Highlights: 

  • These longevity-linked compounds target the underlying cellular causes of aging, including oxidative stress, inflammation, DNA damage, and cellular senescence. 
  • Targeting these hallmarks of aging has led to the protection against several age-related diseases known to shorten lifespan. 

In the realm of aging research, significant advancements have brought forth molecules with the potential to extend lifespan and mitigate the development of harmful age-related diseases. Interestingly, a few of these molecules already exist as medications targeting specific ailments, while others have demonstrated effectiveness in both model organisms and humans. Now, as aging researchers pave the way for a new era of possibilities in the health and wellness space, consumers are piggybacking off the health benefits of several longevity supplements that continue to spark excitement in 2023. 

NMN and NR

To overcome the ongoing battle against the plethora of age-related diseases stemming from DNA damage, our bodies employ a set of safeguarding proteins called sirtuins, which actively repair DNA and strengthen genomic stability. This remarkable family of proteins also tends to our cellular powerhouses (mitochondria), driving cellular energy metabolism and mitigating the buildup of reactive oxygen species (ROS) – compounds that induce oxidative stress. To power sirtuins, our cells need a sufficient pool of nicotinamide adenine dinucleotide (NAD+) – an essential coenzyme that takes part in several pathways critical to survival. 

Given that NAD+ levels significantly plummet with age, researchers have honed in on NAD+ precursors capable of replenishing this life-preserving molecule: nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). These NAD+ precursors have the most recognition for their ability to restore NAD+ levels and stimulate sirtuin activity, both of which contribute to increased lifespan in yeast, worms, and flies. 

Notably, in humans and some model organisms, NMN supplementation has been shown to increase muscle strength, improve exercise endurance, protect against cognitive impairment, and inhibit cancer cell growth. On the other hand, researchers have found that NR attenuates Parkinson’s, reduces stroke-induced brain damage, slows liver cancer progression, and halts age-related hearing loss. All things considered, it’s clear that NMN and NR are front runners among the available longevity interventions. 

(Left Image): "Effect of NMN on NAD+ Levels in Humans: Significant Increase Observed" (Right Image): "Effect of NR on Cancerous Liver Cells in Mice: Halt in Cell Spread Detected"
(Left) NMN significantly raises NAD+ levels in humans. (Right) NR halts the spread of cancerous liver cells in mice. 

Resveratrol

Caloric restriction (CR) – limiting calories without malnourishment – is one of the most popular battle-tested dietary interventions with well-established ties to longevity, increasing the lifespan of multiple model organisms ranging from fruit flies to mice. What drives the benefits of CR is its ability to inhibit the activation of the enzyme mechanistic target of rapamycin (mTOR), a nutrient-sensing complex that modulates cellular growth and protein synthesis. Accordingly, aging researchers have identified the compound resveratrol – a plant-based polyphenol found in wine, blueberries, and certain nuts – as a strong mTOR inhibitor. So for those looking to reap the benefits of CR without dieting, it may be worth trying resveratrol.

Resveratrol is also a powerful sirtuin activator with antioxidative and anti-inflammatory properties, making it a primary candidate for anti-aging interventions. Furthermore, resveratrol revitalizes autophagy – the removal of toxic cellular waste and debris that accumulates with age. Autophagy plays a major role in limiting oxidative stress, inflammation, and mitochondrial dysfunction, all of which are known hallmarks of aging and disease. However, aging naturally slows down this vital process, ultimately disrupting cellular homeostasis and overall health. Currently, autophagy activators have become a research hotspot in the field of aging, and the data continues to highlight resveratrol’s effectiveness at stimulating autophagy. 

Notably, scientists have established resveratrol as a potent activator of AMPK, an enzyme that, upon activation, promotes lifespan extension, ramps up sugar and fat metabolism to boost energy, and stimulates autophagy. Recently, resveratrol was shown to delay cardiac and skeletal muscle aging via activation of autophagy, further demonstrating its potential to mitigate known hallmarks of aging. 

Effect of Resveratrol on Skeletal Muscle and Cardiac Muscle: Treated Mice (60 wo+RSV) show Increased Tibialis Anterior Muscle Size (middle) and Reduced Heart Size (right) compared to Untreated Mice (60 wo)
(Kuno et al., 2023 | Journal of Pharmacological Sciences) Resveratrol increases skeletal muscle size and decreases cardiac muscle hypertrophy. Treated mice (60 wo+RSV) display larger tibialis anterior muscles (middle) and smaller hearts (right) than untreated mice (60 wo).

Berberine

Among the myriad of longevity-linked compounds, one that has stood the test of time and is still at the center of several age-related studies in 2023 is berberine, a natural compound utilized for centuries in traditional Chinese medicine. In addition to amplifying antioxidant defense mechanisms and AMPK activity, studies have shown that berberine exerts neuroprotection, improves memory, attenuates liver disease, and inhibits cancer cell growth in vitro.  More importantly, this organic compound is primarily known for its strong cardioprotective effects, which studies now show are tied to berberine’s function as a senolytic, a compound that selectively targets and eliminates senescent cells – disease-promoting cells that have ceased proliferation. 

Senescent cells accumulate with age and sprout across multiple tissues, driving chronic systemic inflammation and organ deterioration. Additionally, these zombie-like cells contribute to the development of multiple age-related diseases, including Alzheimer’s, Parkinson’s, osteoarthritis, cancer, and heart disease. Granted that cellular senescence seems like an unstoppable force, it’s important to note that senolytics like berberine can target multiple age-related pathways, meaning that berberine can potentially be utilized to treat more than one age-related disease simultaneously. However, further research is needed to confirm this hypothesis. 

Quercetin

Aging scientists have repeatedly touted quercetin – a flavonoid found in various fruits, vegetables, and grains – as a promising anti-aging therapeutic, as it enhances senolytic stimulation,  exhibits anti-tumor effects, and significantly quenches oxidative stress and inflammation. Although quercetin alone has been shown to ameliorate features of aging like cardiac dysfunction, multiple studies show that combining quercetin with the chemotherapeutic drug dasatinib (D+Q) yields more favorable results in terms of longevity benefits. 

Moreover, rodent studies have demonstrated that this senolytic cocktail promotes muscle regeneration and delays age-related muscle weakness. Uniquely, D+Q also stimulates the activation of a longevity-associated protein called a-klotho, which has been linked to lifespan extension in mice when overactivated. Currently, D+Q is undergoing clinical trials to evaluate its effects in adult survivors of childhood cancer and individuals with mild cognitive impairment. 

Curcumin

Another supplement making the rounds in the longevity space is curcumin, the primary active compound in the spice turmeric. Similar to other longevity-linked compounds, curcumin suppresses oxidative stress and inflammation, which have been shown to contribute to improved learning and memory in mice. In fact, curcumin exerts neuroprotective effects in models of Alzheimer’s, further indicating that curcumin mitigates age-related cognitive decline. 

In addition to hindering brain aging, studies have shown that curcumin mitigates muscle decline, another hallmark of aging. Specifically, scientists have found that curcumin boosts muscle strength and exercise endurance, two things that drastically dwindle with age. Collectively, the current evidence strongly supports curcumin’s use as a supplement to thwart common features of aging. 

Paving The Way for A Healthier and Longer Life

The field of aging research has opened up a new world of possibilities for extending lifespan and overall well-being. And the emergence of top longevity supplements such as NMN, NR, resveratrol, berberine, quercetin, and curcumin offers a glimpse into the potential of these interventions to revolutionize health and empower individuals to live longer and healthier lives. As aging scientists continue to unravel the intricate mechanisms underlying these longevity-linked compounds, a clearer understanding of their potential therapeutic applications and their ability to enhance human health will emerge. And this will pave the way for a future where individuals can optimize their health and wellness.