Some proteins in the nuclear pore complex (Nup205, Nup93 etc.)
Nuclear pore complex proteins not turning over in post-mitotic cells suggests a new hypothesis for aging I haven’t heard before:
Most cells turn over, but there are quite a few cell types that don’t or extremely slowly (brain, skeletal muscle, heart (only slowly), oocytes, podocytes etc.). Most things inside of those cells do turn over, but some structures only on the scale of decades (see above). I can see nuclear pore complex damage and histone damage feeding into DNA damage. If cells that don’t turn over spread their damage to cells that do, I could see how this might be the upstream ratchet on the “The DNA Damage <-> Mitochondrial ROS” loop, so it’s not the stem cells after all. A weakness of this model is that nuclear pore protein mutations aren’t really associated with progerias. The first thing I could think of to test this was looking at what happens if you transfer different organs from young to old mice and vice versa. Will report back what I find.
Writing up my thoughts here, since I did some more research a month ago, but unfortunately didn’t write it up at the time. I will probably not get to looking further into this any time soon. If someone else wants to pick up the torch on this feel free to do so. I find this is a good exercise to broaden my biology knowledge.
The number of peptides measured in that study seemed kinda small after looking at the table again. The long lifetime for Histone 3.1 etc. is not super robust. I looked at this other study that measured lifetime of proteins in mice and IIRC the lifetimes were just generally shorter. Also I am not sure how easily the lifetimes from mice translate to human etc., so the protein thing in particular I find less plausible now.
It then also occured to me that maybe Lysosomes filling up with gunk or whatever could be the problem. Currently I don’t have a great understanding of Lysosomes, and Claude Opus 4.6 even tells me there might even be this mechanism how post-mitotic cells get rid of stuff in Lysosomes, also generally they don’t really take up that much mass, so I don’t have great intuitions if this is generally plausible. I was hoping there is maybe just something that you can feed to mice that lands in their lysosomes and can definitely not be digested and then you could check if those mice look like they are suddenly aged by a few years, but I am not sure if something like that exists or could be designed. If that’s a thing, that seems like a great legible experiment.
Also after thinking about it more if it was mostly some specific long-lived cell types that make the difference, I’d expect if something messes with those cell types in particular, it would lead to some type of progerias, so this probably makes the idea of it being the somatic cell types less plausible. I am also not sure, if it is something from the post-mitotic cells that feeds into a self-destructive feedback loop in the mitotic cells, then adding a 70 year old heart or 70 year old brain would not suddently make you 70, it might just give your aging a 2x speedup boost which is harder to distinguish from things that are not the root cause like bad diet. Not sure but that could be tricky. Also if it is just those specific long-lived cell types that predicts you’d expect animals that are selected for different lifetimes or that rely on those cell types more or less to have different adaptions, so that’s a thing to check.
I just quickly tried to actually look at some graphs for some mouse papers that look at organ transplants, but I really don’t have the capacity right now to understand the details of those experiments. But yeah if it was the post-mitotic cells that don’t turn over, you’d expect a mouse to age faster after a heart or brain transplant, than a liver transplant.
Some more completionism for proteins that don’t turn over or only extremly slow in mammals:
Rec8 in Oocytes (it holds the chromosomes together)
Some histones (Histone H3.1 in this rat study)
Some proteins in the nuclear pore complex (Nup205, Nup93 etc.)
Nuclear pore complex proteins not turning over in post-mitotic cells suggests a new hypothesis for aging I haven’t heard before: Most cells turn over, but there are quite a few cell types that don’t or extremely slowly (brain, skeletal muscle, heart (only slowly), oocytes, podocytes etc.). Most things inside of those cells do turn over, but some structures only on the scale of decades (see above). I can see nuclear pore complex damage and histone damage feeding into DNA damage. If cells that don’t turn over spread their damage to cells that do, I could see how this might be the upstream ratchet on the “The DNA Damage <-> Mitochondrial ROS” loop, so it’s not the stem cells after all. A weakness of this model is that nuclear pore protein mutations aren’t really associated with progerias. The first thing I could think of to test this was looking at what happens if you transfer different organs from young to old mice and vice versa. Will report back what I find.
Writing up my thoughts here, since I did some more research a month ago, but unfortunately didn’t write it up at the time. I will probably not get to looking further into this any time soon. If someone else wants to pick up the torch on this feel free to do so. I find this is a good exercise to broaden my biology knowledge.
The number of peptides measured in that study seemed kinda small after looking at the table again. The long lifetime for Histone 3.1 etc. is not super robust. I looked at this other study that measured lifetime of proteins in mice and IIRC the lifetimes were just generally shorter. Also I am not sure how easily the lifetimes from mice translate to human etc., so the protein thing in particular I find less plausible now.
It then also occured to me that maybe Lysosomes filling up with gunk or whatever could be the problem. Currently I don’t have a great understanding of Lysosomes, and Claude Opus 4.6 even tells me there might even be this mechanism how post-mitotic cells get rid of stuff in Lysosomes, also generally they don’t really take up that much mass, so I don’t have great intuitions if this is generally plausible. I was hoping there is maybe just something that you can feed to mice that lands in their lysosomes and can definitely not be digested and then you could check if those mice look like they are suddenly aged by a few years, but I am not sure if something like that exists or could be designed. If that’s a thing, that seems like a great legible experiment. Also after thinking about it more if it was mostly some specific long-lived cell types that make the difference, I’d expect if something messes with those cell types in particular, it would lead to some type of progerias, so this probably makes the idea of it being the somatic cell types less plausible. I am also not sure, if it is something from the post-mitotic cells that feeds into a self-destructive feedback loop in the mitotic cells, then adding a 70 year old heart or 70 year old brain would not suddently make you 70, it might just give your aging a 2x speedup boost which is harder to distinguish from things that are not the root cause like bad diet. Not sure but that could be tricky. Also if it is just those specific long-lived cell types that predicts you’d expect animals that are selected for different lifetimes or that rely on those cell types more or less to have different adaptions, so that’s a thing to check.
I just quickly tried to actually look at some graphs for some mouse papers that look at organ transplants, but I really don’t have the capacity right now to understand the details of those experiments. But yeah if it was the post-mitotic cells that don’t turn over, you’d expect a mouse to age faster after a heart or brain transplant, than a liver transplant.
Mitochondria and Lysosomes could also run into issues in post-mitotic cells, as well as other things I haven’t thought of.