Current Anti-Aging Therapeutics

By webnad

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 helps 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.

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. 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 an enzyme called AMP-activated kinase (AMPK), which has strong ties to several longevity-linked pathways. Upon activation, AMPK ramps up fat and sugar metabolism to boost energy, stimulates autophagy, increases antioxidant defense systems, and importantly, decreases inflammation. 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 have been shown to 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.

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 at improving frailty and inflammation in older adults. 

Another senolytic combination is the chemotherapeutic drug dasatinib plus the plant-based polyphenol quercetin (D+Q), which has been shown to improve muscle regeneration in 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 this senolytic translates to humans. 

The only 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.

Metformin

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 AMPK and hinders inflammaging, indicating that 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.

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. In fact, Elon Musk’s mother recently developed a UA supplement called Mitopure that is advertised as a mitochondrial booster. What’s more, a clinical study in American adults (aged 20-80 years) confirmed that Mitopure supplementation outperforms pomegranate supplementation at restoring circulating UA levels, further highlighting its potential to increase longevity.

References
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  7. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015.
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