In mice.

Humans have the same protein. Knock out studies in mice have historically been very informative about human biology (with some exceptions). That’s very different from drug studies, where the molecules not only have to have the same effect in the model species, but also all off target effects have to be similar. That’s a higher barrier to clear and why mice studies of pharmaceutical interventions should (and do) face higher scrutiny.

interesting, i exactly read the opposite position from biologists that the mice experiments are now very useful when it comes to applicability to humans. I guess we have every possible oppinion.

The reasoning they gave seems plausible, what reasoning do your biologists give for holding the opposite position?

I don't think that any self-respecting biologist would actually make any sort of categorical dismissal of research in mice. That kind of research has been the basis of noble prize-winning advancements in immunotherapies that now positively impact cancer survival rates for humans.

I'm sure the totality of opinions from biologists is vast and complex, but there is no way that "all opinions have been expressed" is a faithful report of the state of our knowledge on biology.

The "in mice" meme needs to be retired. We share critical similarities in DNA, proteins, immune systems and immune responses that already have been the basis for impressive advances in research applicable to humans when it comes to immunotherapies.

We shouldn't overhype research done on mice but we also shouldn't reflexively dismiss it as unrelated to humans.

There is a natural tendency to hype basic research as having human applications because perhaps that will attract funding. But most of us are reading science news without any practical use for it. It's useful to have a succinct reminder to avoid getting too excited about it.

I think more people mean it and understand it in a literal sense than you seem to appreciate.

And yet the only human data they found to substantiate their claim is that little Figure 7.

Which is why I stressed the human relevant merits of "in mice" research in the part of my comment you're not responding to.

Paper: https://www.cell.com/immunity/fulltext/S1074-7613(26)00440-1

Granzyme K is the protein.

Great, finally Leonardo DiCaprio will be able to find his life partner.

Granny Enzyme, you say?

Thank God! Finally, mice that don't age!

I’d unironically love to have a pet rat that lives longer than a few years.

A good idea for a startup might be a pet shop where you can buy all kinds of weird genetically altered mice! Or custom order!

Heh Heh Heh. There's even "optically transparent" mice:

https://www.jax.org/news-and-insights/2014/august/transparen...

"We're not sure what's eating our fields, but it smells like rats...!"

Thank God! Finally, mice you can't see!

and then we can have pets stuck forever at shelters!

... :( I'll see myself out.

If it's your pet I'd guess you don't need the unironically? Anyway - new word for me!

I don't think it's the correct word here though, given the meaning of the word; people similarly mix up jealousy and envy.

Just get the right turtle or parrot? Mammals might be more difficult, though.

Can't wait for this to escape in New York City. Ageless undying sewer rats - what a utopia haha.

Interestingly, their lifespans would probably be affected very little.

> GzmK does not affect steady-state immune aging or aged immune responses after challenge

Virtually all old mice die of cancer, especially in the lab. If GzmK doesn't mitigate immune system aging, GzmK-null mice are still going to die of cancer, for little or no change in lifespan. (But presumably an improved healthspan due to reduced soft tissue and bone aging.)

> Virtually all old mice die of cancer, especially in the lab

Is this related to them being cloned? Did anyone try to get some random mice or is that too taboo?

No, even wild mice or rats are cancer magnets. If you have a pet rat, it will likely die of cancer.

This is a huge problem for medical research. Imagine that you conduct a safety test of your compound on mice, and 25% of the test group die of cancer within 1 year. That's bad, right? Well, the control group also has 20% cancer rate.

> Virtually all old mice die of cancer, especially in the lab

Bret Weinstein did research on this topic which suggested that this is caused by lab mice having extraordinarily long telomeres which cause them to be good at cell repair but bad at limiting neoplasm growth due to delayed apoptosis. The result of this combination would be that lab tests on potential damage done by preparations on these mice is less valid 'cause they are better at repairing such damage than the average mammal due to those long telomeres. It also means nearly all these mice succumb to cancer. They're not normal mice, at all.

The reserve-capacity hypothesis: evolutionary origins and modern implications of the trade-off between tumor-suppression and tissue-repair

Bret S Weinstein 1 , Deborah Ciszek

https://pubmed.ncbi.nlm.nih.gov/11909679/

This paper examined captive wild mice, which they caught themselves on school grounds, and noted that "mice in both feeding groups died from various causes, chief among these a range of cancers":

> https://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2006...

So I think that even wild mice are prone to immune aging and cancer development.

> Virtually all old mice die of cancer, especially in the lab. If GzmK doesn't mitigate immune system aging, GzmK-null mice are still going to die of cancer, for little or no change in lifespan.

Would introducing the cancer-reducing TP53 genes found in elephants[1][2] to mice help with this? Or would they likely just be too incompatible, with the species difference being too large?

[1] https://news.cancerresearchuk.org/2023/08/12/can-elephants-g...

[2] https://jamanetwork.com/journals/jama/fullarticle/2456041

maybe this is your joke, but we've actually done it many times, even reversed aging... only to find it doesnt work on humans.

Paywall

From the abstract of the paper, significantly more nuance.

> Despite persistent immune aging phenotypes, GzmK deficiency markedly attenuated organ aging, effectively uncoupling immune and tissue aging... These findings identify GzmK as a tissue-specific driver of organismal aging but not immune aging or systemic inflammaging.

I'm not sure I see what you mean. To me the original headline seems pretty accurate in view of the paper: the protein causes ageing markers in multiple tissues, however its action is not actually coupled to inflammaging.

Found another protein? Shiiiit.

I was having the same old boring debate with someone the other day: "why would you want to live forever when after age 80 ~ 90+ there's no point in living anymore?"

Most people, even technical people, can't imagine being 90 years old and being indistinguishable visually and in terms of mental capacity from a 20-year-old. They imagine decades of suffering with bone aches, diseases and dementia... even technical people who should know better that when you optimize a system that's full of technical debt, it's almost all upside.

I'll have plenty to do and plenty to think about when I'm 100 years old, assuming I have a body and brain capable of it.

"Yes, but what about all the people you'll have lost by then?"

First of all, if I get to live a long and healthy life they probably do too.

Second of all, we adapt. It's not all sunshine and rainbows, but getting to live for as long as you want, as healthy as you want, is worth the grief.

I can only imagine it being a defense mechanism because ultimately, you'd still have the option of dipping out whenever you wanted.

Well you personally can dip out but your kids will have to live in a fucked up society run by the old and wise. I would rather them dipping out too.

That's true, but also feels like a separate concern.

It's like saying that famine is a separate concern from drought.

Continuous renewal of humans plays an extremely important role in our society, it's a huge blessing. Get rid of it and it's all fucked.

What I mean is that when I hear oppositions like in the oc, it doesn't seem like it's about some consideration of what the world would be like, just strictly about the idea itself. Like they aren't saying that it will result in the worst people in the world becoming even more powerful and not even their mortality can save us and we'll live in a dystopian hellscape.

  > It's like saying that famine is a separate concern from drought.

Well... they are. They have different solutions. They have different roots. Famine can by created by many things besides drought. You can have a drought and no famine. This still holds true when talking about old people.

> but getting to live for as long as you want, as healthy as you want, is worth the grief.

If wishes were fishes there'd be no room for water.

No, it's not that. Even if at 90 I had a body of a 20 year old, I would still have the mind of 90 year old. With all the experience, all the mistakes and presuppositions and biases.

Luckily there is in fact a procedure that allows to reset BOTH the body and the mind into a clean healthy state. It's called "having kids".

Age does bring wisdom, at least for most. They look back at the stupid things they did in their twenties, and see twenty year olds doing the same as they did. Youth is wasted on the young.

Saying that youth are stupid and old are wise is nearsighted. Both play important roles. I would never ever voluntarily confine myself to a society where everyone is wise and no one does stupid things. Nor would I want that for my kids.

Yes both have important roles. The older you are the more experienced you are, while I expect societies would stagnate without the young. However I would myself like to be in a society where everyone was wise and didn’t do stupid, meaning harmful, things.

I'd give anything to be 14 again.

> there is in fact a procedure that allows to reset BOTH the body and the mind into a clean healthy state. It's called "having kids".

You must have not met many parents because this procedure you speak of isn't guaranteed at all to do this reset you speak of. One could even argue that this outcome is the outlier. Go work as a teacher at a secondary school and tell us the percentage of parents whose mind and body is in a "clean healthy state".

> Even if at 90 I had a body of a 20 year old, I would still have the mind of 90 year old. With all the experience, all the mistakes and presuppositions and biases.

I think you're underestimating how many of your thoughts, inclinations, moods and attitude are driven by the body (hormones, energy, etc). The mind is not separate from the body, they are one system. If you rejuvenate the body, the mind is also changed. I agree neuroplasticity is something that needs care as well, but it's simply not the case that it's a separate thing.

150 years ago a third of all white families in the southern states owned slaves and there were 3 million slaves.

If you think either group would have let the other live forever after the civil war I have a stone that grants you immortality to sell you.

I think that's also a conversation that comes from younger people struggling with encountering the first signs of physical aging being a limitation. One thing that sticks out from when it comes up on reddit is people (claiming to be) in their 50s to 70s basically saying you don't really realize it's happened.

And I mean certainly I'm not constantly aware I'm in my 40s. And the healthy 80 and 90 year olds I've known don't seem "over it" - and the unhealthy ones aren't ready to give up either, they're usually just frustrated their body can't keep up.

I had a moment when I was around 25... I was very active, but I was noticing that I was starting to heal and recover more slowly than I did when I was 19. Then it hit me, this is basically just going to get worse and worse over the decades, and then I'm going to die.

It helped, I kept being like "wtf is wrong with me" but actually, no, I was just noticing the first little tiny signs of aging.

Now the trajectory has kept up, and I have to squint to read things that I could once read easily. Both my parents used reading glasses, and in 5 years I'm going to need them myself.

Occasionally you run into a 85 or 90yo that physically is quite limited, but mentally is sharp as f. Some were even learning new things fluidly. It's a bit too rare, but it's something to develop socially.

Sir Roger Penrose springs to mind.

> Most people, even technical people, can't imagine being 90 years old and being indistinguishable visually and in terms of mental capacity from a 20-year-old

Because it never happened. What person is 90 and looks 20?

> assuming I have a body and brain capable of it.

> as healthy as you want

If we are playing thought experiments it is fine but right now there is no reason to think that is possible. This is what people are telling you. They do not lack imagination, they say it does not seem likely. It is fun to fantasize about as a science-fiction topic though.

The 90 to 20 contrast may be too large a spread to be anything but hyperbolic at this time, however:

when seeing someone like Larry Ellison speak and move, it is very clear that dedicated optimization has major benefits and productive results.

Show a recent interview of Ellison to a random person and ask them how old the guy is - the responses I often get from people are estimates in the 40-50's range.

While obviously this is not '20', it is still almost a halving in how old one is perceived (if you didn't know his temporal age, go watch a few minutes of a recent interview, then guess how old he is, then look up his actual age). Though this comment may bias one to guess on the older side, that's why we can blind the experiment by asking someone else you know.

> dedicated optimization

So, plastic surgery, and hair dye?

and a couple of islands

Islands have been known to be sources of youth.

Nah he’s got the youthful quickness to go with it

The better argument I have heard is optimizing/stabilizing one subsystem, while not finding ways to stabilize or prevent natural rate of decay of other subsystems causes gaps in keeping things in sync. The gaps then grow with time. System fails in new ways.

I could get on board with being 90 in the body of a 20-30 year old, but I really don't see that being the situation we arrive at to start. Isn't it much more likely that we incrementally extend life by preserving the function of one system or another while the others continue to deteriorate? Or do you think that there's going to be a single switch (or maybe a small handful) that will stop or reverse aging across systems?

> Or do you think that there's going to be a single switch (or maybe a small handful) that will stop or reverse aging across systems?

there's not even a switch that turns _on_ ageing (https://en.wikipedia.org/wiki/Evolution_of_ageing)

im beginning to think its all in the mind (your cohort forces you to age as you watch them think they should age)

You believe aging is psychosomatic? This seems unlikely, to put it mildly. Any evidence for this?

easy: i feel younger when i hang out with people who feel that life is to be lived, and i feel older when i hang out with people that act like they are dying before their time. i dont even need to know their biological age

my results at least confirm my hypothesis for a sample of one, try it out and lmk :)

> but I really don't see that being the situation we arrive at to start

there are people who by following fitness/diet routine have good physique in 60-70 (face is aging, but body looks young). I am waiting to see how that generation will push limits in 80-90.

I live in a rural area and know / have known a number of people in their mid 90s who were still getting around pretty well, including climbing on their roofs to remove snow, etc. One in particular was really sharp-minded right up to his last year at 95.

There are a lot of factors, but there's a lot we can do to make that more likely for ourselves. Never guaranteed, but most of the diseases of the elderly are not simply caused by old age, there are contributing factors from lifestyle.

I don't want or expect to live forever but I want to have a sharp mind, good memory, and be as mobile as I can be right up to near the end, if I'm lucky, hopefully in my 90s or 100s.

> One in particular was really sharp-minded right up to his last year at 95.

imo this is not correct example. That guy just survivor who was not hit by many other health risks from leaving in rural area and climbing to roofs.

Good example would be someone who has good life basics (work/life balance, income covering all his basic needs, healthcare and safety), following good balanced fitness protocol (e.g. running + compound movements + rest + good split program) and healthy diet (fiber, protein, healthy-fats, micro-nutritions, reasonable calories).

I believe if we would have some A/B trial, we would see that this cohort would be healthier and more active by like factor 10x compared to avg Joe when reaching 70yo age.

> Most people, even technical people, can't imagine being 90 years old and being indistinguishable visually

But this assumes that you'd stay with all these problems. Why would this be the case? You seem to connect that one has to be old and frail. I don't see the connection.

> Second of all, we adapt. It's not all sunshine and rainbows, but getting to live for as long as you want, as healthy as you want, is worth the grief.

You think this is a good trade-off? To me it does not appear to be a good trade-off at all. I fail to see why health-related issues related to aging components would be anything good.

Also, not everyone makes it to a long life anyway; some people may die early due to a heart attack.

[delayed]

> I’ll argue that even a short life in a mental hellscape of unreflected living is worse than physical death

Sounds like mental hellscape of too much reflection( and early death).

Happiest ppl i know just go with flow and dont worry too much. My own parents are on two extreme ends. My dad worried all his life about all sorts of stuff, was healthnut did yoga for 50 plus years every single day, ran 5k 4 times a week, did hard gardening all that stuff. My mom on other hand just let life happen to her and enjoy whats happening along the way. Guess which one died an early death from cancer and who is alive playing with grandchildren.

The common theory is men die younger because they have more stressful lives. I imagine some stress is optional, though for too many people most stressors is outside their control.

men die younger because they have worse lifestyle choices on average.

I'm 42. I struggled financially my 20s and 30s, now I'm finally doing OK. Now I want to live longer to compensate for the lost years.

:) what do you do now?

> when after age 80 ~ 90+ there's no point in living anymore?"

ive met people who didnt see the point of life at 20; ive also met 80+ year olds begging for just one more day

its not the years, its what you do with what you got

Physically 25 might be peak, but mentally there's still a long way to go.

Which might even be due to anatomy, who knows.

But hey, being mentally 25 would also be quite more fun and careless I guess

I'm 38 and my body is still getting better. The hack is to have a bad start and not be so healthy at young age, it seems.

We don't do very well at giving people good lives with the years they have now. Let's work on that instead.

I think what helps. The conversation is really admit. It will also bring challenges and not just upside.

Even if you’re able to preserve a healthy body, the increased lifespan will strain society resources, require people to have longer and longer careers, more income, less opportunity for next generations, etc.

Human lifespan has increased markedly since say the middle ages, but has done so on a slower timeline. I am actually pretty nervous about a rapid transition to life spans dramatically increasing. I don’t think that will be a fun point in history.

Concur.

A comment from age 77: the single thing I am most grateful to have retained at the same intensity it was in my youth is my curiosity.

You assume the intelligence that you perceive as you is the main show rather than an accident that improved reproduction chances for the main show, your body. I think this is a common error and so the consequences of near immortality will be a surprise to you when you get there, rather than a modelled acceptable cost.

Honestly it gets kind of boring and mentally painful. You either die a hero or living long enough to see yourself become the villain. If you live forever, you're guaranteed to become the villain.

I wonder though what these proteins do to earn their presence in the genome.

I guess there is a large evolutionary advantage to a population with fast replace rates.

Aging and sexual reproduction seems to be equally essential to the explosion of variety of life.

I think a somewhat overlooked aspect is that it's also essential to the evolution of society and cultural norms. If aging was solved in the ancient Egypt we would probably be still slaves building the pyramids. I'm genuinely scared of a society run by never ageing gerontocrats.

How would a power structure stay entrenched like that if there's no risk of just riding it out though? If anything the apathy of today is based on the assumption that you can just wait out he current unfavorable leaders and hope you'll get better ones.

When the promise is "nothing ever changes unless you change it", then your motivations will change pretty substantially.

One practical problem is that rollout of anti-senescence will not be evenly distributed. In the early days of its availability, the oligarchs will use it to accelerate the growing chasm between the haves and have-nots, aiming to make their advantage permanent by pulling up the ladder behind them.

It's not just about power structure: if you never known anything but pharaohs and pyramids your whole life, it's extremely hard to imagine anything else. The youth is programmed to revolt against the old ideas to test them, no youth no revolt.

I also you think both your assumption and the reasoning behind it are wrong. Humanity as a whole is the opposite of apathetic, it's boiling with life. There are occasional pockets of apathy here and there, but they never last long.

And the reason why people on average are active and risk-taking is because their life is worth nothing. You lose your life no matter what you do, so you can as well do something good. And if you want to see change in your lifetime you better hurry up.

No one would risk their precious eternal lives if aging is gone. And if you want change you can safely wait forever without taking risks, maybe a meteor will fall in 10000 years and change things — who knows!

I'm mostly wondering how would compound interest work if we'd live forever.

Likely: taxation. And probably not waiting for a taxable event either. Otherwise what's to stop the bezos and musk's of the future generation locking up a significant portion of the world's wealth and hoping on a relativistic ship for 100-200 years?

That's why life extension has to come with health span extension and ways of resetting neuroplasticity. Otherwise life extension leads to a super-gerontocracy that would be hyperconservative and extremely risk and change averse.

Yeah, but if you want to reset both the body and the mind then it's not clear to me how is it better than just having kids. Nature already solved that for us and it's extremely efficient.

It's a known protein that is needed for defence against pathogens.

Soon we will have the technology to become mice and take advantage of the infinite wonders of these discoveries.

The title already makes no sense because it all depends on how one defines ageing.

In reality you will often find trade-offs. Sickle cell anemia is one example of many more: https://www.redcrossblood.org/donate-blood/blood-types/diver...

If people live forever, or even just a significantly longer time than they do now, we will need to find alternatives to the benefits of death. In other words, progress does often happen one death at a time so we need mechanism that achieve that same effect. Will politicians or CEOs voluntarily move on and make room for new people and new ideas if they can live to 300? Will department chairs and heads of research step away voluntarily and let new ideas, not their own ideas, start taking center stage without some active force pushing them? We need to start developing the mechanisms that cut ties automatically and force renewal just like death does now or society will find new ways to bring unnatural death in for us.

If you think that younger people have new ideas and are more open-minded and drive progress, why do you think that isn't a product of youth itself rather than experience? If so, then rejuvenating old people would make them more open minded and open to progress as well.

I think you've invented a problem we don't even know exists yet.

[delayed]

> Will politicians or CEOs voluntarily move on

Well, politician already refuse to move on; The US is already a gerontocracy. The solution is term limits for all political positions, not just the president. Less of an issue for private companies, but smart boards would establish term limits for CEOs and board members also.