Evidence Against the Role of Nuclear DNA Damage in Aging

In some circles within the aging research community it is taken as read that accumulating damage to nuclear DNA - the DNA that resides in the nucleus of your cells - contributes to degenerative aging, most likely by causing cellular maintenance and other programs to run awry to an ever increasing degree. The nucleus of the cell is well protected, and equipped with extremely efficient DNA repair mechanisms, but nonetheless damage accumulates across the years. Being alive necessarily involves the generation of reactive chemical compounds, and sooner or later some of them run into the structure of DNA within a cell and react with it. The processes of DNA repair, while ever watchful, slip up once in a while and fail to fix the resulting breakage. Every cell bears its load of unrepaired mutations.

This sort of ongoing stochastic damage is certainly a contributing cause of cancer: the more mutations you suffer, the greater the chance that one or more of them manage to alter cellular programming in just the right way to create a cancerous cell, readily to act as the seed of a malignant neoplasm. That's just a numbers game - you can be unlucky and suffer cancer young, but you are far more likely to suffer cancer later in life.

But is nuclear DNA damage a cause of general degenerative aging? Is it actually a contributing cause of frailty, failing tissue maintenance, failing organs, and so forth? The point can be argued; Aubrey de Grey puts forward the position that the levels of nuclear DNA damage experienced don't rise to producing any significant effect outside of cancer risk over a human lifetime. If we live far longer than our ancestors, as we hope we might, this damage will probably become something that has to be dealt with at some point - perhaps via swarms of adaptive medical nanorobots akin to the chromallocytes envisaged by Robert Freitas.

Standing on the side of those who argue for DNA damage as a cause of aging is the data resulting from the study of various DNA repair deficiency conditions, many of which present what appear to be the symptoms of accelerated aging, in addition to raised cancer risk. There is also the connection between DNA damage and increased cellular senescence - an accumulation of senescent cells is also thought to cause some portion of degenerative aging, and recent work has shown benefits in mice by their removal.

Via Extreme Longevity, my attention was drawn to a recent paper that adds more weight to the idea that nuclear DNA damage isn't in and of itself as important to aging as might be thought:

DNA damage in normally and prematurely aged mice

Steady-state levels of spontaneous DNA damage, the by-product of normal metabolism and environmental exposure, are controlled by DNA repair pathways. Incomplete repair or an age-related increase in damage production and/or decline in repair could lead to an accumulation of DNA damage, increasing mutation rate, affecting transcription and/or activating programmed cell death or senescence. These consequences of DNA damage metabolism are highly conserved and the accumulation of lesions in the DNA of the genome could, therefore, provide a universal cause of aging.

An important corollary of this hypothesis is that defects in DNA repair cause both premature aging and accelerated DNA damage accumulation. While the former has been well-documented, the reliable quantification of the various lesions thought to accumulate in DNA during aging has been a challenge.

Here, we quantified inhibition of long distance PCR as a measure of DNA damage in liver and brain of both normal and prematurely aging, DNA repair defective mice. The results indicate a marginal, but statistically significant, increase of spontaneous DNA damage with age in normal mouse liver but not in brain. Increased levels of DNA damage were not observed in the DNA repair defective mice. We also show that oxidative lesions do not increase with age.

These results indicate that neither normal nor premature aging is accompanied by a dramatic increase in DNA damage. This suggests that factors other than DNA damage per se, e.g., cellular responses to DNA damage, are responsible for the aging phenotype in mice.

Nuclear DNA isn't your only DNA. The mitochondria swarming in your cells carry their own lesser portion of DNA - this is far more vulnerable to harm, and damage has far greater consequences given the central importance of mitochondria in metabolism. Progressive damage to mitochondrial DNA most likely provides one of the greatest contributions to degenerative aging, given that mitochondrial function and resistance to damage appear to be one of the most important determinants of differences in life span between species.


Only nuclear DNA damage in neurons would pose an obstacle to the SENS approach. Nuclear DNA damage in cells that turn over throughout life could be bypassed by renewing the progenitor stem cells with fresh, undamaged ones from an external source. Even cells that don't normally turn over could be induced to do so, except in the case of neurons for obvious reasons.

In that light, it's encouraging that age-related nuclear DNA lesions were not detected in the brain cells.

Posted by: José at March 21st, 2013 5:22 PM
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