Results from a Preliminary Human Trial of Nicotinamide Riboside Supplementation
What sort of evidence would it take to challenge my assessment of the data to date that methods of raising NAD+ levels with age, such as nicotinamide riboside supplementation, are not worth pursuing as a major area of focus in research and development? Given the history of work in this area of metabolism, mostly that relating directly to sirtuins and their manipulation, one has to be a little skeptical. Initially promising (and overhyped) results in mice went essentially nowhere, or turned out to make the condition of obesity a little less harmful, while showing little evidence of utility for healthy individuals.
To answer the question, human data showing meaningful benefits that could not be achieved via exercise or calorie restriction would be very interesting. Human data showing some reliable level of reproduction of the benefits of exercise or calorie restriction without side-effects would be good news for the present majority who don't put in the effort to stay in shape. Good news for supplement sellers as well - there is no shortage of people who would pay rather than exercise or eat less, even if the results were mixed or marginal.
In either case, the cost-benefit analysis runs along the lines of (a) as an individual, how much it is worth spending on a supplement that can capture a fraction of the benefits of exercise or calorie restriction, but also (b) is it worth making this a major focus of the research community, versus the rejuvenation biotechnology that can achieve far greater gains? I think (b) is always going to be answered in the negative, for me at least. No calorie restriction mimetic or exercise mimetic can possibly be as good as functional SENS repair biotechnologies. They cannot achieve the results produced by senolytics, or any of the other ways to remove the root causes of aging. If one looks at NAD+ research as the final stage of sirtuin-related calorie restriction research as a whole, it has taken as much funding to get here as it would to completely implement the SENS rejuvenation therapy package in mice. Yet we know that exercise and calorie restriction cannot add decades to healthy life, as is possible in principle for repair therapies.
The data here on human nicotinamide riboside supplementation seems promising in comparison to the results of past sirtuin research, but I'd like to see a larger study group. If that larger group shows similar results, then maybe this is worth it for individuals. Either way, it is appreciated that the authors avoided running a study in overweight individuals - in this part of the field, that just muddies the waters, given the very different effects of sirtuin manipulation on thin versus fat animals. Nonetheless, it still appears to be the case that this is essentially a way to gain some of the beneficial long-term effects of fitness without putting in the physical effort. I expect future NAD+ studies and exercise studies in older individuals to converge in some ways, showing overlapping effects on cellular biochemistry. It is arguable as to whether taking up exercise, eating less, or artificially increasing NAD+ levels should be termed rejuvenation. There is certainly a sizable grey area at the intersection of repair, compensation, and overriding regulatory signals that respond to aging.
A pill that staves off aging? It's on the horizon
Scientists have long known that restricting calories can fend off physiological signs of aging. A new study indicates that when people consume a natural dietary supplement called nicotinamide riboside (NR) daily, it mimics caloric restriction, aka CR, kick-starting the same key chemical pathways responsible for its health benefits. "This was the first ever study to give this novel compound to humans over a period of time. We found that it is well tolerated and appears to activate some of the same key biological pathways that calorie restriction does."
Researchers included 24 lean and healthy men and women ages 55 to 79. Half were given a placebo for six weeks, then took a 500 mg twice-daily dose of nicotinamide riboside (NR) chloride (NIAGEN). The other half took NR for the first six weeks, followed by placebo. The researchers took blood samples and other physiological measurements at the end of each treatment period. Participants reported no serious adverse effects. The researchers found that 1,000 mg daily of NR boosted levels of another compound called nicotinamide adenine dinucleotide (NAD+) by 60 percent. NAD+ is required for activation of enzymes called sirtuins, which are largely credited with the beneficial effects of calorie restriction. It's involved in a host of metabolic actions throughout the body, but it tends to decline with age.
Research suggests that as an evolutionary survival mechanism, the body conserves NAD+ when subjected to calorie restriction. But only recently have scientists begun to explore the idea of supplementing with so-called "NAD+-precursors" like NR to promote healthy aging. "The idea is that by supplementing older adults with NR, we are not only restoring something that is lost with aging (NAD+), but we could potentially be ramping up the activity of enzymes responsible for helping protect our bodies from stress."
The new study also found that in 13 participants with elevated blood pressure or stage 1 hypertension (120-139/80-89 mmHg), systolic blood pressure was about 10 points lower after supplementation. A drop of that magnitude could translate to a 25 percent reduction in heart attack risk. "If this magnitude of systolic blood pressure reduction with NR supplementation is confirmed in a larger clinical trial, such an effect could have broad biomedical implications."
Nicotinamide adenine dinucleotide (NAD+) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD+ precursors to augment NAD+ bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD+ precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD+ metabolism in healthy middle-aged and older adults.
Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group.
We cannot always wait for the theoretical SENS rejuvenation technology as it may take a decade or more before it becomes available. Thus, I think it is prudent to take some NAD+ in the form of NR and combine it with an extensive exercise and sirtuin and FOXO3A activators and a mild CR diet to extend healthspan until something better comes along. I currently do some of each, like take a 250 mg NR capsule a day, resveratrol, quercetin, exercise and try not to consume any extra calories.
"Study pills, NR standards for metabolite analyses and partial funding support were provided by ChromaDex, Inc."
So partially funded study by Chromadex the sole maker of NR. Yeah, sounds legit, not a huge red flag at all.
@Biotechy, of course that is good news that Sinclair finaly make something useful! :3 NMN and NR will be good as an intermediate solution - will help to preserve health a little for middle aged people. Hovewer, that is better to rise NAD+ level not by excessive consumption of their precursors as it takes place in present broken compensatory medicine. But by repair the cellular and molecular damage after the SENS approach which will allow the cells support high level of NAD+ by their own. I hope everyone understands that falling level of NAD+ is a consequense of cell ageing.
As for "theoretical SENS rejuvenation technology" as you call it, the fact is that it is "theoretical" only for one reason -- lack of funds. If nearly billion of $ spent on Sirtuins research in recent 10 years would spend on SENS, now we wouldn't need any NMN or NR research which can easily consume another billion in next 10 years.
@Reason, why in your wiew do newspapers make such promising provocative headlines on Resveratrol, Sirtuins, NMN or any CR mimetics while ignore real rejuvenation biotechology like glucosepane work in Spiegel Lab or Oisin's work which is so powerful that will make a revolution in nearly all areas of rejuvenation biotechnology? Maybe when they publish their papers all will change?
@Ariel
That is purely a result of the "single magic bullet" philosophy that has been promulgated by pharma since 1897 when Bayer first started working on aspirin (maybe technically even a little earlier)
The media, and big pharma's DTC campaigns, have conditioned the public to beleive that the "cure" for anything will be a single, little white pill, that you will get in a little bottle, from your local pharmacy
Anything more exotic in its physiochemcial composition or administration method does not register as being interesting or "Sexy"
@Ira, so we need to make them sexy! ;-)
NAD+ depletion is a fundamental feature of aging. Lower NAD+ will cause accelerated aging that we see from late 40s. Increasing NAD+ from using precursors will remain the most important anti aging therapy forever. Dreaming about a way to maintain body at age 20 forever is not realistic. Niagen is the best we have now.
I received 18 days of intravenous NAD with amino acids six months ago. The treatment had a profound affect on my nervous system and overall health. Since that time I have followed developments and plan to supplement with NAD precursors because my first hand experience leaves no doubt in my mind about the efficacy of NAD. There is much more to the story than just anti-aging.
@James Watson
Could you be more specific about the effects you experienced? Did you measure any biomarkers before and after your treatments? What amino acids did you receive and what was the rationale behind combining them with IV NAD+?
I am an 80 year old male slightly overweight pre diabetic individual and have been taking 1000 mg NMN sublingually for about 5 months. I myself have not noticed any benefits but associates have noticed that I have significantly increased overall vitality mainly mental. My son and daughter in law aged 47 have been taking the same amount for about 4 weeks and have noticed a huge difference in their overall well being
In Jan. At 61 years old, I was diagnosed with moderate PAD of both lower extremities and a calcified aorta in the thoracic and abdominal region. I was experiencing fluid in my lungs and s.o.b.
I began nmn 250 mg daily in Dec. along with K2-7 while waiting to see my carfiologist for further testing. In Jan. I underwent artetiorgram with arterial catheterization. It had been 1 month since beginning the non. The test revealed my plaque was not as bad as the prior test (blood pressure cuff) had indicated. My doctor noted stronger pulses and improved circulation after one month on nmn. While he had fully expected the need for surgery he was able to place me on Pletal. Two months later the supply if nmn ran out in the US and legs ballooned again. Now after 1 weeks therapy the edema has reduced by 75% and continues to reduce. Before running out my right leg was completely without edema and was almost gone in the left.
NMN has had additional benefits. I no longer have the cardiac arrhythmia, I am losing weight at a healthy pace with reduced appetite. My skin is softer and my previous itchy dry skin is gone.
Also notable- I no longer experience joint pain. I even have a 95% reduction of pain in a T7 spinal cord compression. There have been other benefits but these are the most notable.
Anybody has any comments on this 2016 warning from a researcher that a side effect from NMN and higher NAD is it feeds brain tumours? "Pathway linked to slower aging also fuels brain cancer"
The pathway, known as the nicotinamide adenine dinucleotide (NAD+) pathway, is overactive in a deadly form of brain cancer known as glioblastoma, according to a study by researchers at Washington University School of Medicine in St. Louis. Glioblastoma is the most common and aggressive brain cancer in adults. Over 70 percent of patients with glioblastoma die within two years of diagnosis. The new research showed that glioblastoma patients with high expression of an NAD+ pathway gene known as NAMPT died sooner...
"There's a lot of buzz about taking NAD+ precursors for their anti-aging effects, which is based on a lot of great science," said Albert H. Kim, MD, PhD, an assistant professor of neurological surgery and the senior author on the study. "We didn't directly demonstrate that taking NAD+ precursors makes tumors grow faster, but one implication of our work is that if you want to take anti-aging NAD+ precursors, you might want to keep in mind that we don't yet understand all the risks."
https://www.sciencedaily.com/releases/2016/12/161206103526.htm
I have now been taking daily 1000mg sublingually of NMN for about 9 months and apart from a definite significant increase in mental vitality which friends and family have noticed, I myself have not noticed any physical change of note. This is somewhat disappointing as I was hoping some if the mice experimental youthful changes might have been seen in myself. I am continuing to take 1000 mg daily and I will report back after 12 months
@David Brown
When the changes are see and gradual were like the proverbial frogs. As for where you did see more effects, the brain and neurons have the highest concentration of mitochondria, then the hearty muscles and some other muscles. There you might have a better stamina or reduced inflammation. Or probably, be just keeping the status quo...
Wrt cancer, the mice were treated with what would be 40g daily dosage for a human. I bet eating that much sugar will get you cancer.
40g sugar daily are not that much, impress you have diabetes. Probably a can of Coke had almost as much
My husband was diagnosed with vascular dementia in the fall of 2016. He is currently in a longterm care memory facility. Might NMN be a helpful substance to add to his already lengthy list of meds? (Lamictal, Seroquel, Namenda, Paxil, Buspirone). Are there harmful side effects?
I am an 81 year old male still working full time and have now been taking daily 1000 mg NMN sublingually for 12 months. A recent complete blood check has revealed that a lot of minor marginal deteriorating conditions have now disappeared. I have not changed anything in my life style or diet except taking NMN. I can only deduce that taking NMN has caused a significant improvement in my overall health and biological well being. I will post again in 3 - 6 months months time
I'm 66, have been taking it for almost a year now. I take two caps equaling 300mg in the morning first thing. I'm 5'9", 175lbs, retired, year round golfer in the Mid-Atlantic region. I'm not on any other meds. I take supplements daily. Two Triple strength Fish oil caps morning and evening, D3 cap, Garlic cap, Ubiquinol CoQ10, and Sytrinol for Cholesterol. I walk, do light arm weights a couple times a week, hit golf balls every day. I feel good. Have not had a physical this year yet. 12/4/19.
I am a 49 year old healthy, male eating a plant based diet the last 16 years. I have been taking 750mg of NMN, 500mg of Resveratrol and 500mg of metformin for 9 months. I have noticed almost zero effect but my homo-cysteine level was lower than two years prior after taking this concoction for a few months. Doesn't seem worth the nearly $2000 price tag yearly for all this so I have stopped.
I have now been taking 1000 mg per day of NMN sublingually for about 18 months. I am an 82 year old male and still working full time. Apart from my general well being I have not noticed any particular definitive improvement. Further, I have not noticed any biological deterioration whatever. I will continue taking NMN at the same level for the foreseeable future and I will report back in 6 months
David Brown
34 yo female. The most noticable effects NMN had were a massive improvement in how far I can run, general energy levels bumped a bit higher, circadian rhythm improved a bit (more prone to waking up with the sun), and improved metabolic flexibility in the form of SIGNIFICANTLY less hunger cravings when it's not time to eat. (And to be fair, I'm not in the age range for a lot of it's other potential effects to be more obvious.) My assessment when adding the NMN to my regiment, specifically: You will pry it from my cold dead hands.