New insights into transcription factors and chromatin remodeling | Hacker News Reader

New insights into transcription factors and chromatin remodeling

longevity.technology

115 pointsbirriel68 comments

> “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.

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.

We're still terrible at treating cancer though. And the treatments very likely cause other health issues that can actually reduce life expectancy.

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.

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.

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/

> 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.

Early detection when treatment is easier is better treatment.

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.

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.

Yes, of course! As I said, that’s good news.

Remission rates are higher the earlier you catch it

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.

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.

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.

It is true. Stage 3 used to be a death sentence in early 1990s. It is survivable now for most kinds of cancer.

It is a really fair question, and I do not think it is totally clear cut. There are some cancers which are significantly more treatable than previously, but the numbers are also getting juiced from other directions.

We are detecting cancers earlier than before. Which can mean that, without any change in treatment efficacy, people are "surviving longer" with the disease. Another biggie is that people are smoking significantly less than 20+ years ago (both smokers and secondary exposure). While we are continually finding new ways to slowly poison ourselves (eg PFAS), we have also reduced exposure to other environmental toxins: lead paint/gas, DDT, etc,

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.

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).

Fascinating.

https://en.wikipedia.org/wiki/Henrietta_Lacks

Amazingly, her immortal cell line was instrumental in polio eradication! https://en.wikipedia.org/wiki/HeLa#Polio_eradication

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.

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?

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.

One step closer to longevity escape velocity

You mean a slower life is a longer life?

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.

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.

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.

metabolically, yes

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.

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).

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

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.

https://www.sciencedirect.com/science/article/pii/S155041312...

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.

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.

It still is believed to play an important role in aging: https://www.nature.com/articles/s43587-022-00191-2

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?

Unfortunately this site doesn't work properly with blockers enabled and redirect cycles. Unfortunately, won't be reading.

It works with curl

Loads perfectly with Firefox for Android and uBlock.

It's like the world is some kind of clockwork. Or computer. Or a field of barley? What metaphor are we using these days?

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.

I wonder how this fits together with heterochronic parabiosis.

... 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

Having worked in cancer hospitals at the age of 16 (35 years ago) and having a father a doctor who coordinated long term cancer treatment in our country, I can say that cancer treatment has come on in leaps and bounds. What was once a death sentence is now likely treatable, and more treatments are coming online almost by the day. We will never beat cancer as we will never beat death, but we can prolong life, prevent pain, and always make sickness easier to bear both for those who suffer it and their loved ones.

C'mon the Science!

Oh great, everyone in positions of power will be Biden-like. That bodes well for society.

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.

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.

We could always regulate that politically. An age limit for public service, though I guess that doesn’t cover most powerful people. Overall I hope that if we had figured out aging we’d be smart enough to deal with the consequences well but who knows.

Hard to get the gerontocracy to vote against a gerontocracy. We can't even get proportional representation voting systems (at least not in the USA). Quite unfortunately, our system is built to protect the power of those who created it; it is not built to be smart.

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.

Additionally there are cancer risks with modifying this process. Sounds similar to the telomere conundrum

What's the telomere conundrum?

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/S155041312...):

"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)."

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