Even a single cell without dividing can, theoretically, stay alive indefinitely if its endogenously deleterious metabolic processes are suitably counter-weighed by repair and disposal (autophagy).
Right, but with hundreds of trillions of cells, statistics is our enemy. Only one has to go down the path to cancer to kill us. Given 50,000-100,000 DNA mutation/epimutation/damage events per day, we're talking about roughly 10^21 events per year that our bodies have to deal with. Frankly, I'm impressed that cancer is kept in check as well as it is, but it doesn't take a biologist to figure out that something can go wrong without "perfect" repair systems, and there simply hasn't been enough of a selective pressure to evolve perfect repair systems. You yourself hold such as a tenet of evolvability.
I'm saying that cancer incidence rates would hardly be affected if we maintained our youthful repair mechanisms. It's reliability theory. You have a dozen or so genes that need to be (epi-)mutated, and these mutations happen at a fairly regular rate throughout life. Because of the way reliability math works, cancer rates might be negligible until we reach our 40's, and then balloon to the #1 cause of death just a couple decades later. This isn't because repair rates of cancer-causing mutations dropped. It's just statistics.
nuDNA mutations hardly accumulate with age in humans, due in large part to our very efficient repair systems. Nevertheless, damage does accumulate, and while this partially may be due to relaxed repair, I contend it is partially due to accumulation of damage that isn't repairable with even youthful repair systems. Perhaps it's because a repair mechanism itself was damaged, preventing it from doing its job properly. Perhaps it's because the damage itself is invisible to the repair system. Or perhaps it's because evolution hasn't perfected repair systems yet.
Damage accumulates, and cancer is the result. That's leaving aside all the other problems of DNA damage, as well as all the other problems of currently irreparable non-DNA damage, e.g. certain crosslinks, etc.
I contend that a biological 10-year-old would still get cancer or heart disease before reaching age 100 most of the time. A decline in repair rates may accelerate the process, but I'm not convinced that maintaining youthfulness might not increase cancer incidence rates. Some aspects of aging seem programmed, and they may be programmed to make us live *longer*. A loss of youthfulness makes us less fit against extrinsic mortality factors, but may in fact increase our resistance to intrinsic mortality factors.
You suggest that either
a) repair systems are not in sufficient abundance even during youth, or,
b) they do not functionally cover the whole spectrum of metabolically induced damage.
I have yet to see any evidence to support the latter - that damage exists for which a strategy to repair has not evolved - and whilst there is much evidence to support that repair systems enter into an age-related functional decline, there is no evidence to support that youthful repair rates are insufficient to sustain life (i.e. compare the damage accumulation in the cells of individuals between the ages of 10-20 versus 50-60)
(my emphasis, italicized portion quoted below by osiris)
I have yet to see any evidence to support the latter - that damage exists for which a strategy to repair has not evolved
mtDNA and nuclear DNA damage inevitibly accumulate as I explained in my paper. Secondary metabolic end points can take a great many forms, while some damage is specific and can be specifically repaired, much is not. There is no reason to suspect that we have evolved the ability to repair all of it (since much of it is on pathalogical only at ages which our species did not live to until recently).
Indeed, I feel this may be the case with certain types of mtDNA damage. Clonal expansion of a single mutation or deletion in mtDNA would take a minimum of 15-20 mitochondrial turnover cycles, and that's assuming that it had a 100% selection advantage. Assuming a more reasonable 20%, it may take 75-100 cycles. At 2-3 months per cycle, this means a single mtDNA mutation or deletion would take about 15-25 years to expand. With only a 10% advantage, it could take 30-50 years. So perhaps the reason that such damage accumulates measurably only in middle age isn't a sign that middle age is when repair is relaxed, but simply a sign that that's how long it takes the damage to be accumulate to a measurable level.
In other words, a 10-year-old might not have clonally expanded mtDNA mutations/deletions because those mutations/deletions are still busy clonally expanding. If it takes 50 years to clonally expand completely, then after 25 years, we'd only see half as many copies of the mutation/deletion... Half as many on a logarithmic scale, that is, which means there may only be less than a dozen mitochondria that are homochondric for the mutation/deletion, far below the detection thresholds I've seen in studies (10%-20%).
Don't get me wrong, I'm not saying that it's not possible that aging is only the result of relaxed repair. I'm just saying that there's a very weak case that this is true. I doubt there is any single cause of aging (unless you just want to attribute it to entropy, but that seems like a cop-out). Damage accumulation is probably about as important as relaxed repair, maybe less important, but maybe more important. We'll know in a few decades, perhaps a century. Until then, we need to keep our options open. SENS focusses on cleaning up accumulated damage, or at least it claims to. Digging deeper, we see that increased repair and maintenance have mischievously been hidden between the lines. What else is lysosomal enhancement, other than an increase in repair capacity? What else is allotopic exp
ression, but a robust method of maintenance?