
A dietary supplement makes old mice youthful, but will it work in people? - gscott
https://www.statnews.com/2018/03/22/dietary-supplement-makes-old-mice-spry/
======
1024core
The compound in question is nicotinamide mononucleotide (NMN).

Back in 2016, Keio university in Japan started a human study on its effects on
aging: [https://www.keio.ac.jp/en/press-
releases/2016/Dec/27/49-1931...](https://www.keio.ac.jp/en/press-
releases/2016/Dec/27/49-19313/)

I haven't heard anything since about what happened to the study.

~~~
AstralStorm
Exactly nothing. NMN failed exploratory trials multiple times. (Similar to
resveratrol.) It is just that the regulations ate not being published due to
not being interesting to investors and sponsors.

NMN might be useful for people with niacin metabolism issues perhaps.

------
reasonattlm
If you are old enough to remember the hype about resveratrol and sirtuins,
that eventually resolved to nothing at all of any great use for human
medicine, this is basically the same people singing the same song about
roughly the same area of biochemistry. On the face of past events, they can't
really be trusted to tell you how great it is and how promising it is, so just
read the facts and compare with other studies.

About the most one can say about this is that manipulation of NAD+ levels is a
better exercise mimetic than manipulation of sirtuins proved to be. What it
helps to do is explain some of the underpinnings of studies that show a great
deal of muscle loss is secondary aging - i.e. disuse. It also suggests that
loss of capillaries is a more important mechanism in sarcopenia than other
groups believe to be the case, though I think it very possible that this is
secondary to stem cell activity loss. The evidence for stem cell decline to be
the primary cause of sarcopenia is very good. [1] There is a faction that
thinks capillary loss is important in all tissues. [2]

Go look at the studies showing resistance training to be pretty effective in
seniors before getting excited about NAD+ boosters. The resistance training is
probably cheaper and better. One still has studies such as the one showing
that dietary nicotinamide doesn't do a great deal in mice [3] - like sirtuin
manipulations, it helps fat mice a little, but is distinctly unimpressive
otherwise.

Remember that calorie restriction extends life by 40% in mice, but probably
five years or less in humans - the effects of all these stress response
related mechanisms of metabolic manipulation work through a few overlapping
core processes, and scale down with species longevity. That's why I see them
as a dead end in comparison to other strategies.

[1]: [https://www.urmc.rochester.edu/news/story/4788/stem-cells-
ma...](https://www.urmc.rochester.edu/news/story/4788/stem-cells-may-be-the-
key-to-staying-strong-in-old-age.aspx)

[2]: [https://doi.org/10.1159/000477402](https://doi.org/10.1159/000477402)

[3]:
[https://doi.org/10.1016/j.cmet.2018.02.001](https://doi.org/10.1016/j.cmet.2018.02.001)

~~~
xcavier
There are quite a few supplements that operate to boost NAD+ levels.

The one I take personally is [https://www.iherb.com/pr/Thorne-Research-
Niacel-250-Nicotina...](https://www.iherb.com/pr/Thorne-Research-
Niacel-250-Nicotinamide-Riboside-60-Veggie-Capsules/69577)

For general background on the science + nutrition approaches, see
[https://www.selfhacked.com/blog/nad-important-
increase/](https://www.selfhacked.com/blog/nad-important-increase/)

~~~
intrasight
I see Thorne has for $39 and Amazon has for $79. Looks to be same product, so
I don't understand why it's so much more at Amazon.

~~~
robear
There are 125mg and 250mg versions at those two price points.

~~~
intrasight
They are both 250mg. The expensive one has "vegetarian" in the name. I can't
find any explanation anywhere.

------
stevenwoo
I heard about this on NPR last week - even if it could make old people's blood
vessels youthful, it seems like it would be better to just make the person
change their diet and their exercise regimen, assuming exercise was possible.
This chemical only affected blood vessel health. This is only one component of
health. Bone density requires load bearing exercise. Another recent study
pointed out lack of exercise led to nerves to major muscle groups fading away
with lack of use - led to muscle loss - one has to use those muscles to use
the nerves, age related muscle loss can be staved off by exercise of the
muscle groups in question.

~~~
themodelplumber
The supplement or the pill has magical abilities though. Many people who will
say "I die when I die" when told to diet or exercise will take a pill with no
complaints.

And as a hobby dieter & big loser: Once you realize diet is something
requiring long-term conscientiousness, the truth and enormity of the change
can hit very hard. It is an emotional roller coaster that can just as easily
make people more fat than when they started.

~~~
jack_pp
If they don't care about their own health and longevity I would argue their
lives shouldn't be extended against their own will.

Should we also give free houses and luxury cars to people who refuse to work?

~~~
Erlich_Bachman
If they are willingly taking the pill then it's not "against their will" at
all?

The difference is crucial.

Is it true that you have to work, put in effort for most things in life? And
that people need to learn that? Yes.

But isn't it also true that the science is largely an endeavor of decreasing
the amount of work people need to put in to achieve the same result in some
area? If you look at almost all of the history - that is also true. This is
just another installment of that same centuries-old trend.

Science wants (and should rightfully want) to make a pill that will make
something require less effort (staying healthy for long time). If some people
would not put in the big effort, but would put in the small effort, given the
opportunity - than all the power to them. It's the ultimate goal of science
anyway.

~~~
chiefalchemist
Is that what science seeks, or is that what society necessitates science seek?

Take Type 2 Diabetes. Science is putting a significant amount of time and
money to "cure" it. The sad irony is, we have a cure. Yes, that takes -
evidently - too much effort. But isn't that a matter of perspective?

Cancer is also a byproduct of diet and lifestyle. Seems to me that cancer is
more difficult than changing diet and lifestyle.

The point is, science is forced (so to speak) to seek things that are already
found. "Easy" or not, what other unintended consequences does "easy" create?
Science should be seeking best solutions, at which point it could move on to
other things.

~~~
Erlich_Bachman
I'm not sure what the problem is with "society necessitates the direction of
science".

What else do you propose the science be directed by? What else is really
there? Are there any other real reasons for science at all?

Science is for us, the humans, the society. Studying things with no reason or
benefit for the society, somehow detached from humanity, for what, some vague
abstract reasons? I'm not sure I would want to put my effort into that, either
in the specific sense, or even in the more implicit sense of funding it
through my taxes.

Doing science for the sake of science? What's the point?

Looking at the question from another perspective though - I think a good
direction for science would to study how would it be possible to make people
take the extra effort, make the difficult choices - that would lead to a
natural resolution of many of their problems (like exercise would lead to less
cancer). But in this specific case, stopping science from looking for anti-
cancer pills, for example, does not seem like a proper way to go. Willingly
preventing progress in making lives easier with low-effort methods like pills
(if they really do work) does not seem like the best way to promote otherwise
healthy behavior.

~~~
chiefalchemist
No problem. Provided the bigger most important things have been solved. When
first world science is "forced" to focus on self-inflicted first world
problems, __and__ that focus is accepted, if not encouraged, then something is
seriously wrong.

------
JulianMorrison
1\. Headline ends in "?". The answer is "no".

2\. Longevity breakthrough discovered in mice. Mice biology doesn't bother
picking the low hanging fruit of longevity. Said breakthrough picks some of
that low hanging fruit. Chances are near-certainty it won't work in humans.

~~~
yodsanklai
> Chances are near-certainty it won't work in humans

Still an interesting result, even though it can't be applied directly to
humans. I'm not familiar with the field, but it sounds like an extraordinary
feat to be able to rejuvenate an animal.

~~~
Retric
It might sound that way, but it's really not difficult to rejuvenate mice. The
metabolic burden associated with living longer is not worth it for wild mice.

------
KaoruAoiShiho
I'm not a biologist so here's a dumb question. There's a lot of talk about
replicating the study experimentally but do we simply not understand biology
well enough to make a theoretical analysis? Basically can we not understand on
a fundamental level why it works in mice and why it might or might not work
for humans?

~~~
toolbox
The short answer here is yes. We're constantly working to get more complete
models, but surprisingly big effects can come from surprisingly small pieces
of the puzzle. We still don't even really understand how
Tylenol/Paracetamol/Acetaminophen works!

A great example of the gap between our current models and what would be
sufficient comes from the COX-2 inhibitors (Vioxx/Celebrex). Ibuprofin
(Motrin/Advil) and other NSAIDs modulate both COX-1 and COX-2 receptors in the
body to reduce inflammation, but inhibiting COX-1 also causes stomach damage.
The early COX-2-specific inhibitors were designed from the ground up using our
best models, which were thought to be well-understood. Unfortunately, after
several years on the market, it was discovered that this also came with a
large increased risk of heart attacks and strokes.

The body just has so so many moving pieces, and while we're getting better,
it's going to be some time before we are able to base these studies entirely
on theory, and when we get there we'll be able to skip the mice entirely!

~~~
amelius
Is somebody maintaining the relationships between compounds, genes, and their
high-level effects somewhere? I'm aware of biological pathway diagrams (e.g.
KEGG), but they seem so unreadable, and for me they don't connect the dots
between substance and effect.

~~~
toolbox
The relationships and high-level effects are maintained in our body of
literature. It's hard to resist wanting to put it all in some sort of
megachart, but even the pathway diagrams vastly simplify the real
interactions. The reason they don't seem to connect substance and effect is
because often the substances are very far removed from effect, or may not lie
on a known pathway at all.

It's still very much a "we don't know what we don't know" situation, which is
both intimidating and exciting. There's a lot to be done before our models are
even adequate, but we at least get to be part of that learning process.

------
mhuffman
A link[1] to the actual research says "Treatment of mice with the NAD+ booster
nicotinamide mononucleotide (NMN) improves blood flow and increases endurance
in elderly mice by promoting SIRT1-dependent increases in capillary density,
an effect augmented by exercise or increasing the levels of hydrogen sulfide
(H2S), a DR mimetic and regulator of endothelial NAD+ levels."

[1]
[http://www.cell.com/cell/fulltext/S0092-8674(18)30152-1](http://www.cell.com/cell/fulltext/S0092-8674\(18\)30152-1)

------
kuwze
I think the future of age-related research is going to focus on inflammation.
There is already a term for it: Inflamm-aging[0].

[0]:
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963991/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963991/)

~~~
reasonattlm
A good recent paper on sources of inflammation in aging:

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850851/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850851/)

As it points out, the most obvious and promising of current prospects for
reducing inflammation is the selective destruction of senescent cells. Though
I think that the clearance and recreation of the entire immune system, to
remove all of the senescent, exhausted, misconfigured, etc, immune cells is
also a promising path, albeit further away from being safe enough to apply to
old people.

------
pmoriarty
_" In the latest advance, biologists reported on Thursday that a molecule
already sold by supplement makers (even as scientists scramble to understand
it) restored youthfulness to blood vessels in 20-month-old mice, an age
comparable to 70 years in people..."_

So which supplement is it?

If it's already sold by supplement makers, have there been any reports of
similar effects in people?

~~~
bitL
There was a thread a year or so ago on HN where some people mentioned that
they narrowed down their supplements to NMN and something else and were happy
about that.

~~~
zspade
I believe it was NMN and Resveratrol (or Pterostilbene.).

------
FlyingSideKick
I’ve been considering taking these supplements but I’m concerned about
increased risk of cancer. Have there been updates on this since the
publication of this study? [https://siteman.wustl.edu/pathway-linked-slower-
aging-also-f...](https://siteman.wustl.edu/pathway-linked-slower-aging-also-
fuels-brain-cancer/)

~~~
partiallypro
Just skimmed the article, and it seems to me that they are more looking into
this to find a treatment for brain cancer than making a direct causality from
the supplement itself. Basically when someone does have brain cancer, they
could limit NAMPT to help in treatment. That's how I read it at least, maybe
I'm misinterpreting. There is these quote:

“We didn’t directly demonstrate that taking NAD+ precursors makes tumors grow
faster, but one implication of our work is that if you want to take anti-aging
NAD+ precursors, you might want to keep in mind that we don’t yet understand
all the risks.”

"Furthermore, the scientists found that glioblastoma cells responded to
radiation therapy – a standard therapy used to treat the disease in people –
by increasing expression of NAD+ pathway genes, and that inhibiting NAMPT
before dosing the cells with radiation made them easier to kill."

------
Empact
This article prompted me to research and write a plea for my friends to take
this supplement (I've been on it for a few months, before that took
Nicotinamide Riboside, NMN's precursor):

Please consider taking NMN for health and longevity. Nicotinamide
Mononucleotide (NMN) is a direct precursor of NAD+ which broadly
activates/energizes the Sirtuin pathways. Previous interventions either
activated only one of these pathways[1] or activated them less effectively[2].

Why all the fuss about Sirtuin pathways? Well, it makes sense that your body
would have a built-in maintenance system, right? It seems the seven Sirtuins
are that.

Take SIRT6, for example. Evidence points to it being essential to / directly
enabling DNA repair[3], and telomere maintenance[4], while reducing
gluconeogensis[5] and inflammation.

SIRT2 supports insulin sensitivity through multiple pathways[6], and helps
regulate proper cell division, i.e. in the ordinary case, helps prevent the
formation of tumors[7]. __IMPORTANT NOTE __This may only be beneficial if you
don 't already have cancer - in the other case more SIRT2 could help to
stabilize your cancer cells in their division and increase proliferation.[8]
So please, talk to your doctor.

One more, because I'm enjoying this: for SIRT3, researchers studied a
population and found that genes enhancing its production where "virtually
absent" in men older than 90.[9] Mice bred to lack SIRT3 developed breast
cancer, and the researchers proposed "that SIRT3 is ideally situated to
function as a mitochondrial fidelity protein, and by extension, loss of
function could result in a damage permissive and tumorigenic cellular
environment" [10]

That's three of seven. Other multi-SIRT effects include:

* possibly preventing stroke and improving recovery in its aftermath [11]

* being essential to retinal function / vision [12]

So Sirtuins are important, and they're powered by NAD+, but NAD+ availability
declines as we age, reducing their ability to play that role, and contributing
to consequent decline and dysfunction with age. Supplementing NMN helps offset
that decline, to keep those systems working as they should.

So I'm calling it here. My best minimal health / longevity stack is: NMN,
Kado-3, and Magnesium.

If you want to add another for good measure, look at bioflavonoids Quercetin
or Apigenin, both inhibitors of CD38, one probable cause of age-related NAD+
decline.[13]

Thanks for reading. Live long and prosper.

Disclaimer: I'm an engineer, not a scientist or a doctor, so my preference is
to support actions which I expect to work, rather than ones which I know with
certainty will work. Ergo, this is not medical advice, this is my judgment
based on my limited and potentially misguided analysis of the human body as a
system.

Footnotes:

[1] As with Resveratrol, which activates SIRT1

[2] As with Nicotinamide Riboside, which is the precursor to NMN and
externally mediated by NAMPT, etc. NMN needs no co-factor.

[3] "SIRT6 is [...] is _required for normal base excision repair of DNA damage
in mammalian cells_. Deficiency of SIRT6 in mice leads to abnormalities that
overlap with aging-associated degenerative processes."
[https://en.wikipedia.org/wiki/Sirtuin_6](https://en.wikipedia.org/wiki/Sirtuin_6)

[4] "We propose that SIRT6 contributes to the propagation of a specialized
chromatin state at mammalian telomeres, which in turn is _required for proper
telomere metabolism and function_. Our findings constitute the first
identification of a physiological enzymatic activity of SIRT6, and link
chromatin regulation by SIRT6 to telomere maintenance and a human premature
ageing syndrome."
[https://www.ncbi.nlm.nih.gov/pubmed/18337721](https://www.ncbi.nlm.nih.gov/pubmed/18337721)

[5] As with Metformin, which has evidence for longevity effects.

[6] "SIRT2 inhibits adipogenesis by deacetylating FOXO1 and thus may protect
against insulin resistance. SIRT2 sensitizes cells to the action of insulin by
physically interacting with and activating Akt and downstream targets."
[https://en.wikipedia.org/wiki/Sirtuin_2](https://en.wikipedia.org/wiki/Sirtuin_2)

[7] "SirT2-deficient animals exhibit genomic instability and chromosomal
aberrations and are prone to tumorigenesis"
[http://genesdev.cshlp.org/content/early/2013/03/04/gad.21134...](http://genesdev.cshlp.org/content/early/2013/03/04/gad.211342.112)

[8] "Our data suggest that SIRT2 is the sirtuin predominantly involved in
breast tumourigenesis and prognosis. It indicates that SIRT2 acts as a tumour
suppressor or tumour promoter dependent upon breast tumour grade."
[https://www.ncbi.nlm.nih.gov/pubmed/24183459](https://www.ncbi.nlm.nih.gov/pubmed/24183459)

[9]
[https://www.sciencedirect.com/science/article/pii/S088875430...](https://www.sciencedirect.com/science/article/pii/S0888754304003088?via%3Dihub)

[10]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711519/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711519/)

[11] "NMN and NAD treatment also enhanced proliferation and differentiation of
cultured neural stem cells in vitro. Knockdown of sirtuin deacetylases (SIRT1,
SIRT2, or SIRT6) significantly reduced the proneuro-genesis effect[...]. Thus,
we provide the first evidence that Nampt–NAD cascade is not only crucial
against acute brain ischemic injury but also important for postischemic
regeneration."
[http://stroke.ahajournals.org/content/strokeaha/46/7/1966.fu...](http://stroke.ahajournals.org/content/strokeaha/46/7/1966.full.pdf)

[12] "We further demonstrate that the NAD+-dependent mitochondrial deacylases
SIRT3/SIRT5 play important roles in retinal homeostasis and that NAD+
deficiency causes SIRT3 dysfunction. These findings demonstrate that NAD+
biosynthesis is essential for vision"
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104206/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104206/)

[13] "These findings suggest that the efficacy of NAD+ precursors may be
enhanced by co-supplementation with CD38 inhibitors"
[https://www.sciencedirect.com/science/article/pii/S155041311...](https://www.sciencedirect.com/science/article/pii/S1550413116302443)
[http://www.timelesslifemag.com/index.php/2016/06/29/querceti...](http://www.timelesslifemag.com/index.php/2016/06/29/quercetin-
apegenin-may-slow-down-the-escalating-nad-consumption-by-cd38-as-we-age/)

~~~
Erlich_Bachman
Do you have a blog? ;)

------
clumsysmurf
I'm confused, as already mentioned at the bottom of the article, there are
other supplements to boost NAD+ like nicotinamide riboside.

Is this research pointing to NMN having a greater impact on NAD+ than
nicotinamide riboside ?

------
wakkaflokka
So if one were to try taking NMN as a supplement but had no idea which brands
were legitimate, what should they do? Go off Amazon reviews? Recommendations
anybody?

~~~
shurth
I use Amazon reviews but I try to stay conscious that sexy labels/marketing
influences people. When in doubt, stick with the high quality, no additives,
stuff like Thorne.

~~~
CodeWriter23
Yeah also pay attention to the review dates. I wanted to buy a lightning /
audio split cable for my iPhone. I noticed the vendor had 800+ 5 star reviews
and none for 1-4 stars. Then I noticed all the reviews had been entered in the
previous 3 days. /fakereviews

------
kup0
The risk of causing autoimmune diseases due to increased sirtuins seems like
it should give companies like Elysium Health some pause on this. It is
possible the risks are low, but that is an incredibly severe, permanent side-
effect.

That said, they know far more about the compounds/molecules involved than I
do.

------
mjhoyer
FOXO4-DRI seems much more promising with less side effects (none known) than
NAD+

