[HN Gopher] New insights into transcription factors and chromati...
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New insights into transcription factors and chromatin remodeling
Author : birriel
Score : 108 points
Date : 2024-07-09 19:09 UTC (3 hours ago)
(HTM) web link (longevity.technology)
(TXT) w3m dump (longevity.technology)
| tomrod wrote:
| ... In mice.. And human! cells.
|
| From the paper:
|
| * Multi-omic analysis of maturation and aging across >45 mouse
| and human cell types
|
| * Common transcription factor pattern for chromatin remodeling in
| maturation and aging
|
| * Encoded via relative abundance of AP-1, CTCF, and cell identity
| factor binding sites
|
| * Remodeling mechanism activated by AP-1, stress, systemic
| factor, or PRC2 inhibition
| jbandela1 wrote:
| > "By pinpointing AP-1 as a master controller linked to aging
| across cell types, we can now study the effects of drugs that
| reduce its activity to extend quality of life," he said [2].
| Targeting AP-1 and its associated pathways could lead to
| interventions that slow down or even prevent the onset of these
| diseases, marking a significant advancement in geriatric
| medicine.
|
| Unfortunately, AP-1 is also involved in cancer.
|
| From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361657/
|
| > Activator protein-1 (AP-1) is a transcription factor that
| consists of a diverse group of members including Jun, Fos, Maf,
| and ATF. AP-1 involves a number of processes such as
| proliferation, migration, and invasion in cells. Dysfunctional
| AP-1 activity is associated with cancer initiation, development,
| invasion, migration and drug resistance.
|
| Mentioning AP-1 without mentioning its role in cancer is
| misleading. Many of the mechanisms that are involved with aging,
| likely have a role with controlling cancer by keeping cells,
| especially cells with damage, from proliferating or invading
| nearby or distant tissue.
| CuriouslyC wrote:
| True, but we're getting a lot better at treating cancer, so I
| suspect that it is going to end up that we try to target it
| semi-selectively for life extension with the knowledge that it
| may cause cancer, then try to treat any cancers that emerge.
| aflag wrote:
| We're still terrible at treating cancer though. And the
| treatments very likely cause other health issues that can
| actually reduce life expectancy.
| fzeroracer wrote:
| We've massively improved in cancer treatment in just the
| past 20 years alone. Every year we get more and more
| precise with our ability to both map and target tumors,
| which in turn means less damage to the body as a whole
| during treatment and better odds of tumor elimination. This
| goes for both chemo and radiation.
| Tade0 wrote:
| You'd need a particularly good (and cheap!) screening method
| to catch them before they become fatal.
|
| Digestive tract cancers in particular are often confused by
| patients with other, benign issues and are therefore
| diagnosed too late.
| toomuchtodo wrote:
| https://grail.com/ seems like the path we're on for that
| sort of screening (blood borne cancer biomarker
| surveillance)? AP-1 tweaks + mRNA and immunotherapy
| protocols for detected cancer + continued cancer screening
| developments might be a material longevity improvement.
| Typically, you're trying to die before any cancer gets you
| long term, so the need is to continually improve cancer
| detection and treatment.
|
| https://www.cancer.gov/about-
| cancer/treatment/types/biomarke...
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9074993/
| gumby wrote:
| > we're getting a lot better at treating cancer,
|
| Is this really true? I know we are getting better in
| _diagnosing_ cancers, so the time from initial diagnosis to
| death is longer, but it 's not clear that overall lifespan of
| people with all cancers is any longer. If anything, because
| treatment starts sooner, quality of life may have diminshed.
|
| It is definitely true that treatments for _some_ cancers have
| improved over the last couple of decades. I find the
| immunotherapies particularly exciting and seemingly
| promising.
|
| But in the broader cases I am not sure I could agree with
| your statement.
| jagger27 wrote:
| Early detection when treatment is easier _is_ better
| treatment.
| cellularmitosis wrote:
| They asked "are we decreasing the slope of this graph"
| and you replied by pointing to the graph and saying "if
| you choose a lower value of x, you get a lower value of
| y".
|
| That's good news, but that's not what they asked.
| jagger27 wrote:
| But early treatment does lead to better longterm outcomes
| for a whole bunch of cancers, so I take issue with your
| facile reply.
|
| A mole removal with local anesthetic by your local
| dermatologist will almost always lead to better outcomes
| than two rounds of surgery, chemo, and radiation to treat
| stage 4 metastatic melanoma.
| kortilla wrote:
| Remission rates are higher the earlier you catch it
| arcbyte wrote:
| Yes, having just gone through this i was surprised to find
| that cancer of almost all kinds is rapidly becoming more
| manageable. Prognosis is quite good for most people and
| most cancers when caught early enough.
|
| It is still an artform though and procedures that lead to a
| long healthy life in a majority of patients still cause
| deaths in some others.
| jszymborski wrote:
| Progress in treatment isn't uniform across all cancers,
| but yes we are getting a lot better at it.
|
| Hope you are doing well, and wishing you the very best.
| TheRealPomax wrote:
| Your comment answers itself. There is no such thing as
| "cancer, singular". It's a catch-all term for a wide range
| of conditions relating to uncontrolled tissue growth.
|
| We have gotten a lot better at treating cancer, in general,
| literally because we've gotten a lot better at treating
| specific types of cancer. There are no "broader cases",
| only cases of specific cancers which we've either gotten
| really good at treating, or which we haven't gotten really
| good at treating _yet_.
| varjag wrote:
| It is true. Stage 3 used to be a death sentence in early
| 1990s. It is survivable now for most kinds of cancer.
| overstay8930 wrote:
| Cancer treatment is still objectively primitive, unless you
| catch it early it still mostly boils down to balancing
| keeping you barely alive and hoping the cancer dies first.
|
| Cancer survival rate has gone up because of treatment
| accessibility and testing, not because of any major
| breakthroughs.
| futureshock wrote:
| I have often heard it said that if we found a cure for cancer
| we would also get a cure for aging. The one immortal human I
| know is Henrietta Lacks (or her cancer rather).
| jonathanlydall wrote:
| Fascinating.
|
| https://en.wikipedia.org/wiki/Henrietta_Lacks
| evanmoran wrote:
| Amazingly, her immortal cell line was instrumental in polio
| eradication!
| https://en.wikipedia.org/wiki/HeLa#Polio_eradication
| onlyrealcuzzo wrote:
| I have heard that we age, primarily, to prevent ourselves
| from dying of cancer even faster than we already do.
|
| Animals that don't really age like the lobster, giant
| tortoise, bowhead whale, elephant, etc - also get cancer much
| less than we do.
| jacobn wrote:
| Is it known why/how those animals have reduced / negligible
| senescence? Like do they have some other variant of the
| AP-1 gene(s), or some such?
| sterlind wrote:
| one factor is how many copies of the p53 tumor suppressor
| gene they have. larger animals (with more cells) tend to
| have more copies of p53. p53 causes cells to self-
| destruct if they go off-script. many cancers have p53
| mutations to thwart this.
|
| iirc senescence blocks damaged (potentially pre-
| cancerous) cells from reproducing, but unlike p53 doesn't
| kill them. replacing sensescent cells means more cell
| divisions, which also risks a cancerous mutation. so
| reducing senescence probably means making p53 more
| sensitive and redundant.
| newzisforsukas wrote:
| https://www.sciencedirect.com/science/article/pii/S155041312...
| personalityson wrote:
| One step closer to longevity escape velocity
| ulf-77723 wrote:
| You mean a slower life is a longer life?
| exe34 wrote:
| escape velocity in this context means that you stay at least
| one step ahead of dying, through medical advances, to the
| point that the first immortal human (at least one who will
| not die of old age) may have already been born.
| dangerwill wrote:
| Not the OP but I believe they are referring to the idea that
| if longevity research causes lifetime extension to be
| possible, then some folks think they can then avoid age-based
| death entirely. I think that the crux of the argument is that
| once we find "THE reason" why we age and if we can halt/end
| that process then we have beaten senescence.
|
| I personally think this view is too simplistic about how our
| bodies work and overly optimistic that we a) won't hit other
| limiting factors that aren't hit today by ~100 and b) that
| interventions to stop senescence won't have unexpected side
| effects.
| wincy wrote:
| I forget where I've read it (I feel like slatestarcodex or
| gwern or one of those folks) but basically our bodies are
| constantly fighting megaloviruses (various forms of herpes)
| and we'd inevitably lose the battle if we lived to 120 or
| so.
| zebez wrote:
| metabolically, yes
| nmca wrote:
| worth noting that longevity escape velocity is well-posed but
| typically badly miscalculated. You care about the right tail of
| ages, not the mean, and the tail has moved slowly if at all.
| Tracking rate of increase of max or 99th percentile will give a
| more reasonable (but sadly less inspiring) number.
| levzettelin wrote:
| Can you post any evidence for this? I somehow have it in my
| mind that it's the other way around (i.e., mean doesn't grow
| anymore, but 99th percentile still does).
| daedrdev wrote:
| There is a chart floating around showing the mean age
| increasing the but the 99% age has been completely flat for
| at least a century
| grishka wrote:
| You can't make any conclusions about LEV by just looking at
| current stats.
|
| Medicine in its current form is just not prepared to deal
| with these things. It evolved to deal very well with
| infections and injuries, in both cases helping the body to
| heal itself, which it wants to do anyway.
|
| Aging is different. An aging body actually _wants_ to destroy
| itself. It _intentionally_ disables self-repair mechanisms,
| allowing the diseases of old age to take over. It 's the
| first time we have to override these internal goals. Treating
| these diseases individually, like we do now because it's the
| best we have to offer, is a losing game.
| gcp123 wrote:
| The gist of it in plain english:
|
| 1. Our genes change as we age with some becoming more active,
| while others become less active.
|
| 2. The researchers found a special protein called AP-1 that acts
| like a master switch. As we get older, AP-1 becomes more active.
|
| 3. AP-1 turns on "adult" genes and turns down "young" genes. This
| happens in many different types of cells in our body.
|
| 4. These changes in gene activity are linked to the aging process
| and may explain why we experience age-related health issues.
|
| 5. Understanding this process could help scientists develop new
| ways to prevent or treat diseases that commonly affect older
| people, like Alzheimer's or diabetes.
| spacephysics wrote:
| Additionally there are cancer risks with modifying this
| process. Sounds similar to the telomere conundrum
| throwaway743 wrote:
| What's the telomere conundrum?
| vikramkr wrote:
| To clarify, they didn't "find a special protein called AP-1".
| AP-1 is a well known, well studied family of transcription
| factors.
|
| From snippet in background for
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678392/:
|
| "The Activator protein-1 (AP-1), is a group of transcription
| factors consisted of four sub-families: the Jun (c-Jun, JunB,
| JunD), Fos (c-Fos, FosB, Fra1, Fra2), Maf (musculoaponeurotic
| fibrosarcoma) (c-Maf, MafB, MafA. Mafg/f/k, Nrl), and the ATF-
| activating transcription factor (ATF2, LRF1/ATF3, BATF, JDP1,
| JDP2) protein families [21], characterized by pleiotropic
| effects and a central role in different aspects of the immune
| system such as T-cell activation, Th differentiation, T-cell
| anergy and exhaustion [22,23]. "
|
| They found a correlation between AP-1 binding sites/motifs and
| genes with age related changes in expression through their
| analysis (https://www.sciencedirect.com/science/article/pii/S15
| 5041312...):
|
| "This revealed that age-opening DARs had the highest enrichment
| for a subset of bZIP motifs, including AP-1 subunits FRA2, FRA,
| JUN, JUNB, FOS, ATF3, and BATF, compared with the other peak
| categories (Figures 4C and S5B). Conversely, age-closing DARs
| had the lowest AP-1 enrichment (Figures 4C and S5B). As broadly
| expressed pioneer factors,39,40 AP-1 family members are
| responsive to a variety of stimuli41 and have been linked to
| potentiating age-related pathologies and
| phenotypes.12,13,42,43,44,45 This makes them strong candidates
| for driving age-related chromatin opening. Highly stable cCREs
| showed intermediate enrichment levels for these AP-1 motifs
| (Figures 4C and S5B). However, a distinct feature of highly
| stable cCREs was very high CTCF motif enrichment levels and
| binding relative to all other peak categories (Figures 4D, S5B,
| and S5C)."
| fifteen1506 wrote:
| Oh great, everyone in positions of power will be Biden-like. That
| bodes well for society.
| jszymborski wrote:
| W/o commenting on gerontocracies, this would mean that folks
| Biden's age wouldn't suffer as they do now from the deleterious
| effects of ageing.
|
| Put otherwise, Biden wouldn't be old at 81 if we completely
| understood the molecular biology of ageing. Unfortunately, we
| don't.
| TaylorAlexander wrote:
| Tho these people might not update their politics (I don't
| have a sense that Biden ever did) and so while they may not
| suffer mental decline, we could find ourselves deprived of
| new thinking.
| 1propionyl wrote:
| Unfortunately this site doesn't work properly with blockers
| enabled and redirect cycles. Unfortunately, won't be reading.
| boznz wrote:
| In my sixties and If longevity of life comes with full cognitive
| and physical health for the individual so they can continue
| contributing to society, then I'm all in. Otherwise what is the
| point, I will just be a burden on the world and reduced to a
| market for big pharma and big health care to get richer and the
| economy to get poorer as health care spending increases.
|
| I guess these are hard questions for everyone and I don't want
| individuals reduced to a number in a dataset but mankind has
| certainly gotten itself in a bit of a pickle.
| swayvil wrote:
| It's like the world is some kind of clockwork. Or computer. Or a
| field of barley? What metaphor are we using these days?
| begueradj wrote:
| It's strange that mitochondria is not mentioned in this article.
| For a long time, it was believed to play a paramount role in
| aging.
| vikramkr wrote:
| It still is believed to play an important role in aging:
| https://www.nature.com/articles/s43587-022-00191-2
| grishka wrote:
| I wonder how this fits together with heterochronic parabiosis.
| vikramkr wrote:
| Edit: Thanks to whoever changed the title for the post!
|
| jfc the media telephone chain here is absurd. "Revealing a master
| controller of development and ageing" becomes "AP-1: The Master
| Regulator." A -> the is a pretty big jump.
| (https://www.uq.edu.au/news/article/2024/06/revealing-master-...)
|
| Also - ugh these content mills are so lame. The university PR
| departments aren't helping - why a university feels it needs to
| contribute to lowering public trust in science by claiming every
| paper is a generation defining breakthrough is beyond me. But
| maybe pause for a second before breathlessly passing along a
| headline like 'master controller of aging and development
| uncovered'? And the underlying research
| (https://www.sciencedirect.com/science/article/pii/S155041312...)
| and techniques used etc is pretty interesting - please don't cut
| research funding to genetics a few years down the line when
| immortality fails to materialize like longevity.whatever
| promised.
| Unbefleckt wrote:
| I'm sure I read about this in New Scientist maybe 12 years ago?
| They found this "switch" and turned it off in mice. We basically
| age and die so that we don't have denisovans running around
| mating with people who have hundreds of thousands of years of
| adaptations that have been tried and tested, but you can just
| turn that feature off. Right?
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