
In a small trial, drugs seemed to rejuvenate the body’s ‘epigenetic clock’ - headalgorithm
https://www.nature.com/articles/d41586-019-02638-w
======
scottlocklin
1) DHEA is not a diabetes med. In fact it's a steroid (not really an anabolic
one, though it is a precursor to anabolics) and illegal in the EU. It is a
substance which is lowered in older people, so older people supplement with
it.

2) Metformin is a diabetes med, and it's used by antiaging enthusiasts
independently and along with growth hormone

3) Fasting creates larger growth hormone spikes, and improves sugar clearance.
Dunno what it does to DHEA; eat lots of eggs for that one.

So, this (lousy, but interesting) study is basically "fasting by using drugs."
Meat heads and antiaging people have done stacks like this for years. Unclear
whether or not it actually helps with longevity, but it probably improves
quality of life. So does fasting, and it don't cost as much.

~~~
Wowfunhappy
> So, this (lousy, but interesting) study is basically "fasting by using
> drugs."

That sounds to me like a big deal, given that most people find fasting
difficult (and unpleasant).

~~~
arcticbull
Fasting is easy and fun, you just have to work up to it. You can just go from
zero to not eating for a week. Building up your tolerance to it takes a bit,
like anything else, but when you do it improves mental acuity, gets you a
general sense of well-being and energy too.

~~~
stickfigure
Your idea of 'fun' and my idea of 'fun' are _wildly_ different.

~~~
jvagner
The idea of fasting and the reality of fasting are different. The idea is more
painful than a committed effort. Once you accept and embrace the fast, it’s
freeing. Like running every day.... once you know you’re going to do it, the
resistance withers.

~~~
badestrand
After doing intermittant fasting for half a year I think you shouldn't
generalize too much from your own experience. Yes, it gets easier but it stays
painful and requires a lot of willpower ime.

~~~
yhoneycomb
I’ve been doing it for about a year and a half, just skipping breakfast each
day and lunch one or two workdays a week.

At this point, most days it’s not even hard. When I’m hungry I just realize
that the hunger is temporary, and it’s honestly unrelated to the degree to
which I need food. And tbh nowadays I can tell when my body actually feels
weak and needs food, and when it’s just whining.

I think of it like getting sleepy. Just because I feel sleepy doesn’t mean I
should just take a nap right there and then.

~~~
AnIdiotOnTheNet
> I’ve been doing it for about a year and a half, just skipping breakfast each
> day and lunch one or two workdays a week.

You call that a fast? As someone who's lost and kept off about half their body
weight, I feel qualified to tell you that skipping a meal here and there is
not fasting. In fact, if you're eating every day you're not fasting. Fuck, I
mean, I only eat about 1.5 meals a day as a requirement of merely maintaining
my current weight (and even that doesn't always work).

~~~
qnsi
this is just different definition of what fasting is. What he's doing is time-
restricted eating but it is a form of fasting. You are just doing longer
fasts. No need to gatekeep

~~~
AnIdiotOnTheNet
So is it a fast just whenever you're not eating?

~~~
qnsi
technicly fast is defined as not eating.

"Intermittent fasting means different things to different people, even among
the research community. This lack of specificity has been a source of
consternation for experts in the field of fasting, with some advocating that
the phrase be retired. Often, when someone uses this phrase they may actually
mean one of the following:

Time-restricted eating Alternate-day fasting Periodic or prolonged fasting
(multi-day) - less frequently referred to as intermittent"

------
magna7
I'd wager that it's the metformin. Metformin inhibits pathways associated with
mTOR (the growth signaling protein). When you inhibit this pathway, it tells
the body to start the process of autophagy. It's the same process that occurs
during fasting, and it's the same reason that the mTOR inhibitor Rapamycin has
been shown to extend lifespan in mice and dogs. This is also why fasting has
been shown to increase lifespan. It seems like if you don't constantly tax
your body with food (growth signaling), then you can allow the body to repair
itself. If you don't give it a break through fasting, then your growth
hormones will be continually signaling to activate mTOR within your cells and
thus never start the process of autophagy (cell death, and regrowth).

~~~
jostmey
Biology is not that simple. There's not going to be a single magic compound.
Slowing the aging process is massively complex and will probably require a
cocktail of treatments

~~~
darkerside
Why do you say that? Biology is usually very simple. Eat food, live. Don't eat
food, die. Drink water, live. Don't drink water, die.

Just because you don't happen to know the answer doesn't mean the answer is
complicated.

~~~
powersnail
Just because you can say something in four words, doesn’t mean it is simple.

You eat, you live. Sure. But why? What happens to the things you eat? What can
you eat? What/how/why is the pain in your stomachs?

~~~
darkerside
Ugh, please take it in context. That was in response to something.

> There's not going to be a single magic compound. Slowing the aging process
> is massively complex and will probably require a cocktail of treatments

My counterpoint is, slowing aging could easily be the result of a very simple
compound. It's irrational to assume it must be complex just because we don't
know it.

------
flyGuyOnTheSly
It just dawned on me that getting old and dying is most likely an evolutionary
chicken and egg problem.

If you didn't get old and die, evolution of your species would grind to a
halt.

Getting old and dying is required for evolution to transpire.

I can't see any reason why it must be an absolute truth.

~~~
jhedwards
I would imagine there's a fundamental limitation in DNAs ability to be copied
over and over without information loss.

~~~
SolarNet
Sure, but we can correct for that, we have the ability to reliably store
copies of the information in DNA (a person's full genome is only a few
gigabytes) with error correction (or at least verification).

~~~
thfuran
Our cells are mostly diploid. But some organisms have many more copies of each
chromosome - strawberries have eight. With that kind of redundancy, it should
be vanishingly unlikely for a random error in DNA replication to make it into
a majority of copies and any systematic error severe enough to cause it
probably messes up the cell enough for it to be culled by other mechanisms.

------
dingdingdang
What is the "third" drug in this combo, the article says: ".. growth hormone
and two diabetes medications". So far only the DHEA and Metformin has been
discussed and I have no access to the source article.. any takes?

edit-1: the answer is that the nature.com article got it wrong and other net
sources parroted that article, [https://www.leafscience.org/study-results-
suggest-human-agin...](https://www.leafscience.org/study-results-suggest-
human-aging-can-be-reversed/) is more accurate overview: there is no third
drug involved.

edit-2: scratch edit-1, HGH was obviously the primary growth hormone given and
for some reason DHEA was counted as an anti-diabetic rather than a hormone (it
is both) together with Metformin. Now I would just like to know the dosages
involved!

~~~
greatpatton
It is in the paper:

 _of the trial, rhGH alone (0.015 mg /kg) was administered to obtain an
initial insulin response, and during the second week, rhGH was combined with
50 mg DHEA to evaluate insulin suppression by DHEA alone. During the third
week, the same doses of rhGH and DHEA were combined with 500 mg metformin.
Beginning at the fourth week, all doses were individualized based on each
volunteer's particular responses._

------
LeonB
It’s not worth reporting at all on such a small uncontrolled trial. There is
no value in this other than providing funding for a larger trial.

Discussing “why” this outcome occurred is ridiculous. Look at the numbers.

~~~
nabla9
>It’s not worth reporting at all on such a small uncontrolled trial.

You can't categorically say so.

Even sample size of one can be significant if the effect size is large enough
or the outcome is surprising (like reversal instead of slowdown).

Online forums suffer from "sample size meme" and "correlation is not
causation" meme. People just drop them into discussion as a counterargument
because that's all they know. Both of them can be proper counterarguments
after you consider the context and other factors.

------
tobr
9 people, no control group.

~~~
jjoonathan
"Enough for Nature! Next time, let's see if we can get away with 8!"

~~~
red75prime
I would say that even one person experiment with documented deep reversal of
age-related changes deserves publication and further research.

~~~
jjoonathan
The fact that it deserves further research is precisely why we shouldn't
frontload the prestige incentives. That's how you get clickbait. We don't want
clickbait, we want further research, but if we incentivize based on clickbait,
clickbait is all we're going to get. Let's not.

------
bennylam
Though it happened some times ago, the TRIM clinical trial was really a real
small scale research. According to the following info:
[http://interveneimmune.com/?ignition_product=the-triim-
trial](http://interveneimmune.com/?ignition_product=the-triim-trial)

[http://interveneimmune.com/?page_id=1200](http://interveneimmune.com/?page_id=1200)
This company is found by Greg Fahy, PhD, Chief Scientific Officer, Co-founder
-Published the first report of thymus regeneration in a normal human; Granted
patents on methods for and applications of human thymus regeneration –Fellow
of the American Aging Association (since 2005), Former Director of the
American Aging Association (16 years) –Editor-in-Chief, The Future of Aging:
Pathways to Human Life Extension –Awarded the Society for Cryobiology’s Luyet
Medal in 2016 –In 2009, showed indefinite survival of rabbit kidney
transplanted after cooling to -130° Celsius; Led 21CM team as co-winner of
Small Mammal Brain Preservation Prize, 2018 winner of Large Mammal Brain
Preservation Prize and Steve Horvath, PhD, Scientific Collaborator -Professor
of Human Genetics & Biostatistics at UCLA -Developer of the DNA methylation
clock of human aging, as well as author of seminal papers demonstrating
ability to accurately predict life expectancy, onset of Alzheimer's, cognitive
decline, and more -Paul G. Allen Distinguished Investigator -Ph.D. Mathematics
at UNC, Sc.D. Biostatistics from Harvard University

------
nikkwong
Can someone enlighten me as to why a study such as this one may be undertaken
without a control group? I mean, what's the point? If the study ends up
landing on some exciting conclusions, not having a control group creates more
questions than answers. Is there a budgetary constraint at play here or are
researchers sticking their feelers out in all kinds of directions
simultaneously trying to figure out which direction may be the most promising?

~~~
driverdan
Because the larger the group the more expensive it is to run. This is a very
early experiment to see if there's anything worth doing a larger study on.

~~~
James_Henry
Yes, this is very standard practice. You can still learn a lot with a small
sample size and no control, especially when you don't know much.

It's a big deal that they are able to see a full on reversal of Horvath's
clock whether or not it was in a handful of people or a thousand!

------
amai
„The atrophy [of the thymus] is due to the increased circulating level of sex
hormones, and chemical or physical castration of an adult results in the
thymus increasing in size and activity.“ (
[https://en.wikipedia.org/wiki/Thymus](https://en.wikipedia.org/wiki/Thymus) )

So the study might simply have show, that by decreasing sex hormones the
thymus is stimulated to grow. But the side effects of no sex hormones might be
much greater than the advantages of a younger immune system.

------
Amygaz
I have no ef-inf clue why it was a total surprise. Metformim, is already known
to affect in multiple ways the epigenetics, and the immune system.

Also the so-called epigenetic clock is based on the observation that as we age
we are more methylated. Reversing this has not been shown to be true, but it
was shown to improve certain functions, like our production of T cells.

This such a click-bait piss-poor paper I can’t believe it’s in Cell. There’s
absolutely nothing new, and no proof of anything telling me they have reverse
of stopped aging, or even a fraction of it.

~~~
busyant
> This such a click-bait piss-poor paper I can’t believe it’s in Cell.

There's a lot of politics in what gets published in prestigious journals like
Cell (also, this paper was published in Aging Cell, so not quite as
prestigious).

Amusing anecdote: In grad school, one of the profs in my department submitted
a manuscript to Cell (this was back in the 1990s). His lab had done an amazing
genetic study. There was a more famous lab at another University (run by a
future Nobel prize winner) that had performed a complementary research study
using an in vitro system. Both labs submitted their papers to Cell "back to
back." Ben Lewin rejected the genetics manuscript (one reviewer said the
genetics research belonged in a more 'archival' journal).

Lewin accepted the manuscript describing the in vitro work of the more famous
lab.

A few months later, the anonymous reviewer was visiting our department (to
give a talk) and he revealed himself as the reviewer to the professor who had
submitted the manuscript. Professor asks, "I was honestly shocked by the
review. <famous lab's manuscript> was just dotting the Is and crossing the Ts
of our research."

Reviewer responded with, "I thought [rejecting your manuscript was] what Ben
wanted me to do." Probably did not help that the reviewer had been a post-doc
in the famous prof's lab.

That's just one story that I am pretty familiar with. I have heard many others
(e.g., famous prof telling editors stuff like "<shitty> paper gets accepted or
we will submit our next groundbreaking paper elsewhere."

------
ThinkBeforeDo
Where's a link to the actual paper/ peer-reviewed publication?

~~~
qnsi
Should be here but can't get it on sci-hub

Fahy, G. M. et al. Aging Cell
[https://doi.org/10.1111/acel.13028](https://doi.org/10.1111/acel.13028)
(2019).

~~~
Tringi
I'm searching for it too, and I can't find the actual text. Somebody doesn't
want us to begin mixing that cocktail ourselves :D

~~~
Camisade
When I first saw that article, I swear it contained a link to the associated
paper in Aging Cell. Now when I go to the Nature.com article, that link is no
longer there.

How many people are currently thinking, "All three drugs/compounds are pretty
well understood, and reasonably benign when administered under a Doctor's
supervision with periodic blood testing; in the absence of specificity, let's
just start with fairly standard daily prescription doses and see what
happens..."

As someone afflicted by 'chronic aging' (at the rate of one year, per year),
I'm hugely fascinated by prospective "cures." ;-)

------
sebringj
I would point toward someone like David Sinclair at Harvard Med and his team's
more rigorous approach and more measured progress rather than some study of 9
people. Nothing to see here.

------
kgin
Everybody's a critic about study design, geez.

Studies cost a ton of money. If you can get an interesting signal in a small
study, that can be a good reason to invest more money. If you get s strong
signal for a surprising result, it's worth talking about and can get into
serious journals.

------
gwern
Fulltext:
[https://www.gwern.net/docs/longevity/2019-fahy.pdf](https://www.gwern.net/docs/longevity/2019-fahy.pdf)

------
DuskStar
Some people seem to think that there'll be a single cure for aging - a miracle
drug, health regimen, or whatever flavor of the week happens to be in the news
at the time. I think that if we get a cure for aging in our lifetimes it'll be
things like this - killing aging with a thousand tiny cuts.

Assuming that this replicates and actually increases either lifespan or
_healthy_ lifespan, of course. (I'd rather have a 50s body until I'm 75 than
continue aging past that point, even if I'm still dying at 76)

~~~
magna7
Centenarians have been shown to have increased healthspans. They still get the
same diseases as everyone else, however they get them much later in life (90s,
100s). That's all I'd want. If we can get medical science to a point where
healthily living to 100 is common, then that's a win for everyone and it'll
save us a ton of money. The problem is, like you said, that it's unlikely to
be some miracle drug; it's going to be small routines and habits throughout
your life that will require willpower and discipline, so that'll exclude a lot
of people unless we restructure society in a fundamentally different way.

------
kunkelast
I think I can make a study/research of this size on my own, among a small
group of friends :)

------
chiefalchemist
>“But the results are not rock solid because the study is very small and not
well controlled.”

That's a significant disclaimer. I wish they'd not even call such things a
trial.

------
rwj
The sample size is so small, that the results are nearly meaningless.

~~~
ALittleLight
If 9 people took a substance and died that would be a compelling enough sample
size for me not to take thing. Likewise, 9 people reporting a positive result
seems meaningful enough to encourage further study (provided effect size is
large enough)..

~~~
nikolay
With the placebo being so strong, sample size of 9 is too small for any
conclusion.

~~~
James_Henry
Do you know how strong the placebo works on Horvath's epigenetic clock? I
don't think that research has been done, but it will be soon I am sure and it
will be incredibly interesting to find out.

Even without knowing that though, I'm surprised, and so is Horvath himself,
that they found a full-on reversal of the clock. I don't think anyone was
expecting that. I'm betting we won't see that kind of reversal in a future
placebo group, though if we do I'm going to be getting myself some good
placebo!

~~~
nikolay
The placebo itself is magical enough so it could be extended to pretty much
anything and that's why quality studies are done certain way. If can
understand the placebo, then and only then we can then explain what it could
do and it can't do.

~~~
James_Henry
This is false. We can explain a lot without a placebo comparison. Also, the
placebo isn't magic, we just haven't studied exactly what it is. It clearly
does have limitations: look at all the studies where the placebo only does so
much!

~~~
nikolay
We have studied it and there are some hypotheses, but that's it.

