New research finds NR may be harmful for heart function in mice – ALIVE BY SCIENCE – Bioavailable NAD+ Boosters

New research finds NR may be harmful for heart function in mice

Instability in NAD+ metabolism leads to impaired cardiac mitochondrial function and communication

This study examined  the effect on NAD+ levels from DNA damage leading to heart failure in mice, and the efficacy of Nicotinamide Riboside (NR) supplementation to restore NAD+.

They found the increased activity of PARP enzymes required to repair the DNA damage resulted in diminished NAD+ levels.

NR supplementation did not increase NAD+ levels in the heart, or improve heart function.

In addition, they found that treatment with a larger dosage of NR may have negative effect on heart function.

This larger dosages was 1,000 Mg per Kg of NR in the chow which is roughly equivalent to 569 mg a day for a 70 kg human.

DNA damage lowers NAD+ levels

As expected, they found the increased activity of PARP enzymes required to repair the DNA damage resulted in diminished NAD+ levels.  According to the authors,

“depletion of the NAD+ pool would cause cellular harm due to loss of sirtuin activity and a dysregulation of a number of protective pathways”.

 

NR supplementation improved NAD+ levels in the liver

Supplementation with 400 mg/kg a day of NR did improve NAD+ levels in the liver.

“We did detect an increase in NAD+ levels in the livers of mutUNG1-expressing mice”

 

NR supplementation did not improve NAD+ levels in the heart

Supplementation did not improve NAD+ levels in the heart of control mice (Wt), or the experimental mice with DNA damage (mU1)

“We did not see any increase in cardiac NAD+ levels with NR supplementation”

NR supplementation did not restore  heart function

They also found no improvement in heart function.

The chart at right shows the Ejection Fraction which measures the efficiency.

NR supplementation did not have a significant effect.

 

“NR supplementation did not lead to any significant changes in the cardiac phenotype”

Higher dosage of NR had a negative effect on heart function

The researchers wanted to find if a higher dosage of NR might be more effective, so increased the dosage.

They were surprised to find the higher dosage was detrimental to heart health, possibly due to excessive buildup of Nicotinamide (NAM) which inhibits Sirtuins.

The chart above shows that protein acetylation was increased (bad) in mice with DNA damage in heart tissue (mU1).  Acetylation was greatly increased with 1,000 mg/kg of NR in the chow.

“To our surprise, a high dose of NR caused an even higher overall mitochondrial protein acetylation than the lower dose”

“Treatment with a high dose of NR as a tool to increase NAD+ levels may inhibit rather than increase sirtuin activity due to accumulation of nicotinamide (NAM). Our findings suggest that NR might have disadvantageous effects on cardiomyocyte mitochondria, at least in high dosages.”

Small dosage of NR did not have negative effect

400 mg/kg of NR supplementation did not have a significant effect on heart Ejection Fraction or protein acetylation.

“NR supplementation had no effect on the acetylation status”

Increasing doses of NR progressively inhibit deacetylation and PARP cleavage

The researchers tested varying dosages of NR to quantify the decreased PARP activity as dosage increased.

They found increased dosages of NR result in other negative consequences for heart health:

Our findings so far suggest that increasing doses of NR could have non-beneficial effects on cardiac mitochondria.

All together, these results indicate stronger sirtuin inhibition with higher NR doses, in line with the observed inhibition in mouse cardiomyocyte mitochondria

Conclusion: Large dosages of oral NR supplementation may have negative consequences

According to the authors:

“While NR has been suggested to restore NAD+ levels and thereby improve mitochondrial function and SIRT3 activity, we show that NR, particularly at high doses, had the opposite effects in cardiac tissue potentially secondary to enhanced NAM levels that would inhibit SIRT3 activity.”

“These data also suggest that the use of NR in rescuing these cardiac events should be reevaluated, in particular at higher dosages”

Excess NAM may be responsible

The authors of this study believe that the negative effects from large dosages of NR may be due to excess NAM production, which is known to inhibit Sirtuin activity (r,r)

While NAM is beneficial for many health conditions, excessive NAM levels can be detrimental to your health.

“high doses of NAM can cause genomic instability, reduce cellular methyl pools, and cause insulin resistance through methylated NAM” (r,r)

Where does the excess NAM come from?

There is a big bioavailability problem with oral NR (and NMN) supplements

The Liu/Rabinowitz study in 2019 found that oral supplements of NR and NMN are almost entirely degraded to NAM in the stomach and liver, with very little escaping beyond the liver to tissues elsewhere (r).

The poor bioavailability can result in excess NAM buildup when higher dosages of oral supplements of NR or NMN are used.

Can NMN supplementation also result in excess NAM?

The 2019 research by Liu/Rabinowitz found that  oral supplements of NMN and NR are also almost entirely degraded to NAM before exiting the liver.

But in 2020, this research found that bacteria in the stomach process NMN to NaMN and other metabolites.

Also, this study shows NR is  far more unstable than NMN and any NR that does make it to the bloodstream is quickly degraded to NAM.

So it is likely that NMN supplementation will result in less NAM production than supplementation with NR.

The solution to excess NAM buildup

We previously wrote about problems with excess NAM here.

We have long believed that taking standard capsules of NR or NMN that are known to be almost completely digested to NAM is not the best solution.

A much better solution is Sublingual or Liposomal delivery of NAD+ and NAD+ precursors.

 

Addendum

Conversion of dosages used in study to Human Equivalent

This study added NR to the chow used to feed the mice, with varying quantities of NR per Kg of chow. Quote below is from the study.

“NR was added to the diet, either as 400 mg/kg chow (medium dose) or 1000 mg/kg chow (high dose), after 6 weeks of mutUNG1 induction (with a total of 2 weeks of NR treatment). These numbers were chosen based on the parameters that a mouse in average weighs 30 g, and eat 3 g chow per day”

There was originally much confusion about the dosages as they did not report the dosage in the more traditional Mg/Kg of bodyweight.  Per the authors:

“We apologize for making this part of the manuscript uncertain and this issue has now been more clearly stated in the revised manuscript.”

We have adjusted the dosages now per their explanation and we show those calculations in the chart below along with the Human Equivalent dosage.