Targeting Longevity: NMN vs. NR for NAD+ Restoration

In this episode of Daily Value, we look at science of Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR), two NAD+ precursors gaining traction in longevity research. Both supplements aim to restore NAD+ levels, critical for energy metabolism and cellular repair, yet their distinct pathways and tissue-specific effects suggest considerations for choosing one over the other.

Discussion Points:

-The metabolic pathways of NMN and NR, highlighting how their mechanisms of action influence NAD+ synthesis across tissues.

-Insights from a 2024 study (in rodents - PMID: 38645109) demonstrating the dual effects of NMN: improvements in cardiac and liver function, alongside kidney inflammation linked to toxic metabolite accumulation at high doses.

-Clinical dosing strategies, safety considerations, and how age and tissue-specific needs may guide the choice between NMN and NR.

https://pubmed.ncbi.nlm.nih.gov/38645109/ 

https://iadns.onlinelibrary.wiley.com/doi/10.1002/fft2.511 

Transcript

Speaker 0: 0:00

Hello everyone, welcome back to Daily Value. I'm William Wallace, and today we're diving into one of the generally most popular topics in longevity and health, that being NAD plus metabolism, but focusing on two supplements and nicotinamide riboside, or NR. Both compounds have captured public attention for their potential to restore cellular energy and combat age-related decline, but, as we'll see, the benefits may not be universal, and tissue-specific effects found in a few animal models might raise important questions about their broader applications. So let's start with a quick overview of NAD and its role in our cells. Nicotinamide adenine dinucleotide, or NAD, is a coenzyme present in every cell of the body. It plays a central role in metabolic pathways, including oxidative phosphorylation and the activation of sirtuin and PARP enzymes associated with DNA repair and longevity. As we age, nad levels decline, which results in impaired mitochondrial function and cellular repair mechanisms. Nmn and NR serve as precursors for NAD through one of the three major NAD synthesis pathways, that being the salvage pathway, which produces up to 85% of the body's NAD. Nicotinamide riboside, or NR, is converted into NMN inside of a cell before being transformed into NAD.

Speaker 0: 1:38

Both compounds are available as supplements, with dosages in human trials typically ranging, on average, from 100 to 900 milligrams per day. That's the most consistent dosing range for these compounds, with average NR dosing tending to be slightly less than NMN. Preclinical trials, however, often use significantly higher doses. For instance, a recent study by Yang et al highlights the metabolic improvements observed in mice supplemented with NR at 300 mg per kg per day. That's equivalent to 2,400 mg in average adult human, 1,250 milligrams of NMN given to healthy adult men and women for up to four weeks and 2,000 milligrams of NR given for 12 weeks in obese men. When we look at studies using NR, doses of 100, 300, and 1,000 milligrams taken for two weeks increase NAD levels in a dose-dependent manner by 22, 51, and 142 percent respectively. It's important to note that both NMN and NR are considered to be GRAS in the United States. Gras means generally recognized as safe. However, there are more clinical studies in humans using NR versus NMN.

Speaker 0: 2:59

Now, very interestingly, a study in rodents published in 2024 by Sala et al administered NMN at 300 mg per kg per day in aged mice, which is roughly equivalent to 1500 mg of NMN in people, demonstrating notable improvements in cardiac and liver function but uncovering unexpected kidney complications. So what did they find? Well, when we talk about anti-aging interventions, it's essential to recognize that their effects are rarely universal across all tissues in the body. Nmn and NR are no exceptions. Both compounds have demonstrated considerable benefits in preclinical models, but in this study by Sala et al, systolic and diastolic cardiac function in 26-month-old mice, roughly equivalent to a 79-year-old human, were improved. However, the kidney, an organ with high mitochondrial demand, presented a different picture. In aged mice, nmn supplementation significantly upregulated interleukin-1-beta, that's a cytokine associated with senescence-associated secretory phenotype, or SASP. Elevated interleukin-1-beta expression was accompanied by markers of kidney injury molecule 1, or KIM1 as it's called Now. Importantly, these effects were mitigated when NMN was co-administered with a drug used to protect mitochondria, suggesting a protective role of a more robust intervention.

Speaker 0: 4:27

The metabolic analysis revealed that aged mice treated with NMN accumulated what are called uremic toxins, such as methyl nicotinamide or MNA and its derivatives, 2-py and 4-PY, at levels significantly higher than their younger counterparts. These methylated metabolites of NAD and niacinamide break down in the salvage pathway. These metabolites are naturally occurring byproducts of NAD metabolism, but become toxic when their excretion is impaired and their levels get too high, as seen in aging kidneys. In this particular instance, this suggests that different doses would be more or less suitable for different tissues in the body at different life stages. Renal clearance of metabolic byproducts goes down as we get older, so it's possible that frequent high doses of NMN may not always be beneficial in all tissues and in all cases. An important consideration when choosing between NMN and NR may be their distinct metabolic pathways to NAD synthesis and how these might influence their efficacy and safety.

Speaker 0: 5:36

Nr, as nicotinamide riboside, enters the NAD salvage pathway by being converted to NMN through the enzyme nicotinamide riboside kinase, or NRK. This enzyme's activity varies between tissues. Organs like the liver and muscle, where NRK activity is relatively high, are better equipped to efficiently convert NR into NMN and subsequently NAD. However, in tissues with lower NRK expression, the conversion efficiency of NR may be limited, but that's really more conjecture. In contrast, nmn bypasses this enzymatic step, entering the salvage pathway directly, but there still isn't strong evidence that it enters a cell, as NMN Cells generally can't transport nucleotides like NMN, and so NMN has to be broken down to NR and then reassembled into NMN. These differences raise important questions for supplementation strategies. For example, individuals targeting muscle health may benefit more from NR, given its compatibility with NRK activity in muscle tissues.

Speaker 0: 6:41

When looking at the most commonly used doses in clinical trials, nr tends to show more effectiveness at lower doses than NMN, where 250 to 500 milligrams is a common effective dose, compared to NMN, where doses of 500 to 1,000 milligrams are more common. The findings on renal inflammation do highlight the importance of considering age and tissue specificity when evaluating NAD precursors in humans. In human studies, nmn doses have ranged from 100 to 900 milligrams per day, well below the 1.5 gram day equivalent used in Sala's preclinical work. However, there was also a 2021 study by Yoshino et al administering NMN at 250 milligrams per day to postmenopausal women, and they reported increased circulating levels of MNA, a metabolite implicated in adverse kidney outcomes. Similarly, while NR has shown benefits in enhancing NAD levels and improving metabolic health, questions still remain about long-term safety, particularly at higher doses.

Speaker 0: 7:48

Researchers in this area do emphasize the need for further studies to establish optimal dosages and evaluate potential risks, including tissue-specific inflammatory responses. While NMN and NNR hold immense promise, their effects vary significantly depending on the organ system, age of the individual and underlying health conditions. The renal-specific inflammatory response to NMN in aged mice serves as a bit of a cautionary tale, emphasizing the need for personalized and evidence-based approaches to supplementation with NMN and NAD precursors. Ultimately, which precursor you use, if any does, come down to the most basic consideration of what is available to you and what is most cost-effective, before moving on to layer two of considerations, those being age, tissue-specific effects and so on. If you found today's episode insightful, don't forget to subscribe and share Daily Value with your network, as always. Thank you and stay healthy.