The Relationship between Fasting, NAD+ Levels, and Anti-aging
Nicotinamide adenine dinucleotide (NAD+) has a key role in countless reactions; some of the most important reactions are those that help produce energy, repair DNA, express our genes, signal nutrients, and guard cells from infections and inflammation. In short, NAD+ helps to keep our cells healthy. (1)
Low levels of NAD+ are associated with cellular aging and a higher risk of chronic disease. In fact, one of the major causes of cell death caused by genotoxic stress is likely the depletion of NAD+ from the cell. As a result, scientists have been interested in identifying lifestyle patterns and choices that can increase NAD+ levels and fight aging. (2)
One of the lifestyle choices that has increasingly gained the interest of health and wellness professionals is intermittent fasting. Fasting is the intentional abstinence from food for prolonged periods of time, usually at least 10 hours.
Fasting has been associated with weight loss and insulin management. More recently it has also been associated with lower rates of cellular aging.
In this article we review what the research says about the connection between NAD+ levels and periods of fasting. We also help answer some popular questions around NAD+ levels and fasting.
Scientists have long known that fasting can extend the lifespans in many species while mitigating diseases associated with aging in mammals; research has shown that calorie restriction can increase the lifespan of rodents, non-human primates (such as rhesus monkeys), and potentially in some species of birds, as well. (3, 4, 5)
Most studies on the effects of fasting on NAD+ levels have been conducted on mice, a species whose genetic, biological, and behavioral characteristics closely resemble that of humans. These studies have helps to understand the mechanism of action of fasting on NAD+ levels.
This is what we know: (6)
- Sirtuins, such as the SIR2 and SIRT 1 family of genes, are lifespan regulators that have been conserved through evolution.
- Sirtuins encode a deacetylase that is dependent on NAD+
- SIR2, a type of sirtuin, regulates lifespan and mediates calorie restriction (fasting) in lower species
- Modulating the activity of sirtuin through calorie restriction, such as fasting, may help to combat the diseases of aging
- Fasting promotes the expression of SIRT1 and NAD+-levels in mice. (6, 7)
- The anti-aging effect of fasting may be enhanced with the addition of NAD+, such as through supplementation. (6, 7)
- Both caloric restriction and intermittent fasting may prolong the healthspan of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate lifespan. (6, 7)
Some researchers question whether the findings of animal studies are transferrable to humans. As of yet, there are only a handful of human clinical studies that examine NAD+ and sirtuin expression as a result of fasting protocols like intermittent fasting.
Initial studies suggest, however that periodic or intermittent fasting may have a similar effect on the biological and chemical processes that fight aging as has been observed in animal species.
For example, a study that enrolled participants in a protocol of periodic fasting for five days found that they had elevated levels of SIRT 1 and SIRT 2 sirtuin expression in humans (8).
Additionally, improvements in the composition of gut microbiota were also improved. Gut microbiota diversity is linked to immune health and to a longer healthspan. (9, 10)
Another study set out to assess the tolerability of an intermittent fasting protocol and to explore the biological mechanisms related to aging and metabolism (11) . To carry out the study, researchers recruited 24 yearly individuals for a double-crossover, double-blinded, randomized clinical trial. Participants went through two study periods that were three weeks each.
For the first study period participants adopted an intermittent fasting protocol, and for the second period they combined intermittent fasting with antioxidant vitamin supplementation (vitamins C and E). Researchers found that during the short study period, participants had an increase in SIRT3 sirtuin expression due to intermittent fasting, whether or not they were taking antioxidant supplements.
In short, initial evidence is promising; intermittent fasting may positively stimulate NAD+ concentration and activate signalling pathways that fight aging. However, it is still unclear how much fasting increases NAD+ levels, and whether intermittent fasting is safe and beneficial in the long term. Larger, well-designed studies with human voluntary participants is necessary to understand whether intermittent fasting might be a recommendation for people looking to naturally increase their NAD+ levels.
In many ways the role of NAD+ in antiaging is one of the newest and most exciting frontiers of research. While the role of NAD+ for normal metabolic processes that support health and prevent age-related aging is not a question, the research on different lifestyle choices that we can make with the goal of lengthening health span through increasing NAD+ levels is just beginning.
We know that NAD+ supplements increase NAD+ levels in the blood and have multiple therapeutic functions. Lifestyle choices, like diet composition and timing, including intermittent fasting, are not as clear.
Intermittent fasting and calorie restriction has been demonstrated to lengthen the lifespan and healthspan of multiple species, including mammalian species, by way of modulating sirtuin activity and increasing NAD+ levels. A handful of studies on the impact of intermittent fasting on human aging mechanisms seem to have similar results. However, more, wide-scale studies are required to make definitive assertions related to the role of intermittent fasting and calorie restriction in antiaging in humans.
If you are looking for a way to increase NAD+ levels, NAD+ supplements are the most efficient way to do so.
Braidy, N., Berg, J., Clement, J., Khorshidi, F., Poljak, A., & Jayasena, T. et al. (2019). Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes. Antioxidants & Redox Signaling, 30(2), 251-294. https://doi.org/10.1089/ars.2017.7269
Yang, H., Yang, T., Baur, J., Perez, E., Matsui, T., & Carmona, J. et al. (2007). Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival. Cell, 130(6), 1095-1107. https://doi.org/10.1016/j.cell.2007.07.035
Speakman, J., Mitchell, S., & Mazidi, M. (2016). Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone. Experimental Gerontology, 86, 28-38. https://doi.org/10.1016/j.exger.2016.03.011
Kemnitz, J. (2011). Calorie Restriction and Aging in Nonhuman Primates. ILAR Journal, 52(1), 66-77. https://doi.org/10.1093/ilar.52.1.66
Ottinger, M., Mobarak, M., Abdelnabi, M., Roth, G., Proudman, J., & Ingram, D. (2005). Effects of calorie restriction on reproductive and adrenal systems in Japanese quail: Are responses similar to mammals, particularly primates?. Mechanisms Of Ageing And Development, 126(9), 967-975. https://doi.org/10.1016/j.mad.2005.03.017
Chen, D., & Guarente, L. (2007). SIR2: a potential target for calorie restriction mimetics. Trends In Molecular Medicine, 13(2), 64-71. https://doi.org/10.1016/j.molmed.2006.12.004
Hayashida, S., Arimoto, A., Kuramoto, Y., Kozako, T., Honda, S., Shimeno, H., & Soeda, S. (2010). Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice. Molecular And Cellular Biochemistry, 339(1-2), 285-292. https://doi.org/10.1007/s11010-010-0391-z
Lilja, S., Stoll, C., Krammer, U., Hippe, B., Duszka, K., & Debebe, T. et al. (2021). Five Days Periodic Fasting Elevates Levels of Longevity Related Christensenella and Sirtuin Expression in Humans. International Journal Of Molecular Sciences, 22(5), 2331. https://doi.org/10.3390/ijms22052331
D’Amelio, P., & Sassi, F. (2017). Gut Microbiota, Immune System, and Bone. Calcified Tissue International, 102(4), 415-425. https://doi.org/10.1007/s00223-017-0331-y
Keenan, M., Marco, M., Ingram, D., & Martin, R. (2015). Improving healthspan via changes in gut microbiota and fermentation. AGE, 37(5). https://doi.org/10.1007/s11357-015-9817-6
Wegman, M., Guo, M., Bennion, D., Shankar, M., Chrzanowski, S., & Goldberg, L. et al. (2015). Practicality of Intermittent Fasting in Humans and its Effect on Oxidative Stress and Genes Related to Aging and Metabolism. Rejuvenation Research, 18(2), 162-172. https://doi.org/10.1089/rej.2014.1624
