Pharmaceuticals and Nutraceuticals
As a new era of aging science has progressed, scientists have discovered molecules capable of increasing the lifespan of model organisms, including rodents. Some of these molecules already existed as drugs for specific diseases. Others have shown efficacy in model organisms and humans, but have not been approved by the Federal Drug Administration (FDA) to treat aging, largely because aging is not considered a disease.
A potential anti-aging drug that has been on scientists’ radar for over 60 years is the FDA-approved drug metformin, originally designed to treat patients with diabetes. Although the cellular mechanisms of metformin aren’t fully understood, research suggests that metformin activates an enzyme called AMPK, which has strong ties to several longevity-linked pathways. Upon activation, AMPK ramps up fat and sugar metabolism to boost energy, stimulates cell debris cleanup (autophagy), increases antioxidant defense systems, and importantly, decreases inflammation. With this in mind, metformin is a primary candidate for anti-aging therapeutics.
Research has demonstrated that “the use of metformin results in a reduction of all-cause mortality associated with diseases that accelerate aging, including cancer and cardiovascular disease.” In multiple rodent studies, metformin was also shown to increase lifespan. Still, there is controversy surrounding metformin’s ability to increase lifespan in humans. Be that as it may, the evidence clearly shows that metformin improves overall healthspan, meaning that metformin supplementation could help us live more years disease-free.
Researchers believe rapamycin’s effects come from its ability to mimic the effects of a calorie-restricted diet. Rapamycin supplementation inhibits activation of the enzyme mechanistic target of rapamycin (mTOR), an important node in nutrient sensing pathways. In a similar way, lack of food also switches mTOR off and allows us to survive prolonged starvation periods.
Rapamycin supplementation also activates autophagy, which reduces the accumulation of cellular waste that clogs our tissues as we grow older. In this way, rapamycin supplementation slows and may even reverse aging. Previous studies have shown that late-life rapamycin treatment extends the lifespan of male (23%) and female (26%) genetically heterogenous mice. What’s more, a recent study found that rapamycin supplementation increases lifespan only in male mice but inhibits growth, thus highlighting that rapamycin’s effects are potentially sex-dependent. However, more studies are needed to confirm this theory. Currently, there’s an ongoing clinical trial (NCT04488601) evaluating rapamycin’s longevity-boosting effects in healthy older adults.
Sirtuin Activators and NAD+ Precursors
To thwart the myriad of age-related diseases that stem from damage to our genetic blueprints (DNA), our bodies harness the power of guardian proteins known as sirtuins. These longevity-boosting molecules play an active role in maintaining the fitness and function of our cellular power plants, the mitochondria, which help prevent the onset of multiple age-related disorders. Activating sirtuins requires the life-preserving enzyme nicotinamide adenine dinucleotide (NAD+), which progressively decreases with age. Studies have demonstrated that boosting NAD+ levels increases sirtuin activity and promotes increased lifespan in yeast, worms, and mice.
NMN and NR
One way to elevate NAD+ levels is through supplementation with NAD+ precursors such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), both of which are readily available on the market. Harvard scientist Dr. David Sinclair, who is also an NAD+ expert, states,
“Feeding or administering NAD+ directly to organisms is not a practical option. The NAD+ molecule cannot readily cross cell membranes to enter cells, and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ must be used to increase bioavailable levels of NAD.”
With this in mind, NAD+ precursors come into favor when it comes to elevating NAD+ levels and triggering sirtuin activity to boost longevity.
Sirtuin activity can also be increased by a plant-based polyphenol called resveratrol, known to reduce oxidative stress, lower inflammation, and combat cognitive decline. Resveratrol can be found in foods like blueberries, the skin of grapes, and peanuts. What’s more, resveratrol has also been shown to activate AMPK and hinder inflammaging. Uniquely, scientists coined the term “inflammaging” due to the fact that inflammation contributes to the progression of multiple age-related ailments. Furthermore, the fact that resveratrol combats inflammaging and has been shown to increase the lifespans of worms and flies, demonstrates resveratrol’s potential as an anti-aging therapeutic.
Our cells are continually exposed to stress and damage, prompting some to enter a zombie-like state known as cellular senescence where they can no longer divide and replicate. While senescent cells are important during embryonic development and wound healing, overwhelming evidence shows that senescent cell accumulation, which occurs with aging, triggers chronic systemic inflammation. This inflammation contributes to inflammaging and the progression of age-related diseases like cancer.
To effectively target and eliminate senescent cells, scientists have honed in on a group of compounds known as senolytics, which exhibit anti-aging properties and protect against age-related pathologies like Parkinson’s and Alzheimer’s disease. Known senolytic targets include the lungs, muscle, liver, blood, brain, bones, and metabolic pathways linked to obesity, cancer, and diabetes. With the wide variety of potential targets, it’s possible that senolytics can target multiple age-related pathways simultaneously.
Fisetin and Quercetin
One of the most potent senolytics that can be found in plants and various fruits (apples, strawberries, cucumbers) is the polyphenol called fisetin, which has also been found to extend the lifespans of mice. Fisetin is currently being tested in a clinical trial (NCT03430037) for its effectiveness in improving frailty and inflammation in older adults.
Quercetin is a plant-based polyphenol with powerful senolytic capabilities. However, research suggests that combining quercetin with the chemotherapeutic drug dasatinib (D+Q) may provide superior outcomes when it comes to longevity. In addition to D+Q improving muscle regeneration in mice, Mayo Clinic studies show that D+Q counters age-related muscle weakness and restores a longevity-linked protein called a-klotho, which, when overactivated, has been shown to extend the lifespan of mice. The D+Q cocktail is currently undergoing clinical trials in adult survivors of childhood cancer (NCT04733534) and patients with mild cognitive impairment (NCT04685590). However, until these trials are completed, we won’t know how the potential benefits of this senolytic translate to humans.
Another senolytic shown to extend lifespan in flies and mice is the organic compound called berberine, which has been utilized for centuries in traditional Chinese medicine. Berberine contributes to antioxidant defense mechanisms and activates AMPK, demonstrating that it holds anti-aging properties. Taken together, the available research suggests that senolytics may be key players in the fight against age-related diseases.
Other Longevity-Linked Compounds
Urolithin A (UA)
This longevity-linked molecule is no stranger to the scientific community, with studies already confirming its ability to delay the onset of muscular aging in mice. Furthermore, research demonstrates that UA is an effective autophagy activator and NAD+ booster, making it a primary candidate for anti-aging therapeutics. However, obtaining sufficient amounts of UA through natural sources like pomegranates and walnuts is extremely difficult. With this in mind, researchers have turned to developing UA supplements. What’s more, a clinical study in American adults (aged 20-80 years) confirmed that UA supplementation outperforms pomegranate supplementation at restoring circulating UA levels, further highlighting its potential to increase longevity.