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COMMENT PAGE FOR:
URI Epigenetic age oscillates during the day
V__ wrote 14 hours 31 min ago:
I mean epigenetic clocks are extremely unreliable and have enormous
error bars. It is not surprising that they are easily influenced by
additional variables.
kkoncevicius wrote 14 hours 19 min ago:
Epigenetic clocks are one of the (if not the) most accurate ways to
estimate someone's real chronological age using molecular level data.
So not sure what you mean by "extremely unreliable".
V__ wrote 13 hours 9 min ago:
They probably are the most accurate way, but that still doesn't
make them good. If there haven't been any recent breakthroughs I
missed, then we are talking about getting it right +/- 4 years
under ideal conditions. Repeating these test on the same subjects
can result in fluctuations of 8 to 12 years [1].
Additionally, there are a lot of biotech/junk studies claiming some
new intervention reduces/reverses biologic age using these
epigenetic clocks as evidence. Making me very wary of the whole
thing, though unfairly to those actually doing sound studies I
admit.
URI [1]: https://clinicalepigeneticsjournal.biomedcentral.com/artic...
kkoncevicius wrote 12 hours 43 min ago:
I think we mostly agree. If you are interested, there are
developments that reduce the fluctuations of clock predictions -
like principal component based clocks [1], where the authors
claim average difference between replicate measurements of 1.5
years.
And the study you are citing (8 to 12 year errors) - seems to
report maximum errors, not averages. These might be caused by
poor quality samples, so it's unfair to report it like that. Also
the publication under discussion (epigenetic age oscillates)
would answer where the fluctuations observed by the article you
linked to come from - part of them are of course technical due to
measurement error, but part of them are influenced by differences
in sample collection times.
I also share your skepticism about intervention research and
using "biological clocks" to measure how healthy you are.
Curiously chronological clocks seem to not be easily affected by
interventions. And I would guess this is why most people doing
epigenetic aging for sport use biological clocks (like
DunedinPACE). But then the question - if you are younger
according to "biological age", but we still can measure your true
chronological age accurately - are you actually younger in a
meaningful sense.
[1]
URI [1]: https://www.nature.com/articles/s43587-022-00248-2
V__ wrote 11 hours 20 min ago:
Thanks for the link, that would be a great improvment. I really
hope they get their someday.
epistasis wrote 14 hours 8 min ago:
I disagree, because "real age" is defined in terms of the
epigenetic clock. We don't have enough time observing them with
humans to connect them to real age, at least as far as I have ever
seen. If there's some major paper I have missed, and my other
sources have missed, I'd love to see it.
pc86 wrote 13 hours 34 min ago:
Real age is chronological age, full stop.
If you were born 50 years ago today, you're 50 years old. Age is
a concrete, mathematical thing. That your cells appear to be
younger or older to your actual (chronological) age is
irrelevant. You don't get to say your "real age" is 45 because
your cells are slightly better than they "should be."
voisin wrote 13 hours 24 min ago:
I think you two are talking past each other.
âI am 50 years oldâ is a statement of fact like you refer.
âReal ageâ is essentially a term of art used to describe
your relative health - a single number to indicate the
cumulative impact of your lifestyle, genes, etc.
No one says âI have a real age of 50â to the question
âhow old are you?â
epistasis wrote 12 hours 22 min ago:
Thanks. Moreover nobody would use an epigenetic clock to
refer to chronological age, because it's inferior in every
way for that purpose.
The purported use of an epigenetic clock in humans is that it
predicts either aging effects of remaining life span in some
sense; neither of these have been proven to be biologically
true because in the first we don't necessarily have the
definition of aging, and certainly don't have it down to a
single axis, at best it is understood along many different
dimensions, many of which are not captured by epigenetic
measures.
And second sense, predicting remaining life span, is
completely unproven. Even more speculative is whether
measures which change a person's epigenetic age will result
in changes in remaining lifespan.
There's a chance that epigenetic age becomes useful for
something, but it's just a chance. It's not established
science.
claytongulick wrote 15 hours 10 min ago:
One of the "dirty secrets" in healthcare is similar issues with BP.
Things like posture, white-coat syndrome, having to pee, cuff
placement, cuff size, arm position, muscularity, arm diameter, time
sitting, and many other variables have a massive influence on blood
pressure.
BP is kind of like weight - it should be taken at regular intervals
during the day, at the same times, and averaged out over time to look
at trends. "Snapshot" BP readings are most useful for things like
hypertensive crisis, not ongoing BP management.
Unfortunately, we see a lot of people put on BP meds where other
interventions may be more appropriate based on bad BP measurements.
I think there are a lot of things in healthcare like this, where our
models are too simplistic and result in flawed understanding and
consequently ineffective treatments.
Zenzero wrote 9 hours 11 min ago:
This should be basic knowledge for any provider. I don't really agree
that it is a model that is too simplistic. It is a tool that has
considerations for accurate use based on physics and physiology.
greenish_shores wrote 10 hours 51 min ago:
"Cuffless" blood pressure measurements, which could be easily used to
measure BP continuously, could easily solve this problem.[0][1]
[0] [1]
URI [1]: https://www.frontiersin.org/articles/10.3389/fcvm.2019.00040...
URI [2]: https://www.cnet.com/health/medical/i-have-high-hopes-for-th...
importantbrian wrote 13 hours 4 min ago:
I have really bad white-coat hypertension. Like 150-90 in the drs.
office. So every time I go in they send me home with a chart and I
have to dutifully record my blood pressure a couple of times a day
for 2 weeks and send it back to them, and when measured at home it's
totally fine.
Since I have the cuff I check it every so often to make sure it's
still fine and it is, but the moment I get in a drs. office boom it
spikes. This is even true when I'm there for someone else like my son
or my wife. I can feel that my blood pressure is high.
I have absolutely no explanation for why except that I had a major
surgery when I was 5 and there must be some suppressed trauma from
that that comes out physically when I'm in a doctor's office.
kyleee wrote 5 hours 9 min ago:
To my mind itâs a very natural reaction. We rarely are in
situations, like a doctorâs office, where out of the blue you may
be told you are dying, etc.
voisin wrote 13 hours 28 min ago:
Question, since you seem to know a lot about this: is high blood
pressure meant to be a description of a persistent condition (I.e.
took a reading at 5, 10, 20 minute intervals at rest and stayed
elevated) or is it meant to be a description of something else (after
standing up, or after walking, etc etc)?
claytongulick wrote 9 hours 12 min ago:
Generally, it's referring to a chronic condition, meaning that your
blood pressure is elevated as a trend over time.
Everyone goes through huge peaks and troughs with BP - at the gym,
sleeping, etc... will have massive changes in BP.
There are certain conditions where "instant" BP can become a
problem, both high and low. Orthostatic hypotension, for example,
is a condition where you can get dizzy or black out from changing
position too quickly.
There's also a condition known as labile hypertension that can
cause random high spikes in BP.
nradov wrote 14 hours 0 min ago:
Yes, blood pressure measurement is a real mess. Besides the factors
you listed, I have found that temperature has a surprisingly large
impact. If your hands are cold, then that causes peripheral
vasoconstriction and raises BP.
devmor wrote 14 hours 2 min ago:
I realized this a couple years ago when I moved and started getting
my blood tests done at a new lab that was nearby.
My entire life Iâve had perfect blood pressure, but suddenly this
lab thinks I have hypertension. After 3-4 visits and checking my own
BP during the day, I realized that my blood pressure is just higher
in the morning - I never set appointments in the morning previously
because I lived too far from a lab to make morning appointments
convenient.
greenish_shores wrote 10 hours 49 min ago:
What makes them think you have hypertension with purely blood
laboratory tests? Electrolyte levels ratios? They aren't changed in
all types of hypertension (won't be changed in most, probably), but
that's just my wild guess.
devmor wrote 5 hours 15 min ago:
Just the blood pressure. It wasnât a diagnosis so much as a
âthis seems concerning, you should get this checked outâ.
hzay wrote 14 hours 45 min ago:
Is it really secret though? It's the first thing you learn when you
google "how to take bp". Like I'm not a medical person but when I was
pregnant, I was asked to check BP and I asked the doctor "should I
like average 3 readings or something?" and she said "just take one,
don't stress it".
This is well known re thyroid medication as well. Also re weight,
progesterone, a bunch of things.
claytongulick wrote 8 hours 29 min ago:
I suppose "well known" is relative, it may surprise you how little
agency some people have over their health.
>It's the first thing you learn when you google "how to take bp".
The populations that I frequently deal with are not in a
life/financial/cognitive place where this is a thing they would
think of doing, or be capable of doing.
Take a look at this [1] about over treatment of mild hypertension.
It's not a new problem, and potentially affects millions [2].
There can be enormous pressure on physicians to treat certain
conditions from a population-health standpoint with medications if
they fit certain clinical criteria.
The recent (2017) change in standards for hypertension [3] have
been controversial. It put millions of people into the category of
hypertension that weren't previously. Coupled with certain clinical
criteria that recommend medication prescription even for mild
hypertension, it's concerning that there may be an overprescription
issue.
Many busy clinics don't have time to have a patient sit for the
recommended 5 minutes of rest before taking BP (though I've seen
this improving). Many medical assistants are poorly trained in BP
measurement, and are overworked - I've seen many cases where a
harried MA will do things like sit a patient down, put a cuff on
them over-the-sleeve, as the patient slouches in a chair, with the
arm in an incorrect position, a poorly fitted cuff, and just write
down the number the machine spits out.
Of course, a good PCP will double check this and look for a trend.
Not all PCP's are good and go to this effort.
(I am not a physician, I'm a tech nerd with a clinical background,
but I've worked in healthcare for decades)
I've also experienced it personally. I went to the doc once about
ten years ago for a wellness check. Based on the in-office BP
reading and labs, the NP prescribed me five different medications,
including BP meds, statins and others.
I decided to focus on lifestyle changes instead and that's worked
well for me, but that's not an option for everyone. [1] [2]
URI [1]: https://www.youtube.com/watch?v=cZCuJheVJA0
URI [2]: https://www.umassmed.edu/news/news-archives/2014/11/umms-f...
URI [3]: https://www.health.harvard.edu/heart-health/reading-the-ne...
pc86 wrote 13 hours 37 min ago:
It's not a secret. Most of my immediate family is or was in
healthcare and nobody is getting put on BP meds because of a single
errant reading. They're getting put on meds because of persistent,
uncontrolled elevated BPs and with non-pharmaceutical interventions
not addressing it. Everyone, especially physicians, know there's a
list of 20-30 things that can give you temporarily elevated BP that
won't respond to BP meds.
claytongulick wrote 9 hours 9 min ago:
> nobody is getting put on BP meds because of a single errant
reading
I'm glad you've had good experiences and relationships with what
sound like quality healthcare professionals.
Others have had different experiences.
importantbrian wrote 13 hours 1 min ago:
Yeah, that's been my experience. Everytime I see my primary my BP
is elevated in the office and they send me home with a log and I
have to take my BP multiple times a day for 2 weeks and at home
it's fine, so I've never been put on meds for it even though it's
very high in the office.
renewiltord wrote 15 hours 34 min ago:
Haha it's really a marketing tool for bespoke medicine. Not really that
useful in that field but people like it.
JumpCrisscross wrote 15 hours 33 min ago:
> Not really that useful in that field
Source? Because I know people working on it as a target measure at a
national lab in India as well as at Pfizer (in America) and Novartis
(in Switzerland).
dahinds wrote 10 hours 35 min ago:
That doesn't really contradict the post you're responding to, does
it? (they say it is not that useful for bespoke medicine, you say
that people are using it for research purposes, both can be true?)
JumpCrisscross wrote 9 hours 0 min ago:
> they say it is not that useful for bespoke medicine, you say
that people are using it for research purposes, both can be true?
They said it is âreally a marketing for bespoke medicine.â
That implies only (or mostly) useful to bespoke medicine as a
marketing tool. Demonstrating any significant other utility
falsifies that statement.
TeMPOraL wrote 2 hours 34 min ago:
Still both can be true. I'd say it's even a common thing in
medicine. Researchers may be researching something real with
well-defined range of effect/application, meanwhile many a
scoundrel will pick up the same term to market their bullshit
treatments or lifestyle advice, and when interrogated, they'll
actually point at some of the published studies of the real
thing, hoping people won't understand the difference.
nradov wrote 13 hours 50 min ago:
Here's one source. [1] Epigenetic alterations such as DNA
methylation are only one hallmark of aging, and not the most useful
one in most cases. Interventions to reduce those epigenetic
alternations have generally not proven effective in extending
lifespans or improving health outcomes.
URI [1]: https://doi.org/10.1016/j.cell.2022.11.001
JumpCrisscross wrote 13 hours 24 min ago:
> Epigenetic alterations such as DNA methylation are only one
hallmark of aging, and not the most useful one in most cases.
Interventions to reduce those epigenetic alternations have
generally not proven effective in extending lifespans or
improving health outcomes
Thank you. And I totally agree. It reminds me of telomere craze
in the early noughties.
It not being a panacea, however, is different from it being
useless. Marking it as pure marketing makes it sound like it's
cosmetics. It's not. The first research on chronological age
prediction dates from 2011; we're still in the basic research
phase. (Which the article mentioned is. It's not marketing any
treatment.) To the degree it's being turned into a scam it's in
supplements, not bespoke medicine.
renewiltord wrote 15 hours 9 min ago:
If they think so, and I don't, then we just disagree on this and
history will see who is right.
JumpCrisscross wrote 14 hours 36 min ago:
> then we just disagree on this and history will see who is right
Thatâs not how science works.
Epigenetic age prediction is an area of active research for
general diagnostic and treatment vectors [1]. There are
peer-reviewed studies on the stuff. You claimed âreally a
marketing tool for bespoke medicineâ. That appears to be false.
URI [1]: https://pubmed.ncbi.nlm.nih.gov/34415665/
renewiltord wrote 14 hours 14 min ago:
All right. Use it as a health target for yourself. It's no skin
off my back.
biomcgary wrote 15 hours 40 min ago:
I work at a biotech that does intersecting research (predicting disease
risk). We obsess about temporal variation at various time scales and
the effects are quite real. We use multiple data planes (multi-omics)
to evaluate temporal effects across diverse biology. Our goal is to
ensure that our long-term predictions are minimally impacted by
short-term fluctuations.
canadiantim wrote 13 hours 37 min ago:
What's your company? I'd be interested in learning more about
(multi-omics, etc.)
biomcgary wrote 11 hours 45 min ago:
We're still in lite stealth mode, so posting the name on HN isn't
the best idea. :-)
greenish_shores wrote 10 hours 56 min ago:
I think I can relate to this, even despite mine is just purely
software startup (but it's low-level software/firmware for
off-the-shelf devices, which can only run commercial closed ones
at the moment). Too much attention before our product is mature
enough would be easily able to kill that. We won't be able to
handle whatever could arise from that with our several-person
team.
But that's me. Mind sharing your reasons? Of course could be
obscured as much as you need.
biomcgary wrote 10 hours 16 min ago:
In this context, stealth helps with trust and communication.
Although that might seem paradoxical, we are initially working
with a small number of members reached by word of mouth.
We walk members through our data usage policies in person and
ask questions to ensure we understand both their health and
privacy concerns. Without long-term trustworthiness on our
part, we won't get the longitudinal data that we need to ensure
that we continue building the best in class predictive models.
There are other reasons, but that's the biggest one.
huytersd wrote 15 hours 51 min ago:
Even things like posture seem to affect my parameters. My temp will be
98.4 while seated but if I stand up and check it, it drops down to
97.9.
lowestprimate wrote 9 hours 37 min ago:
How are you taking your temperature? Infrared sensor on the forehead?
Infrared only measures surface temperatures and can give false
readings of temperature based on how the body "radiator" system is
working.
TeMPOraL wrote 2 hours 45 min ago:
The fluctuations aren't that bad. Now, I don't trust the infrared
sensors myself, because I can't see the "local gradient" of what
they're measuring, nor how it changes momentarily (why does it
always take a second or two to measure?), and there certainly are
areas on the face that vary by whole degree centigrade in
temperature.
How do I know? Because I got so annoyed at the IR thermometers that
I recently got myself one of those USB-C thermal cameras (UTi721M,
specifically). It's like a 256x192 array of IR thermometers,
measuring continuously, so you actually see what's going on. Lots
of interesting things you can learn that way, for example that
cheeks, chin and nose can easily be 1-2â cooler than the
forehead, or that the neck/throat shows about the same temperature
that the forehead, but seems more stable. And, it's much faster to
take temp of everyone at home in one go. And then you also can
learn a lot about your own environment, too. I highly recommend
this to anyone.
That said, I found in-ear IR most reliable, and use it as a
baseline for health checkups. You do however need to watch out for
insertion - if you put the head in the ear too fast and measure
immediately, you can get a result that's a degree or two centigrade
above correct, which I imagine is because of momentary friction
heating.
huytersd wrote 4 hours 39 min ago:
Under the tongue.
Aurornis wrote 15 hours 29 min ago:
> My temp will be 98.4 while seated but if I stand up and check it,
it drops down to 97.9
Body temperature measurements from outside the body are impacted by
changes in blood flow, which will happen when you stand up.
Your core body temperature isn't fluctuating, the temperature at the
measurement point is changing slightly because you've changed your
blood flow.
We're constantly losing heat from our bodies to the environment. You
could probably get similar measurements if you heavily insulated the
entire area around the thermometer and let measurements stabilized.
In other words: Don't read too much into this experiment.
jajko wrote 15 hours 38 min ago:
Maybe its just not a good enough measure for any form of age? Some
folks get obsessed with numbers without seeing bigger picture and
focusing on actually important things in life (just general
observation, please don't take any of this personally)
Terr_ wrote 16 hours 8 min ago:
That certainly breathes new life into old metaphors like "twilight
years".
It sounds like the most immediate takeaway is that anyone analyzing
this stuff needs to control for when measure individuals.
gwern wrote 15 hours 12 min ago:
The potential for systematic bias here is also quite concerning.
Imagine your experimental group tends to come in the morning (maybe
because they're on-site) but your control group is scheduled to come
in the rest of the day...
biomcgary wrote 11 hours 41 min ago:
This problem is VERY real and happens in surprising ways. My
biotech has a dataset that was collected over several years and we
found this pattern of older people having more Vitamin D in their
blood than younger people, which is the opposite of the published
literature. It turns out that the sample collection was initially
year round but switched to summer only and everyone in the cohort
was older, by definition, in the later collection.
kkoncevicius wrote 15 hours 34 min ago:
And not just this stuff but a lot of health metrics probably have
this occult dependence on the time of day. For example MRIs [1]:
URI [1]: https://www.nature.com/articles/s41467-023-42588-6
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