Nicotinamide mononucleotide (NMN) has been a front-running supplement in the anti-aging world due to its ability to convert to nicotinamide adenine dinucleotide (NAD+), a key component that activates a group of enzymes called sirtuins. Dubbed the “longevity genes,” sirtuins can help reverse DNA damage and reduce inflammation, both of which are major contributing factors to overall health degradation due to NAD+ depletion as we age. Another set of enzymes that require NAD+ to be activated are DNA-repairing genes called poly (ADP-ribose) polymerases (PARPs). Without adequate NAD+ levels, genes like sirtuins and PARPs can’t efficiently express themselves. This leads down a rough road that most people accept as the imminent phenomena of “getting older.”But what if getting older didn’t need to be so rough? It seems plausible that we can slow the aging clock if we simply boost our NAD+ levels by taking its precursor, NMN. However, a question is being raised by the longevity community as to whether NMN supplementation may work best when combined with methylation support.Let’s take a closer look at methylation, ways to support this vital biological process of the body, and maximize your NMN supplementation.What is Methylation?Methylation is a fundamental biochemical process in which CH3 (one carbon atom and three hydrogen atoms) is transferred from one molecule to another. This process is responsible for many of our body’s most important functions, such as:・Forming neurotransmitter・Producing free radical scavenging antioxidants・Clearing histamine・Cell division・Cellular energy production・Metabolism・DNA expression (epigenetics)We have a “methyl pool,” a storage center of sorts, containing CH3 methyl groups that we draw upon whenever transfers need to be made for these biochemical processes. If we have enough methyl groups stored in the pool, methylating typically isn’t a problem. However, there are reasons why methylating may pose a challenge for some people or change throughout one’s lifespan. Before exploring NMN supplementation and methylation, here are some common causes of decreased methylation.1. MTHFR VariantsMethylenetetrahydrofolate reductase (MTHFR) is a gene with common mutations that can cause high levels of homocysteine in the blood and low folate levels. Two main MTHFR variants — heterozygous and homozygous — are found worldwide spanning many ethnicities, although some variants seem to affect certain people more than others. Up to 40% of the population may have one or both genetic mutations. However, having an MTHFR mutation does not mean you will display symptoms of a disease or require treatment. Oftentimes, supplementing with methylated B vitamins or other methyl donors, such as TMG, is all that is necessary to support methylation.2. Aging and Epigenetics Methylation of DNA plays a crucial role in epigenetics — the expression of DNA. Methylation does not change the DNA sequencing itself, but rather it switches on and off different sequences of your genetic material when needed. Our methylation ability and subsequent DNA expression declines with age. Though we have a lot to learn about genetics and aging, changes in DNA expression may be linked to disease-related biomarkers, which may contribute to age-related diseases like cancer, osteoarthritis, and neurodegenerative conditions, suggests a study in Rejuvenation Research.NMN Supplementation and Methylation SupportThe ultimate goal of supplementing with NMN is to facilitate the conversion of NAD+ in our cells, thereby activating sirtuin genes and promoting longevity. This action is a part of the salvage pathway that involves the creation of nicotinamide (NAM). When the NAM compound is formed, it also needs to be expelled as a part of this natural pathway. To do this, NAM is methylated into N-methylnicotinamide, which is a metabolite found in our urine. When taken as a supplement, NMN may require the use of methyl groups to create and excrete N-methylnicotinamide. Currently, there is no evidence suggesting NMN’s natural methylation of NAM depletes our methyl pool. Even so, safeguarding against depletion and supporting methylation may be a proactive step to augmenting your NMN intake.How do top anti-aging experts suggest supporting this valuable methyl pool? By adding additional methyl donors to it. At the top of the list — trimethylglycine (TMG). Using TMG to Replenish the Methyl PoolTMG, an amino acid known as betaine, has three methyl groups attached to each molecule of glycine and operates along a pathway similar to B12, a crucial methyl donor. Methyl donors can replenish the methyl groups to support healthy methylation. After experimenting with methyl B-12 and methylfolate for methyl donation, anti-aging guru David Sinclair, Ph.D., switched to TMG as a singular methyl donor — purely as a preventative measure to protect against potential methylation depletion by way of NMN supplementation. “As a precaution, I take trimethylglycine so that I continue to give my body a source of methyl groups,” says Sinclair in an interview with Joseph Mercola, DO. “I don’t see any downside. It’s not an expensive molecule. The upside is that I’m preventing my body from being drained of methyl groups.”If you're currently taking NMN or thinking about starting, consider pairing it with TMG as an added support for methylation. Other methyl donors that may be useful include methylated B6, B12, and folate. Side Effect and ContraindicationsTMG is generally well-tolerated, but side effects such as mild digestive upset or headaches may occur in some people. Primary contraindications are for pregnant or breast-feeding individuals. Talk with your doctor if you have questions or concerns regarding the use of TMG as a part of your supplement protocol. The Bottom LineUltimately, supporting your body’s ability to maintain an adequate methyl pool by supplementing with TMG is worth considering as a precautionary measure. Taking the best NMN supplements along with a methyl donor such as TMG offers the most protection by aiding numerous body processes that require methylation — especially activation of longevity-promoting and reparative genes like sirtuins and PARPs. 

There is an irreversible and unavoidable aspect of reproductive aging that begins when a female reaches her late 30s. As women are now waiting longer to start families, this biological race against time is one of the main contributors to the increasing rates of infertility worldwide.Although we can't stop the years from going by, new research in mice has found that there may be a way to mitigate some of the effects of female reproductive aging and increase fertility as we reach the years approaching 40 and beyond.The Stats on InfertilityApproximately 12% of women in the United States in their reproductive years have trouble getting pregnant or maintaining a pregnancy, reports the Centers for Disease Control and Prevention (CDC). Additionally, one in four couples has been affected by infertility worldwide, suggests finding from the World Health Organization (WHO).After reaching age 35, the likelihood of having infertility struggles jumps to one out of every three women. With statistics like these, it's no wonder that women and couples are looking for solutions to help increase fertility. However, advancing maternal age isn't the only reason behind the rise in infertility rates. Given that the female reproductive system is made up of the ovaries, fallopian tubes, and uterus, dysfunction, or disorders in any of them could contribute to reduced fertility. Other factors that can impact fertility include:・Obesity・Exposure to endocrine disruptors (like BPA in plastics)・Polycystic ovarian syndrome・Endometriosis・Hypothyroidism・Other underlying medical conditionsPlus, it's important to mention that men also play a crucial role in fertility; 20-30% of infertility cases can be linked back to issues with the male reproductive systems as well.Although there are options for those struggling with infertility, like assisted reproductive technologies that include in vitro fertilization (IVF), these treatments can be costly, invasive, pose a risk, and don't necessarily have a high success rate, especially as women age.However, there may be a new option on the horizon to help increase fertility. Emerging research has found that a low supplemental dose of nicotinamide mononucleotide (NMN) was able to restore fertility in aging female mice. NMN is a precursor to NAD+, a crucial coenzyme needed for healthy aging, DNA repair, and metabolism.As NAD+ levels decline with age, so does the quality and number of oocytes, which is the technical name for egg cells before they fully mature into eggs. Oocytes are not self-renewing cells - the amount a woman has at birth will be the highest number she ever has. Due to this finite number of cells that decrease year after year, a woman's fertility is largely based on both the number and the quality of oocytes she has left. While there's no way to increase the number of oocytes, we can improve the quality and functioning of the ones remaining.Based on this, the researchers behind this new study, published in the February 2020 issue of Cell Reports, hypothesized that boosting NAD+ in the oocytes of mice through supplemental NMN may be a low-risk and non-invasive method to increase fertility.What Did the Researchers Find?In this study, the researchers tested several different ways in which NMN could be used to improve fertility or oocyte quality, both of which begin to decline at around eight months of age in mice. Let's take a look at the three most important results that were reported in Cell Reports:1. NMN supplementation increased NAD+ in oocytes.When comparing mice between four and five weeks old to 12-month old mice, the older mice had reduced levels of NADPH in their oocytes, as is to be expected with increasing age. NADPH, a required cofactor for anabolic reactions, is the phosphorylated form of NAD+ (meaning it has a phosphate group attached). The researchers measured this form rather than NAD+ due to bioanalytical challenges of measuring NAD+ in oocytes; nonetheless, the function of both NAD+ and NADPH are very similar - both decline as we (and mice) age. After the 12-month old female mice received water that was treated with NMN at 2 g/L for four weeks, levels of NADPH in their oocytes did increase significantly, indicating that NMN was able to restore the age-related decline in NAD+ seen in the female reproductive system.2. The low dose demonstrated a greater impact on fertility than the high doses.The most interesting outcomes of the study resulted when the researchers gave 13-month old mice two different doses of NMN for four weeks. At 13 months, these mice are very near the end of what's considered their "reproductive years."The low-dose group received 0.5 g/L of NMN-treated water, while the higher-dose group received 2 g/L of NMN in their water. After introducing male mice for breeding, the low-dose group saw significant increases in the number of live births, as well as reductions in the time it took to get pregnant. In contrast, the higher-dose group did not see the same benefits of increased fertility.3. NMN supplementation improved IVF outcomes.Lastly, the researchers also looked at how the oocytes of aged female mice responded to IVF when receiving NMN treatment. After the 12-month-old mice received 2 g/L NMN in water for four weeks, their oocytes had larger diameters - oocytes with smaller diameters are linked to worse outcomes after IVF. When the oocytes of the mice received IVF plus NMN-water for two, seven, 14, or 28 days, a longer treatment of NMN led to improved inner cell mass size, which is linked to improved fertility outcomes after IVF.Similarly, IVF was performed using in vivo oocytes from 12-month-old or 4-week-old female mice, and the embryos were then cultured with or without NMN. After supplementation with NMN, the embryos from the oocytes of the older mice had improved blastocyst formation, but the younger mice did not see similar benefits. This improvement in embryo development solely in the aging mice suggests that NMN supplementation during IVF in younger years may not provide the same therapeutic benefits, likely because NAD+ levels have not yet declined.The Caveats to ConsiderWhile this study does provide encouraging and hopeful results for improving fertility, there are a couple of important points to consider when interpreting the research.Less is MoreThese results of the study suggest that while a larger dose of NMN did benefit oocyte quality by increasing NAD+ levels, it did not actually improve fertility and birth outcomes in the same way the lower dose did.This could be due to an upper limit of NMN tolerability or an increase in nicotinamide, a degradation product of NMN that inhibits sirtuins, which are a family of NAD+-dependent proteins that regulate cellular health and promote healthy aging. Although nicotinamide (the amide form of vitamin B3) does have anti-inflammatory and neuroprotective benefits, it may also increase oxidation when consumed or produced in excess. If NMN was consumed in excess of what is needed, then nicotinamide would be produced as a byproduct in excess as well.In regards to the current study, although the fertility benefits were not seen in the higher dose group, it's important to note that no adverse effects were observed either. Moreover, the aging mice in this study did not have to take NMN long before seeing benefits: 50% of the mice on the low dose of NMN achieved pregnancy by the third week of supplementation, indicating that favorable fertility outcomes may be achieved in a short amount of time.But Humans are Not MiceYes, we know that humans are not mice, and mice are not humans. We can't automatically extrapolate data from mouse studies and assume that they will apply to humans - especially a specific subset of humans like reproductively-aging females.But there are several reasons that mice have been used in medical research for decades. Perhaps surprisingly, humans and mice have very similar genomes, genetics, anatomy, and physiology, which make comparing results a bit more useful. In regards to this study, mice have very similar reproductive systems to humans, albeit a shorter gestation period. Mice also have much shorter lifespans than humans, allowing us to study disease development and longevity more easily, as one mouse year equates to approximately 30 human years.Again, although we can't directly apply these results to us, as humans, the researchers of this study acknowledge that this may be a clinically relevant treatment for infertility by improving outcomes of both natural fertility and IVF.A low dose of NMN may be an appropriate and simple solution to helping the millions of women worldwide who want to get pregnant yet have been struggling in their fertility journey for too long. As always, further research - especially in human clinical trials - is warranted before anything can be said definitively. Nonetheless, the risk of taking a low dose NMN supplement is low, and the benefits to fertility may be high.Your Takeaway: Can NMN Increase Fertility?・In reproductively aging mice, a low dose of NMN was able to increase birth rates and reduce the time to pregnancy more than a higher dose of NMN・The higher dose of NMN was able to restore the age-related decline in NAD+ levels and oocyte quality of aging female mice, as well as improve outcomes of IVF in cultured media・In the future, we may see that low-dose NMN supplementation could be a non-invasive and low-risk way to increase fertility or allow for pregnancies at an older age to remain viable, compared to the invasive and expensive IVF treatment・Research on this topic in humans is needed before any definitive claims can be made about the impact of NMN supplementation on improving or increasing fertility outcomes  

Nicotinamide mononucleotide (NMN) is showing promising health and longevity benefits due to its unique ability to convert into oxidized nicotinamide adenine dinucleotide (NAD+), a coenzyme found in all cells that assists with energizing everyday bodily functions such as energy production, metabolism, and gene expression. As we age, NAD+ levels naturally decline and our cells stop dividing, which contributes to the loss of function seen in people who are aged and those who suffer from chronic disease. This process is called cell senescence. By increasing levels of NAD+ in our system by taking NMN supplements, we can offset senescence and improve our cellular health.The most well-known NMN benefits include:・Improved mitochondrial healt・Increased energy productio・Cognitive improvemen・Reduced obesit・Healthy metabolis・Increased fertilit・Healthy gene expressionJust as people’s immunity is impacted by different variables like genetics, environmental influences, diet, and lifestyle, NMN supplements are also composed differently. You should know what to look for in NMN supplements and be aware of which products blend best with your body and personally provide the most value. Let’s take a look at how you can determine what the best NMN supplement is for you.How to Choose the Best NMN Supplement for You: What to Look For1. A Supplier with an Excellent ReputationQuality NMN comes from quality suppliers. But how can you tell a company is reputable? You can check the Better Business Bureau to see how long the company has been in business, what their current rating is, and if there have been any complaints filed against them. An esteemed company will have good reviews and ratings across multiple platforms and is a great place to start when deciding on the right product so you can get the benefits of NMN. Check the company website or do an internet search to see if they have accumulated positive NMN supplement reviews.2. Good Manufacturing Facility PracticesA respected NMN supplier will have ethical operating procedures when it comes to manufacturing. A facility producing NMN should be FDA-registered and FDA-compliant in current Good Manufacturing Practice (GMP) regulations. Being GMP-certified means the FDA has found the company’s facilities, equipment, and ability to manufacture NMN products up to par with the standard regulations. You may also consider looking into whether the facility is climate-controlled. NMN supplements can quickly degrade at high temperatures, which is why they should be produced in a facility where appropriate temperatures are kept during the manufacturing process.3. Third-Party TestingOne of the most important things to check when determining which NMN supplement is the best is whether or not the manufacturing company submits its product for independent, third-party testing. Testing by a non-biased party will ensure the product is pure (99% or higher) pharmaceutical-grade NMN, free of heavy metals. You can check the supplier’s website for third-party testing information, or contact their customer service directly. Verification of third-party testing is a simple way to ensure you’re buying from a reputable source. Any company using third-party testing should be happy to share that information with you.4. Product PurityAs previously mentioned, the best NMN supplements will have 99% purity or higher. It will also not contain any fillers or byproducts such as GMOs, dairy, egg, soy, gluten, artificial chemicals, heavy metals, or solvents used in the actual processing of the product. Check labels for any of these ingredients, or you can always directly contact the company to ask about their NMN production process.5. PricingIt’s always tempting to try to save money every chance you can get, but with NMN specifically, you get what you pay for. Low-cost NMN will likely be food-grade, not pharmaceutical grade, which means the NMN benefits aren’t the same. It comes back to the involved process required to create a product with 99% purity or higher. If the price is low, the percentage of NMN is likely also low — if it exists at all. Considering your budget is important when determining where to buy NMN supplements, but you may end up paying more in the long run when opting for lower-priced NMN products if you don’t see any health benefits from them.6. Consumer-Satisfaction GuaranteeHighly regarded NMN supplement companies usually provide some kind of guarantee of compensation should you find yourself not fully satisfied with the results of your purchase. Check the fine print on a supplier’s website or call the company to verify whether they afford any money-back guarantees if returned by a specific date. For example, some companies may offer a 30-day money-back guarantee, which should be enough time to determine if the NMN supplement product is a good fit for you.7. Product ResearchWith NMN being more heavily researched for its benefits to overall health and longevity as a necessary NAD+ precursor, the chances of a particular NMN product being used in human clinical trials exist. Only NMN products whose quality and purity can be verified are used for studies, so you may want to see if the product you’re interested in is being considered or used for research purposes. While most companies proudly display this online, you can always call customer service to double-check if you can’t locate that information yourself.8. Form of DeliverySupplementary NMN can be purchased as powder, lozenges, tablets, and capsules, each having a unique ability to get into your system in different ways. When figuring out how to choose NMN supplements, your personal preference is really the key. If tablets and capsules are difficult to swallow, starting with NMN powder or a lozenge may be the best option for you. For convenience purposes while traveling, for example, an easy-to-carry pill or lozenge may provide the best solution. A good company will likely have a variety of NMN forms available to suit your needs, so consider which form may be best for you. No matter which form you take, NMN is absorbed from the gut and into the blood within two to three minutes, and completely absorbed into tissue within 15 minutes, according to a study in Biomolecules. Once in the liver, it is then converted and stored as NAD+ and persists for 30 minutes.Key TakeawaysFinding the best NMN supplement to assist in your efforts to recapture and maintain your youth can be easy when you know what questions to ask and what answers to listen for. A supplier with a long-standing, good reputation that adheres to FDA regulations will most likely provide you with a high-quality, third-party tested, pharmaceutical-grade NMN product. Don’t forget to read NMN supplement reviews, and when in doubt, go directly to customer service with any concerns or questions you may have. When you get close to committing to a purchase, remember to check for any satisfaction guarantees to confirm you are making a risk-free, sound investment in your health.ReferencesCenter for Drug Evaluation and Research. (n.d.). Current Good Manufacturing Practice (CGMP) Regulations. Retrieved June 15, 2020, from https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulationsOffice of Regulatory Affairs. (n.d.). Registration and Listing. Retrieved June 15, 2020, from https://www.fda.gov/industry/fda-basics-industry/registration-and-listingPoddar SK, Sifat AE, Haque S, Nahid NA, Chowdhury S, Mehedi I. Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules 

Sirtuins are a family of proteins that function as enzymes and play a key role in cellular health, aging, and longevity. Nicknamed as the “longevity genes,” the seven sirtuin family members are susceptible to the age-related decline in function seen with many other cellular processes. This article will detail the basics of how sirtuins function, the recent research on how they impact lifespan and chronic disease, and how to best activate them to ensure a long lifespan and healthspan.Sirtuins: The BasicsSirtuins are dependent on NAD+ (nicotinamide adenine dinucleotide), the coenzyme needed by every cell in our bodies. However, NAD+ levels naturally decline with age, and the functioning of sirtuins declines right alongside it. Maintaining NAD+ levels can reduce the decline in sirtuin function, as well as minimize cellular aging and chronic diseases. Although you can’t supplement directly with NAD+, you can take one of its precursors, such as NMN (nicotinamide mononucleotide), to boost it.Each of the seven sirtuins behaves slightly differently but has the same goal in mind: regulating cellular health and controlling the aging process. The sirtuins are classified as SIRT1-7. Although the seven sirtuins are found in different areas of the body — SIRT3, 4, and 5 are located in the mitochondria, SIRT1, 6, and 7 are in the nucleus, and SIRT2 is in the cytoplasm — all can slow down cellular senescence, the process by which cells stop dividing and lose function, ultimately leading to accelerated aging.  Some of the main functions of sirtuins include: ・Repairing damaged DNA, which is thought to be a leading cause of cellular senescenc・Upregulating mitochondrial activit・Increasing antioxidant pathways, which reduces oxidative damag・Responding and adapting to cellular stressor・Regulating telomere activity — telomeres are the “endcaps” of DNA that protect our chromosomes and shorten with age.・Controlling inflammatio・Generating cellular energy through ATP productioSirtuins and LongevityAs NAD+ levels decline with age, sirtuin activity is reduced, which impacts cellular communication and contributes to the pathogenesis of aging and related diseases. Although sirtuins were only discovered approximately 20 years ago, the body of research is ever-growing as scientists aim to determine just how sirtuins impact longevity in humans.Initial research into sirtuins was done on yeast and animals. A 1999 study published in Genes and Development found that overexpression of SIRT2 extended the lifespan of yeast by 30%, fueling the idea that sirtuins promote longevity and reduce age-related diseases. Additionally, a 2013 study in Cell Metabolism found that increasing SIRT1 in the brain led to delayed aging and extended lifespan in mice, adding credence to the idea that sirtuins are involved in brain health.To date, however, research on the sirtuins’ impact on longevity has been largely confined to yeast and animal studies. The primary correlation involves SIRT3. Single nucleotide polymorphisms (SNPs) in SIRT3 have been linked to increased human lifespan in centenarians. Although these results are promising, it should be noted that further research is needed in humans.Recent Research on SirtuinsAlthough SIRT2 was the first sirtuin to be discovered, SIRT1 is the most commonly studied of the bunch. The reduction in SIRT1 levels widely seen with age is linked to dysfunction in the arteries, liver, blood vessels, endothelial cells, and brain. However, all seven sirtuins play an essential role in health and longevity. The top-researched areas in which sirtuins have been studied for their actions in human health are related to cardiovascular, metabolic, and neurodegenerative diseases.1. Cardiovascular DiseaseThe main players associated with mitigating the age-related decline in cardiovascular health are SIRT1, 3, 6, and 7. These sirtuins have been found to protect cardiac muscle cells from oxidative stress, suppress cardiac hypertrophy, and reduce dyslipidemia and the stress response in the heart. Due to the high energy requirements of the heart, the sirtuins’ ability to increase mitochondrial function and ATP production is a primary mechanism in which they protect the heart. Of the sirtuins, SIRT1 and SIRT3 are likely the two that prevent cardiovascular disease the most, as they function to reduce oxidative stress and mitochondrial dysfunction while protecting the endothelial cells that line the circulatory system.2. Metabolic DiseasesDisorders involving dysregulated metabolism include type 2 diabetes, obesity, and insulin resistance. As the sirtuins are involved in metabolism through their effects on mitochondria and ATP, it’s not surprising that they benefit metabolic diseases. Many of the sirtuins, specifically SIRT1, have been studied for their ability to suppress inflammation, which is a root cause of many chronic diseases. Humans with reduced SIRT1 expression tend to have increased glucose intolerance, insulin resistance, and metabolic syndrome. In diabetic mice, administering NMN enhanced insulin sensitivity and glucose tolerance. In a study published in Cell Metabolism, the authors indicate that SIRT1 was likely the primary mechanism through which these beneficial effects were seen.3. Neurodegenerative DiseasesNeurodegenerative diseases, like Alzheimer’s disease, dementia, and Parkinson’s disease, have also been mitigated by sirtuin activation or upregulation.In the brain, SIRT1 is expressed in neurons of the hippocampus, the primary center associated with memory and learning. In a July 2010 study published in the Journal of Neuroscience, mice who did not have SIRT1 had impaired cognition, memory, and synaptic plasticity.In humans, a decrease in SIRT1 levels in the brain of patients with Alzheimer’s disease was paralleled with the stage and duration of the disease. The study also found that greater SIRT1 levels were linked to a reduction in the duration of Alzheimer’s-related symptoms and an increase in brain weight.Sirtuin ActivationAlthough sirtuin functioning decreases with age, there are plenty of ways to prevent or slow down this degradation.Activation of sirtuins can be achieved by several mechanisms, including caloric restriction, certain supplements, and, of course, maintaining adequate NAD+ levels. Supporting your body’s NAD+ levels as you age is essential to ensure proper sirtuin activation. This can be achieved through supplementation with NAD+ precursors, which include NMN and NR (nicotinamide riboside). The Top Ways to Activate Sirtuins:・NMN supplementation increases NAD+ levels, which will activate sirtuins. NMN has also been found to reverse the age-related decline of SIRT1・Exercise, including aerobic, interval, and resistance training, can activate SIRT1 and SIRT3・Caloric restriction activates SIRT1, SIRT3, and SIRT6; sirtuins are thought to be the driving factor behind how calorie restriction extends lifespan.・Resveratrol, specifically trans-resveratrol, may preserve sirtuin function.・Curcumin can activate SIRT1 expression.Key Takeaways・Sirtuins are a family of proteins that play a role in aging and age-related diseases.・They are dependent on NAD+; both sirtuin and NAD+ levels decline with age.・Increased sirtuin activity has been linked to increased lifespan in yeast and animals and reduced risk or progression of cardiovascular, metabolic, and neurodegenerative diseases in humans.・Sirtuins can be activated by increasing NAD+ through NMN supplementation, caloric restriction, exercise, trans-resveratrol, and curcumin.