
Pomegranate compound with anti-aging effects passes human trial - lelf
https://medicalxpress.com/news/2019-06-pomegranate-compound-anti-aging-effects-human.html
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dannykwells
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.

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strainer
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. "

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fabian2k
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.

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strainer
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?

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fabian2k
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.

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strainer
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 ?

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gbrown
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.

~~~
strainer
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 ?

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gbrown
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.

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strainer
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.

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arkades
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.

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utopcell
Do all "we have identified a dose range that doesn’t immediately sicken
people” studies make it to Nature journals ?

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arkades
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.)

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utopcell
Thank you for the thorough explanation.

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orbifold
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...](https://story.californiasunday.com/resnick-a-kingdom-from-dust). 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.

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clairity
she's the first person i thought of when i read the title of this story (i saw
her speak once).

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fasteo
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...](http://pdf.amazentis.com/pdf/Nestl%C3%A9_Health_Science_&_Amazentis_Press_Release_April_2_2019.pdf)

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TheKIngofBelAir
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...](https://sci-
hub.tw/https://www.nature.com/articles/s42255-019-0073-4)

Yellow raspberries seems to contain bigger amounts of ellagic acid than
pomegranates

[https://en.wikipedia.org/wiki/Urolithin_A#Dietary_sources](https://en.wikipedia.org/wiki/Urolithin_A#Dietary_sources)

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Neil44
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](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.

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Circuits
So there are products on the market already or no one has a product on the
market yet?

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gpm
Quite possibly pomegranate... It's unclear how much it has though.

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gpm
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.

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strainer
Your statement reads as though the research tested lower doses and 500mg was
the lowest which "saw any effects". Is this accurate?

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gpm
Yes, specifically 250mg saw none (or at least no statistically significant
ones).

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strainer
Thanks, I hadn't time to check.

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dractori
Is there a way to tell who funded this study?

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ry_ry
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...](http://pdf.amazentis.com/pdf/Nestl%C3%A9_Health_Science_&_Amazentis_Press_Release_April_2_2019.pdf)

