Throughout the ages, humans have searched for the Fountain of Youth. Today, the search for eternal youth continues; however, we are no longer looking for a hidden fountain but instead, for lifestyle, dietary, and technological hacks we can use in attempts to delay the aging process. A significant amount of research has been devoted to finding the best ways to decrease the rates of chronic diseases and increase lifespan. At a cellular level, aging is determined by factors including shortening of telomeres, epigenetic changes, genomic instability, and mitochondrial dysfunction. These are strongly influenced by physiological stresses such as high glucose levels, inflammation, or oxidative reactive species exposure, all of which can have direct consequences on longevity and the susceptibility to chronic diseases. This article will break down part of the research on some of the top contributors to longevity including intermittent fasting, nicotinamide adenine dinucleotide, oleic acid, and resveratrol, to provide you with important information you need to know about this fascinating topic in the context of naturopathic medicine.

Intermittent Fasting

One of the most well-researched ways to expand lifespan is intermittent fasting (IF). IF involves consuming no or minimal amounts of food and beverages for periods that range from 12 hours to as long as 3 weeks. In humans, 12–24 hours of fasting may encourage a metabolic energy switch from relying on glucose and glycogen to ketone bodies and free fatty acids.¹ This alternative fuel for energy production aids in the regulation of glucose, insulin, and insulin-like growth factor (IGF‑1). At a cellular level, IF improves cellular function by increasing antioxidant expression, DNA repair, and mitochondrial health; and reducing inflammation as well as anabolic processes, which assists with disease resistance.^2, 3 These processes in a larger scale may enhance lifespan and decrease incidence or death of chronic disease.

Animal studies have consistently shown that decreased food intake increases lifespan. A study reported that the lifespan of rats increased by up to 80% when put on an alternate-day feeding protocol as young adults versus an every-day feeding diet.⁴ Further, animal studies demonstrate evidence that IF may delay or improve metabolic syndrome, diabetes, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, cancer, and multiple sclerosis.^{5, 6, 7, 8, 9, 10, 11}

In humans, IF diets have been shown to be an effective dietary approach for treating metabolic syndrome alongside other therapies, to reduce abdominal fat, improve insulin sensitivity, and reduce blood pressure.¹² Additionally, it has been found to be beneficial in patients with rheumatoid arthritis, by providing symptom reduction.¹³ Further, this dietary strategy has high potential in cancer prevention and treatment, due to enhanced apoptosis and DNA repair.¹⁴ A review on IF summarizes the preclinical and clinical studies in cancer patients adhering to an IF dietary regime to determine the safety, compliance, and measurement of biomarkers alongside standard therapy, but as discussed, no studies on IF and cancer recurrence have been conducted.²

The lifestyle of people living in Okinawa in Japan includes IF and correlates low rates of obesity and diabetes mellitus with high longevity.¹⁵ Overall, IF seems like a viable tool to extend longevity through enhancing cellular stress responses and improving resistance to certain diseases.

Nicotinamide Adenine Dinucleotide

Nicotinamide adenine dinucleotide (NAD) is a molecule that is responsible for hundreds of cellular processes, with demands that depend on diet, exercise, and age.¹⁶ NAD⁺, the oxidized form, is a coenzyme for redox reactions, making it central to energy metabolism. It is a member of the poly (ADP-ribose) polymerase (PARP) family, that regroups proteins involved in numerous cellular processes such as gene expression and DNA repair. Additionally, it is closely tied with NAD⁺-dependent molecules called sirtuins. These have influence on many factors of health and longevity including inflammation, cell growth, energy metabolism, and stress resistance.¹⁷ Animal research has shown that restoring NAD⁺ levels in old or diseased animals promoted health and extended lifespan.¹⁸ This initiated a search for ways to increase NAD⁺ levels safely and effectively in humans.

The first approach to increasing NAD⁺ levels is supplementation with NAD⁺ precursors such as nicotinamide mononucleotide (NMN), or the two forms of vitamin B3: niacin and nicotinamide riboside (NR). Niacin supplementation has been found to decrease risk of mortality from myocardial infarction, stroke, and cardiovascular disease.¹⁹ Homeostatic levels of NAD⁺ can be achieved by ingesting 15 mg daily of vitamin B3. The dose of this is limited by a flushing response which occurs as an adverse effect. NR has not been as extensively studied on disease and longevity, but it remains a contender, since a bioavailability study has shown that it can increase NAD⁺ in blood with no adverse effects.²⁰

A second way to increase NAD⁺ in the body is by stimulating its synthesis, which depends on the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) in the biosynthesis of NAD from nicotinamide.²¹ NAMPT has been found to become less active with age and is also impacted by the presence of several disease states including acute lung injury, atherosclerosis, cancer, diabetes, rheumatoid arthritis, and sepsis.²² P7C3, a neuroprotective drug, is the only known activator of the NAMPT enzyme at this time.²³ However, de novo and salvage pathways for NAD⁺ synthesis have also been researched and it has been found that EGCG, a component of green tea, is a potential activator for these alternative pathways.²⁴

Finally, NAD⁺ levels can be increased by inhibiting the enzymatic degradation. Ingesting even low concentrations of flavonoids such as luteolinidin, kuromanin, luteolin, quercetin, and apigenin have been found to inhibit NADases (enzymes that degrade NAD).²⁵ These are found in plants and vegetables, but they can also be supplemented if an individual is not consuming enough fruits and vegetables in their diet. Overall, the research on NAD⁺ and longevity seems overwhelmingly positive, and further research will help to understand these processes.

Oleic Acid

Oleic acid is classified as a monounsaturated omega‑9 fatty acid (MUFA) and is primarily known for its high content in olive oil, but is also found in meat, cheese, nuts, sunflower seeds, eggs, and avocados. The research on oleic acid is not as substantial as on intermittent fasting and NAD⁺, but it still deserves to be highlighted in this article.

Olive oil is believed to be one of the components of the Mediterranean diet that is tied to improving overall health; reducing mortality; increasing longevity; and reducing the risk of cardiovascular disease, cancer, Parkinson’s, and Alzheimer’s.²⁶ A study compared the effects of a diet high in saturated fat, a low-fat / high-carbohydrate diet, and a Mediterranean diet enriched with MUFAs. It was found that after 4 weeks, the MUFA-rich diet reduced the number of cells with telomere shortening and was correlated with lower reactive oxygen species.²⁷

Oleic acid is also known to be a sirtuins activator, contributing to NAD⁺ and energy production in the cells.²⁸ Independently, oleic acid has been found to decrease the expression of a specific oncogene that is found in 20–30% of breast cancers.²⁹ In summary, oleic acid seems like a great candidate for future studies to fully determine the benefits of this compound. It presents low risk and can easily be added into the diet via increased olive-oil consumption.

Resveratrol

Resveratrol is a polyphenol found in grapes, peanuts, pistachios, some berries, and cocoa. You may have heard of it for providing antioxidant benefits from red wine. This capacity is due to its ability to enhance antioxidative enzymes including superoxide dismutase and catalase.

Currently, most of the research has been done on animal models and has shown that resveratrol holds the power to provide similar protection against age-related diseases in a similar way to intermittent fasting. As well as for oleic acid, research has shown that resveratrol activates sirtuin.³⁰ This offers the same capacity to influence oxidative stress and energy metabolism. Studies on mice have found that resveratrol holds high treatment potential in obesity, with improvements in glucose homeostasis, endurance, and survival.^31, 32 Additionally, it has been shown to benefit bone mineral density and vascular function in animal models.³² An interesting note is that it seems to have a higher affinity for certain tissues including liver, muscle, and adipose tissue.³²

Research on humans has shown that low doses of resveratrol can decrease inflammation as reflected through lowering C‑reactive protein levels.³³ Additionally, it has been shown to mimic the effects of caloric restriction through increasing sirtuins, reducing energy expenditure, and improving mitochondrial function in skeletal muscle.³³ All of this points towards the potential for resveratrol to play a role in health and longevity.

In conclusion, intermittent fasting is one of the most well-evidenced ways to delay age-related disease onset. NAD⁺, oleic acid, and resveratrol appear to be other options that can easily be incorporated into people’s lifestyles to promote healthier and longer living. More research in humans with these compounds is warranted, but what has been uncovered is promising.