"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?
"The new study, in Cell, found that boosting mice’s levels of the naturally occurring molecule NMN, which humans also have, increased levels of another called NAD+."
NMN is nicotinamide mononucleotide, available on Amazon.
It's NMN (NICOTINAMIDE MONONUCLEOTIDE) and sold through everyone including Wal-Mart and Amazon. Whether it works... on humans? I don't know and I'm not aware of any (completed) human studies.
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.
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."
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.
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.
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?
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!
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.
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.
The issue with simulations is they're only as good as our models and evolution has not laid out a simple system. The same chemicals are used in very different ways throughout the body.
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.
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.
> Should we also give free houses and luxury cars to people who refuse to work?
I know you meant this as a rhetorical question, but yes, I think society should provide free basic housing for those that can't afford it, whatever the reason.
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.
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.
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.
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.
Should we provide medical treatment to people with HIV because they refused to use a condom and had promiscuous sex with multiple partners or were drug users?
True, but one of them is unfortunately common. Some people desperately want to change their harmful behaviors and just can't. I know someone who just had their teeth removed after 30+ years of an eating disorder (acid destroys teeth over time).
(1) I can will to change my diet and exercise. In which case my will is free, OR
(2) I can't will it. In which case, given that some people have successfully made the change, factors other than diet and exercise must have been involved, so it can't 'just' be a matter of diet and exercise.
In case 2, losing weight is still down to diet and exercise, it's just that these options aren't currently available to you. Neither of these options is at the root of the causal tree (if you can will to change your diet an exercise, there's a reason why) but they're both required at some level.
>Nowadays many of us believe both that we have no free will
I think the difference between nowadays and the past, isn't so much attitude as it is food abundance.
It's easy to blame individuals and say they need more self control. but the reality is we're at a place in history we have likely never been in before.
Well if you eat healthfully and exercise regularly, I think it's a rational question to ask if this pill would give additional benefits. No one is arguing not to eat good food and exercise.
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?
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.
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
I read a lot of complaints about counterfeits on Amazon (not this particular product), so I'm avoiding them especially when it comes to food and supplements.
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.
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
[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
[5] As with Metformin, which has evidence for longevity effects.<...
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."
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.
> 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.
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.
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.
64 comments
[ 3.1 ms ] story [ 149 ms ] threadSo which supplement is it?
If it's already sold by supplement makers, have there been any reports of similar effects in people?
"The new study, in Cell, found that boosting mice’s levels of the naturally occurring molecule NMN, which humans also have, increased levels of another called NAD+."
NMN is nicotinamide mononucleotide, available on Amazon.
[1] http://www.cell.com/cell/fulltext/S0092-8674(18)30152-1
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...
I haven't heard anything since about what happened to the study.
NMN might be useful for people with niacin metabolism issues perhaps.
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...
[2]: https://doi.org/10.1159/000477402
[3]: https://doi.org/10.1016/j.cmet.2018.02.001
The one I take personally is https://www.iherb.com/pr/Thorne-Research-Niacel-250-Nicotina...
For general background on the science + nutrition approaches, see https://www.selfhacked.com/blog/nad-important-increase/
Correct. We understand bits and pieces of biology but we don't understand the entire system well enough to predict anything with any confidence.
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!
So add up random biochemical pathway * X million years of evoltion, and one begins to understand the fun of drug discovery and testing.
"We know this is the pathway involved in heart disease. We know this chemical compound is effective against that pathway.
... Now why are all our mouse models getting erections?"
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.
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.
Should we also give free houses and luxury cars to people who refuse to work?
The answer is obvious yet you're not seeing it.
I know you meant this as a rhetorical question, but yes, I think society should provide free basic housing for those that can't afford it, whatever the reason.
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.
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.
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.
That's the easy (conceptually) way. If we wanted that, we would have done it.
But we want to have our cake AND eat it.
(1) I can will to change my diet and exercise. In which case my will is free, OR
(2) I can't will it. In which case, given that some people have successfully made the change, factors other than diet and exercise must have been involved, so it can't 'just' be a matter of diet and exercise.
I think the difference between nowadays and the past, isn't so much attitude as it is food abundance.
It's easy to blame individuals and say they need more self control. but the reality is we're at a place in history we have likely never been in before.
[0]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963991/
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.
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
[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
[5] As with Metformin, which has evidence for longevity effects.<...
“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."
Is this research pointing to NMN having a greater impact on NAD+ than nicotinamide riboside ?
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.
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.
That said, they know far more about the compounds/molecules involved than I do.