> Indeed, the research team could extend mouse lives by nearly 3 months—the equivalent of about nine human years—just by gently squeezing their leg bones.
Assistant, your assignment for the next year is to give massages to these mice.
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 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.
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.
Cancer is known to be an entirely metabolic disease. Aging, likewise, is a metabolic failure (either implicitly or by natural design ie evolution, for whatever reason). Restoring metabolic function of cells always deages them. Restoring metabolic function of cancer cells always "decancers" them, for instance transplating mitochondria from a cancer cell to a healthy cell or viceversa. Curing aging necessarily cures cancer.
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/
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.
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.
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.
Thank you, bones
Somebody tell Brian Johnson all he needs is bones!
> Indeed, the research team could extend mouse lives by nearly 3 months—the equivalent of about nine human years—just by gently squeezing their leg bones.
Assistant, your assignment for the next year is to give massages to these mice.
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).
> In which situations a normal mammal find its bones squished (but not crushed)?
Running, exercising, etc.
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.
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.
Cancer is known to be an entirely metabolic disease. Aging, likewise, is a metabolic failure (either implicitly or by natural design ie evolution, for whatever reason). Restoring metabolic function of cells always deages them. Restoring metabolic function of cancer cells always "decancers" them, for instance transplating mitochondria from a cancer cell to a healthy cell or viceversa. Curing aging necessarily cures cancer.
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?
What do people even mean by "curing cancer", "curing aging", it's not like a single thing in the first place
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
Good thing I decided not to turn into a mollusk!
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.
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
The mandatory Bone Song[0].
0. https://www.youtube.com/watch?v=kHgRlsOvN3M
The leg bone connected to the aging bone.
Was kind of expecting/hoping for this bone song: https://www.youtube.com/watch?v=pDJKgi2e-Aw