> the findings are not “a demonstration of a new antiaging treatment for people,”

Regardless, every other study shows only positives of lifting and regular exercise, so just do it!

> If these all actually worked, I'd presume that there would have been a study on the miraculously healthy 80 year old mice.

That assumes the techniques compound additively, which is not necessarily the case. Even the best things for you, like water, become detrimental when you have too much. It may also be that some beneficial actions reduce the benefit of different ones.

It's always nice to get a new data point confirming that exercise and lifting is good your you, even better if it's through a new mechanism like this one.

this is not a data point that confirms that exercise and lifting is good for you. think of it like telomeres: they give you a choice, "cancer or youth, pick two or don't play"

science like this is very useful like one puzzle piece is very useful: only in the context of many other puzzle pieces, but they're also jumbled together from many different complete puzzles.

It's said cats purr to strenghten their bones. Perhaps the mechanism is related. It would be interesting to see if besides exercise, vibration can trigger it in humans as well, perhaps checking people that worked with pneumatic hammers or other vibration exposed workplaces.

The feline purring for healing is in Margaret Atwood’s MaddAddam trilogy and I just blew it off as too fantastical, but I’m prepared to eat my words metaphorically speaking.

>In 1995, Metcalfe argued that the Internet would suffer a "catastrophic collapse" in the following year; he promised to eat his words if it did not. During his keynote speech at the sixth International World Wide Web Conference in 1997, he took a printed copy of his column that predicted the collapse, put it in a blender with some liquid and then consumed the pulpy mass.[26][27] He had suggested having his words printed on a very large cake, but the audience would not accept this form of "eating his words."

https://en.wikipedia.org/wiki/Robert_Metcalfe#Predicted_Internet_collapse

After a broken foot, my mother was prescribed a vibrating Bone Healing machine. I thought it might be placebo, maybe not.

Why would it be a Placebo? It physically stimulates the body, a placebo would be rather a sugar pill.

In general, everything that moves/activates the body in a non damaging way is good for recovery.

With a broken foot I would be rather worried that it stimulates too much. But bodies are not made to lie around.

Placebo doesn’t mean literally a sugar pill. It means something that has a positive effect based on perception.

  > Placebo doesn’t mean literally a sugar pill. It means something that has a positive effect based on perception.

It literally means "that which satisfies", from the same root as the word pleasure.

It does not have to have a positive effect. A placebo can have no affect at all, perceived or otherwise. It must have no active mechanism to improve the specific condition being treated.

Maybe it's just a TV shopping gimmick that only has a negligible effect. My bet would be that it does much less than any actual loading of bones and muscles.

Edit: I missed that it was prescribed, so maybe it does have a serious effect after all.

"In general, everything that moves/activates the body in a non damaging way"

So sure, some injuries require not moving to heal. But at the cost of degradation of everything else. And also there activation of the tissue around to keep the blood and lymph flowing is beneficial or rather crucial.

Also since I like extreme sports, I kind of was made an expert in recovery by life.

> perhaps checking people that worked with pneumatic hammers or other vibration exposed workplaces.

Those probably add too much variance. For example, someone working with pneumatic hammers likely works in construction and has a likelier chance to also be exposed to harmful dust, or being in the sun a lot, or getting injured on the job. It may also be that too much vibration (too long and/or too strong) would be harmful.

I’m probably too old to see any benefit from the coming anti aging treatments and societal turmoil. I’m ok with that. Getting old does suck though. The proteins in question are piezo1 and pigment epithelium-derived factor (PEDF).

If you can why not test that probability? You might get a surprise.

If this were a mechanism that appeared under some kind of evolutionary pressure. What would that be? In which situations a normal mammal find its bones squished (but not crushed)? Or is it just a side effect of something else going on?

Pure speculation on a few possible explanations (noting that TFA describes ordinary exercise as generating enough squishing force, any other actions the researchers did being to isolate the causal factor):

1. Mammals don't naturally exist in environments where exercise isn't mandatory. _Some_ system had to generate those compounds, and there was never any pressure to keep it from being tied to the other stress-related changes bones undergo (like density changes). Once it evolved once somewhere in some critter once via that machinery, the advantage was large enough that it was locked in.

2. Exercise directly contributes inflammatory factors. Tying the cure to those to a measure of exercise intensity (bone squishing) helps calibrate the dosage. Even if an imperfect measure, the proxy of bone loading might confer some advantage in, e.g., not wasting energy on unnecessary proteins.

3. Exercise indirectly suggests a resource-poor environment, leading to lower chance of offspring succeeding and needing longer lives to produce enough viable offspring. The compounds in question aren't free to produce, so there's an advantage in only providing them to organisms who will meaningfully benefit. Mind you, resource-poor environments often promote shorter lifespans and faster growth cycles as an evolutionary trait, _but_ without a mechanism to force your offspring to mature more quickly the osteocyte-mediated lifespan could allow for resource-dependent lifetime offspring counts.

4. The mechanism could have evolved for unrelated reasons, perhaps directly contributing to the bone density calibration osteocytes already mediate. Any impact on lifespan is incidental or otherwise produces less evolutionary pressure for or against the feature than the direct purpose of the compounds.

5. More than having evolved for unrelated reasons, the fact that the compounds have any effect at all might not be evolutionarily selected for. We produce plenty of unimportant metabolic byproducts that we don't particularly care about, and it could be that some more important osteocyte function incidentally produces these "waste" proteins.

Your third point makes a lot of sense and matches a similar mechanism with all the 'caloric restriction' relations with longevity.

It would seem plausible that there may be more than one mechanism via which resource scarcity creates pressure for increased longevity (to increase the odds of offspring).

I'm pretty skeptical of this idea. I would almost expect the opposite, that if you're not exercising than you're likely not contributing to the group so your offspring has a better chance of survival if you die. We know ancient humans often took care of their elderly well beyond the point of being able to physically assist with daily tasks so I would almost expect this to be an end of life marker than anything to do with resource scarcity.

Also, I think studies of poverty show generally show that resource scarcity is almost always worse for health outcomes. Resource over-abundance is maybe also damaging but the idea that being resource scarce is beneficial for longevity because you need longer to mate seems almost certainly false to me.

I think 3 is the most speculative.

Caloric restriction is probably exactly like exercise in that it was normal, so "scheduling" autophagy for the "famine" times meant it happened regularly and alongside similar systems.

What did it for me was that IF comes with muscle growth hormones increase.

I mean a 3-5 day hunt can look a lot like a marathon and a fast / IF mashed together.

I know people asked for it, but I find these types of evolutionary explanations to be very unconvincing. The primary reason is they are largely unfalsifiable narratives. The secondary reason is they are sometimes used to justify positions and viewpoints that would otherwise be unjustifiable.

Evolution is the unifying concept underlying all of biology. Finding and testing evolutionary explanations may be difficult, but not looking for such explanations is akin to saying to someone speculating about why, say, some wooden structures are stronger than others, that "I find these explanations of physical effects in terms of gravity and electromagnetism very unconvincing". Wood is a complex material, so understanding its properties is difficult. But if your explanation of wood's properties is incompatible with fundamental physics then there's something wrong with it.

Similarly, explanations of aging that amount to "the body just for no reason fails to do something that it easily could even though it's obviously beneficial" are pretty much like explanations of physical processes that violate conservation of mass/energy. There had better be some possible evolutionary explanation, since otherwise it's very likely that the result is due to some experimental error.

> unfalsifiable

If we're trying to piece together how the past actually happened based on the shadow it left on the present, yes, falsifiability is hard, sometimes possible to achieve. Most of the speculations I provided could be reasonably well tested though.

Take (5) as an example. If you find other important byproducts from the associated genes, those strengthen (5)'s argument. If you find significant negative effects from the new "miracle" proteins, those strengthen (5)'s argument. If you find an organism with an energetically intensive mechanism for removing these new "miracle" proteins, those strengthen (5)'s argument. If you apply a medicinal intervention to allow the gene to be enabled but those particular "miracle" proteins to be disabled in a wild population and observe the gene frequency dwindle, that strengthens (5)'s argument.

None of it's perfect, but there are a variety of experiments and observations you can do to strengthen or weaken your belief in specific causal mechanisms.

> used to justify unjustifiable positions

I go back and forth on this one. Should you hide information (in this case, not even very good information, just plausible mechanisms, provided because somebody was a bit curious and I thought scratching that itch might help them on whatever journey they're currently undertaking) just because it's possible to misunderstand it? Because it's prone to misuse?

Like, obviously if people are concluding from a list of guesses appropriately described as such that osteocytes evolved to extend life as a poorly calibrated part of the exercise process, that's not justified. What happens when people extend similar wild speculation to gender or racial differences? You're right, it's a touchy subject.

On the other hand, that's an argument against:

- Data-driven organizations -- a common cognitive bias is the spotlight effect, and applied to "data-driven" organizations it often leads to abandoning intuition and reason when the best proxy measurements you're able to perform incorrectly suggest a different course of action to be optimal.

- Giving correct estimates to your PM -- you know the organization will run more smoothly if you start unraveling the spaghetti sitting in fromt of you, but (in many orgs) it'll take longer to argue that point than it will to just do your job correctly, so you fudge ticket descriptions and estimates to make sure critical maintenance happens.

I try to evaluate that sort of thing on a case-by-case basis. I think it's fine here. I don't have a good justification for why I think that.

The skeleton is economical:

Repair pays off only when the skeleton is used -- we can invest in repair because we know the animal is active/foraging and we will get paid back on the investment.

Low loading is a sign that we should cut back on maintenance -- the animal is sick, injured, starving etc and it's better to conserve energy.

The optimal amount of exercise is what tells your body to invest in repair, without acquiring repair debt. Sedentary life is the misleading signal, because it tells the body you're declining when you aren't.

I live in a ski town. Every day, particularly in winter, provides opportunity for expending effort. I don't have kids, but my friends do, and a decent amount of my efforts at least amount to teaching them how to ski and shoe and whatnot (and generally mucking around).

Given two tribes, one where their elderly are contained at home, and another where they're wandering and learning and teaching, I guess I could see a hypothetical fitness function.

I can't imagine it's too strong, though. A simpler, more-mechanical explanation may make more sense: when you stress bones, you set off all kinds of repair processes, many of which have systemic effects.

Why stressing bones leads to repair processes but stressing other parts lead to inflammation?

inflammation _is_ a repair process (part of it)

Also, bones specifically need to adjust to the weight distribution that they're supporting. Bend a bone, and over time it'll add material on the inward side and lose it on the outward (convex) side. This is a normal, ongoing process. It's why bones are piezoelectric.

> In which situations a normal mammal find its bones squished (but not crushed)?

Running, exercising, etc.

In the article they mention exercise. Basically your muscles squish your bones while you do physical activity.

What evolutionary pressure led to that? If I have to guess animals that were still able to hunt/move/... for longer were also able to mate for longer.

This reminds me of the relatively recent discovery/realization of the “second heart” in our calves that pumps blood from the legs.

I thought that was pumping the lymph system. For which there is no heart (other than the muscle pumping?)

For me, a more interesting question is that if our bodies can arbitrarily slow down aging by releasing proteins, why wouldn’t they just do that?

Maybe there is some evolutionary trade-off behind it?

Why do we die of old age in the first place? My money's on it being a strongly positive evolutionary force for a species. Almost all organisms age. It would make sense to me that the ones that tried not aging are gone now, likely because they were much much worse at adapting to changing conditions than ones that could reroll the dice every generation. I would further guess that the healthy oldsters filled up their ecological niche and blocked the young individuals from gaining a foothold.

But that argument doesn't prevent limited mechanisms, and conditional mechanisms in particular would still be rewarded. Conditional mechanisms provide much more short term adaptability to changing conditions, without damaging the long term species-wide adaptation.

There are intriguing parallels with centrally planned vs market economies.

My guess is that anti-aging traits don’t get selected by evolution since reproduction has already happened in the younger years of the organism.

Natural selection doesn't work like that. Having two offspring is good. Having three offspring is even better. Having ten offspring is really great. More than than ten is greater still...

There's a common theory that for mice, they're unlikely to survive for many years because of predation, so there's not much benefit to preventing aging in later years. Small benefit means any counterbalancing disadvantages (lower vigour?) could outweigh the anti-aging benefit, or that the force of selection is insufficient to overcome random mutations that degrade the anti-aging mechanism, but "that's good enough, no need for more" is not how evolution works.

I don't know if any bodily phenomena are so easily explained. The insides of a single cell are insanely complex, and to try to apply a singular causal explanation to macro phenomena seems implausible.

I wonder how much older adults could benefit from adding simple squats or sit-to-stands to their daily walking routine.

I've found standing is hard. However a treadmill desk isn't too bad. I'm not able to run while I work, but a somewhat slow walk is easy and I can do that for hours.

I wonder if that explains the benefits of walking, despite being a light activity. Also the paradoxal fact that being slightly overweight appears to decrease mortality.

Slightly overweight also gives you some more buffer if you get a disease that screws with eating/digestion/metabolism. Skinny and old is a bad combo for mortality.

William Shatner.

What are the proteins??

So in mice running doesn't do it but vice grips on the bones do?

How would that translate to lifting weights or other exercises?

It's not quite vice grips; I had to dig into the paper to understand it. Their specific DTAL protocol provided "moderate mechanical loading" of "2 N at 2 Hz for 300 cycles, twice/week, [for] 3 months". For reference, a 200g stationary object exerts that much force on a surface due to gravity. With 300 cycles at 2Hz, the exercises lasted for 150 seconds, or 2.5 minutes, and the exercises occurred twice a week.

Note, however, that their experimental model section says they applied axial force (think columns, not joists) to the tibia using an ElectroForce 3300 (https://www.tainstruments.com/3330-system/) while the mice were under anesthesia. From this, it seems like they knocked out the mice and placed their legs underneath a mechanical ram to apply axial compressive forces.

Because people are typically awake when exercising, given that muscles are designed to carry forces around the skeleton, I imagine, even after scaling from a mice to a human purely by sizing, the human force equivalent will be many times higher.

If you're looking to try this out for yourself, the seated leg press will most closely simulate the study's method. Figure out what "moderate" loading is for you, and shoot for 3 sets x 10 reps at least twice a week. Overall, choose skeletally-compressive exercises where you're "pushing," such as weighted squats (e.g. barbell squats) and any type of "press" exercise like the leg press, chest press, military press, and even cycling (you push your pedals). For the purposes of this study, avoid exercises with any pulling motion, including pull-ups, pull-downs, rows, and swimming.

From a force perspective, running has some compressive elements, but the load comes from gravity alone, and good runners minimize compressive forces. Since running therefore is primarily a pulling exercise, I can sort of see what they're getting at.

The paper mentions briefly how it would translate as human therapy:

> Importantly, DTAL was safe as the internal loads on the human tibia were predicted to be as high as 4.7× body weight, which is within physiological limits67 (∼3,000 N for a 65 kg individual), as instantaneous contact forces to the tibia can reach 6× body weight during running.68

I wonder if skipping rope/hopping might be the best way.

TFA explicitly calls out exercise as something which would generate those compounds. Exercise has many other impacts though, so if you're trying to isolate osteocytes as a causal factor you want an experiment which avoids interacting with those other systems as much as possible.

Lots of kinds of interactions with the physical world could potentially compress or jostle bones

Actually, this reminds me of how use of mobility devices is closely associated with mortality.

One has to wonder what will become of cancer if aging is ever cracked. I really think cancer is the reason life evolved to have age. Because then most cancers can age rapidly and die out early, before they've taken their host with them. We still get cancers, but I would guess we'd get a lot more without age, and not just because we'd live longer.

There are actually multiple forms of cancer that don't reactivate telomerase, and as a result age rapidly and die out on their own. Sometimes these are called pre-cancers, because they could still end up reactivating telomerase before they fully die, and then becoming a full cancer. A lot of them don't however, and a naïve solution to aging would remove this pre-cancer grace period entirely.

Isn’t it the case that the average size of an organism (at least in mammals) correlates a lot with lifespan and cancer rate?

Elephants and whales get cancer much less than humans and humans get it much less than rats. If cancer mutations are a dice roll than the more cells an organism has the more “will I become cancerous” rolls happen, so larger organism had to evolve better mechanisms to kill cancerous cells before they get out of control.

I would guess that smaller animals typically die quickly in the wild, so they don't really face selection pressure against cancers. Larger animals live longer and select for more cancer suppression, including because of their vastly increased number of dice rolls, but also because the longer lifespan leaves more room for cancer over time.

Cancer sort of is a single type of thing, which is any mutation that succeeds at uncontrolled division. This can happen as a replication error, or from radiation damage, etc. There are an infinite number of particular mutations that can succeed, and so you get infinite expressions of cancer. But fix the mutations in general, and you fix the cancer.

Aging we don't fully know about yet. Naïvely you would definitely run into cancer problems without it, so that's why I wonder. We'll have to see.

https://news.ycombinator.com/item?id=49832938

I think you're downplaying the complexity of cancers, viruses are also sort of a single thing, if you don't think too long about it, yet you will never find a single "cure for viruses"

There sort of is a "cure for viruses", actually, but it requires perfectly controlling environment and intake rather than only altering the body, so it's less realistic to live with. Compare replacing unstable RAM sticks to cutting all network access.

This doesn't stop viruses from existing in the first place, though, only from reaching you. If you wanted to stop them from existing in the first place, well, you would indeed have a bit of a hard time. Controlling mutation could theoretically stop cancer from emerging in the first place, if we solve the somewhat less hard problem of altering the whole body (rather than altering the whole planet, as with viruses).

Radiation damage causes the replication error.

Aging and cancer have some shared metabolic pathways, but your framing is an extreme oversimplification.

Consider the accumulation of mutation that would occur in a cell not subject to aging.

You could just as easily find support for the counterposition: aging, in a sense, prevents cancer. [0]

0: Judith Campisi, "Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors," Cell 120:513–522 (2005). https://pubmed.ncbi.nlm.nih.gov/15734683/

Edit: you edited your comment to talk about mitochondria transplants, but the science I am aware of actually points in the opposite direction: https://pubmed.ncbi.nlm.nih.gov/25565207/

Do you have supporting evidence?

I have to thanks gym bros on Instagram for making me start squating. Your legs are your biggest and strongest muscles, so even we ignore this research, they your biggest ally to control insulin/blood sugar.

The identified factor is exercising one’s own bones, not eating them.

Exercising them to make them release a factor, which must mean some specific protein. Maybe that could be obtained elsewhere, and eaten.

"..and eaten"

Probably not effective, our gut is very good at splicing up proteins into constituent amino acids.

If you want specific proteins/peptides in your bloodstream*, for now the most reliable way is generally to inject them.

But yeah, it is very much not necessarily the case that our own bodies will produce the same proteins under similar exercise, or that the mouse proteins released would have the same effects in us as in them, or that proteins released under similar exercise would actually de-age us.

It's interesting to track down the mechanisms in mice (exercise induces protein release - how? - which then de-ages the mice - also, how?) but you have to reproduce the work entirely separately in humans. Not just because it might not work, but because it is very important (and neat!) to understand the biochemical mechanisms of human ageing and de-ageing, and that understanding of How Things Work is a big part of the long-term reward.

[*] I'm not advocating for injecting untested/unregulated proteins or peptides, only speaking of ROA, route of administration