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."

Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults

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.

Comments

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.

Posted by: Biotechy at March 30th, 2018 1:30 PM

"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.

Posted by: Steve Hill at March 30th, 2018 4:22 PM

@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.

Posted by: Ariel at March 30th, 2018 4:23 PM

@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?

Posted by: Ariel at March 30th, 2018 4:38 PM

@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"

Posted by: Ira S. Pastor at March 31st, 2018 5:54 AM

@Ira, so we need to make them sexy! ;-)

Posted by: Ariel at March 31st, 2018 8:17 AM

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.

Posted by: Mike at April 3rd, 2018 12:03 PM

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