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NAD+ Restoration Therapy_Risk-Benefit Analysis


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#1 Engadin

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Posted 22 August 2019 - 03:25 PM

S O U R C E :   forever healthy







Special thanks are extended to the Rejuvenation Now team at Forever Healthy for their friendly contributions.




Section 1: Overview 


This analysis of NAD+ restoration therapy is part of Forever Healthy's "Rejuvenation Nowinitiative that seeks to continuously identify new therapies and systematically evaluate them on their risks, benefits, procedures and potential application.





NAD+ is a pyridine nucleotide found in all living cells. It plays an important role in energy metabolism and is a substrate for several enzymes (including those involved in DNA repair). NAD+ levels may decline markedly with age (Massudi et al., 2012Clement et al., 2019Zhu et al., 2011) and restoring those levels to a youthful state is believed to have beneficial effects on health and longevity. 



Key Questions 


This analysis seeks to answer the following questions:

  • Which health and/or longevity benefits result from raising NAD+ levels in humans? 
  • Which risks are involved in raising NAD+ levels (general and method-specific)?
  • What are the potential risk mitigation strategies?
  • Which method or combination of methods is most effective in raising NAD+ levels?
  • Which of the available methods are safe for use? 
  • What is the best therapeutic protocol available at the moment?  




Section 2: Methods


Analytic model


The RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development (Sarac et al., 2012).



Literature search


A literature search was conducted on Pubmed and the Cochrane Library using the search terms shown in Table 1. Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms.


The inclusion criteria for human studies were necessarily broad as there is a scarcity of evidence. We chose to include any trial that was conducted in humans using NAD precursors other than niacin/nicotinic acid as the majority of those trials used cholesterol-lowering as the primary endpoint and don't mention NAD+ levels. Additionally, niacin/NA results in uncomfortable flushing in many people at relatively low doses and is therefore not generally used for NAD+ restoration therapy. 



Table 1: Literature Search 


Search terms                                                                                                   Number of publications               Number of Relevant studies


(NAD+ OR nicotinamide adenine dinucleotide) AND supplementation)            535                                                Clinical: 41


((NAD+ OR nicotinamide adenine dinucleotide) AND benefits)                         475                                                Preclinical: 145


(((NAD+ OR nicotinamide adenine dinucleotide))) AND

((risks OR harms OR side effects OR adverse events)))

AND supplementation                                                                                        108


NAD+ (filters: clinical trials, humans)                                                                 323


NMN OR nicotinamide mononucleotide                                                          1505


Nicotinamide riboside                                                                                        264


NAM OR nicotinamide (filters: clinical trials)                                                    1343



Other sources


Discussion with experts (names cited in the text)


A manual search of the reference lists of the selected papers 



Recommended Reading


The following sites offer information on NAD+ at a consumer level and are useful as an introduction to the topic:



Abbreviation list


MeNAM methylated nicotinamide MN myristyl nicotinate NA nicotinic acid NAAD nicotinic acid adenine dinucleotide NAD+ nicotinamide adenine dinucleotide (oxidized) NADH nicotinamide adenine dinucleotide (reduced) NADP nicotinamide adenine dinucleotide phosphate NAM nicotinamide NMN nicotinamide mononucleotide NR nicotinamide riboside NRPT nicotinamide riboside and pterostilbene



Section 3: Existing evidence



Summary of results from clinical trials (humans)


We identified 41 completed clinical trials and 29 that are ongoing (aboutnad.com). The majority of published clinical trials have been performed for dermatological conditions and used NAM as the study compound. Only two human studies used NAD+ as the study compound, one as i.v. therapy and the other topically. The other trials examined various precursors that have been shown to raise NAD+ levels. We identified a case report series but were unable to find any RCTs on systemic NAD+ i.v. or patch therapies.



Table 2: Clinical Trials



Summary of results from preclinical trials (animals & in vitro)


Due to the lack of evidence from clinical trials, a decision was made to include results from preclinical studies (animals/in vitro) in order to gain more data to aid in the assessment of the risk/benefit ratio. We identified 145 preclinical trials with potentially clinically relevant risk/benefit criteria. The majority of the studies were conducted in rodents and studies on NAD+ itself as well as all known precursors exist.



Table 3: Preclinical trials 




Section 4: Risk-Benefit Analysis


Decision Model


Risk and benefit criteria


The decision profile is made of up risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and include the type, magnitude, and duration of the benefit as well as its perceived importance to the patient. The risk criteria are organized by category, type, severity, frequency, detectability, and mitigation. All are assigned numerical values: 


1 = low

2 = moderate

3 = high


The numerical values for both risk and benefit criteria are then summarized serving as the justification for the weighting in the following column.





The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). Each benefit and risk criteria is assigned a weight/importance of 1 (low) 2 (medium) or 3 (high).


Weighting is independent of data sets and the final weights are based on consensus with justification based on the preceding columns of the table.



Each category is assessed according to the performance of NAD+ restoration therapy against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior) and +1 (superior) to the comparator.




Uncertainty is determined according to the amount and quality of the evidence, whether it came from human or animal studies and whether methodological flaws, conflicting studies, or conflicts of interest (funding) by the authors are present. Human evidence is initially assigned a score of "1", evidence from rodent studies, "2", and in vitro or lower animal studies, "3". The uncertainty score is then adjusted by upgrading or downgrading using the above-mentioned criteria. 


Weighted score


The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted using the uncertainty score. Weighted scores may be upgraded where the uncertainty of the evidence is low or downgraded where the uncertainty of the evidence is high. 




... / ...



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Edited by Engadin, 22 August 2019 - 03:26 PM.

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