Supplementing with Naturally Produced Metabolic Molecules to Promote Longevity

Highlights

• Certain naturally produced molecules (known as endogenous metabolites) mediating metabolic responses link the body’s nutrient status to genetic changes.
• These genetic changes entail alterations to molecular tagging patterns on DNA (epigenetic programs) and modulators of gene expression (transcriptional programs).
• Some endogenous metabolites, reviewed in this article, have emerged as key regulators of longevity through their influence on epigenetic and transcriptional programs, the mechanisms of which scientists are still trying to unravel.

Aging encompasses multiple processes under the influence of genetic, environmental, and metabolic factors. More specifically, dysregulations in nutrient sensing and metabolic dysfunction serve as critical hallmarks of aging. To counter these hallmarks, calorie restriction, a dietary pattern involving significantly reducing calorie intake, has been shown to significantly extend lifespan across multiple species. Intriguingly, research has demonstrated that naturally produced molecules (called endogenous metabolites) are associated with the pro-longevity effects of calorie restriction.

Now, as published in Aging Cell, Jiang and Han from Peking University in China summarize evidence supporting the lifespan-extending effects of key endogenous metabolites across model organisms. They also discuss these metabolites’ potential mechanisms of action, their possible capabilities to target metabolism, and whether supplementing with them may be a strategy to delay aging.

Physiological Effects of Endogenous Metabolites

Endogenous metabolites are small molecules produced by an organism’s metabolic processes. They include a wide array of molecules, such as protein building blocks (amino acids), fats (lipids), building blocks of DNA and RNA (nucleotides), and sugars. These endogenous metabolites have pivotal roles in the cellular function of an organism.

Endogenous metabolites serve as precursors in physiological reactions for protein synthesis, energy production, and metabolic regulation. Moreover, many of these metabolites function as modulators of cell signaling and gene regulatory networks, influencing which genes are expressed and which proteins are produced. They do so, in part, by modifying chemical tagging patterns (epigenetic programs) on DNA as well as proteins that modulate gene expression patterns (transcriptional programs). Along these lines, research is ongoing to untangle the myriad of ways that endogenous metabolites influence epigenetic and transcriptional programs.

Alterations to levels of endogenous metabolites have been associated with chromosomal instability, metabolic dysfunction, and age-related diseases. These associations have motivated the study of endogenous metabolites as both markers and functional modulators of aging. For example, research has uncovered characteristic changes in endogenous metabolite levels in diabetes, cardiovascular disease, and Alzheimer’s disease, suggesting that endogenous metabolite level changes reflect disease and can actively influence aging pathways. This means that the possibility looms that adjusting metabolite levels in cells through supplementation could serve as a way to counteract age-related processes.

Taurine

Taurine is an amino acid naturally synthesized in the liver and to a lesser extent, the pancreas. This endogenous molecule is present in high concentrations in many tissues, such as the heart, brain, retina, and skeletal muscle.

Taurine is not a typical amino acid, as it is not incorporated into proteins within the body. Instead, it plays roles in critical processes like maintaining cellular calcium balance and neuronal signaling. Additionally, taurine has been implicated in antioxidant and anti-inflammatory defenses, in part, by supporting the function of the cell’s powerhouses (mitochondria).

Also, taurine supplementation shows protective effects against aging in model organisms. In mice exposed to dangerous radiation, taurine preserved skin moisture and significantly reduced wrinkle formation, suggesting that it has the potential to promote skin health. In aged mice, it significantly alleviated an age-related decline in spatial memory. These findings suggest that taurine has effects that counter aspects of aging in mouse models.

Comprehensive analyses of taurine’s association with aging have been mixed. For example, one study measured taurine levels in mice, monkeys, and humans and reported an age-related decline in levels of this endogenous metabolite. The same study found that reversing this decline increased lifespan in worms and mice. In contrast, another comprehensive human study reported that circulating taurine increased or remained unchanged with age and that associations between taurine levels and age-related health outcomes were inconsistent.

Collectively, these findings suggest that although taurine can modulate cellular resilience and mitochondrial function in animal models, it remains unclear whether researchers can use it as a marker of natural aging. Moreover, the applicability of its use as a marker for aging may depend on the species under consideration. Resolving whether declining taurine levels can be used as a marker of aging and whether taurine supplementation can slow aspects of aging will require future, large-scale human studies.

Betaine/Trimethylglycine

Betaine, also known as trimethylglycine, is a naturally-occurring amino acid, present in plants, animals, and humans. It is synthesized within the liver and, to a lesser extent, the kidneys. Betaine can be obtained from the diet, from sources like wheat bran, beets, spinach, and quinoa.

Emerging evidence across animal models suggests that betaine can delay aspects of aging. For example, in aged mice, betaine obtained from dietary sources improved muscle mass, strength, and endurance, and also improved mitochondrial function. Thus, based on these preclinical findings, betaine may improve muscle function and support metabolism with advanced age by boosting mitochondrial function.

Another mouse study has also shown an association between exercising and increased betaine levels, and that betaine supplementation mimics some exercise-induced effects against aging. Relatedly, human research has also revealed that repeated exercise increases circulating betaine. Altogether, these findings highlight betaine’s potential as a circulating endogenous metabolite linked to protective effects against aging.

Despite these promising results, crucial uncertainties remain. For example, large-scale human studies have not consistently linked dietary betaine intake with reduced age-related disease incidence. Thus, evidence for betaine’s possible effects against aging, as well as working out optimal doses for supplementation, remains limited, warranting future large-scale human trials testing betaine against aspects of aging.

Ɑ-Ketoglutarate

Ɑ-ketoglutarate is a crucial endogenous metabolite naturally produced in mitochondria throughout the body. This endogenous metabolite plays a vital role in cell energy production, acts as an antioxidant, supports bone health, and has the potential to help against age-related physiological decline.

In mice, researchers have found that ɑ-ketoglutarate supplementation significantly extends lifespan by somewhere between 8% to 20%. Furthermore, its lifespan extension effects were associated with reduced systemic inflammation.

However, clinical validation of ɑ-ketoglutarate’s possible effects against aging in humans remains preliminary. One human study reported a reduction in biological age, an age assessment based on molecular tagging patterns on DNA, over seven months of ɑ-ketoglutarate supplementation. However, the group analyzed was small, limiting the power of this finding. Furthermore, a detailed protocol for another human study involving ɑ-ketoglutarate supplementation has been published, but no results have been released yet. Therefore, human data on ɑ-ketglutarate are limited, and clinical validation will be necessary before concluding whether supplementing with this endogenous metabolite works for humans.

Oxaloacetate

Oxaloacetate is a key endogenous metabolite that helps enable cellular energy production within mitochondria. Supplementation with oxaloacetate has been demonstrated to extend worm lifespan. However, attempts to translate these results to mammals, like rodents, have given inconsistent findings. For example, a lifelong intervention study using oxaloacetate in mice did not produce a statistically significant extension of lifespan.

Taken together, while oxaloacetate extends worm lifespan, evidence for a similar effect in mammals is lacking. More rigorous testing of different longevity-related parameters at different doses will be necessary to determine whether oxaloacetate supplementation may work to alleviate aspects of aging in humans.

NAD+

NAD+ (nicotinamide adenine dinucleotide) is a molecule found in every cell involved in cellular energy production, DNA repair, and cellular signaling and communication. Cellular NAD+ levels decline naturally with age, and this decline is associated with aging and age-related diseases.

Interestingly, a study has shown that supplementing with the NAD+ precursor, NMN (nicotinamide mononucleotide), extends lifespan in female mice by 8.5%. In the same study, both male and female aged mice exhibited improved metabolic health and delayed frailty. These findings have added to the large body of preclinical evidence suggesting that NAD+ precursors confer pro-longevity effects.

Some human studies have also given support to the notion that NAD+ precursors slow some aspects of aging. For example, a human trial involving 80 healthy, middle-aged adults showed that NMN significantly increased circulating NAD+ levels, improved walking distance over a duration of six minutes, and increased scores on a self-reported health assessment. These promising findings warrant further human trials, perhaps involving older participants supplemented over longer durations, to confirm NAD+ precursors’ potential to delay aspects of aging.

Many More Endogenous Metabolites for Future Research

According to the Human Metabolome Database, which keeps tabs on identified metabolites, there are 222,860 currently known endogenous metabolites in humans. On top of that, there are roughly between 2,000 and 3,000 core endogenous metabolites tracked for health-related analyses in humans. This means that a whole slew of endogenous metabolites have been identified, which are not actively tracked in health examinations, that may work as supplements to potentially ward off aspects of aging. Only further research on these metabolites, not to mention others that scientists have yet to identify, can uncover whether any of them confer pro-longevity benefits.

Moreover, the mechanisms of action of the endogenous metabolites reviewed above remain to be fully elucidated. Once their mechanisms of action, whether through modulating epigenetic and/or transcriptomic programs to alter gene expression, have been revealed in more detail, other analog molecules that may work more potently could serve as ways to counteract aging. Along these lines, it seems that endogenous molecules could hold the keys to extending healthy lifespan, and substantial research on these metabolites in the future could help people extend their healthy lifespans.