Forever Young: how one molecule can lock plants in a youthful state (2025)
omnia.sas.upenn.edu82 points by bryanrasmussen 6 hours ago
82 points by bryanrasmussen 6 hours ago
This is the start of the plot of the book Postmortal by Drew Magary. Not to say that the book accurately depicts what would happen if everyone could freeze their aging, but it does bring up some questions that would need to be answered.
A few of these questions are answered in the Commonwealth saga books of Peter Hamilton
Heterochronic shifts in a timing‑keeping microRNA are associated with multiple instances of neoteny in plants, Aaron R. Leichty and R. Scott Poethig, PNAS. https://www.pnas.org/doi/epdf/10.1073/pnas.2510697122
Key quote: "permanent juvenility has evolved multiple times", nominally making neotony a more highly evolved and expressly desirable characteristic as voted by life itself.
Now we can say certainly, at least in ancient Australia (if you're a plant): growing up is for losers!
The weird thing about death (as in aging, not as in accidents/getting eaten) is that it's "an invention". As in natural selection decided at one point to introduce death. It really is the case that older lifeforms don't die. All mammals do though.
If you study it, it becomes pretty obvious that in most cases reproduction and death are linked. Death is fundamentally a way to optimize reproduction, to control DNA variability and number of offspring.
Also, it is obvious that death has "levels". The cells humans are made of are immortal, in the sense that human cells are capable of living and even reproducing indefinitely, if so directed by DNA. Gametes are meant to survive your death, becoming your children. Now very few cells actually do survive, but that's a constant across pretty much every immortal species. On the other hand, every cell in your body was, in a very real sense, the first bacteria, the first cell ever, billions of years ago. So it certainly is NOT the case that all human cells age, senescence, and die. Only the human as a whole ages, and it is something your cells conspire to do (or conspire not to do, in the case of ovi (~ children), or in the case of cancer cells)
At one point, during the period mammals were all still fish, evolution was still experimenting with death, and so fish have much more variation in their aging and death than mammals do. If you go back further, to reptiles, there's even less death. Most reptiles could be alive for thousands of years (even though the odds are wildly against that). Most reptiles die because of slowly advancing accumulated diseases over time (meaning over hundreds of years, a great many diseases, parasites, even physical damage, ... accumulates. No one cause is really causing their death, but combined they introduce such a strain on the organism as a whole it "dies of old age". Except it's not really of old age in the sense like humans age, it's dying of what you might call 99.9% victories against disease. Eventually the 0.1% damage per incident overpowers the metabolism)
Unfortunately this does mean that death is built into our cells and a lot of processes depend on aging and death. Therefore we are very far away from curing death: you don't just have to fix the mechanism that "ages" our cells, but you have to find alternate ways of working for everything that depends on it. Resetting the clock may be easier, but even the methods that we currently know (ie. regrowing telomeres) have a bad reputation for causing aggressive cancers, and therefore shortening life rather than prolonging it. Plus, at best if you fix aging in humans entirely, we'll be like reptiles. At that point medicine will have to radically change and every tiny trace of every minor infection will have to be treated as a life threatening condition.
Animals minmax on being active. To the point of going into a damaging overdrive when active and repairs when sleeping. The total accumulated wear is massive. Discarding an old animal and booting a new one seems to be more viable than trying to keep the old one going indefinitely.
Is it really "wear and tear?" or is it an evolved mechanism to keep genetic drift and natural selection alive? Alternatively, it could be an evolved mechanism to avoid genetic bottlenecks caused by highly reproductive individuals over long periods of time.
If John and Mary were first, how long until everyone is a descendent of john and Mary?
Just like reptiles, who die from the accumulation of damage, at a time depending on the rate of damage, but their point is that mammals don't merely die from accumulation of damage but also have a built-in clock.
Why assume there is a clock, rather than assume the damage is at the metabolic level? None of the predominant forms of human chronic disease that lead to most instances of death today (artherosclerosis, cancer, neurodegenerative disease, metabolic dysfunction like diabetes) seem like an intentional function. They seem like unintended consequences of other functions, like lipid transport or DNA replication, that don’t get selected against because they fall beyond the natural reproductive lifespan of most people. I suppose you could say that the biological clock in question is the number of eggs a woman has, but a simpler explanation for limitation could be that eggs are just very energetically expensive to produce.
Correct me if I'm mistaken, I was under the impression a human female is born with all the egg she will ever have, so the expensive production bit you're talking about happens during gestation of the human embryo.
Just like an old chat. Start fresh without so much accumulated contextual baggage.
> Most reptiles could be alive for thousands of years
How so? Snakes only live like 30 years. Tortoises are long lived, but it is low hundreds years, not thousands.
> At one point, during the period mammals were all still fish, evolution was still experimenting with death, and so fish have much more variation in their aging and death than mammals do. If you go back further, to reptiles, there's even less death.
Huh?
Fish came before reptiles.
> At that point medicine will have to radically change and every tiny trace of every minor infection will have to be treated as a life threatening condition.
But is this life? I'm wondering if an immortal life can be a well-lived life
I'd wonder more about the mind itself. It didn't really seem to evolve around being an eternal storage device. Slowly going insane wouldn't be so great.
> I'm wondering if an immortal life can be a well-lived life
Why not? It does not mean that we will be some omnipotent god. it just means that we wont age. You can still die from physical trauma, infections, cancer etc. So in practice this would mean that the average human lifespan is not say 70 years, but 120.
I'm pretty sure that humanity will eventually get to immortality (why not? We are already controlling most of our environment) but this will not be like an invention of a magic pill, rather the average lifespan will creep up by a decade or so with every generation.
Now we're at the point where we know whats actively killing you and what to avoid (we can also cure most infections and diseases)
in 30 years most cancers, and likely Alzheimers will be curable too. I'm also sure that lots of aging related conditions will be treatable too (say osteoporosis)
in 60 years we might know enough to start reversing aging effects, and fear of cancer will be a thing of the past, just like now bacterial infections.
.. and who knows when we will start to regrow limbs and fully reverse aging
> It really is the case that older lifeforms don't die. All mammals do though.
Are naked molerats the one weird exception with mammals?
Naked molerats live a relatively long time and have many cool longevity adaptations, but they're far from immortal. Max lifespan is under 40 years.
- (ie. regrowing telomeres) -
Was there any progress at all so far?
We found telomerase and tried a bunch of things with it. We can reset the "clock", or DNA being DNA, at least one of the clocks in cells, at will.
Which mostly causes aggressive cancers.
Some of our aging mechanisms are odometers on cell proliferation. These are adaptations to stop us from getting cancer.
You can be immortal right now. As a blob of cells in culture.
https://en.wikipedia.org/wiki/Henrietta_Lacks
Immortality has quite a history to it!
This makes no sense.
For instance, the statement:
> it's "an invention".
> As in natural selection decided at one point to introduce death. It really is the case that older lifeforms don't die. All mammals do though.
Natural selection is not an entity. It can not "decide" on anything.
What is here implied is that aging is an outcome of natural selection. Well, aging happens for many reasons, and it depends on how one defines aging (see Tom Kirkwood pointing this out decades ago); the implication meant here is that there has not been an optimisation towards perfection on the cellular (or organismal) level.
So, if damage occurs, the ideal situation would be that 100% of it is repaired. This does not happen. In theory it should be possible, but in actual practice, one will never have 100% repair, both on the DNA as well as protein/cellular level. Mutations will arise - that's for certain. There is no 100% perfect repair system. One can see this today with CRISPR-Cas9 promised as gene therapy tool, but whenever people ask about off-target damage and imperfect repair, those researchers dodge the question completely.
> if you study it, it becomes pretty obvious that in most cases reproduction and death are linked. Death is fundamentally a way to optimize reproduction, to control DNA variability and number of offspring.
I can not agree with this either. There are no specific death genes aimed at reducing life span per se (caspases/apoptosis has many functions, including formation of structure or killing virus-infected cells, among more functions). The main reason why reproduction is favoured, is because this is an evolutionarily stronger strategy, for most organisms. So more energy invested into offspring is more stable from an evolutionary point of view.
> The cells humans are made of are immortal, in the sense that human cells are capable of living and even reproducing indefinitely, if so directed by DNA.
Ultimately all cells are. Otherwise life would not be billion years old. The issue is not about immortality but damage and repair.
For instance, resetting telomeres in humans still would not make humans live thousand of years.
> Unfortunately this does mean that death is built into our cells and a lot of processes depend on aging and death.
No, it is not. What should that be? Describe that mysterious word "death". Which genes are related here?
In theory repair or restoration is possible; it is a finite problem. The question is how long it will take to improve on gene therapy on the nanoscale level. For instance, it should be trivial to enhance CRISPR-Cas9 to eliminate off-target effects; and enforce repair only happens in a guaranteed way. But achieving 100% is very hard - biology is nowhere near as strict as physics. Many genes are transcribed in a leaky manner; that has been one problem in biotechnology and synthetic biology as well. You can see this when you ask the Biobricks guys "which synthetic elements give us 100% control over genetic system xyz". Good luck getting them to commit to giving a single example here.
> At that point medicine will have to radically change and every tiny trace of every minor infection will have to be treated as a life threatening condition.
That's also not logical. If repair or genetic change is 100% or close to 100% accurate, why would ANY "infection" matter? In other words: why would infections be immune from genetic change? ALL viruses/bacteria use DNA or RNA. They are not exempt from ANY change here.
>So, if damage occurs, the ideal situation would be that 100% of it is repaired. This does not happen. In theory it should be possible, but in actual practice, one will never have 100% repair, both on the DNA as well as protein/cellular level. Mutations will arise - that's for certain.
I mean, mutation and damage are different sides of the same coin. Without change you don't have evolution.
> ... the implication meant here is that there has not been an optimisation towards perfection on the cellular ...
This is why I'm limiting what I mean by death. Specifically to organism-wide senescence, loss of energy, and the death that follows. That senescence is very much programmed into our cells and is something that can be disabled (but as I pointed out, a lot of "downstream" inventions depend on it, so disabling it using current methods has disastrous consequences in practice)
We are also far short of the limits of human lifespan through damage. Old people die from "natural causes". What that is, exactly, is:
Step 1. the level of energy your metabolism produces within an entire cycle goes negative (ie. a 24 hour cycle, so there can be energy shortage during the day fixed during sleep, that doesn't cause this feedback loop to start)
When you're very young at this point homeostasis intervenes and refills your energy stores and go back to stage 1. However, that stops.
Step 2. In order to keep functioning your body effectively disables a system (there's dozens of ways this happens, from lowering blood suger to cutting blood flow entirely), reducing it's energy use. This starts with repair functions, then goes to immune response, and goes from there.
Mostly, at this point, we go back to step 1, and of course you stay alive while the energy level is dropping. But step 2 fixes less and less.
Step 3. Eventually your body has to cut critical functions. Digestion is not the first critical system to get cut, but let's say it is and keep things simple. You can disable digestion. Even just food intake itself (ie. keep water intake going). This will buy you weeks of energy, maybe months. But of course, this eventually causes more energy loss than energy gain.
Step 4. Your energy level drops to zero.
Very disconcerting is that I very much get the impression that moving from step 2 to step 3 is at least a semi-conscious decision. People decide, to an extent, when they die. Or should I say, people can consciously choose to delay it by a few months, at a cost. And certainly, they know pretty accurately when it will happen. I guess I'll find out sometime.
But this is not "damage". This is a combination of feedback loops, the way all "DNA programming" works. DNA has this death programmed in, and certainly in individuals you can achieve better outcomes by intervening externally. The time it takes for the mechanism to fire is also a parameter in our DNA, and obviously, the only way to implement this is with some sort of clock. Telomeres are thought to be part of the clock mechanism that does this, but they can't be the full answer.
Now you can say this is not "causing death". If anything, this is preventing it. And except for one major detail you're kind of right. That major detail is that increasing energy output is trivial, yet the system stops doing it (permanently increasing energy output is what happens during growth and temporarily increasing energy output is what happens during early aging). Your body restricts itself from that solution to the point that average energy use systematically decreases during your life after a certain point and that is what finally leads to a natural death, what finally fires off steps 2 and 3.
I don't claim that if you fix this there wouldn't be other problems, such as DNA damage, which would require their own solutions (even though we have that too. Crispr-CAS is restricted to short changes. But you can write an algorithm that, by combining literally tens of thousands of little Crispr-CAS cuts, repair essentially any DNA damage. And while that is probably not good enough a solution, you can easily demonstrate it works. Not working well enough, but working)
However, finding ways to do large scale fixing of DNA damage makes little sense until we can reset or disable the death clock.
> No, it is not. What should that be? Describe that mysterious word "death". Which genes are related here?
There are a great many genes involved, and many more regulatory factors. That's the problem. If it was one, "fixing" it would be easy. A famous example is p54, which puts a sort of absolute limit on cell age (when it fires, it activates other proteins that destroy the DNA, it fires off the self destruct mechanism of mitochondria and it rips open the cell membrane). There are also highly regulated genes that delay death under specific circumstances, like TERT changing the time at which such mechanisms will fire during cell division, for example.
You are assigning intentionality to these mechanisms, but as the other commenter pointed out a much simpler way to view it is that death and senescence are just side effects, not actual mechanisms with evolutionary purposes. Organisms get born and need to reproduce, that's the mandate. There is no evolutionary pressure for you to die, so obviously DNA does not have organismal death programmed in, it has cell death which is necessary for organisms to live long enough to reproduce. Many of the things that are optimal for you to reproduce might not be optimal for you to survive a thousand years, and what happens to organisms outside their reproductive cycle is pretty much irrelevant to natural selection.
> Death is fundamentally a way to optimize reproduction
You could equally argue that it's a way to optimize lifetime energy efficiency.
> The cells humans are made of are immortal,
Yes but DNA transcription is not error free and most body parts do not grow back after being lost, most perniciously, our teeth. Elephants grow 6 sets of them, but due to their diet, they can end up fully losing all their teeth before they die.
> it's dying of what you might call 99.9% victories against disease
The planet we live on is warmed by the Sun. The Sun's energy can also destroy our cells. It's not just disease.
Quite true. Regrowing teeth should not be too hard though - after all the information for growing teeth already is in most humans. One just needs the correct transcriptional activations again. I am sure this will be solved eventually; as for how long that will take ... who knows.
The odd thing is in Humans is that if we loose our teeth the jawbone itself also starts to recede. Part of the process of installing an implant is doing either a matrix or a cadaver bone graft in order to overcome this.
We are, in some sense, meant to accept the loss of our teeth, likely because it impacts lifetime energy efficiency in some way that we're not correctly observing yet.
This mammalian hardware we are running on is merely a bootloader, larva state, don’t take it too seriously. It was good enough to run us and I am grateful I woke up running on it.
This was an insightful comment, thank you for writing.
And here's to hoping that the exponentially growing technological capabilities will allow curing death in our (short) lifespans. By God we need that to counteract the ageing population.
having genetically modified human to become immortal sounds good
Not immortal, but virtually immortal. When the super-rich get these treatments and open the gates to live for ever. It will still be possible to kill them. They will not be immortal.
Absolutely, especially if you can mine them for electricity to keep datacentres going
probably easier to clone, and then somehow transfer memories to the new body. This made me think - is it our memories that create our consciousness?
I don't get why many folks are missing the obvious issue - even if you manage all that, its at most a copy command, there is never actual move. You yourself would be staring at this other guy, probably being envious since form now on its him / her having the future, while the actual you who wrote that comment is about to be removed for disposal. And whole representation of universe and Earth you have in your mind would die with you.
You would have to move every electron traveling in between each neuron into exactly same place, same momentum etc. All of them in the same time obviously. I stress the word move. In a system that is constantly moving on molecular level at crazy speed. Even that is only valid in case our consciousness is just electron cloud at given moment travelling in the brain. Maybe its more, all interconnected.
How you want to move that. The science for that won't be around for millennia, if ever (there may be quite hard constraints on quantum level in similar way speed of light is hard limit for Star trek utopias, universe doesn't rearange itself and change its laws just because of our emotional wishful thinking). Once we can do that, it means we could mess with telomeres, DNA etc with 100% precision and knowledge so this will be a moot point. Don't hold your breath for this.
The simplest way to "fix" that is killing the original one as a required and atomic part of the process. Make it so that there is no moment in time when both are awake and concious
But that is still asking people to get into the death box so that a clone of them can live on. Personally, I wouldn't accept certain death so a copy of me could live.
Not really. Having offspring & re-mixing genes in them, is one way how species (not individuals!) adapt to a changing environment.
Bacteria do that in ~hourly intervals, humans take decades, some plants can span millenia.
So you could say the 'update interval' is tuned to how fast-changing a species' environment is. A balance between energy 'wasted' on re-building individuals from scratch, vs wasting energy by having poorly adapted individuals.
So 'immortal humans' to me reads as: humans optimized for a caveman hunter-gatherer lifestyle, while living in Star Trek like tech-heavy surroundings.
If anything, humanity would be served by shorter lifecycles, until tech advances stabilize somehow (?). Okay a few individuals living way longer could be good. Eg. billionaire tech bros taking that spot? Please nooo!!!
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