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 

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Episode Transcript

Speaker 0 (00:00):
Hello everyone, welcome back to Daily Value.
I'm William Wallace, and todaywe're diving into one of the
generally most popular topics inlongevity and health, that
being NAD plus metabolism, butfocusing on two supplements and
nicotinamide riboside, or NR.
Both compounds have capturedpublic attention for their

(00:28):
potential to restore cellularenergy and combat age-related
decline, but, as we'll see, thebenefits may not be universal,
and tissue-specific effectsfound in a few animal models
might raise important questionsabout their broader applications
.
So let's start with a quickoverview of NAD and its role in

(00:49):
our cells.
Nicotinamide adeninedinucleotide, or NAD, is a
coenzyme present in every cellof the body.
It plays a central role inmetabolic pathways, including
oxidative phosphorylation andthe activation of sirtuin and
PARP enzymes associated with DNArepair and longevity.
As we age, nad levels decline,which results in impaired

(01:12):
mitochondrial function andcellular repair mechanisms.
Nmn and NR serve as precursorsfor NAD through one of the three
major NAD synthesis pathways,that being the salvage pathway,
which produces up to 85% of thebody's NAD.
Nicotinamide riboside, or NR,is converted into NMN inside of

(01:34):
a cell before being transformedinto NAD.
Both compounds are available assupplements, with dosages in
human trials typically ranging,on average, from 100 to 900
milligrams per day.
That's the most consistentdosing range for these compounds
, with average NR dosing tendingto be slightly less than NMN.

(01:55):
Preclinical trials, however,often use significantly higher
doses.
For instance, a recent study byYang et al highlights the
metabolic improvements observedin mice supplemented with NR at
300 mg per kg per day.
That's equivalent to 2,400 mgin average adult human, 1,250

(02:21):
milligrams of NMN given tohealthy adult men and women for
up to four weeks and 2,000milligrams of NR given for 12
weeks in obese men.
When we look at studies usingNR, doses of 100, 300, and 1,000
milligrams taken for two weeksincrease NAD levels in a
dose-dependent manner by 22, 51,and 142 percent respectively.

(02:44):
It's important to note thatboth NMN and NR are considered
to be GRAS in the United States.
Gras means generally recognizedas safe.
However, there are moreclinical studies in humans using
NR versus NMN.
Now, very interestingly, a studyin rodents published in 2024 by
Sala et al administered NMN at300 mg per kg per day in aged

(03:09):
mice, which is roughlyequivalent to 1500 mg of NMN in
people, demonstrating notableimprovements in cardiac and
liver function but uncoveringunexpected kidney complications.
So what did they find?
Well, when we talk aboutanti-aging interventions, it's
essential to recognize thattheir effects are rarely

(03:29):
universal across all tissues inthe body.
Nmn and NR are no exceptions.
Both compounds havedemonstrated considerable
benefits in preclinical models,but in this study by Sala et al,
systolic and diastolic cardiacfunction in 26-month-old mice,
roughly equivalent to a79-year-old human, were improved
.
However, the kidney, an organwith high mitochondrial demand,

(03:53):
presented a different picture.
In aged mice, nmnsupplementation significantly
upregulated interleukin-1-beta,that's a cytokine associated
with senescence-associatedsecretory phenotype, or SASP.
Elevated interleukin-1-betaexpression was accompanied by
markers of kidney injurymolecule 1, or KIM1 as it's

(04:15):
called Now.
Importantly, these effects weremitigated when NMN was
co-administered with a drug usedto protect mitochondria,
suggesting a protective role ofa more robust intervention.
The metabolic analysis revealedthat aged mice treated with NMN
accumulated what are calleduremic toxins, such as methyl

(04:36):
nicotinamide or MNA and itsderivatives, 2-py and 4-PY, at
levels significantly higher thantheir younger counterparts.
These methylated metabolites ofNAD and niacinamide break down
in the salvage pathway.
These metabolites are naturallyoccurring byproducts of NAD

(04:56):
metabolism, but become toxicwhen 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 lesssuitable for different tissues
in the body at different lifestages.
Renal clearance of metabolicbyproducts goes down as we get

(05:16):
older, so it's possible thatfrequent high doses of NMN may
not always be beneficial in alltissues and in all cases.
An important consideration whenchoosing between NMN and NR may
be their distinct metabolicpathways to NAD synthesis and
how these might influence theirefficacy and safety.
Nr, as nicotinamide riboside,enters the NAD salvage pathway

(05:40):
by being converted to NMNthrough the enzyme nicotinamide
riboside kinase, or NRK.
This enzyme's activity variesbetween tissues.
Organs like the liver andmuscle, where NRK activity is
relatively high, are betterequipped to efficiently convert
NR into NMN and subsequently NAD.

(06:00):
However, in tissues with lowerNRK expression, the conversion
efficiency of NR may be limited,but that's really more
conjecture.
In contrast, nmn bypasses thisenzymatic step, entering the
salvage pathway directly, butthere still isn't strong
evidence that it enters a cell,as NMN Cells generally can't

(06:20):
transport nucleotides like NMN,and so NMN has to be broken down
to NR and then reassembled intoNMN.
These differences raiseimportant questions for
supplementation strategies.
For example, individualstargeting muscle health may
benefit more from NR, given itscompatibility with NRK activity
in muscle tissues.

(06:41):
When looking at the mostcommonly used doses in clinical
trials, nr tends to show moreeffectiveness at lower doses
than NMN, where 250 to 500milligrams is a common effective
dose, compared to NMN, wheredoses of 500 to 1,000 milligrams
are more common.
The findings on renalinflammation do highlight the

(07:01):
importance of considering ageand tissue specificity when
evaluating NAD precursors inhumans.
In human studies, nmn doseshave ranged from 100 to 900
milligrams per day, well belowthe 1.5 gram day equivalent used
in Sala's preclinical work.
However, there was also a 2021study by Yoshino et al

(07:24):
administering NMN at 250milligrams per day to
postmenopausal women, and theyreported increased circulating
levels of MNA, a metaboliteimplicated in adverse kidney
outcomes.
Similarly, while NR has shownbenefits in enhancing NAD levels
and improving metabolic health,questions still remain about
long-term safety, particularlyat higher doses.

(07:48):
Researchers in this area doemphasize the need for further
studies to establish optimaldosages and evaluate potential
risks, including tissue-specificinflammatory responses.
While NMN and NNR hold immensepromise, their effects vary
significantly depending on theorgan system, age of the
individual and underlying healthconditions.

(08:08):
The renal-specific inflammatoryresponse to NMN in aged mice
serves as a bit of a cautionarytale, emphasizing the need for
personalized and evidence-basedapproaches to supplementation
with NMN and NAD precursors.
Ultimately, which precursor youuse, if any does, come down to

(08:29):
the most basic consideration ofwhat 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 episodeinsightful, don't forget to
subscribe and share Daily Valuewith your network, as always.

(08:49):
Thank you and stay healthy.