Reviewing the Clinical Evidence for NAD+ Upregulation

I recently collaborated on a review paper covering the history of clinical work on upregulation of nicotinamide adenine dinucleotide (NAD) as an approach to therapy. This is of interest to the aging research community because NAD is important to mitochondrial function. NAD levels diminish with age, alongside a loss of mitochondrial function that is known to contribute to the onset and progression of many age-related conditions. Animal studies and a few clinical trials have indicated that increased NAD levels may improve, for example, cardiovascular function in older individuals, as a result of improved mitochondrial function in important cell populations.

The most common approaches to increasing NAD levels involve compounds derived from vitamin B3 - niacin, nicotinamide riboside, nicotinamide mononucleotide, and so forth. These are involved in the mechanisms of NAD synthesis or recovery. In that sense research into NAD upregulation has been taking place for a century or more, somewhat unknowingly, as researchers characterized the use of high doses of vitamin B3 as an intervention. The more modern phase of this work, deliberately targeting NAD with methodologies that move beyond the use of vitamin B3, has less of a history, but it is nonetheless interesting to note just how far back it goes.

It is also interesting to note the ragged and haphazard character of the clinical work on NAD upregulation, taken as a whole over the past few decades. Many approaches and indications have been tested, but few more than once, and few in large study populations. Further, the studies that used exercise as an intervention show effect sizes on NAD levels that are comparable or better than those that used other approaches. That, to me, raises the question of just how much effort is actually worth putting into NAD-based approaches to the treatment of age-related declines.

Clinical Evidence for Targeting NAD Therapeutically

A number of clinical trials have been conducted recently, with more underway, to rigorously assess NAD pharmacology in the context of aging and metabolic and age-related disease. We have conducted a review of the literature in an attempt to determine whether or not the present human evidence for the potential benefits from NAD pharmacology supports an expansion of efforts to assess this approach to age-related conditions. Of the 36 human trials with published results identified in our literature review, 18 reported on oral administration of NAD precursors, such as nicotinamide, nicotinamide mononucleotide, or nicotinamide riboside, while 8 employed oral administration of NAD. The remainder used an eclectic mix of exercise programs, antioxidants, forms of topical, intravenous, or intramuscular administration of NAD, as well as compounds targeting NQO1 activity. Of the 36 trials, 7 assessed only pharmacokinetics, safety, or biomarkers, and 17 reported beneficial outcomes. The remaining 12 reported no benefits to patients.

Our review reveals that the upregulation of NAD has been studied for a wide range of medical conditions, only a few of which are addressed by more than one study. These conditions include acute kidney injury, Alzheimer's disease, chronic fatigue syndrome, dementia, hyperphosphatemia, hypertension, obesity, Parkinson's disease, photoaging of skin, psoriasis, skin cancers, type 1 diabetes mellitus, type 2 diabetes mellitus, and schizophrenia. NAD levels after intervention were measured in only 11 trials, in blood samples or tissues. In all cases, increased NAD was observed, but the size of the effect varied widely. These changes were almost incomparable due to the current lack of standardization, as variance may be due to differences in methodology of measurement, in interventions, or other factors.

The earliest deliberate attempts at NAD pharmacology, as distinct from the extensive study of vitamin B3, involved the delivery of niacin or formulations of NAD in the treatment of schizophrenia, beginning in the 1960s. This intervention was based on a variety of hypotheses linking NAD biochemistry to the neurobiological changes thought to be involved in schizophrenia. More modern hypotheses of NAD-related redox dysfunction in schizophrenia continue to be debated today; mitochondrial dysfunction and oxidative stress are thought to contribute to the pathogenesis of the condition. Available reports refer to positive results in earlier studies, but the authors reported no benefits to patients resulting from their small clinical trials. Beginning in the 1990s, NAD pharmacology was assessed as a basis for the treatment of Parkinson's disease and Alzheimer's disease, efforts that have since expanded to other forms of dementia. To date, the results of clinical trials have been mixed for Parkinson's disease and largely negative for Alzheimer's disease. Further trials are in progress.

NAD upregulation prevents actinic keratosis and improves some measures of photoaging. While the mechanisms of action are not fully understood, NAD is a co-factor for the PARP enzymes that play a key role in DNA repair. Skin is exposed to UV damage, causing frequent DNA breaks. Improving PARP function, and thus improving DNA repair, might protect from precancerous skin lesions and other consequences of photoaging. This mechanism may also influence the skin pathology associated with dysregulated skin cell division in conditions, such as psoriasis.

Only limited data is available for the use of NAD boosters in the treatment of metabolic conditions, such as obesity and metabolic syndrome. While some studies report improvement in lipid profile, exercise capacity, and muscle fiber composition despite a sedentary lifestyle, others show no benefit of supplementation in the prevention of type 1 diabetes, and no improvements in insulin resistance.

Based on the human trials conducted to date, NAD pharmacology is a promising treatment strategy that is likely to be safe for human use. However, despite several decades of active investigation, there is still only suggestive evidence, in the form of a few successful and sufficiently powered clinical trials, for NAD upregulation to be effective for any of the many potential indications where it may benefit patients. More and larger studies are required to produce robust data in support of NAD pharmacology. This includes in particular studies in which different forms of NAD upregulation are compared consistently with one another. For example, exercise programs tailored to older individuals may be more effective than all of the existing approaches to NAD pharmacology. Whether or not this is the case is one of the more important questions for the research community to answer.

Comments

@Reason
I'm wondering whether someone is looking into the synergistic effects of NAD+ boosters, exercise, and intermittent fasting in older people?

I'm in my mid 60ties and do daily intermittent fasting (16:8), take an NAD+ booster before my gym workout, and break my fast after I finish the workout. I'm feeling great and also noticed that I'm less fatigue during and after my resistance exercise.

Posted by: Stephan at September 22nd, 2020 3:50 PM

@Stephan: I am not aware of anyone who is checking in a rigorous, clinical trial setting, though I am certain many clinics are providing clients both high dose vitamin B3 and structured exercise programs. I don't have a strong opinion on whether vitamin B3 derivatives and exercise will stack in providing benefits via improved mitochondrial function. One could argue either way.

Posted by: Reason at September 22nd, 2020 5:38 PM

I am always delighted to hear about progress towards defeating the greatest problem of life.

What if life wasn't about health deteriorating for the longer part of it and then dying?

Life would certainly be more prosperous and beautiful with indefinite health and well-being for oneself, family and friends instead of everyone's certain decades-long and painful decline into death.

Posted by: A. Sharafi at September 22nd, 2020 8:23 PM

How many of the studies were free of conflicting interests?

I (50yo) have been supplementimg NMN, NAD and finally high dosed Niacin for 3 years.
Noticeable results? Besides a bit of restored workout capacity.... none.
If NAD upregulation had an effect size significantly greater than 'healthy living' we would have seen it by now, considering the tons of NAD supplements sold each year.

Posted by: Jones at September 23rd, 2020 2:28 AM

Published: 31 August 2011

Believe it or not: how much can we rely on published data on potential drug targets?

https://www.nature.com/articles/nrd3439-c1#article-info
A recent (now 10 years ago) report by Arrowsmith noted that the success rates for new development projects in Phase II trials have fallen from 28% to 18% in recent years, with insufficient efficacy being the most frequent reason for failure (Phase II failures: 2008-2010. Nature Rev. Drug Discov. 10, 328-329 (2011))1. This indicates the limitations of the predictivity of disease models and also that the validity of the targets being investigated is frequently questionable, which is a crucial issue to address if success rates in clinical trials are to be improved...

We received input from 23 scientists (heads of laboratories) and collected data from 67 projects, most of them (47) from the field of oncology. This analysis revealed that only in ∼20-25% of the projects were the relevant published data completely in line with our in-house findings (Fig. 1c). In almost two-thirds of the projects, there were inconsistencies between published data and in-house data that either considerably prolonged the duration of the target validation process or, in most cases, resulted in termination of the projects because the evidence that was generated for the therapeutic hypothesis was insufficient to justify further investments into these projects.

Posted by: Jones at September 23rd, 2020 2:56 AM

"If NAD upregulation had an effect size significantly greater than 'healthy living' we would have seen it by now, considering the tons of NAD supplements sold each year."

And the same applies to any other "treatment" that has been out there for years, like metformin, plasmaferesis, and possibly senolytics.

Posted by: Barbara T. at September 23rd, 2020 4:19 AM

"These conditions include acute kidney injury, Alzheimer's disease, chronic fatigue syndrome, dementia, hyperphosphatemia, hypertension, obesity, Parkinson's disease, photoaging of skin, psoriasis, skin cancers, type 1 diabetes mellitus, type 2 diabetes mellitus, and schizophrenia. "

Though the idea that NAD+ or its precursors can cure or reduce these various conditions, my experience is that these type of supplements do far better at keeping healthy middle age and older people ... healthy. That's another way of saying 'extending healthspan', which is a far more reasonable goal, abiet much hard to quantify, forget proving that the NAD+ is the magic bullet that is doing so.

Too bad more research money is not aiming at this goal, rather than only focusing NAD+ against disease. Keeping people out of hospitals and doctors offices is as useful an end goal as treating them once they get there.

Posted by: Rolle at September 23rd, 2020 9:40 AM

@Barbara
unfortunately you are right. However, there might be some beneficial effects that were under the radar. Those effects are unlikely to be large, though.

Posted by: cuberat at September 23rd, 2020 12:12 PM

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