Stochastic Nuclear DNA Damage in Aging
Nuclear DNA in every cell accumulates random mutational errors over time. DNA repair mechanisms are highly efficient, but nonetheless, some damage slips through. It is still an open question as to whether this damage is important over the course of the present human life span, at least beyond the matter of cancer risk, where it is well proven that more mutational damage means more cancer. Putting aside cancer for the moment, is there enough random DNA damage occurring in normal individuals to produce enough dysregulation of cellular behavior to in turn lead to meaningful levels of other forms of harm and lost function in tissues? The consensus among researchers is that this is the case, and nuclear DNA damage is listed in the noted hallmarks of aging paper, but that consensus has been challenged. This is largely a debate over theory and indirect evidence at the present time, however: is difficult to produce an animal study in which only random DNA damage is altered in degree, so as to definitively establish differences in outcome. There have been a few promising starts in that direction in the past few years, but much more work remains to be accomplished.
The cells in our bodies are constantly churning out proteins and other structures, built according to the blueprints contained in their DNA, which are crucial to supporting those cells' functions. And while in each cell most of the information contained in its DNA will be ignored, if an area of the genome important to the cell's function is damaged or develops mutations, the cell may produce misshapen proteins or simply stop functioning altogether. The effects of misshapen proteins can range from useless to actively harmful, as when neurons in a brain with Alzheimer's disease produce excessive amounts of the neurotoxic protein amyloid beta.
A few dysfunctional cells here and there don't pose much of a problem, but as more and more cells in a tissue accumulate damage over time, the health of the entire tissue or organ may be compromised. The body's normal way of dealing with such cells is to remove them through a type of programmed self-destruction called apoptosis, making way for new cells. Some cells, however, fail to die and enter a state of senescence, where they are incapable of replicating but are still left to take up space in the tissue. But especially dangerous is the case of a cell with damaged DNA that doesn't enter either apoptosis or senescence: damage drives mutation rate up each time the cell replicates, and if a mutation provides a survival advantage or switches off the cell's protective mechanisms against tumor formation, this can eventually lead to cancer. Cells that divide frequently, such as skin or lung cells, are most susceptible to this danger.
Our bodies may have evolved an impressive variety of damage repair mechanisms, but with increasing exposure to damage-causing agents in the environment and the damages caused by our own internal processes, compounded with the declining effectiveness of our protective mechanisms over time, DNA damage and mutations are bound to accumulate as we age. Some evidence suggests that caloric restriction may mitigate these effects. However, since no drugs yet exist that will prevent or repair DNA damage, all we can do at the moment is try our best to avoid harmful agents like excessive sun exposure and smoking.
One of Aubreys mentions of this matter is etched in my brain, he essentially seemed to consider it impossible to repair human nDNA anytime soon.
But he hoped it would not be a big deal for SENS since it already had "Nuclear bunker level protection by nature" or something like that.
But I never got that part, surely some AI+nanomachines could fairly easily (as far as sci-fi goes) figure out a way to fix it?
Might not be a problem that requires fixing.
Simply print DNA, pack it into cells and transplant into the body.
We can print DNA at the moment and we do stem cell transplants. We still don't know how to pack the DNA inside the cell as such. But we'll figure it out eventually. These are all near future technologies.
I wouldn't bank anything on nanomachines. Who knows when and if they will become a reality.
@Arren - Basically Dr de Grey is assuming that because we need such good DNA repair mechanisms to avoid cancer, the level of repair already performed by our cells means that non cancerous mutational load is unlikely to reach a level where it affects cellular function within a normal human lifespan.
Whether this is true or not is open to debate as it is difficult to test experimentally.
Mmm, can't we test it by removing telomerase gene from mice? Or do they have ALT too?
Antonio: there have been several strains of such mice around for decades now: they are immune from most forms of cancer (they activate ALT in some cases, and in other cases involving first-generation mice the tumors are able to grow big enough with mice's long baseline telomere lengths that an otherwise-nonfatal tumor kills them without becoming a cancer proper (no metastasis)). They only show only very mild phenotypes until you breed them for four generations, during which their long background telomeres get shortened with each generation; once you get to Gen 4, their remaining telomeres are short enough that they get a lot of stem cell dysfunction and can't properly renew their skin, guts, lungs, etc.
But this doesn't address the question of non-cancer (and non-senescence, non-apoptosis) mutations' role in aging, and Dr. de Grey's strong argument in favor of the position laid out by Jim above. These mice have short telomeres and no telomere maintenance mechanism (except when they activate ALT), but they don't have an excess of nuclear mutations.
Hi Michael,
My point is: have these cancer-immune mice being subjected to increased mutation rates by radiation or whatever? I mean, enough radiation to (supposedly) accelerate aging but not enough to cause radiation poisoning. If so, do they age faster than WT mice or non-radiated cancer-immune mice? Do they have shorter lifespans? (And the same questions but being administered senolytics.)
Hi, interesting !
2c. I think that nuclear DNA damage is far more important than we give it credit and to say that the current cancer-repairing mechanisms are so strong/that non-cancerous mutational load will be futile and that, thus, we won'T have to worry about that type of Damage, is wishful thinking.
You just have to look at certain mutational diseases like progeria, which an accelrated form of aging, they show a high number of short(er) telomeres and the rate of telomere shortening is dramatically faster (on order of 500 nucleotide bp per year (progeria) vs 50 bp/y (healthy)), equalling to about nearly 10 biological years lost each subsequent chronological year (1 kb (1000bp telomeric DNA = roughly 20 chronoligcal year human life); meaning they age almost
10-times faster. They accumulate nuclear DNA Damage and mutations
by chromosome/histone dysfunction in Lamin A/Progerin; one study found out that 'healthy aging' is just a form of 'slowed' progeria; the study demonstrated that Chromosomes become decompacted (decompaction of coiling, become 'loose') and decondensed, this in turn affects Histones and Lamin (the study showed that the exact same order of mutation appeared (like Lamin and histones loss in chromosomes) in healthy aging people, just spread longer over time by the reduce amount of oxidative stress (progeria people having ten times more oxidative stress, dying 10 times quicker).
Mice that have shortened telomeres die much quicker because of impossibility to rejuvenate dying organ tissues (stem cell telomere attrition, thus lack of stem cell differentiation into said tissues), they may have very long telomeres but studies show that mice's telomeres who shortened faster/accumulated tons of 'small telomeres' in the lott of tall ones - die quicker too; another study showed that telomeres size at birth (in birds) determine the complete lifespan and that there is a pretty linear loss until death (they followed that telomeres length from birth to death).
we give not enough credit to nuclear DNA telomeres because they are not accurate like DNA methylation clock aging method (S.Horvath method), but yet they are clearly the major determinant of our lifespan (in tandem with DNA methylation changes elicting telomeres structure changes too). As for non-cancerous mutational load having an impact or not, I think it does have an impact and we shoud not downplay it;
the fact that these mice with smaller telomeres who are cancer mimmune die of sort of late progeria is a demonstration that it all ends up into the senescence realm one way or another (replicative, oncolytic, DDR stress-induced types). Because telomeres are the deciders in many of these diseases (being guardians of cell cycle and senescence/apoptosis), they may not display telomere shortening but definitely 'telomere signaling/Nuclear DNA signlaing' which can alter cell cycle dynamics (cell cycle arrest, such as p53, p16, p21 oncogene caused) and thus cause inflammation/inflammation driven diseases; which are tantamount to accelerated 'helthy intrinsic' aging (just through another pathway than regular long-span replicative senescence-aging in healthy people which makes for telomere shortening over long decades (a slow progeria of slowed telomere attrition by reduced oxidative stress burden but that gets heavier with age (altering the Redox)) rather than a couple of years in advanced diseased states that are fatal). So to sum, stochastic nuclear DNA damage is the most major determinant of aging (as seen in progeria who acquire nuclear mutations and accelerated telomere loss/genomic dysfunction), because nuclear DNA is housed in nuclear telomeres and chromosomes (which they themselves dictate maximum lifespan). Just a 2c.