NR

NAD+ Supplement Increases Muscle Mitochondria and Beneficial Gut Bacteria: Finland Study

The supplement NR raises blood NAD+ and muscle mitochondria levels while improving the gut’s bacterial composition in humans.

By Bennett M. Sherman

Highlights

  • Supplementing nicotinamide riboside (NR) to middle-aged humans for five months more than doubles their blood nicotinamide adenine dinucleotide (NAD+).
  • NR increases the production of mitochondria in a tissue-specific way – in muscle but not fat tissue.
  • NR modulates the gut’s bacterial composition, increasing the abundance of a species that turns NR and nicotinamide mononucleotide (NMN) to NAD+.

Rodent studies suggest that increasing levels of an essential molecule for mitochondrial function, NAD+, combats obesity and its related disorders. Along those lines, supplementing with the NAD+ precursor NR increases mitochondrial production (biogenesis) and function, protects against obesity, and improves the gut’s microbial composition in mice. However, so far, studies in humans haven’t provided evidence that NR enhances mitochondrial production, and they’ve all been short, lasting no longer than 12 weeks.

Published in Science Advances, Pirinen and colleagues from the University of Helsinki in Finland show that treating middle-aged adults with 1 gram of NR per day for five months more than doubled blood NAD+. Moreover, muscle mitochondria exhibited an increase in abundance, and levels of a gut microbe that promotes metabolic health and anti-inflammatory responses increased. These findings suggest that supplementing with NR for extended periods enhances muscle mitochondrial production and improves the gut’s bacterial composition.

Chronic NR Supplementation Increases NAD+, Muscle Mitochondria, and Beneficial Gut Bacteria

To find whether people’s body fat affects NR’s influence on NAD+ levels, mitochondrial production and function, and gut microbes, Pirinen and colleagues used pairs of twins – one leaner and another heavier – to conduct their study. The researchers found no difference between leaner and heavier twins when it came to NR’s ability to increase blood NAD+ levels. NR increased blood NAD+ levels ~2.3-fold over the five-month dosing regimen. These results suggest that, despite one’s body fat content, when taken for extended periods, NR can substantially increase blood NAD+ levels.

(Lapatto et al., 2023 | Science Advances) Five months of NR supplementation raised blood NAD+ levels an average of ~2.3 fold. The figure shows blood NAD+ levels before NR supplementation (Pre) and after five months of NR (Post) for 14 twin pairs/ 28 individuals each represented with a line. The black lines show that blood NAD+ increased for the leaner of the twins, while the red shows how it increased for the heavier individuals. No significant differences were found comparing heavier to leaner individuals, and NAD+ levels increased an average of ~2.3 fold for all participants.

Since mitochondria are the components within cells that generate cell energy and drive healthy metabolism, the Finland-based team sought to determine whether extended NR supplementation could increase their abundance. Increased mitochondrial production would then serve as an indicator of elevated mitochondrial production (biogenesis). They compared the leaner and heavier individuals from twin pairs and found no differences in the effect that NR had on increasing mitochondrial biogenesis. In both leaner and heavier individuals, NR increased muscle mitochondrial abundance by ~14% at the end of the five-month dosing regimen compared to the beginning of the study. This effect was tissue-specific since NR didn’t increase mitochondrial biogenesis in fat tissue (white adipose tissue). These results suggest that by increasing muscle mitochondrial production, NR may boost metabolism in a tissue-specific way. Interestingly, NR didn’t diminish fat content in any of the individuals included in the study, so it’s unclear whether the increased mitochondrial abundance boosts metabolism in a way that would eliminate fat.

(Lapatto et al., 2023 | Science Advances) The number of muscle mitochondria increased ~14% following five months of NR supplementation. For 11 twin pairs/ 22 individuals who were classified as either leaner (black lines) or heavier (red lines), NR taken for five months significantly increased muscle mitochondrial numbers by an average of ~14%. Each line represents the individual muscle mitochondrial muscle gains following five months of NR (Post) compared to before taking NR (Pre).

Since metabolism is also closely linked to the gut’s microbial composition, Pirinen and colleagues used genetic sequencing of the microbes in fecal matter to determine changes that occurred over the five-month NR dosing regimen. Based on their genetic sequencing analyses, the researchers found that a bacterial species that promotes metabolism and anti-inflammatory responses called Faecalibacterium prausnitzii increased ~1.7-fold in abundance. Moreover, this bacterial species has been shown to metabolically utilize NMN and NR, converting them to NAD+. This means that the increased abundance of F. prausnitzii could be yet another way that NAD+ levels increase with NR supplementation.

(Lapatto et al., 2023 | Science Advances) Taking NR for five months increased levels of the pro-metabolism and anti-inflammatory bacterial species Faecalibacterium prausnitzii in the gut. Supplementing NR for five months moderately increased levels of the beneficial bacteria F. prausnitzii by ~1.7 on average for each individual from 11 twin pairs/ 22 individuals. Each line represents an individual’s increase for this bacterium after the NR dosing regimen (Post) compared to before (Pre). The black lines represent leaner individuals, and the red lines represent heavier individuals. No differences were found for the increase of this bacterial species comparing leaner and heavier individuals.

“Overall, our data underscore the role of NR as a potent modifier of systemic NAD+ levels, muscle mitochondrial biogenesis, … and the gut microbiota in humans,” said Pirinen and colleagues.

Finding How Increasing Muscle Mitochondria Affects Metabolism and Muscle Strength

The study provides the first evidence that NR supplementation over extended periods boosts mitochondrial biogenesis in muscle. This effect was tissue-specific since the researchers found that NR has no effect on mitochondrial production in fat tissue (white adipose tissue). Since NR didn’t have an effect on the study participants’ body fat, it’s unclear how increased muscle mitochondrial biogenesis affects overall metabolic physiology.

Since increased muscle mitochondria could affect muscle function, future studies should examine whether NR-induced muscle mitochondrial biogenesis increases muscle strength. They should also analyze whether coupling NR supplementation with exercise routines that include weightlifting can further enhance mitochondrial biogenesis and the power that muscles generate.

Model and Dosage

Model: Humans with an average age of 40 years

Dosage: Initial 250 mg of NR per day increased by 250 mg per week so that 1 gram per day of NR was reached by the end of the first month; 1 gram per day of NR for the remainder of the five-month study duration

Source

Lapatto HAK, Kuusela M, Heikkinen A, Muniandy M, van der Kolk BW, Gopalakrishnan S, Pöllänen N, Sandvik M, Schmidt MS, Heinonen S, Saari S, Kuula J, Hakkarainen A, Tampio J, Saarinen T, Taskinen MR, Lundbom N, Groop PH, Tiirola M, Katajisto P, Lehtonen M, Brenner C, Kaprio J, Pekkala S, Ollikainen M, Pietiläinen KH, Pirinen E. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study. Sci Adv. 2023 Jan 13;9(2):eadd5163. doi: 10.1126/sciadv.add5163. Epub 2023 Jan 13. PMID: 36638183.

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