre-training in the D-ribose group at a faster rate than the placebo group.¹³

In 2020, Amazentis Nutrition commercialized a proprietary form of urolithin A, branded as Mitopure. Urolithin A is a postbiotic compound shown in clinical research to increase mitophagy. Mitophagy is the selective breakdown of defective mitochondria to prevent them from accumulating and causing cellular degeneration. Urolithin A was studied as a common postbiotic compound produced by the breakdown of several precursor polyphenols found within food.

Urolithin A has a central role in mitochondrial function, in turn implicating its involvement in the essential functions of all organs. To date, most human clinical studies on Urolithin A supplementation have centered around healthy aging and muscle function.

In a study involving 66 older adults between the ages of 65 and 90, researchers found that Urolithin A supplementation resulted in some exercise-like effects, such as progressive improvements in muscle endurance, and an improvement in a walking test, that were not found in the placebo group after a 4-month period. There were significant reductions in acylcarnitines, ceramides, and C-reactive protein, which suggested a counteraction of age-associated muscle decline.¹⁴

In another study on 88 middle-aged adults, 4 months of Urolithin A supplementation was linked to improvements in muscle health, with a dose-dependent relationship. Both the 500 mg and 1,000 mg doses significantly increased muscle strength in the leg, with improvements also noted for VO2 max and a 6-minute walking test. Muscle biopsies demonstrated activation of mitophagy in the cells, and plasma markers demonstrated improvements in mitochondrial health and inflammation in the treatment groups.¹⁵

TSI Group recently launched Hobamine, a branded form of a compound called 2-HOBA that is extracted from buckwheat. In an NIH-funded study published in Inflammation in April, 2-HOBA supplementation was linked to positive changes in 15 inflammatory biomarkers in two small cohorts of younger and older adults. The ingredient, according to researchers, showed potential to ameliorate age-related declines in the immune system’s ability to self-limit its responses. 2-HOBA scavenges a pro-inflammatory reactive lipid, IsoLG. This can prevent the body’s formation of reactive oxygen species (ROS) from cascading out of control. As a result, ROS are neutralized before they react with DNA, proteins, and other components of the cell.¹⁶

“Normal, healthy levels of ROS are important for cellular signaling and immune defense and are something our bodies can deal with when production and removal are in balance,” said Baier. “The problem happens when we experience sustained excess ROS formation. When our bodies have excessive ROS formation, there is a chain reaction of events resulting in detrimental effects on our cells. IsoLGs are one of the common downstream products of oxidative stress and have been specifically linked to dysfunction in many different cell types.

“2-HOBA’s success owes much to the speed at which it can sequester IsoLGs and prevent downstream modification of DNA and proteins,” Baier continued. “Without 2-HOBA supplementation, damaging compounds formed during times of oxidative stress can run rampant in the cell, binding to and irreparably damaging cellular components like lipids, proteins, and DNA. This damage results in the dysfunction of these cellular components and eventually, the dysfunction or even death of the cell.”

Brand Platforms

Legacy brands are taking notice of emerging understanding about the mechanisms at play on a microscopic level, and are carving out a spot in the cellular health market. In 2020, Nestlé Health Science launched Celltrient, a brand on a mission to “help address the three main drivers of age-associated cellular decline.” The company launched with three products: Celltrient Cellular Protect, a formulation of glycine and N-acetyl-Cysteine (NAC), two precursors to glutathione; Celltrient Cellular Energy, which features Tru Niagen; and Celltrient Cellular Strength, which features Mitopure Urolithin A.

Another brand in the cellular aging arena is Healthycell, which harnesses bioactives and other ingredients to support cellular function. Its portfolio of healthy aging products includes Telomere Length, a formula containing ginseng, cat’s claw (Uncaria tomentosa), astragalus, and silymarin extracts in addition to B vitamins, L-citrulline, and zinc. Preliminary research indicates the formula may have a role to play in human telomere length, overall cellular function, and enhanced DNA repair.

The company has conducted research on its broad-spectrum dietary supplement branded as AM/PM Healthspan System, which concluded that supplementation resulted in decreased DNA damage and a decrease in a profile of biomarkers associated with chronic inflammation. The formula was most efficacious in the older adults who participated in the study. In addition to 24 essential vitamins and minerals, the product includes several blends of five or more herbal extracts, including: the Nucleus and Cell Membrane Antioxidant Protection Blend; the DNA Repair Blend; the Telomere Health Blend; the Stem Cell Health Blend; the Mitochondria Health Blend; the Cell Regulation Blend; the Gene Expression Support Blend; and the Absorption Enhancing Blend. Altogether, the supplement contains over 80 ingredients.¹⁷

Cellular aging is also a target for beauty-from-within products and brands. A new ingredient marketed by Monteloeder as Eternalyoung, for example, was based on preclinical data that suggested the polyphenol-rich blend of four botanicals maintained telomere length in human dermal fibroblasts. This translated to statistically significant improvements in wrinkle depth, elasticity, firmness, skin thickness, moisturization, epidermal water loss, and dark spot pigmentation in a 12-week randomized, controlled clinical study on women who supplemented with the ingredient daily.¹⁸

Differentiating Through IP

With so many relatively novel compounds in the space of cellular aging, a heavy emphasis on intellectual property exists compared to other areas of the market populated with commodity ingredients.

“Patents are granted based on the clinical work conducted to support your product and deem it patentable, otherwise, you can’t support your product; and what do you have if you don’t have anything to support it?” said McDonagh. “Our company was built on research and IP development with the discovery and launch of the multifunctional D-ribose, branded as Bioenergy Ribose, which is popular in a variety of cellular aging products.”

“The most robust and protected portfolios have some combination of patents within three categories: methods of manufacturing, composition of matter, and methods of use,” said Shao. ChromaDex’s portfolio consists of 60 owned or licensed patents in the three categories, which protect Tru Niagen, and other proprietary NAD+ precursor ingredients.

“Collectively, these patents provide strong protection for NR through the next decade that will allow ChromaDex to launch future innovations,” Shao said. “To our knowledge, no other company can produce NR including NRCI and other salt forms of NR at a commercial scale without violating one or more of these patents. Unlike commodity ingredients and products, which compete for market share with mostly fancy marketing and price, the emerging category of cellular aging requires significant attention to science to translate findings to humans.”

Regulatory Concerns

There is reason for concern that FDA could target a number of dietary supplement ingredients aimed at cellular aging.

For instance, at the end of last year, FDA declared that NMN may not be sold or marketed as a dietary ingredient, claiming the compound was first investigated for use as a drug. However, that determination only came after the agency had acknowledged a New Dietary Ingredient Notification (NDIN) for NMN without objection.

Cara Welch, PhD, director of FDA’s Office of Dietary Supplement Programs (ODSP), addressed the matter at SupplySide East in April, saying it was “unfortunate” that “we didn’t have all the information available to us,” at the time the agency acknowledged the NDI filing for NMN. Once the agency “connected the dots,” it had to backtrack.

Welch also noted that the agency hoped this case wasn’t perceived as a penalty. “We do our best to work with firms ... to ideally set companies up for success.”

While the FDA has taken years to develop new guidance on the NDIN process, Welch said it is still a priority for the agency. “The NDI notification process is an important part of how we regulate the industry,” she said. “The safety information that’s included in these [filings] is so important to us.”

Groups such as the Natural Products Association (NPA) and Alliance for Natural Health USA have argued that the agency has not provided evidence that NMN was ever approved as an investigational new drug (IND) prior to it being researched and marketed as a dietary ingredient.

“The current situation with NMN is yet another example of the inconsistent and mercurial way in which FDA chooses to both interpret DSHEA and use its limited resources to supposedly protect the public health. FDA has not articulated any risk to the safety of the public posed by NMN when marketed as a dietary ingredient or dietary supplement,” said Daniel Fabricant, PhD, president and CEO of NPA and Gretchen DuBeau, executive and legal director of Alliance for Natural Health, in a joint Citizens Petition to FDA.

At this point, “no ingredient is safe,” said McDonagh. “The NMN decision was just another example of the gray area that surrounds the overall dietary supplement industry,” she said. “This gives companies like BLS that have done the scientific development work more reasons to bring these ingredients to market, stand together, and support the industry.” 

However, Shao said that confidence can be placed in some novel ingredients for which one can be certain no drug studies have ever been conducted.

References

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