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