A Deep Dive Into the Top 20 Compounds for Anti-Aging and Longevity

Over the last few decades, studies have zeroed in on compounds that slow aging and increase the healthy lifespan of organisms from yeast, flies, and rodents to non-human primates. These compounds each have their mechanisms, but most fall into one of a few categories. ProHealth Longevity here reviews the categories of natural products with properties that slow aging and promote healthy lifespan extension and the mechanisms of targets for anti-aging evaluation. Let’s take a closer look into these compounds that could support healthy aging and have a potential role in life span extension.

Antioxidants

Cells are always trying to fight off the buildup of harmful molecules called reactive oxygen species (ROS) with antioxidants. But when the scales tip towards ROS buildup, cells begin to experience oxidative stress, which has been proposed to be a central driver of aging. Emerging research has suggested that natural compounds can reduce oxidative stress.

Glutathione (GSH) and N-acetyl cysteine (NAC)

Glutathione (GSH) is the most abundant cellular antioxidant. ROS are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS. But GSH has a low half-life and plasma membrane permeability. That’s why you can find different kinds of GSH supplements touting improved uptake, sometimes by using liposomes — spherical vehicles made out of the same fats as cell membranes that can deliver molecular cargo.

While GSH is a popular dietary supplement and since cells have the ability to generate GSH if supplied with the right starting material, it’s worth taking a look at one of its precursors, N-acetyl cysteine (NAC). Recent research has shown that human consumption of NAC in combination with another GSH precursor, glycine, is safe to take daily (up to 7.2 grams per day) and can boost GSH levels. This is interesting in light of some research showing that mice supplemented with glycine and NAC lived 24% longer than their counterparts and showed support for healthy aging.

Astaxanthin

Astaxanthin is a nutrient and antioxidant that has safely shown various health-supporting effects and holds promise to slow age-related decline. Clinical trials have examined astaxanthin doses ranging from 5 mg to 40 mg, demonstrating that it is safe for human consumption. These studies show that astaxanthin supports: antioxidant activity, blood flow, immune and nervous system health, and cognition.

Astaxanthin cannot be produced in the human body and is mainly ingested through the diet, and almost all of the dietary intake containing astaxanthin comes from seafood. In nature, astaxanthin is produced by algae, bacteria, and fungi. Because these primary producers are often used as food, the substance is concentrated at the top of the food chain. It turns the flesh, skin, or exoskeleton of animals such as shrimp, krill, crayfish, lobster, crab, salmon, and trout into a natural intense red illumination.

Synthetic astaxanthin is also emerging as an important product. Natural and synthetic astaxanthin differ in chemical composition, bioavailability, purity, or quality. The vast majority of new dietary supplements approved by the FDA for natural astaxanthin use algae extracts. Natural astaxanthin extracts usually contain other carotenoids (canthaxanthin, β-carotene, and lutein), which have similar biological activities depending on the source. Natural astaxanthin has shown a good clinical safety profile, with no serious adverse side effects observed in any clinical studies, even at high doses (45 mg in 15 patients).

Curcumin

Curcumin is a natural yellow pigment that can be widely applied in cakes, sweets, drinks, ice cream, wine, and other foods as a colorant and is considered one of the most valuable natural edible pigments.

Curcumin has been shown to support aging and immune health. A version of curcumin (tetrahydrocurcumin) was reported to extend lifespan in a study of male mice. In adult mice, curcumin improved synaptic plasticity, neuronal repair, and hippocampal neurogenesis. Another study showed that curcumin improved synaptic structure and quality in the hippocampus — the brain region associated with learning and memory — in mice. However, to date, no studies have evaluated the effects of curcumin on cognitive performance in humans.

Curcumin is an unstable, reactive, poorly bioavailable compound and, therefore, not a lead compound. Still, crude curcumin extracts may be beneficial to human health. A study suggests that curcumin may affect the intestinal microflora, which is associated with many aspects of health. This hypothesis has not been fully tested but may eventually provide a focal point for research into the therapeutic effects of curcumin.

Curcumin is lipophilic (fat-loving) and hydrophobic, rather than hydrophilic (water-loving). Because our digestive tracts are so full of water, it can be difficult to absorb curcumin. HydroCurc®'s proprietary delivery technology, LipiSperse®, provides a solution to curcumin's hydrophobia problem. LipiSperse®, also known as a Cold Water Dispersible (CWD) powder, uses repulsive interactions between curcumin particles to increase bioavailability. These factors prohibit curcumin from effectively dispersing by preventing it from aggregating. Curcumin's antioxidant and anti-inflammatory effects will come through due to its enhanced bioavailability, promoting optimal health and lifespan at any age.

Coenzyme Q10

Coenzyme Q10 is a fat-soluble substance directly involved in the body’s energy production system and plays an important role in the mitochondrial electron transport system. In addition, it has recognized roles in antioxidant and regulating gene activity. Coenzyme Q10 was first synthesized in 1958 and was approved to treat certain heart disorders in Japan in 1974. Since then, a lot of research has been conducted worldwide on the function and action of coenzyme Q10. The data confirmed that the compound is safe and effective.

In the United States, coenzyme Q10 has been sold as a dietary supplement under the Dietary Supplement Health and Education Act since 1994. However, when coenzyme Q10 is taken with meals, intestinal absorption does not exceed 3% of the dose given. In addition, the enrichment of coenzyme Q10 in functional foods is very limited due to its lipophilic (fat-loving) properties. In a clinical study, 3 months of administration of a combination of water-soluble coenzyme Q10 (50 mg) and fish collagen (4 grams) exhibited some beneficial effects on the skin as it increased dermal density, reduced periorbital wrinkle (around the eyes), and improved skin smoothness.

Sulforaphane

Found in broccoli and other cruciferous vegetables, sulforaphane works by promoting antioxidants. Sulforaphane itself is not an antioxidant — rather, it boosts the levels of a molecule called Nrf2 that protects cells from damage by switching on antioxidant genes that help protect against oxidative stress. Nrf2 has been shown to be critical to maintaining heart, kidney, and metabolic health during aging, which is why sulforaphane is an exciting longevity supplement.  Sulforaphane has been shown to increase the lifespan of roundworms. In mice, sulforaphane promotes healthy kidney function during aging.

Nobiletin

This plant-derived compound is usually derived from citrus peels. Numerous elegant studies have swiftly identified biological targets for nobiletin in the years that have passed by. Research has shown that nobiletin enhances healthy aging because the small molecule prevents disruptions to the body’s internal clock (circadian rhythm).

Furthermore, several labs have revealed exquisite activity details of nobiletin during aging, which revolve around antioxidation, metabolism and inflammation regulation, and cellular senescence amelioration. In roundworms, nobiletin enhances longevity and alleviates aging-related detrimental abnormalities by increasing resistance to biologic and environmental stresses, enhancing physical performance, and scavenging reactive oxygen species. These studies suggest that nobiletin dampens age-related functional declines in multiple tissues and organs and may promote healthy aging.

Metabolic Regulators

Aging is accompanied by a host of metabolic changes. As we age, our mitochondria function differently and we see declines in insulin sensitivity, which results in less sugar getting inside of cells and, instead, higher levels of sugar in the blood. These changes may contribute to aging and predispose an individual to age-related conditions. 

Reducing calories has been considered by some as the best way to approach aging. Data shows that rodents living their entire lives on calorie-restricted diets can live up to 50% more than their free-feeding counterparts. The magnitude of this effect has prompted considerable efforts to understand how limiting food intake translates into longer life and, in particular, the pathways mediating this effect in order to identify compounds that can push these processes in a way that mimics calorie restriction.

Rapamycin

Rapamycin is isolated from a bacteria found in soil samples from Easter Island. Initially, rapamycin was discovered as a new antifungal agent. Rapamycin interacts with pathways that control growth, metabolism, and aging. Several studies have led researchers to propose that rapamycin has the potential as an anti-aging therapy. But Rapamycin is an FDA-approved drug for select indications, so a diverse set of negative side effects may preclude its wide-scale deployment from supporting healthy aging.

One study showed that even when the treatment was started at a very old age, female mice lived a remarkable 14% longer, and male mice lived 9% longer. Rapamycin supplementation increases median and maximum lifespan in male and female mice. Results from several independent research groups have shown that rapamycin extends the lifespan of different strains of mice. Beneficial effects have been reported for various treatment strategies, from the age of onset (i.e., middle-aged, late-aged) to duration of treatment (i.e., transient, intermittent) to mode of administration (oral, injection). In mice, rapamycin supplementation supported the health of muscle, immune, cardiovascular, and brain tissue during aging.

Spermidine

Named in relation to the cell in which it was principally discovered, spermidine has been found to be key to what keeps sperm, as well as other cells, young. However, spermidine decreases during the body's natural aging process. High spermidine levels are found in a wide range of foods, such as fresh peppers, wheat germ, broccoli, cauliflower, and cheeses, while higher levels are found in products such as the soy-based natto, shiitake, and durian.

As a mimetic of caloric restriction, spermidine has significant cardioprotective and neuroprotective effects in rodent models. Spermidine maintains mitochondrial function, shows anti-inflammatory activities, and prevents stem cells from aging. Administration of spermidine increased the survival of yeast, roundworms, fruit flies, and human immune cells and reduced age-related mortality in mice. In aging flies, spermidine treatment improved memory, an effect associated with increased autophagy in neuronal tissue. In rats, spermidine treatment (5 and 10 mg/kg) improved motor performance and reduced pro-inflammatory cytokines and oxidative stress in the striatum — a brain region implicated in regulating movement and responses to rewarding and aversive stimuli.

Several studies have been conducted on spermidine treatment in humans. Long-term spermidine supplementation (1.2 mg per day) is safe and well-tolerated in the elderly. Food questionnaires have shown that high dietary intake of spermidine lowers blood pressure and benefits cardiovascular health, while spermidine supplementation (1.2 mg per day for 3 months) improves memory performance in older adults (60 to 80 years) with subjective poor cognitive health. A study reportedly aimed to test a potential link between dietary spermidine levels and mortality in humans. Their findings provide epidemiological support for the concept of spermidine-rich nutrition and improved human survival.

Minerals

A number of minerals are essential for health, including calcium, potassium, sodium, iron, copper, and zinc. But did you know that certain minerals are correlated with whether you’ll be a centenarian? For example, centenarians often appear to have higher systemic levels of iron while having lower levels of copper than other older people.

Selenium

Selenium is an essential trace mineral that is important for many functions in the body. The majority of selenium from our diet gets stored in muscle tissue, though the thyroid is the organ with the highest concentration. Recent research suggests that selenium has anti-aging properties and may even protect against age-associated disease. Adding the nutrient selenium to diets supports healthy metabolism and provides metabolic benefits to mice. Researchers also believe that higher levels of selenium are associated with longevity, as the all-cause mortality of older adults with low levels of selenium is significantly higher than that of the elderly with a high level of selenium. 

Selenium is an important component of enzymes and proteins known as selenoproteins that play a key role in reproduction, thyroid hormone metabolism, and DNA synthesis. Selenoproteins also act as powerful antioxidants that help protect against damaging particles in the body called free radicals. According to some research, selenoproteins are primarily responsible for many of the health benefits of selenium. For example, one 2021 review found that selenoproteins play a key role in controlling and removing misfolded proteins, which accumulate as we age. Specialists note that the accumulation of misfolded proteins is a common characteristic of aging and age-related diseases.

Nicotinamide adenine dinucleotide (NAD+) precursors and boosters

Nicotinamide adenine dinucleotide (NAD+) is an indispensable molecule that cells use for many key cellular processes, including DNA repair, regulation of gene activity, energy production, cell signaling, and immune function. It is well known that NAD+ concentration increases with reduced energy load. These activities include fasting, glucose deprivation, calorie restriction, and exercise. However, NAD+ levels decreased in high-fat diet animals and during aging.

Considering that NAD+ levels increase with increased life or healthspan and decrease with accelerated aging or reduced healthspan, it suggests that reduced NAD+ levels may be a major aspect of the aging process. Therefore, NAD+ supplementation and its precursors may be a potential therapeutic strategy that mediates protection against inflammation and the accumulation of oxidative stress during aging. But studies have found that oral supplementation of NAD+ did not significantly increase  NAD+ levels in plasma or tissue, which may be due to poor bioavailability due to the inefficiency of gut NAD+ metabolism.

NAD+ Precursors

Nicotinamide mononucleotide (NMN)

Among various anti-aging health products, nicotinamide mononucleotide (NMN) — an NAD+ precursor — has been gaining the attention of consumers and the scientific community. Research has shown that long-term administration of NMN in mice mitigates age-associated physiological decline effectively without generating noticeable toxicity, deleterious side effects, or increased mortality.

The human data is just starting to come along. A non-blinded clinical trial using ten healthy men to investigate the safety of oral NMN administration found that single oral administration of 100, 250, and 500 mg of NMN doses was well-tolerated and safe since it did not cause any observable clinical symptoms or changes in body temperature, oxygen saturation, blood pressure, and heart rate. In addition, there weren’t any negative changes in brain health after NMN administration. There were no changes in the results of laboratory analysis of urine and blood as well as sleep quality and score before and after the NMN administration. NMN administration did not increase nicotinamide in blood to the level which causes adverse effects associated with a high dose of nicotinamide.

Further clinical investigations are essential to be performed to assess the safety and efficacy of long-term administration of NMN in humans. The organs and the tissue NMN levels have not been analyzed in this study, which should be considered in future clinical studies. At least three more human clinical studies are being carried out to evaluate the safety concerns of NMN administration.

Nicotinamide riboside (NR)

Nicotinamide riboside (NR) has recently become one of the most studied nicotinamide adenine dinucleotide (NAD+) precursors, due to its numerous potential health benefits mediated via elevated NAD+ content in the body. NR has been examined in six clinical trials, where it has been established that it is safe for short-term (8 days) and long-term (6 weeks) supplementation in compliance with confirmed oral availability. These values have not been established regarding NMN supplementation.

Oral supplementation with NR has been shown to increase NAD+ levels in multiple human tissues as well as improve mitochondrial function and stem cell health. Furthermore, NR is currently regarded as a favorable precursor since it has not been implicated to have serious side effects or flushing as opposed to other NAD+ precursors like niacin. NR chloride has been given an important status known as GRAS (generally regarded as safe), which further supports its rapid implementation.

However, to adapt NR technologies for therapeutic use, it is necessary to determine oral availability, therapeutic dosage, and utilization in different tissues. Human digestion and the microbiome additionally play important roles in NR metabolism, which has yet to be characterized in detail. The use of NR as a nutritional supplement still has certain limitations concerning its production methods, including low yield, the use of expensive or hazardous reagents, and pharmaceutically unacceptable species that may be toxic or biologically intolerable by other means.

NAD+ Boosters

Urolithins

Urolithins are intestinal metabolites produced by plants rich in ellagitannins — blackberries, strawberries, pomegranate, tea, walnuts, and raspberries. Urolithins have a variety of biological activities, including supporting healthy aging, and have attracted increasing interest in recent years. The results of studies to date confirm that urolithins can regulate oxidative stress and ameliorate tissue damage through different mechanisms.

Anti-aging activity is the most intriguing and perhaps the most critical property of urolithin A. It has been intensively studied in recent years due to its unique role in activating mitochondrial autophagy and mitochondrial biogenesis. A recent clinical study shows long-term urolithin A supplementation benefits muscle endurance and may counteract age-associated muscle decline. Another clinical trial showed that urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults

Given the importance of mitochondria in the pathophysiology of many diseases, urolithins deserve further in-depth study, especially in clinical trials, to reveal their additional clinical significance.

Apigenin

Apigenin blocks the breakdown of NAD+ by blocking an enzyme that degrades the vital molecule CD38. This NAD+ booster has been shown to support healthy aging in several animal models. Apigenin increases the lifespan of flies and reduces markers of aging in mice. The use of apigenin supplements, with purified apigenin in capsules, can achieve biologically relevant plasma concentrations that would be capable of influencing cellular behaviors. Apigenin is considered safe, even at high doses, and no toxicity has been reported. However, at high doses, it can trigger muscle relaxation and sedation.

Sirtuin Activators

Sirtuins are enzymes that have been thought of by some researchers as the keys to aging and longevity. This family of molecules has its hands in many functions that ultimately support increased survival and healthy metabolic regulation of cells and have been shown to be important for the health of the nervous and immune systems. These enzymes depend on NAD+ to execute their function, which is why sirtuin activators often go hand-in-hand with NAD+ precursors or boosters.

Fucoidan

Extracted from brown algae, fucoidans are molecules that can activate sirtuin 6 (SIRT6). Interestingly, SIRT6 has been shown to play a role in longevity in several animal models, including flies and mice. Several studies have shown that increasing levels of SIRT6 via genetic manipulation increases the lifespan of these animals. Additionally, fucoidans have numerous other health-promoting effects, such as supporting immune health and working as an antioxidant.

Pterostilbene

Pterostilbene is an analog to resveratrol — a natural compound found in red wine that has been suggested to exert its potential health benefits through the activation of SIRT1, a crucial member of the sirtuins. Plants manufacture pterostilbene to defend themselves from sickness, viral infections, dangerous microorganisms, and too much sunshine. It is very similar to resveratrol, except pterostilbene is much more bioavailable. Pterostilbene has an 80 percent bioavailability (absorption) in animal trials, compared to 20 percent for resveratrol. This increases its potency and the potential for considerably larger health, well-being, and lifespan advantages. This sirtuin activator has been shown to affect various hallmarks of aging, including oxidative stress, immune health, and senescence. 

Senolytics

With aging, our cells stop growing and replicating the way they did when we were younger. This phenomenon, known as cellular senescence, has been shown to be a direct cause of aging. With this understanding, researchers have been trying to identify natural senolytics as well as develop synthetic senolytics — molecules that specifically eliminate senescent cells.

Fisetin

Fisetin is a senolytic widely found in vegetables and fruits such as strawberries, apples, persimmons, cucumbers, and onions, with the highest concentration in strawberries. This highly fat-soluble compound easily crosses cell membranes and is assembled inside cells. These properties likely drive fisetin’s beneficial effects, including supporting immune, neuronal, and metabolic health. Most importantly, fisetin can extend mouse lifespan. In addition, fisetin is a potent compound in reducing aging markers in mouse and human cells. Fisetin treatment increased health and longevity in adult mice and aged mice, extending lifespan.

Hormones and Steroids

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal gland in a pattern associated with age. It is present in plasma in higher concentrations than any other steroid hormone. Adrenal secretion of DHEA begins at puberty, peaks at the age of 20, and then declines with age. However, the effects of DHEA supplementation on biological functions have not been really explored. But by age 80, blood levels have dropped 95%, to about 10 to 20% of what they were at age 20. DHEA is known to extend the lifespan of rodents by 50%, making them look younger. Animals taking DHEA supplements retained glossy black hair, while others turned gray in the process.

Melatonin

Melatonin is a neurohormone produced at night that regulates our circadian rhythm — the clock that critically aligns us with the day-night cycle so that we function properly. That’s why melatonin is often said to support sleep. Interestingly, it seems like melatonin is involved in aging-related processes because the loss of melatonin secretion and decrease in circadian melatonin rhythm amplitude is closely related to different age-related pathological conditions. Its potential to prolong longevity has been repeatedly described in fruit flies and mice. Many studies have shown that it can act as a potent antioxidant that can cross physiological barriers, such as the blood-brain barrier, thereby reaching the nervous system. In addition, melatonin’s anti-aging effects may be associated with its ability to modulate inflammation and immune responses by activating or inhibiting these processes. The therapeutic effects are thought to be associated with anti-inflammatory roles via antioxidant responses.

One strategy to rule them all?

The best anti-aging supplement regimen is unclear. Arguably, attacking aging from several angles — an antioxidant like astaxanthin or curcumin, a senolytic like fisetin, an NAD+ precursor like NMN, and a sirtuin activator like resveratrol, for example —could support healthy aging the most.

But the truth is that, right now, we just don’t know…