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
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.
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.
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.
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).
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'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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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).
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/
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 live long enough for natural selection 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.
> 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.
But also, no need to exercise - just have something push on your bones gently all the time, right?
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.
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.
I’m probably too old to see any benefit from the coming anti aging treatments and societal turmoil. I’m ok with that. The proteins in question are piezo1 and pigment epithelium-derived factor (PEDF).
There are some signs that heat stress hormones may protect against Alzheimer’s.
They studied a family in which early onset Alzheimer’s was strongly prevalent. In the subject’s family tree, 32 cases, but he was older than his deceased relatives at the time they developed symptoms, despite carrying the markers. The only thing they could track down was that he had an elevated level of heat stress proteins in his blood and brain, and they seemed to be slowing down plaque buildup. More study needed.
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.
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.
If these all actually worked, I'd presume that there would have been a study on the miraculously healthy 80 year old mice. As it stands I have to assume that most of these mouse studies are fundamentally flawed to begin with and we simply don't check for adverse reactions/overlapping mechanisms/long-term maladies.
> 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.
I wish there was some nuanced line for science journalists to not hyperbolize about nothingburger studies in dire need of replication while also making the science exciting, slow of a process as it is. Maybe every article includes a history of the that very specific and narrow sub-branch of the field? That would be really interesting to read, and to have a gauge on how far we've come.
The issue is mainly with HN users not bothering to read the submissions and just writing armchair commentary on either side of the debate.
The authors of this study have identified the upstream protein responsibile for the anti-ageing effects in mice, that this protein has anti-senescent effects on human cells, that this protein drops with age in humans, that it drops more in humans with age-related disease and that this protein could have a protective effect in multiple chronic diseases in humans based on mendelian randomization.
This implies a stronger therapeutic potential than just a "nothingburger study".
Lovely response. I do this kind of work (recent Nature paper below) and my main concern is demonstrating that effects are first replicated in multiple genomes of mice.
The Cell Metabolism paper is a study on one genetic background. Mendelian randomization helps but is a tricky suite of methods that makes strong assumptions. In vitro also great but gameable.
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.
> 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 wor too strong) would be harmful.
110 comments
[ 0.20 ms ] story [ 28.8 ms ] threadHow would that translate to lifting weights or other exercises?
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.
> 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
0. https://www.youtube.com/watch?v=kHgRlsOvN3M
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.
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.
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).
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.
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.
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.
Running, exercising, etc.
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.
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.
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.
Maybe there is some evolutionary trade-off behind it?
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.
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.
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
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).
This one seems pretty obvious. Even the *The Emperor of Maladies manages to bookend it.
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?
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.
for good bones and calcium
Assistant, your assignment for the next year is to give massages to these mice.
But also, no need to exercise - just have something push on your bones gently all the time, right?
They studied a family in which early onset Alzheimer’s was strongly prevalent. In the subject’s family tree, 32 cases, but he was older than his deceased relatives at the time they developed symptoms, despite carrying the markers. The only thing they could track down was that he had an elevated level of heat stress proteins in his blood and brain, and they seemed to be slowing down plaque buildup. More study needed.
Has me wondering about Alzheimer’s prevalence in Nordic countries and whether we need to be doing genetic screening for differential analysis.
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.
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.
Logic reminds me of: https://www.youtube.com/shorts/-XAXwIOC3po
I wish there was some nuanced line for science journalists to not hyperbolize about nothingburger studies in dire need of replication while also making the science exciting, slow of a process as it is. Maybe every article includes a history of the that very specific and narrow sub-branch of the field? That would be really interesting to read, and to have a gauge on how far we've come.
The authors of this study have identified the upstream protein responsibile for the anti-ageing effects in mice, that this protein has anti-senescent effects on human cells, that this protein drops with age in humans, that it drops more in humans with age-related disease and that this protein could have a protective effect in multiple chronic diseases in humans based on mendelian randomization.
This implies a stronger therapeutic potential than just a "nothingburger study".
The Cell Metabolism paper is a study on one genetic background. Mendelian randomization helps but is a tricky suite of methods that makes strong assumptions. In vitro also great but gameable.
https://pubmed.ncbi.nlm.nih.gov/42020758/
Regardless, every other study shows only positives of lifting and regular exercise, so just do it!
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 wor too strong) would be harmful.
See https://en.wikipedia.org/wiki/Hand_arm_vibrations