Just fyi, the primary endpoint was safety, so to pass it just needed to not be toxic. The secondary endpoint was a biomarker of mitochondrial health. So no clinical effects are included here.
That seems overly dismissive of the finding on mitochondrial activity:
" The team then assessed the efficacy of UA by looking at cellular and mitochondrial health biomarkers in the participants' blood and muscle tissue. The results were compelling: UA stimulates mitochondrial biogenesis—the process by which cells increase mitochondrial mass—in the same way as regular exercise.
UA is the only known compound that re-establishes cells' ability to recycle defective mitochondria. "
Biomarkers are not a clinical effect, this doesn't tell you whether this compound has any anti-aging effects. This is still an early point in the development of a drug.
What particular anti-aging effects do you regard? Are not improvements in mitochondrial health practical indicators of anti-aging as improvements in skin elasticity or bone strength?
They didn't actually measure mitochondrial health, they measured acylcarnitine levels. Those levels indicate that certain metabolic pathways happening in the mitochondria are working better. This is still very far from any practical effect on the whole organism. Biomarkers can also be misleading, you're not measuring the actual process you're interested in directly, you're measuring a particular aspect that you think is strongly correlated with what you're actually interested in.
Is the article wrong in stating "UA stimulates mitochondrial biogenesis". Did the measurements of acylcarnitine levels not actually show this? Have any other substances been found to affect acylcarnitine levels or stimulate mitochondrial biogenesis ?
That's orthogonal to the point you're responding to - the point is that while this is a promising avenue for research, it does not provide evidence of a meaningful effect on the actual outcome of interest: aging/longevity.
The point of a biomarker is that we think/hope/hypothesize that we can use it as a surrogate for the thing we're actually interested in, so that we have something measurable on shorter timescales. Unfortunately, this assumption is often incorrect, and we won't actually know for years.
1. Each biomarker has to be validated independently. 2. There's a huge difference between something used for testing, and something used for intervention. Grey hair is a pretty OK test for aging, but clearly dying it isn't going to arrest the aging process.
Long term degenerative conditions are some of the most difficult problems for such validation, due to time, cost, and the complexity of risk in real populations.
I don't know anything about how well the current study actually links to mitochondrial biogenesis, but I know that we don't have satisfactory interventional biomarkers for a process as complex as aging. By all means continue researching this, but I think it's eminently sensible to be skeptical at this point.
Be as skeptical as you wish, but that is all very orthogonal to my requests to substantiate claims here that the biomarker examined is unreliably interpreted. They have not been substantiated. Discussion of what qualifies as "anti-aging" is another matter . Anti-aging is not a clinical term, there have been no claims made about general reversal of aging.
Skin elasticity is directly useful. Stronger bones are probably less likely to break, although this isn’t quite a given. Improved mitochondria are improved mitochondria and are not at all guaranteed to be beneficial.
Improved mitochondria function means improved energy conversion (in other words greater ATP with less calories)...that seems pretty useful all by itself.
Improving ATP efficiency is huge... i agree with you it may not mean stronger bones and more elastic skin...but we do know aging (less elastic skin and weaker bones) is related to the bodies breakdown in ATP supply/demand/conversion.
I just don’t think you can gloss over mitochondria inprovement as no benefit...it’s literally an improvement in energy (more energy with less calories), it’s a benefit unto itself.
> it’s literally an improvement in energy (more energy with less calories), it’s a benefit unto itself.
It's entirely plausible that, in the modern world, this is actually a negative.
Also, for all anyone knows, just "improving" mitochondria might also hurt due to increased production of free radicals and other strongly oxidizing species by those improved mitochondria.
No, you are extrapolating that based off your understanding. Improved mitochondria might...mean nothing.
In cancer, we see all the time the ability to get a cell we know is important into a tumor does not, necessarily, associate with clinical benefit. The same goes here. The ability to improve one small piece of biology does not mean, necessarily, that you will see a larger, emergent effect. Biology is much more complicated than that.
Not that this will stop every cosmetics line having a pomegranate version with adverts extolling "proven by science!" in a matter of months, if they don't already have one nearly ready to ship.
1) Metabolic side effects tend to be slow and subtle. Vioxx caused increased heart attacks over time. Passing a phase 1 safety trial is fine and dandy, but it’s a far cry short of long-term safety in a drug targeting metabolism, and it’s not even where most drugs fail.
2) Lab evidence for a biomarker for a metabolic process is so far short of evidence of clinical improvement that it’s a joke. I will never stop deriding studies that point to proxy markers (or in this case, proxy proxy markers) as evidence of benefit. This has been proven to be inadequate so many times, across so many different studies, that it’s just not worth talking about anymore.
This is a perfectly fine and valid phase 1 study. It says “we have identified a dose range that doesn’t immediately sicken people.” That’s what phase 1 trials do. The rest is press release hype.
Nature is a high impact factor, prestigious journal. It’s million sub-journals, like Nature Metabolism ... well, vary. A lot. They mostly coast on papa’s brand recognition.
Nature Endocrinology Reviews is a relatively ranking journal in endocrinology - roughly second place, by impact factor. This didn’t get published there.
Nature Metabolism was only opened in 2017, as an online-only journal. It doesn’t even rank in the top 50 for endocrine and metabolism journals - granted, that may be in part because it doesn’t even have an impact factor yet (calculating impact factor requires two years of publication history preceding the year being calculated for. In 2020, we should see a 2019 IF.)
So, one can say they might be enormously prestigious, and we just won’t see until 2020. It’s more likely that people aren’t bothering publishing their best articles in a 0 IF journal, because in academic circles the Nature Subbrand is recognized as not inherently meaningful, so the 0 IF pub just hurts (unless you think your pub would otherwise end up in an unimpressive journal, and you want to gamble that the future IF will be higher and pay off.)
There was a pretty nice portrait in the California Sunday magazine of a billionaire (Resnick) couple who owns a lot of land and water and are producing different kinds of citrus fruits and nuts in the south of California: https://story.californiasunday.com/resnick-a-kingdom-from-du....
Lynda Resnick has been heavily promoting pomegranate juice. Of course they have a lot to gain, because they are one of the leading branded producers of pomegranate juice. With these types of studies it is always a good idea to follow the money.
Just finished reading the paper, particularly interested in the mitochondrial biogenesis part. They make several comparisons with exercise adaptations, and the authors conclude:
>>> The present study reveals that UA induces a molecular signature
response, in both the plasma and skeletal muscle of humans, resembling
that observed as a consequence of a regular exercise regimen.
The also selected sedentary people only (from their participant inclusion criteria). Note that this is somehow normal: I have been rejected twice in 2 clinical trials for mitochondrial myopathy because I was too fit.
>> body mass index 18-32 kg/m2 and demonstrated sedentary behavior
All the authors declare a conflict of interest with Amazentis. Nestlé just signed a partnership agreement with them [1] to help them develop the product.
I guess they are actively seeking the exercise in a pill product. If they make it, it would be one of the biggest blockbusters in the history of medicine.
"A compound called urolithin A (UA) was the focus of the study, after previous experiments with it showed promise in extending the lifespans of worms and mice. The compound appears to fight aging by improving the function of mitochondria – the energy-producing part of a cell – in a way similar to the benefits of exercise. While it's not found naturally in any known food, biomolecules in fruits like pomegranates and raspberries do break down into UA in the human gut"
From the Wikipedia link someone else posted it looks like 100g of pomegranate is approximately 250mg, so 200g pomegranates a day to get to the point where they saw any (non clinical still) effects.
If they’ve raised capital for a series of clinical trials, you can reasonably assume the doses at which they expect to see clinical effects are much higher than you’re likely to get just from food ingestion - otherwise their competition would just be pomegranate juice pills or something, sold as a food supplement and requiring no trials of safety or efficacy. They’d never have been able to raise a cent.
In other words, no one would fund a penicillin trial if they thought people could get by eating moldy bread from GNC.
I don’t know. The dose of broccoli you need to see clinical effects from the sulforaphane it contains is extremely high, but concentrated sulforaphane capsules are sold as a food supplement without needing to go through any FDA process.
What criterion does the FDA use to distinguish a food-derived chemical that needs to be treated as a drug, from one that’s still just seen as an extract/essence of the food itself, and therefore can be treated as a supplement? It seems very opaque to me.
First we should see if this study was funded by that one giant pomegranate farm in California.
If Wikipedia is correct, we should start eating yellow raspberries instead; they offer about seven times as much of the compound this study is investigating the effects of. https://en.wikipedia.org/wiki/Urolithin_A#Dietary_sources
We can "just" start eating Pomegranates, absolutely. Personally, I find them pretty tasty, and they remind me of the Greek myth of Persephone's abduction by Hades. So I'm all for them.
But how much you'd need to eat for a clinically noteworthy benefit is the question. That's what the follow-on studies are for.
The article states that Urolithin-A is not produced by everybody. That acid in these fruits needs to be converted to UA in our gut. So no, it’s not always as simple as eating these fruits.
However at the same time, the gut is so confoundingly complicated that substances in concentrated tablet form are often less readily absorbed than less concentrated amounts occurring in food.
Nestlé signed a deal with them at the beginning of April, according to TheKingOfBelAir's comment above, which would lead me to believe they were at least involved with the study.
Pomegranate fasting and/or Aronia ("chokeberry") fasting (30 to 60 days) are incredible healers of all "diseases" known to man kind. Do your own research.
Just fyi, the primary endpoint was safety, so to pass it just needed to not be toxic. The secondary endpoint was a biomarker of mitochondrial health. So no clinical effects are included here.
That seems overly dismissive of the finding on mitochondrial activity:
" The team then assessed the efficacy of UA by looking at cellular and mitochondrial health biomarkers in the participants' blood and muscle tissue. The results were compelling: UA stimulates mitochondrial biogenesis—the process by which cells increase mitochondrial mass—in the same way as regular exercise.
UA is the only known compound that re-establishes cells' ability to recycle defective mitochondria. "
Biomarkers are not a clinical effect, this doesn't tell you whether this compound has any anti-aging effects. This is still an early point in the development of a drug.
What particular anti-aging effects do you regard? Are not improvements in mitochondrial health practical indicators of anti-aging as improvements in skin elasticity or bone strength?
They didn't actually measure mitochondrial health, they measured acylcarnitine levels. Those levels indicate that certain metabolic pathways happening in the mitochondria are working better. This is still very far from any practical effect on the whole organism. Biomarkers can also be misleading, you're not measuring the actual process you're interested in directly, you're measuring a particular aspect that you think is strongly correlated with what you're actually interested in.
Is the article wrong in stating "UA stimulates mitochondrial biogenesis". Did the measurements of acylcarnitine levels not actually show this? Have any other substances been found to affect acylcarnitine levels or stimulate mitochondrial biogenesis ?
That's orthogonal to the point you're responding to - the point is that while this is a promising avenue for research, it does not provide evidence of a meaningful effect on the actual outcome of interest: aging/longevity.
The point of a biomarker is that we think/hope/hypothesize that we can use it as a surrogate for the thing we're actually interested in, so that we have something measurable on shorter timescales. Unfortunately, this assumption is often incorrect, and we won't actually know for years.
I'm questioning the idea that this particular biomarker - doesn't actually mark what the report claims it marks (mitochondrial bio-genesis).
How do we often test for diabetes.. cancers.. many many clinical conditions? Biomarkers. So they are not practically unreliable in general.
What do you know about the particular biomarker employed in the study to say that it is unreliable ?
1. Each biomarker has to be validated independently. 2. There's a huge difference between something used for testing, and something used for intervention. Grey hair is a pretty OK test for aging, but clearly dying it isn't going to arrest the aging process.
Long term degenerative conditions are some of the most difficult problems for such validation, due to time, cost, and the complexity of risk in real populations.
I don't know anything about how well the current study actually links to mitochondrial biogenesis, but I know that we don't have satisfactory interventional biomarkers for a process as complex as aging. By all means continue researching this, but I think it's eminently sensible to be skeptical at this point.
Be as skeptical as you wish, but that is all very orthogonal to my requests to substantiate claims here that the biomarker examined is unreliably interpreted. They have not been substantiated. Discussion of what qualifies as "anti-aging" is another matter . Anti-aging is not a clinical term, there have been no claims made about general reversal of aging.
Skin elasticity is directly useful. Stronger bones are probably less likely to break, although this isn’t quite a given. Improved mitochondria are improved mitochondria and are not at all guaranteed to be beneficial.
Improved mitochondria function means improved energy conversion (in other words greater ATP with less calories)...that seems pretty useful all by itself.
Improving ATP efficiency is huge... i agree with you it may not mean stronger bones and more elastic skin...but we do know aging (less elastic skin and weaker bones) is related to the bodies breakdown in ATP supply/demand/conversion.
I just don’t think you can gloss over mitochondria inprovement as no benefit...it’s literally an improvement in energy (more energy with less calories), it’s a benefit unto itself.
> it’s literally an improvement in energy (more energy with less calories), it’s a benefit unto itself.
It's entirely plausible that, in the modern world, this is actually a negative.
Also, for all anyone knows, just "improving" mitochondria might also hurt due to increased production of free radicals and other strongly oxidizing species by those improved mitochondria.
No, you are extrapolating that based off your understanding. Improved mitochondria might...mean nothing.
In cancer, we see all the time the ability to get a cell we know is important into a tumor does not, necessarily, associate with clinical benefit. The same goes here. The ability to improve one small piece of biology does not mean, necessarily, that you will see a larger, emergent effect. Biology is much more complicated than that.
>No, you are extrapolating that based off your understanding. Improved mitochondria might...mean nothing.
No...there are numerous studies on the proven benefits of improved mitochondrial function/capacity. One of the benefits is cellular anti-aging.
Citation needed.
Also, you’re assuming that “cellular anti-aging” is good for your health. You could be right, but you could be wrong.
Exactly. Promising biology != clinical activity.
Not that this will stop every cosmetics line having a pomegranate version with adverts extolling "proven by science!" in a matter of months, if they don't already have one nearly ready to ship.
1) Metabolic side effects tend to be slow and subtle. Vioxx caused increased heart attacks over time. Passing a phase 1 safety trial is fine and dandy, but it’s a far cry short of long-term safety in a drug targeting metabolism, and it’s not even where most drugs fail.
2) Lab evidence for a biomarker for a metabolic process is so far short of evidence of clinical improvement that it’s a joke. I will never stop deriding studies that point to proxy markers (or in this case, proxy proxy markers) as evidence of benefit. This has been proven to be inadequate so many times, across so many different studies, that it’s just not worth talking about anymore.
This is a perfectly fine and valid phase 1 study. It says “we have identified a dose range that doesn’t immediately sicken people.” That’s what phase 1 trials do. The rest is press release hype.
Do all "we have identified a dose range that doesn’t immediately sicken people” studies make it to Nature journals ?
Nature is a high impact factor, prestigious journal. It’s million sub-journals, like Nature Metabolism ... well, vary. A lot. They mostly coast on papa’s brand recognition.
Nature Endocrinology Reviews is a relatively ranking journal in endocrinology - roughly second place, by impact factor. This didn’t get published there.
Nature Metabolism was only opened in 2017, as an online-only journal. It doesn’t even rank in the top 50 for endocrine and metabolism journals - granted, that may be in part because it doesn’t even have an impact factor yet (calculating impact factor requires two years of publication history preceding the year being calculated for. In 2020, we should see a 2019 IF.)
So, one can say they might be enormously prestigious, and we just won’t see until 2020. It’s more likely that people aren’t bothering publishing their best articles in a 0 IF journal, because in academic circles the Nature Subbrand is recognized as not inherently meaningful, so the 0 IF pub just hurts (unless you think your pub would otherwise end up in an unimpressive journal, and you want to gamble that the future IF will be higher and pay off.)
Thank you for the thorough explanation.
Only if the right people were involved in the study.
Or if it's to do with curing aging, cancer, HIV, or heart disease.
There was a pretty nice portrait in the California Sunday magazine of a billionaire (Resnick) couple who owns a lot of land and water and are producing different kinds of citrus fruits and nuts in the south of California: https://story.californiasunday.com/resnick-a-kingdom-from-du.... Lynda Resnick has been heavily promoting pomegranate juice. Of course they have a lot to gain, because they are one of the leading branded producers of pomegranate juice. With these types of studies it is always a good idea to follow the money.
she's the first person i thought of when i read the title of this story (i saw her speak once).
Just finished reading the paper, particularly interested in the mitochondrial biogenesis part. They make several comparisons with exercise adaptations, and the authors conclude:
>>> The present study reveals that UA induces a molecular signature response, in both the plasma and skeletal muscle of humans, resembling that observed as a consequence of a regular exercise regimen.
The also selected sedentary people only (from their participant inclusion criteria). Note that this is somehow normal: I have been rejected twice in 2 clinical trials for mitochondrial myopathy because I was too fit.
>> body mass index 18-32 kg/m2 and demonstrated sedentary behavior
All the authors declare a conflict of interest with Amazentis. Nestlé just signed a partnership agreement with them [1] to help them develop the product.
I guess they are actively seeking the exercise in a pill product. If they make it, it would be one of the biggest blockbusters in the history of medicine.
[1] http://pdf.amazentis.com/pdf/Nestl%C3%A9_Health_Science_&_Am...
pomegranates and raspberries as well
"A compound called urolithin A (UA) was the focus of the study, after previous experiments with it showed promise in extending the lifespans of worms and mice. The compound appears to fight aging by improving the function of mitochondria – the energy-producing part of a cell – in a way similar to the benefits of exercise. While it's not found naturally in any known food, biomolecules in fruits like pomegranates and raspberries do break down into UA in the human gut"
Here's the study https://sci-hub.tw/https://www.nature.com/articles/s42255-01...
Yellow raspberries seems to contain bigger amounts of ellagic acid than pomegranates
https://en.wikipedia.org/wiki/Urolithin_A#Dietary_sources
The Wikipedia page for the compound being discussed has a table of food and drink sources for it.
https://en.m.wikipedia.org/wiki/Urolithin_A
Not everyone’s body can create UA from these natural sources so the idea is to just make a pill for it that will work on anyone.
So there are products on the market already or no one has a product on the market yet?
Quite possibly pomegranate... It's unclear how much it has though.
From the Wikipedia link someone else posted it looks like 100g of pomegranate is approximately 250mg, so 200g pomegranates a day to get to the point where they saw any (non clinical still) effects.
Your statement reads as though the research tested lower doses and 500mg was the lowest which "saw any effects". Is this accurate?
Yes, specifically 250mg saw none (or at least no statistically significant ones).
Thanks, I hadn't time to check.
pomegranate
There are raspberries and pomegranates on the market, yes.
Phase 1 study. Years from market.
...or we could just start eating Pomegranates?
If they’ve raised capital for a series of clinical trials, you can reasonably assume the doses at which they expect to see clinical effects are much higher than you’re likely to get just from food ingestion - otherwise their competition would just be pomegranate juice pills or something, sold as a food supplement and requiring no trials of safety or efficacy. They’d never have been able to raise a cent.
In other words, no one would fund a penicillin trial if they thought people could get by eating moldy bread from GNC.
I don’t know. The dose of broccoli you need to see clinical effects from the sulforaphane it contains is extremely high, but concentrated sulforaphane capsules are sold as a food supplement without needing to go through any FDA process.
What criterion does the FDA use to distinguish a food-derived chemical that needs to be treated as a drug, from one that’s still just seen as an extract/essence of the food itself, and therefore can be treated as a supplement? It seems very opaque to me.
First we should see if this study was funded by that one giant pomegranate farm in California.
If Wikipedia is correct, we should start eating yellow raspberries instead; they offer about seven times as much of the compound this study is investigating the effects of. https://en.wikipedia.org/wiki/Urolithin_A#Dietary_sources
We can "just" start eating Pomegranates, absolutely. Personally, I find them pretty tasty, and they remind me of the Greek myth of Persephone's abduction by Hades. So I'm all for them.
But how much you'd need to eat for a clinically noteworthy benefit is the question. That's what the follow-on studies are for.
The article states that Urolithin-A is not produced by everybody. That acid in these fruits needs to be converted to UA in our gut. So no, it’s not always as simple as eating these fruits.
However at the same time, the gut is so confoundingly complicated that substances in concentrated tablet form are often less readily absorbed than less concentrated amounts occurring in food.
who doesn't?
Is there a way to tell who funded this study?
Nestlé signed a deal with them at the beginning of April, according to TheKingOfBelAir's comment above, which would lead me to believe they were at least involved with the study.
Link here, to save searching. http://pdf.amazentis.com/pdf/Nestl%C3%A9_Health_Science_&_Am...
Pomegranate fasting and/or Aronia ("chokeberry") fasting (30 to 60 days) are incredible healers of all "diseases" known to man kind. Do your own research.