A cell’s DNA is damaged, inducing a damage response.
As part of this damage response, mitochondria are shifted into a lower-efficiency state, producing less energy and more ROS.
The ROS then further damage DNA.
Since this is a positive feedback loop, it has two stable states: one state with low damage and ROS (the “normal” cell state), and one with high damage and ROS (the “senescent” cell state).
So here’s something I find confusing: apparently, nuclear bomb survivors (who almost certainly have incurred more DNA damage than average) do not seem to have an increased risk of dementia or worse cognition compared to controls (in fact, in the study I linked, the risk of dementia was non-significantly lower for those with .005-1Gy of radiation exposure compared to those with <0.005, even though the average age in each group was almost identical).
There’s also the finding that only 30% of the excess mortality in nuclear bomb survivors is not from cancer. This is almost certainly confounded by the fact that cancer usually kills people earlier than other old-age diseases, but perhaps not much, since the decrease in lifespan among survivors seems to be only a few months (2 months on average for those exposed to <1 Gy, which IIRC was probably around 80% or so of them). So it tentatively seems that (as one would perhaps expect) DNA damage from ionizing radiation disproportionately increases cancer risk, rather than uniformly increasing the risk of every age-related disease.
(On the other hand, this study of nuclear weapons workers does find a pretty large increase in dementia risk, even though those workers seemed to have gotten a similar-ish average dose of ionizing radiation as the nuclear bomb survivors did (although we don’t have data for all of them). So I don’t know what is going on here, but I thought this was perhaps interesting enough to share.)
who almost certainly have incurred more DNA damage than average
This is unclear—one-shot DNA damage can upregulate Nrf2/genetic repair, and does not recursively damage DNA the way transposons recursively damage them.
That’s interesting! Thanks for pointing that out. OTOH, they do get cancer at higher rates than the general population, which is suggestive of more DNA damage and/or worse DNA repair.
So here’s something I find confusing: apparently, nuclear bomb survivors (who almost certainly have incurred more DNA damage than average) do not seem to have an increased risk of dementia or worse cognition compared to controls (in fact, in the study I linked, the risk of dementia was non-significantly lower for those with .005-1Gy of radiation exposure compared to those with <0.005, even though the average age in each group was almost identical).
There’s also the finding that only 30% of the excess mortality in nuclear bomb survivors is not from cancer. This is almost certainly confounded by the fact that cancer usually kills people earlier than other old-age diseases, but perhaps not much, since the decrease in lifespan among survivors seems to be only a few months (2 months on average for those exposed to <1 Gy, which IIRC was probably around 80% or so of them). So it tentatively seems that (as one would perhaps expect) DNA damage from ionizing radiation disproportionately increases cancer risk, rather than uniformly increasing the risk of every age-related disease.
(On the other hand, this study of nuclear weapons workers does find a pretty large increase in dementia risk, even though those workers seemed to have gotten a similar-ish average dose of ionizing radiation as the nuclear bomb survivors did (although we don’t have data for all of them). So I don’t know what is going on here, but I thought this was perhaps interesting enough to share.)
This is unclear—one-shot DNA damage can upregulate Nrf2/genetic repair, and does not recursively damage DNA the way transposons recursively damage them.
That’s interesting! Thanks for pointing that out. OTOH, they do get cancer at higher rates than the general population, which is suggestive of more DNA damage and/or worse DNA repair.
What’s confusing?
Maybe you’re conflating an increase in DNA damage with an increase in the rate of DNA damage. The data is consistent with:
One-time exposure to lots of DNA damage (nuclear bomb) → Increased cancer risk
Increase in background rate of DNA damage (aging, working near ionizing radiation) → Increased dementia risk