A decades-old diabetes drug now holds promise for increasing healthspan. Research shows that metformin may reduce the risk of some of the diseases of aging, thus increasing the number of years someone is healthy.
What is metformin?
Metformin, also known as Glucophage, is the most commonly prescribed medication for reducing blood glucose levels. Metformin prescriptions target people with diabetes, prediabetes, and sometimes PCOS (polycystic ovarian syndrome).
Beyond diabetes, there are also many studies pointing to other positive benefits for metformin as a longevity or healthy aging medication.
How does metformin work?
Metformin has a couple of mechanisms of action:
It decreases glucose production in the liver, which is especially important for overnight blood glucose regulations.
It increases the uptake of glucose in muscles and other parts of the body.
Let’s take a close look at all three of these actions of metformin:
Decreases glucose production in the liver:
When glucose levels in the body fall, such as when fasting or even overnight when sleeping, the liver can produce glucose through a process called gluconeogenesis. This keeps glucose levels in the right range all day and night for people without diabetes.
The research on exactly how metformin decreases gluconeogenesis (glucose production) in the liver isn’t fully elucidated. There seem to be several possibilities:
First, metformin may act partially in the mitochondria, inhibiting complex I in the electron transfer chain. This would alter the ratio of AMP (adenosine monophosphate) to ATP (adenosine triphosphate), which triggers AMPK. AMPK does a bunch of things, including decreasing gluconeogenesis.[ref]
Second, metformin may be altering the way mitochondria use lactate for energy. A January 2020 paper contends that metformin works through decreasing glucose 6-phosphate (G6P).[ref][ref]
New research also questions whether metformin reduces glucose production in the liver for people without type 2 diabetes. The studies indicate that glucose production in the liver may not decrease – and may possibly increase a bit to counteract the drop in blood glucose levels.[ref][ref]
Increases glucose uptake:
Blood glucose levels remain tightly regulated, and the release of insulin by the pancreas facilitates the uptake of glucose into cells. For most cells, glucose can’t cross the cell membrane without a transporter. The glucose transporters are known as GLUT1 through GLUT4, with different transporters in different cell types. The GLUT4 transporters are found in muscle tissue and fat cells. When blood glucose levels are high, the GLUT4 transporters are located in the cytosol of the cell (inside the cell), but when glucose levels fall, insulin levels rise. Insulin then binds to a receptor on the cell membrane, causing a cascade of actions that results in the GLUT4 transporters moving to the cell membrane. There, they can move glucose into the cells.
Metformin is thought to work in a way that keeps the GLUT4 transporters available on the cell surface so that the skeletal muscle cells can take up more glucose without needing more insulin.[ref]
Altered microbiome composition: Research also shows that metformin alters the composition of the gut microbiome, promoting Akkermansia muciniphilia, a bacteria associated with a lower risk of obesity and a lower risk of inflammatory conditions in the intestines. The altered gut microbiome composition may also be a mechanism through which metformin helps with diabetes. Additionally, metformin has shown to increase short-chain fatty acid metabolism in the intestines.[ref][ref][ref]
PCOS and metformin:
Polycystic ovarian syndrome (PCOS) is characterized by insulin resistance and altered androgen hormone production. Studies show that metformin may be beneficial for women with PCOS. One study found that 12 weeks of metformin decreased testosterone levels and improved glucose effectiveness.[ref]
Metformin for Longevity and Aging:
Many researchers are now looking at aging as a disease. In fact, the World Health Organization recently added it to its classification system as a disease. With this idea in mind, let’s take a look at the use of metformin to prevent chronic diseases in aging.
Animal studies have repeatedly shown that metformin can increase lifespan. Most of the studies show that starting metformin in middle age or earlier can increase lifespan and healthspan.[ref][ref][ref]
But humans aren’t the same as mice, and the results of animal studies sometimes don’t hold true for people.
Human studies on metformin show:
A large meta-analysis found that people with diabetes and also taking metformin had lower all-cause mortality than non-diabetics. They also had lower cardiovascular disease and cancer rates. That is pretty amazing. The study also showed that diabetics taking metformin had lower rates of cancer than diabetics using other types of diabetes medications.[ref]
Another meta-analysis using data from over 1 million patients found significant reductions in both all-cause mortality and cardiovascular events. (20% for all-cause mortality and over 30% for cardiovascular events).[ref]
Other studies show a reduction in all-cause mortality and cancer-related mortality in people who take metformin.[ref]
Not all human studies show fantastic results:
In a study of heart attack patients, 4 months of metformin did not have beneficial long-term effects.[ref] Other studies show a possible impact that negates the benefits of aerobic exercise.[ref]
How can metformin extend healthspan?
One mechanism (other than decreased blood glucose levels) for a positive effect on healthy aging is that metformin may activate SIRT1. The sirtuins are a family of enzymes that are important for regulating cellular homeostasis, and SIRT1 (sirtuin 1) is important in healthy aging. A link exists between the activation of SIRT1 and lower rates of cardiovascular and metabolic diseases.[ref][ref]
Another mechanism through which metformin has shown to act is in the way that mitochondria use fatty acids for energy. The ACAD10 gene codes for an enzyme needed in beta-oxidation and animal studies show that metformin acts through the inhibition of mTORC1 to upregulate ACAD10.[ref]
Impact on muscles:
A Dec 2019 randomized crossover trial shows that 4 days of metformin doesn’t impact skeletal muscle activity. Interestingly, the authors note that metformin caused the participants to feel like exercise took more exertion. Thus, it may cause people to want to exercise a little less.[ref]
In another study in older adults (age ~62), 3 months of metformin seemed to attenuate the benefits of aerobic exercise.[ref]
Potential negative side effects from metformin:
Most importantly, there is an increased risk of lactic acidosis in people taking metformin. This may be more of a risk for people with underlying kidney problems.[ref]
Some people have gastrointestinal side effects from metformin. People with SLC22A1 variants (below) are more likely to have gastrointestinal problems.[ref]
Metformin metabolism and excretion:
Metformin circulates unbound because its metabolism doesn’t occur in the liver. Instead, the kidneys clear it from the body facilitated by SLC22A2 kidney cells. (more on this below)[ref]
Genetic variants associated with metformin response:
Like almost every drug or supplement, individuals respond differently to metformin. Below you can find some of the genetic variants associated with the altered response to metformin.
Note: This article is also cross-posted on GeneticLifehacks.com.
If you are interested in metformin for longevity, talk with your doctor about whether getting a prescription for it is right for you.
Alternatively, there is an online website that sells 3-month prescriptions of metformin, after you interact with their telemedicine doctor. The website is called qualytude.com. Read through the information and be sure to understand the terms of the website.
Longer-term use of metformin increases the risk of vitamin B12 deficiency.[ref] Consider supplementing with vitamin B12, especially if you don’t eat a lot of foods that contain B12.
Berberine is a natural supplement that is often touted as a natural alternative to metformin in terms of blood sugar control. Read more about berberine.
Have you ever wondered why you are much more likely to have a cold in the winter than in the summer? It turns out that researchers have puzzled over the seasonality of respiratory viruses for decades. In 1926, one scientist proposed that the seasonality was due to the vitamin found in dairy products and produced by sunlight exposure on the skin.[ref] This idea that vitamin D levels influence the seasonality of respiratory viruses had been tossed around ever since, in different variations.
This article will cover the more recent research on vitamin D levels, supplementation, and respiratory infections.
Can Vitamin D reduce the risk of respiratory infections?
First, a little context.
By respiratory infection, researchers are generally referring to colds, flu, and what the CDC calls ‘influenza-like illness’ or ILI. These are the viruses that go around every winter causing coughing, sneezing, wheezing, and runny noses.
The virus families that cause the common cold include rhinovirus, respiratory syncytial virus (RSV), adenovirus, and coronavirus.
The flu is caused by many different strains of influenza A or influenza B.
The CDC reports each year on ILI- influenza-like illness. This is a catch-all for influenza virus, RSV, rhinovirus, adenovirus, parainfluenza virus, coronavirus, and metapneumovirus.[ref]
Why do we care about respiratory viruses? Excluding data from the current COVID-19 pandemic (which is measured differently than previously), about 20% of the US population will get a respiratory infection each year. Several hundred thousand will end up in the hospital, and of those who are hospitalized with a respiratory infection, over 10% will die.[ref]
Additionally, respiratory tract infections statistically have links to an increased likelihood of heart attacks. A study looking at English hospital admission for people with myocardial infarction found that up to 5% of MI admissions may be due to respiratory virus infection in the previous week or two. Influenza was the least likely to be linked to MI, while the common cold viruses were most likely.[ref]
Vitamin D: the sunshine hormone
Vitamin D is produced in the skin as a reaction between UVB radiation from sunlight and cholesterol in the epithelial cells.
Once synthesized (or ingested), the liver transforms it into 25-(OH)D (25-hydroxyvitamin D). This is what you usually see on lab tests.
25-(OH)D is the main form available in the body, and it has a half-life of two to three weeks, so it can hang around for a while.
The kidneys transform 25-(OH)D into the active form of 1,25-(OH)2D. Certain other cells, such as immune system cells, can also transform the storage form of D into the active form. The active vitamin D hormone is transported throughout the body by vitamin D binding protein.
What does vitamin D do in a cell? The active form of vitamin D binds to a vitamin D receptor in the nucleus of certain cell types and then turns on genes for transcription. There are several different types of cells with vitamin D receptors. For example, in macrophages, active vitamin D increases the production of anti-microbial peptides. In T-cells, vitamin D causes a shift towards Th2.[ref] In muscle cells, the binding of vitamin D to the receptor increases calcium and phosphate transport and increases muscle cell proliferation.[ref]
Regulating the immune response:
When challenged by a pathogen, the body needs to respond with enough immune response to vanquish the invader — but not going overboard and killing healthy cells. Many times, death from a respiratory virus is due to ARDS (acute respiratory distress syndrome) which is, at least in part, the body’s over-activation of the immune system in the lungs.
Vitamin D is important in activating immune system cells in a way that keeps the immune response from going overboard. Specifically, it skews the T-cells to mature as a regulatory T-cell phenotype rather than an inflammatory Th1/Th17 phenotype.[ref]
Clinical trials on Vitamin D and respiratory tract infections:
Research clearly shows that low vitamin D levels are associated with an increased risk of respiratory infections in both young and old[ref][ref]. But does that mean that taking a vitamin D supplement will help to prevent illness?
This can be a harder question to answer than you would think. There are a ton of trials on vitamin D supplementation, but many of the trials are small and use low doses of vitamin D in the trial.
A 2019 meta-analysis combined the data from 25 randomized controlled trials to try to answer the question of whether any vitamin D supplementation would reduce respiratory infections. The results showed that overall a daily or weekly vitamin D supplementdecreased the average risk of respiratory infections by about 20%. Large doses via a shot of vitamin D did not have a statistical effect. Unsurprisingly, the benefit of supplementation was much greater in people who were vitamin D deficient (< 25 nmol/l). For vitamin D deficient individuals, supplemental vitamin D reduced respiratory tract infections by 70%.[ref]
What about COVID-19 vitamin D trials?
At the very beginning of the COVID-19 pandemic researchers associated vitamin D levels with a 20-fold increased risk of severe COVID-19.[ref]
But many argued that the association didn’t prove causation, nor did it tell us whether vitamin D supplementation would be beneficial for prevention. Years of previous research on the mechanism of action of vitamin D on the immune system didn’t seem to be enough to ‘prove causation’. Of course, even without clinical trials showing a benefit, there isn’t much of a risk to boosting vitamin D levels via a daily or weekly supplement.
A year down the road, the clinical trial results are rolling in, showing a clear benefit to supplementing with vitamin D, especially for people with lower baseline levels.
A Dec. 2020 study showed a significant reduction in mortality for COVID-19 hospitalized patients given vitamin D in the hospital. The patients who had received a shot of vitamin D (280,000IU) were 87% less likely to die from COVID-19.[ref]
A small trial of vitamin D (1,000 IU), magnesium, and vitamin B12 in hospitalized COVID patients showed a >80% reduction in the need for oxygen or ICU admission.[ref]
In another small trial of COIVD hospitalized patients, 50 of the patients received a large dose of oral vitamin D on days 1, 3, and 7 of hospitalization. All patients (control and vitamin D arm) also received other medications such as hydroxychloroquine and azithromycin as part of the normal hospital protocol. There was a significant difference in the patients needing admittance to the ICU — 1 / 50 for the vitamin D participants vs. 50% of the control group who didn’t receive vitamin D.[ref]
Should you take vitamin D before a vaccine?
If vitamin D modulates the immune response, should you stop taking it before a vaccine? Let’s take a look at the research studies on the topic.
Several studies have looked at the response to vaccines stratified by vitamin D levels. Most studies show that there is no difference in the response to the flu vaccine based on vitamin D levels. There is a difference in response to the rubella vaccine based on vitamin D receptor gene variants, suggesting that vitamin D does play a role in that vaccine. With the hepatitis B vaccine, though, there is a clear association between lack of response to the vaccine and low vitamin D levels. In children, vitamin A and D supplementation increase the response to the tuberculosis vaccine.[ref]
While no overall benefit shows for higher vitamin D levels for the flu vaccine, a benefit for certain strains of influenza might exist.[ref]
What does seem to matter for vaccine response is age, genetics, stress, BMI, season, and time of day of vaccination.[ref] For example, morning vaccinations are more likely to elicit a stronger immune response for certain flu vaccines than later in the afternoon (3-5 pm).[ref]
Vitamin D supplementation reduces viral respiratory illnesses:
Vitamin D deficiency clearly impacts the immune response to viral respiratory illnesses. This has been the theory for over a century and has repeatedly been shown for the past couple of decades in research studies.
With respiratory illnesses either directly or indirectly causing many deaths in people over 65 each year, it seems like a ‘no brainer’ to keep your vitamin D levels up in the normal range. Younger people also benefit from reduced respiratory infections, and even if a viral isn’t likely to kill you, reducing the number of times you are sick in a year is a benefit for everyone.
Sunlight on your skin is a great option for increasing your vitamin D levels. Of course, this is not such a great option in the fall and winter months when UVB rays are scarce and it is too cold to expose much skin.
Supplemental vitamin D is cheap and readily available. Check the label on your vitamin D supplement, though, since a lot comes with cheap soybean or cottonseed oil. A better option is made with coconut or olive oil.
Check your vitamin D levels:
Get your doctor to order a vitamin D test the next time you go. OR – order a test on your own. Ulta Lab Tests offers it for $39, and there are other places online to order it as well.
A recent study in Cell reported on experiments regarding mitochondrial function and amyloid protein accumulation in the muscles.[ref]
The researchers used animal models and human muscle tissue to determine that amyloid-like protein deposits occur in muscle during aging. Amyloid proteins are aggregates of proteins that fold into long fibers. Perhaps the most well-known is amyloid-beta, which is the amyloid version of the APP protein and commonly found in Alzheimer’s brains.
Additionally, the researchers confirmed previous research showing a decline in mitochondrial function. Together, the amyloid proteins and reduced mitochondrial function “may represent a major common hallmark of muscle aging and disease.”
NAD+ also declines in muscle tissue in aging. The researchers showed that blocking the NAD+ salvage pathway, which reduced NAD+ in the cells, robustly induced the muscle cells to produce amyloid protein aggregations.
The opposite also seems to be true – boosting NAD+ attenuated the formation of amyloid protein aggregates in aging cells.
In an animal model, boosting NAD+ in older cells may reduce the amyloid deposits. The researchers tested nicotinamide riboside (NR) and olaparib (AZD). Nicotinamide riboside is commonly available as a supplement, and olaparib is a PARP inhibitor used for cancer treatment. Both were successful at ameliorating amyloid deposits in the muscle cells.
Why is this a big deal?
Loss of muscle mass in aging can lead to devastating health effects such as falling and breaking a hip. Oddly enough, researchers don’t really know what all goes into the loss of muscle in aging. This research is important both in pointing out mechanisms as well as a possible solution.
Note: Please do not take this as an endorsement or as medical advice. Instead, the links are for your reference – do your due diligence before starting on a new supplement or diet.
(Note that this article is cross-posted from Genetic Lifehacks — more to some on this topic)
Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are two supplements that have taken the longevity and anti-aging world by storm. With animal studies showing exciting results including reversal of age-related diseases, these supplements are an exciting glimpse into the future of reversing aging.
Just a heads up, so that you aren’t disappointed: There is little research, as of yet, into the ways that genetic differences impact NR or NMN. Instead, I will dig into the science of how NR and NMN work, the research that has been done on NR and NMN, and then explain the connections with sirtuins, PARPs, and aging. I will also dig into genetic variants that impact the body’s production of NAD+ and the relation to sirtuin gene variants. But…I can’t tell you, based on your genes, whether you should take NR or NMN 🙂
NAD+ (nicotinamide adenine dinucleotide) is an important molecule that all plants and animals produce and use. It is a niacin derivative used in all living cells for a bunch of different purposes. It is one of those ‘can’t live without’ type of molecules!
NAD+ in cellular energy production:
A quick overview of cellular energy production for those for whom high school biology is but a distant memory…
In cellular metabolism, NAD+ is an essential part of energy production. When you eat food, your body converts it into the components needed by the cells for producing energy. For example, carbohydrates break down into simple components such as glucose. The glucose can then be directly used in the cells to produce ATP, which is the molecule your body uses for energy.
During cellular energy production, glycolysis uses glucose to produce a little ATP (net of 2 molecules) and acetyl-CoA. Then, the acetyl-CoA can be used in the mitochondria to produce more ATP via the citric acid cycle (aka Krebs cycle). Additionally, your body can convert fatty acids into acetyl-CoA when it is in ketosis.
NAD+ comes into play within the Kreb’s cycle, shuttling electrons between the NAD+ and NADH. The net result from the Kreb’s cycle is three NADH molecules (and one ATP).
Next up in energy production within the mitochondria is oxidative phosphorylation (electron transport chain). Within the inner membrane of the mitochondria, oxidative phosphorylation takes those intermediates of the citric acid cycle and cranks out a bunch of ATP (energy molecule). This is your body’s main way of producing energy when there is enough oxygen present. In fact, it is the main way that all aerobic organisms with mitochondria produce energy.
An essential step in this process uses NAD+ for the transfer of electrons.
Other roles of NAD+
While the use of NAD+ for cellular energy production is fundamental to life as we know it, this molecule is also used in numerous other reactions in the body.
NAD+ is consumed in the type of reactions known as ADP-ribose transfer reactions. Examples of this include processes such as the repair of DNA and in the maintenance of telomeres, the end caps of DNA that are important in cellular aging.
NAD+ is also used in reactions involving sirtuins. Sirtuins are a family of proteins (SIRT1 through SIRT7) that are essential for turning on and off the translation of genes within a cell. This is foundational for the control of cellular functions. (More on sirtuins to come…)
Additionally, NAD+ involves cell signaling processes both within and outside of cells.
Yep – I’ve used the words essential, foundational, and fundamental here, but these seem like a weak way to explain the necessity of NAD+ in your body.
Let me dive into all of these a bit further…
NAD+ and Aging:
As we age, there are a number of physiological changes that take place. You all know this — you lose your hearing and your hair, muscle mass declines, wrinkles increase, weight tends to rise, along with blood glucose levels. Eventually, you end up with heart problems or diabetes, and then everything goes downhill from there.
NAD+ levels decrease with age and could be at the heart of some of the age-related declines we face. For example, NAD+ is important in DNA repair, and this process is so important for preventing cellular death – or cancer. Mitochondrial energy production decreasing in aging is another big part of why everything goes downhill.
Sirtuins and Aging:
I mentioned above that sirtuins rely on NAD+, and that this is important in gene expression. Let me explain this further…
Sirtuins are a family of genes, SIRT1 through SIRT7. The function of all of them is not yet fully understood.
The regulation of gene expression involves sirtuins. Meaning, the sirtuins must cause the DNA in the cell nucleus to either be accessible or inaccessible for a gene to be transcribed. The ability for the regulation of genes transcribed into proteins is fundamental to cell function. Every cell nucleus contains the same DNA. The differences between a liver cell and a muscle cell are due to the regulation of which genes are transcribed. Thus, disrupting the sirtuins can lead to mucked up cell function and the symptoms of aging.
In the initial studies on the sirtuin genes in yeast, it was found that adding in additional copies of the gene increased lifespan by 30%. [ref] Think about what that could mean for humans — regularly living to 110 instead of 80?
SIRT1 codes for the sirtuin 1 protein. It involves sensing nutrient availability and thus linked to problems with insulin resistance. Studies show animals with insulin resistance have decreased SIRT1 levels. When researchers increase SIRT1 in animals, they are resistant to the problems of obesity and insulin resistance that a high-fat diet induces in them.[ref][ref] Researchers recently discovered that SIRT1 is also important in the development of the egg cell.[ref]
SIRT2 codes for the sirtuin 2 protein that is located in the cytosol of the cell. This important enzyme arranges the chromosomes for cell division in mitosis.
Sirtuins use NAD+ to complete their cellular activity, and it is through that the NAD+ levels may be a sensor for how much energy is available in an organism.[ref]
SIRT3, 4, and 5, found in the mitochondria, are important for oxidative stress and fat metabolism.[ref]
SIRT6 is important in gene expression for metabolic regulation, telomere maintenance, and mitochondrial respiration. Reducing Sirt6 in the liver causes animals to develop fatty liver disease, and knocking out Sirt6 altogether causes animals to die within a few weeks due to severely accelerated aging.[ref]
PARPs and NAD+
Another group of enzymes that consume NAD+ in their reactions is PARPs, which stands for poly(ADP-ribose) polymerase. PARPs are another family of proteins important in DNA repair and genomic stability. They can detect when the DNA breaks and signal for its repair. They can also initiate cell death when the DNA repair doesn’t occur. Again – vital cellular functions, especially in aging.[ref]
PPAR1 uses up a lot of NAD+ in the process, causing a decrease in ATP production for the cell. The DNA damage signal response enacts when DNA replication is poor.[ref] Cell death is necessary, in the right context, but excessive cell death, especially in the brain, is not good.
Excessive DNA breakage can lead to a lot of PARP activation, thus depleting NAD+. What causes DNA breakage? UV light, reactive oxygen species (oxidative stress), lipid peroxidation, and a number of different environmental toxicants. DNA damage occurs all the time in the normal course of cell replication. Thus the importance of DNA damage repair systems in the body.
PARP1 can initiate cellular repair for single-strand DNA breaks. This is important in longevity.
Inhibiting PARP is a way to mitigate the decreased NAD+ and ATP levels and decrease cell death. It doesn’t fix the cause (DNA breakage), but it puts a bandaid on the downstream effects of PARP activation. Atherosclerosis and congestive heart failure are two diseases in which PARP inhibitors might be used. The inflammation within the vascular cells causes PARP1 activation and the subsequent decrease in NAD+ and cellular energy. Inhibiting PARP then slows the inflammatory response and preserves the ATP and NAD+ in the cells of the heart.[ref]
The flip side of inhibiting PARP would be to have plenty of NAD+ available for the rest of the heart cells. Animal studies using a mouse model of sepsis show that, indeed, giving nicotinamide riboside, which increases NAD+, protected the heart and lungs from injury and decreased death due to sepsis.[ref]
Creating NAD+ in the body:
Precursors of NAD+ include different forms of niacin (vitamin B3) and tryptophan. The different forms of niacin, whether from food or from supplements, are nicotinamide (aka niacinamide) and nicotinic acid (niacin). The nicotinic acid form (niacin) is the one that can cause flushing when taken in larger doses.
Foods that are high in niacin include tuna, chicken, beef liver, salmon, and pork. Non-meat sources of niacin include brown rice, peanuts, and potatoes. What doesn’t have niacin?…corn that hasn’t been nixtamalized (processed with limewater). A lack of niacin causes a disease state known as pellagra. Thus, in the late 1800s and early 1900s when people in the US South were dependant on corn for most of their calories, there was an epidemic of pellagra. Symptoms of pellagra include dementia, diarrhea, and a skin rash.
Tryptophan, found in a lot of protein-containing foods, is an essential amino acid. Your body can also convert tryptophan into niacin through the kynurenine pathway. However, this pathway to form niacin isn’t utilized by the body as much as obtaining niacin from foods that contain it.
Another way to create more NAD+ is by converting nicotinic acid. The first step converting nicotinic acid to NA mononucleotide uses the NAPRT enzyme coded for by the NAPRT gene.[ref][ref]
NR and NMN:
Both nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are important in the creation and recycling of NAD+.
NMN, synthesized from nicotinamide (niacinamide) and PRPP (5’-phosphoribosyl-pyrophosphate), uses the enzyme NAMPT.[ref]
NR is another precursor of NAD+ and found in low levels in foods, particularly in milk.
NAD+ doesn’t have to be synthesized continually from the precursors — it can be recycled through the “NAD Salvage Pathways”. Reusing the components of NAD+, specifically nicotinamide, is your body’s main way of having enough NAD+ available in all cells. This salvage pathway uses the supplemental NR and NMN in the body.
Studies on NR and NMN:
Enough background science – let’s get into the interesting research on supplemental nicotinamide riboside and nicotinamide mononucleotide.
Animal studies on NR and NMN:
Here are some of the animal studies on NAD+ precursors that are exciting:
Alzheimer’s: In a mouse model of Alzheimer’s disease, NMN shows the restoration of mitochondrial function in the brain. The oxygen consumption deficits in the brain mitochondria, found in Alzheimer’s showed a reversal. Again, this is a mouse study… but pretty cool.[ref]
Hemorrhagic shock: In a rodent model of hemorrhagic shock, those receiving NMN had less inflammation and better cellular metabolism. Both of which increase survival in hemorrhagic shock.[ref]
Aging: Nicotinamide riboside (NR) was fed to old mice for three months. The NR decreased several of the signs of aging in the mice such as altered fat mass, cholesterol levels, and liver enzymes.[ref]
Fatty Liver Disease: Quite a few studies show that NR can reverse fatty liver disease.[ref][ref][ref]
Cognitive Function: Another mouse study showed that NR could improve cognitive function in a mouse model of diabetes. Not only did cognitive function improve, but inflammatory markers in the brain reduced, as did amyloid-beta.[ref]
Hearing Loss: NR was protective in mice from age-related noise-induced hearing loss. This was through increasing SIRT3 expression.[ref]
Offspring: For postpartum mouse moms, NR was beneficial. It increased lactation, nursing behavior, and transmission of micronutrients to mouse babies. Those offspring grew up to have advantages “in physical performance, anti-anxiety, spatial memory, delayed onset of behavioral immobility, and promotion of adult hippocampal neurogenesis”.[ref]
Mitochondrial Function: A mouse study also found that NMN could dampen the DNA damage response and improve mitochondrial function. It also helped with liver damage.[ref]
Increased Lifespan: A small increase in lifespan (about 4%) has been shown in mice that were fed NR starting in old age.[ref]
Restored SIRT1 Levels: Middle-aged mice fed NMN showed increased Sirt1 levels, similar to younger mice.[ref]
Human studies on NR and NMN:
Safety first: A study looked at the safety of NR (Niagen brand) in healthy men and women over a course of 8 weeks. They used doses ranging from 100 to 1000 mg. All doses increase NAD+ metabolites within 2 weeks, and it was dose-dependent (high doses= high NAD+). Most importantly, there were no differences in adverse events between the NR groups and the placebo group. This study also noted that the NR did not mess up methylation.[ref]
In another trial, 2,000 mg/day of NR in obese, sedentary men aged 40 – 70 was safe (12-week study). But it didn’t show any miraculous effects on insulin sensitivity, glucose disposal, or resting energy expenditure.[ref] In other words, the fabulous metabolic results seen in mice didn’t happen in obese, older men. Or at least the markers that they were looking at (HbA1C, glucose, cholesterol, triglycerides) didn’t change much.
Boosting NAD+: A short, small study examined the effects of NR on healthy volunteers for 9 days. The study participants took 250 mg for the first two days and then titrated up to 1000 mg. On day 9, NAD+ levels had increased by 100%. No NR supplement side effects were reported. Interestingly, most of the individual response curves were similar in the percentage increase, but there were a couple of participants that had a much bigger response.[ref]
Decreased Inflammation: A study of ‘aged men’ looked at the effects of supplementing with 1,000 mg of NR per day for 3 weeks. The results showed an elevation of NAD+ in the muscles and a decrease in inflammatory cytokines levels.[ref]
Heart health: A study that included 30 middle-aged and older men and women looked at the effect of NR vs placebo for six weeks. Oral NR supplementation (1,000mg/day ) raised NAD+ levels by 60% compared to placebo. NR lowered blood pressure and aortic stiffness (a little). Notably, the participants who had stage one hypertension, to begin with, had a 10 point drop in systolic blood pressure. One drawback, in my mind, for this study, is the participants took the placebo or NR for six weeks – and then swap for the next six weeks. Then the comparison of the data was done for the placebo vs. NR. It seems like there should have been lasting benefits from the group initially taking NR and then switching to the placebo group, thus masking some of the statistical differences.[ref]
The human studies are nice from a safety point of view, but more studies are needed on larger groups for longer time periods. Several clinical trials are in the works right now, so hopefully, we will have more answers soon!
Niacin/NR/NMN from food:
Some studies indicate that 20mg of niacin can meet our need for NAD+ biosynthesis. The US government’s daily requirement of niacin is 12 mg and seems to be the amount needed to prevent pellagra. The RDA is set at 16mg/day.[ref]
Broccoli and cabbage contain up to around 1mg/ 100 gm of NMN. Avocados and tomatoes have also shown to contain NMN in the .36 to 1.6 mg/100 grams range. So while food can be a minor source of NMN, body synthesis is more common than obtaining it through the diet.
Tryptophan can also eventually end up as NAD+. But it takes 60-times the amount of tryptophan compared to niacin to get to nicotinic acid mononucleotide (NAMN). Tryptophan can help to prevent pellagra (niacin deficiency), but it isn’t the main source for most people today.[ref] (Read about tryptophan and the kynurenine pathway genes)
Methylation cycle and nicotinamide:
Not all nicotinamide converts back to NAD+. Some of it can degrade through a methylation-dependent pathway. The NNMT (nicotinamide N-methyltransferase) enzyme is key to the reaction between nicotinamide and SAMe.
A mouse model created to have too much of the NNMT enzyme was used for testing the link with fatty liver disease. Mice that produce extra NNMT were fed a high-fat diet and nicotinamide. They had accelerated fatty liver disease.[ref]
Circadian Rhythm and NAD+
I’m sure that most of you who have read a few of my articles have noticed that circadian rhythm is a theme that runs throughout genetics and health. There’s no escaping the fact that circadian rhythm controls so much of what goes on in our bodies. Kind of like the cycle of sunlight and darkness governs all living organisms.
The core molecular circadian clock is driven by the rising and falling levels of four genes: CLOCK and BMAL1 rise and then are suppressed as PER and CRY accumulate. The CLOCK gene expression is controlled by a sirtuin (SIRT1), which is in turn dependant on NAD+ levels.[ref]
I know – you all are thinking, “holy crap! mind blown!” right now. Or you are wondering how deep in the weeds this article will wonder:-)
Let me connect a few dots…NAD+ levels are needed for the sirtuins to work. The sirtuin family of proteins controls whether a portion of the DNA is available to be transcribed – or not. Like a light switch turning on or off.
SIRT1, important for the core circadian clock gene (aptly named CLOCK) to function correctly, rises and falls over the course of 24 hours.
A connection exists between the disruption of the core clock genes and the various chronic disease states associated with aging, such as diabetes, heart disease, obesity, metabolic syndrome, and Alzheimer’s disease.
Thus, one mechanism by which low NAD+ levels impacts us as we age is through altered CLOCK gene expression.
SIRT6 also shows control of the liver’s clock – separately from SIRT1. This leads to the control of lipid metabolism in the liver.[ref]
NR can also be found in the supplement called Basis made by Elysium. It now contains a formulation of NR that is proprietary to Basis. Lots of research (and marketing…) has been done by the developer of Basis, so it may be worthwhile to check out. You have to order directly through the company.
NMN is also available as a supplement. There are several options on Amazon, including GeneX NMN and Mastermind NMN.
Resveratrol is an activator of SIRT1.[ref] Some people stack resveratrol with NR to boost the effects of SIRT1. Resveratrol is available on Amazon or at any local health food store (or grocery store).
Pterostilbene, a polyphenol found in blueberries and an analog of resveratrol, is an activator of SIRT1.[ref] [ref] The nicotinamide riboside supplement BASIS includes pterostilbene. It is also available as a stand-alone supplement on Amazon, or you can eat a lot of delicious blueberries.
Tryptophan is a precursor, albeit a minor one, for the synthesis of NAD+. Even though it is a minor player, it is important to get enough tryptophan in your diet. Most foods that contain protein also contain tryptophan, so people generally get plenty of tryptophan if they eat a varied diet. Foods that contain a lot of tryptophan include cheese, chicken, fish, eggs, beef, pork, beans and lentils.
Don’t want to take supplements?
There may be other ways to reap the NAD+ benefits:
Exercise…It seems that everyone (including me) always recommends exercise for pretty much every health topic. A recent study showed that one way that exercise is beneficial in aging is that it stops the decline in the enzymes needed for NAD+ production. In older people (age 55+), aerobic exercise increased NAMPT.[ref]
Some clinicians seem worried about supplemental NR decreasing methyl groups in the body. One small human study did not find an effect on methyl groups[ref], but individual genetic differences may make this an issue for some people. If this is a problem for you, increasing your methyl donors may help. Choline (from eggs, liver, sunflower lecithin) and folate (from broccoli, legumes, leafy greens) can help increase your supply of methyl groups. Supplements that increase methylation include SAMe, TMG, and methylfolate.