[HN Gopher] Turning back time with epigenetic clocks
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Turning back time with epigenetic clocks
Author : Brajeshwar
Score : 134 points
Date : 2022-01-29 14:32 UTC (8 hours ago)
(HTM) web link (www.nature.com)
(TXT) w3m dump (www.nature.com)
| Metacelsus wrote:
| Stem cell biologist here. Note that different cell types have
| different epigenetics. Most of these studies are looking at white
| blood cells. Effects on these cells may be different from
| elsewhere (brain, muscle, etc.)
| kkoncevicius wrote:
| The epigenetic clock by one of the people quoted in the article
| - S. Horvath, is notable for working across different tissues,
| with a few exceptions like germ cells.
| axg11 wrote:
| I used to work in genomics. I think the quest to have a universal
| epigenetic measure of ageing will end up in a dead end.
|
| Ageing is relative to a starting point and the variability
| between people in terms of phenotype is huge.
|
| By way of analogy, would it be possible to come up with a
| universal measure of ageing for cars? Cars are a complex system
| made of thousands of components, each of which can age
| differently over time. Each car make and model will age in a
| different way. Some of the components even slightly improve in
| performance over time as they "break in".
|
| The best way to measure epigenetic ageing is relative to a
| starting point. There are few studies that follow the same people
| over time (longitudinal) because it's difficult and expensive to
| pull off. We'll eventually get there though.
| jonmc12 wrote:
| Any thoughts on the organ-based biological age score that Bryan
| Johnson presents? More equivalent to monitoring all the
| components of the car.
|
| I think these biological age scores are a really healthy way to
| debate and create broader awareness about a) how our bodies
| work and b) how we understand aging.
|
| https://blueprint.bryanjohnson.co/
| axg11 wrote:
| Organ-specific is the most promising in my opinion. It's also
| more likely to be actionable. Different organs will "peak" at
| different ages.
| amelius wrote:
| Sounds like a task for data science.
| kkoncevicius wrote:
| Counterpoints:
|
| - The accuracy of current epigenetic clocks suggests it might
| not be a dead-end with average error of 2-3 years, across
| multiple tissues (and even Chimpanzees).
|
| - The variability of an aging phenotype is not that high. We
| all loose bone density, loose teeth, hair turns white, memory
| degrades, wrinkles appear, etc. In other words - aging follows
| a pattern.
|
| - The car analogy assumes that aging is caused by damage over
| time. But there is an alternative explanation: aging provides
| and evolutionary advantage for a species and hence is
| predetermined.
| ikrenji wrote:
| aging mostly happens after an organism reproduces, so there
| is no evolutionary pressure to maintain fitness. there is no
| pressure to develop maintenance mechanisms...
| SuoDuanDao wrote:
| There would be plenty of pressure to keep reproducing
| indefinitely, just that then there might be too much
| competition between ancestors and descendants for the same
| resources.
| echelon wrote:
| > The variability of an aging phenotype is not that high. We
| all loose bone density, loose teeth, hair turns white, memory
| degrades, wrinkles appear, etc.
|
| People age at different rates depending on a wide variety of
| factors.
|
| Progeria, over consumption of alcohol, too much stress, too
| much radiation from sunlight, etc.
|
| The things you point to are measures of a biological age, not
| a wall clock age. While they do correlate, they're not 1:1.
| Some people age faster.
|
| > But there is an alternative explanation: aging provides and
| evolutionary advantage for a species and hence is
| predetermined.
|
| I don't buy this. We don't have a pre-programmed death. It's
| rather that we haven't had any genetic pressure to live
| beyond our current lifespan as it doesn't increase our
| offspring's chances of success.
|
| There's little pressure from competing with children for
| resources. Look at how many people there are in the world
| today - the world supports billions of humans. There are far
| greater pressures being exerted in other ways.
| ridgeguy wrote:
| From an evolutionary perspective, I think we can at least
| say that absence of death doesn't confer a selective
| advantage, else it would have appeared and radiated in
| several billion years of biological evolution.
|
| It might even be that death provides selective
| advantage(s), which would account for its being a nearly
| universal feature of known life. A "pre-programmed death"
| mechanism would be consistent with this.
| kkoncevicius wrote:
| I think we do have a pre-programmed death. Almost all
| creatures die when they get older so in order to look for
| evolutionary pressures we have to look across a long time
| period and far back. For one - if organisms wouldn't die
| evolution would not happen. Or at least the non-dying ones
| would stay behind and be left living in environments they
| are no longer suited for. For ancient creatures food and
| resources might have been scarce and so it was advantageous
| for non-evolving old members to die-off sooner.
|
| Also, whatever we think about these epigenetic clocks,
| there are few things to come to terms with: 1) they work
| across pretty much all individuals (and people with
| progeria do exhibit older epigenetic age [1]) 2) they work
| across pretty much all tissues. I don't see how this could
| be explained through "damage over time". The way I see it
| damage should be random and not lead to something so
| predictable that we could use it to guess a persons
| chronological age with 2.5 year accuracy.
|
| [1]: https://pubmed.ncbi.nlm.nih.gov/30048243/
| ddingus wrote:
| I do too.
|
| Look at the tortoise. We know some that have lived two
| centuries. They have their niche, do what they do, and
| live a very long time.
|
| During their evolutionary journey to their current local
| maxima, I wonder whether they lived shorter lives?
| kgin wrote:
| What are your views on the trial that reversed epigenetic age
| in optic nerves, allowing them to regenerate?
| https://www.nature.com/articles/s41586-020-2975-4
| axg11 wrote:
| I think epigenetic age _does_ make sense for very specific
| systems. For example, just focused on the optic nerve. Good
| luck getting an optic nerve sample in a live human though!
| cblconfederate wrote:
| The reason for pursuing clocks is to use them to assess the
| efficacy of longevity interventions. Currently, with an error
| bar ~3 years they are not bad at all, and can be used to assess
| aging relative to a starting point, as you suggest.
| ericmcer wrote:
| A thirteen year old having low bone density, heart problems and
| degenerating joints would be strange, but for someone > 70 it's
| almost expected. The car example is dumb because cars don't
| have a built in mechanism for regeneration that is failing. Our
| bodies mechanisms for self-regeneration weaken and then we see
| all the symptoms of aging.
| elromulous wrote:
| You made good points, but maybe you could have done so
| without calling the parent's analogy "dumb"?
| monkeycantype wrote:
| I believe we have a genetically determined lifespan. There is a
| reason lifespan has been optimised to this duration. As we age we
| accumulate viruses, mutations. The tissues that were positioned
| and differentiated during development accumulate damage. From the
| perspective of the species the only feasible way to get back to a
| healthy state isn't to eradicate the viruses and repair the
| tissues, its to jettison the withered husk and repeat the
| development process with a fresh new body. I we 'reset the clock'
| we're not removing the damage, the mutations, we're just
| overclocking the body. If overclocking can get me another 20%,
| I'll take it. Hell 3%, we'll take it. But what I want I really
| want is the full factory refurb, with a little extra ram please.
| pishpash wrote:
| Many species can regenerate, especially plants.
| f38zf5vdt wrote:
| > In 2019, a small study raised the tantalizing prospect that
| ageing could be reversed. Scientists in California gave 9 men
| aged 51 to 65 a growth hormone and two diabetes medications for a
| year. The drugs seemed to rejuvenate the men's thymus glands and
| immune function. They also shaved 2.5 years off the men's
| biological age, as measured by one of the most talked-about
| technologies in ageing research: epigenetic clocks.
|
| It's also worth nothing that another study shaved "3.2 years" off
| the "epigenetic clock" simply with lifestyle changes over 2
| months. [1]
|
| [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064200/
| mrfusion wrote:
| Doesn't fasting and possibly IF radically raise hgh?
| habitmelon wrote:
| All these measures of biological age might be useful, but the
| real test is just waiting and seeing how long people end up
| living.
| robbedpeter wrote:
| Specifically, watch Bill Gates, Bezos, Branson, Thiel, and
| Musk. They're first in line with all the influence and
| resources needed, so if current life extension efforts pan out,
| we should see it happen.
|
| If it happens soon, the Putin situation could get weird.
| tagoregrtst wrote:
| How so? Are you implying that the only way out of the current
| West-East impasse is through the death of its leaders?
|
| This is not how it panned out in Cuba, China, North Korea,
| Venezuela, etc.
| robbedpeter wrote:
| No - Putin is currently dictator for life. A more or less
| immortal dictator would be an entirely novel, and truly
| weird, situation on the world stage.
| tagoregrtst wrote:
| Is Putin popular with Russians? It seems like an
| important consideration.
| mythrwy wrote:
| There would be a lot to stay current on to stay in power.
|
| How much information can a brain hold assuming it lives
| forever? Does it run out of space at one point?
| robbedpeter wrote:
| It wouldn't be a limitation for centuries, or possibly
| millenia. The brain very efficiently packs information,
| and integrates with external storage. We'll be able to
| digitally augment brains directly long before temporal
| memory capacity becomes a problem.
| tasty_freeze wrote:
| Much of the information we collect has a half life, or
| situations change and that information, while still
| valid, is not applicable to the issues we are facing
| currently. The vast majority of things we learn end up
| getting discarded at some point.
|
| Think of the most recent book you read. How many of the
| details actually stuck with you at the moment you closed
| it. Now think of a book you read 10 years ago. How much
| of that do you remember?
|
| I took years of mathematics and was able to do well on
| tests, but 40 years later I only recall the "shape" of
| PDE solutions and couldn't actually solve anything
| anymore. Instead my brain is stuffed full of arcane
| knowledge I need to do my job, and if I don't use it
| within a year, I probably need to learn it all over
| again.
| robbedpeter wrote:
| This is a valid question for different reasons, too. I
| have a problem with the speech and behavior of immortal
| characters in books - why would a 300 year old powerful
| vampire behave like an immature emo teenager?
|
| There's a reason we associate wisdom with age. The more
| times anyone of reasonable intelligence makes mistakes,
| the more opportunities they have to learn, and their
| behavior changes according to the degree to which they
| take on the lessons of life.
|
| One big danger of immortal dictators is the simple fact
| that they'll stop learning. Through wealth and power they
| shield themselves from the consequences of mistakes,
| getting themselves and their people stuck in a local
| minima.
|
| Imagine immortal Mitch McConnell, ever increasingly
| wealthy through passive income, maintaining power and
| privilege for his constituents and thus his hold on a
| senate seat.
|
| If life extension pans out, liberal societies will have
| to impose term limits in a serious and well considered
| way. Humans aren't ready for the existing pace of
| technological development, and we're going to encounter
| an exponentially increasing number of problems, like the
| politics of immortality. The best thing we could do would
| be to maximize freedom of expression and minimize the
| duration of social institutions to achieve sufficient
| maneuverability to adapt to modern life.
| TeeMassive wrote:
| I think a better question would be not how _long_ but how
| _well_ people live their end of life. Most people would trade
| living up to 90 fully aware and mostly active instead of up to
| 100 in misery and dementia.
| black_13 wrote:
| JohnJamesRambo wrote:
| I really wish they had a group that had the DHEA and metformin
| without growth hormone. I can get those easily and cheaply on the
| internet. I'd like to see how much of the effect they saw was
| just those two.
| jml78 wrote:
| One of the issues with metformin is how many times it has
| gotten recall for cancer causing contamination. Buying on the
| internet, you are never going to get notified
| DeWilde wrote:
| Metformin is not ideal for some if not most men. It wipes out
| testosterone levels.
|
| After a few weeks of taking it my T levels were below average
| and free-T levels were that of 100 year old men. This was a
| huge drop from the above average levels, for men in 20s, that I
| usually have.
| JohnJamesRambo wrote:
| I've had the same experience. Feel like shit every time I get
| hopped up on the latest paper and try it again. I don't want
| to live forever with T levels of an old man. I thought maybe
| I was the only one feeling this way, although I had seen the
| papers about it lowering testosterone.
| DeWilde wrote:
| [0] might be relevant to you, seen other papers that I
| found when I discovered this issue. From what I gathered
| the reason for this is that metformin reduces blood
| cholesterol levels which are important for testosterone
| production.
|
| [0]: https://pubmed.ncbi.nlm.nih.gov/11707532/
| cantrevealname wrote:
| > _Scientists in California gave 9 men aged 51 to 65 a growth
| hormone and two diabetes medications for a year. The drugs seemed
| to rejuvenate the men's thymus glands and immune function. They
| also shaved 2.5 years off the men's biological age_
|
| The study itself says:
|
| _During the first week 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._[1]
|
| So the meds in question are:
|
| - recombinant human growth hormone (rhGH) [2]
|
| - dehydroepiandrosterone (DHEA) [3]
|
| - metformin [4]
|
| If you wanted to have this treatment for yourself, how could you
| proceed? I assume that it would be just about impossible to
| convince your family doctor to prescribe this drug regimen for
| you? If you were to do-it-yourself, what would be the best way?
| It seems that metformin is widely available but I don't know
| about the availability and cost of rhGH and DHEA.
|
| [1] https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028
|
| [2]
| https://en.wikipedia.org/wiki/Growth_hormone_therapy#Recombi...
|
| [3] https://en.wikipedia.org/wiki/Dehydroepiandrosterone
|
| [4] https://en.wikipedia.org/wiki/Metformin
| bleachedsleet wrote:
| AgelessRX will prescribe metformin [1], DHEA is legally OTC in
| the US, and any kind of HGH is probably readily available at
| your local gym (also a number of hormone doctors online will
| prescribe it easily)
|
| [1] https://www.agelessrx.com/metformin
| aaaaaaaaaaab wrote:
| >I don't know about the availability and cost of rhGH and DHEA.
|
| DHEA: available over-the-counter in the US
|
| rhGH: go to your local gym and ask the biggest guy
| hourislate wrote:
| For a more thorough dive into this topic, Dr Brad Stanfield on
| Youtube. I haven't found anyone better in breaking down the
| latest scientific studies on Longevity.
|
| https://www.youtube.com/c/DrBradStanfield
|
| There is evidence that Metformin doesn't extend the life of
| healthy people but does extend the life of Type II diabetics.
|
| https://www.youtube.com/watch?v=iByaqfmWfHQ
|
| I would also caution HGH for men since it can enlarge the
| prostate gland.
|
| David Sinclair had mentioned in a podcast that we use to be
| cold and hungry and now we're warm and fat all the time. Need
| to be cold and hungry more often.
|
| https://www.youtube.com/channel/UCwD5YYkbYmN2iFHON9FyDXg
|
| Peter Attia has said that the number one thing he believes will
| extend healthspan/lifespan (if you did nothing else) is
| exercise. He wish he could prescribe as a medication.
|
| https://www.youtube.com/c/PeterAttiaMD
| XzetaU8 wrote:
| Michael Lustgarten Ph.D is another good source for biohacking
| and longevity matters. he takes a diifferent approach though
| since he's trying to reverse his epigenetic age specifically
| through diet.
|
| [1] https://www.youtube.com/channel/UCT1UMLpZ_CrQ_8I431K0b-g
|
| [2] https://twitter.com/mike_lustgarten
| telxosser wrote:
| The most interesting thing I have heard from Sinclair is the
| studies on mice that eating once a day was what extended
| lifespan the most. Everything else was not that important
| diet wise.
|
| It sounds like to me the method is eat once a day and get in
| the best physical condition possible from working out. Beyond
| that, I am just not going to stress about it. Surely, not
| going to take any reverse risk with HGH or experimental
| drugs.
| wtetzner wrote:
| So, exercise, fasting, and being cold?
| AuryGlenz wrote:
| There are peptides you can buy online that make you overproduce
| HGH, though it's hard to say if the effects would be the same.
| You can also easily buy metformin from Indian pharmacies.
| staticassertion wrote:
| First and foremost I would suggest doing research. A recent
| study showed that in healthy individuals Metformin had no
| impact on all-cause mortality and there are potential side
| effects.
|
| Of course, doing research is hard. Because it isn't really
| research in the sense of running a legitimate study, it's
| research in the sense of studying the work of others as an
| outsider.
|
| Personally, I like Dr Brad Stanfield.
| https://www.youtube.com/c/DrBradStanfield
|
| He's not afraid to reverse positions, he's articulate, he calls
| out when research is or is not compelling and explains why.
|
| Again, personally, I expect the number one thing you can do to
| improve your healthspan is probably focus on what you can stop
| putting in your body vs what things you can add. If you're 40+
| though, might be worth looking at other options.
| sometimeshuman wrote:
| Berberine is commonly promoted as a vitamin alternative to
| Metformin. Even if Berberine also has no impact on all-cause
| mortality (idk), I can anecdotally share that 500mg 30minutes
| before lunch considerably lessens my post lunch fatigue.
|
| As for human growth hormone, this Huberman Labs podcast
| advises against taking it but also offers many natural ways
| you can boost it[0].
|
| [0]https://www.youtube.com/watch?v=x7qbJeRxWGw
| _0ffh wrote:
| Funny to see metformin popping up again, it's already a staple
| in the anti-aging movement.
| ineedasername wrote:
| _> unblinded study with no placebo control arm. "If you have nine
| people," says Horvath, "and you get a statistically significant
| result, it means there's a strong effect."_
|
| Wow, no. Just... No. It doesn't.
|
| That is so wrong that, from a researcher with a doctorate in
| biostatistics, it's very difficult not to infer deliberate
| misinformation on their part. To give some benefit of the doubt
| though, maybe it was just a very poor choice of words.
|
| Statistical significance with 9 samples is suggestive at best. It
| just barely qualifies as a pilot study.
|
| They even say that significance means there's a large effect,
| which again... No.
|
| Significance in small sample indicates practically nothing by
| itself. What was the _actual_ effect size? Though even at 0.8,
| with 9 samples I would be be very cautious in my optimistic.
| SamoyedFurFluff wrote:
| I wonder if, read charitably, the intent is to say with a
| strong enough effect a small statistic size doesn't necessarily
| mean useless. For example, if I removed the hearts from 9
| living people and they all died, I can conclude people need
| their hearts to live.
| ineedasername wrote:
| Yes, I try to allow some benefit of the doubt in my comment,
| but from a doctorate is statistics it's a bit harder to
| excuse.
|
| He doesn't have to make an argument from logical implication,
| there are perfectly good measures of effect size he could use
| that would allow him to say something like "not only was this
| statistically significant but it demonstrated a large effect
| size as well."
|
| My hope is he said something like _" We not only saw a P
| value of < 0.04 but a Cohen's D of 0.7."_ and then the
| reporter was like, "yeah I'm gonna need you to dumb that down
| for our readers"
| naasking wrote:
| > That is so wrong that, from a researcher with a doctorate in
| biostatistics, it's very difficult not to infer deliberate
| misinformation on their part.
|
| We don't really know the context for that statement. The
| journalist could have easily misunderstood something and used
| quoted him in a totally wrong context.
| ineedasername wrote:
| I can give him a little benefit of the doubt, but if he said
| those specific words and it wasn't a misquote then it was an
| extremely poor choice of words. Those words, in that order,
| are so fundamentally wrong that I cannot imagine them being
| correct even in additional surrounding context unless the
| next few words that were cutoff were _"...as measured by
| [insert preferred methodology for effect size] "_ that would
| still be poor phrasing, implying that significance led to
| effect size.
| czbond wrote:
| Also, a drug free option is intermittent water fasting for 6
| consecutive days a month. [Disclaimer: do your own research,
| consult a doctor, blah blah]
| cruelty2 wrote:
| peteradio wrote:
| 2 days per week I do a coffee and beer only fast. I can
| guarantee no toxins survive the resulting torrent. I like to
| know I'm starting the week with a totally blank slate.
| NavinF wrote:
| 6 days a month!? Even if an RCT comes out proving this works,
| I'd prefer to die a little sooner rather than do that my whole
| life lol
|
| The way I see it, you're burning something like (6/30)/2 = 10%
| of your quality-adjusted life years. Fasting had better
| increase lifespan by 7-8 years to be even close to worth it
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