Nuclear DNA Damage Correlates With Aging

The overwhelming balance of scientific evidence shows that damage to nuclear DNA increases with age. This is one of the reasons why cancer is an age-related condition: as time goes by there is an ever greater chance of some cell somewhere in the body suffering just the right combination of mutations to become cancerous. The mainstream position is that this damage also provides a meaningful contribution to the broader aging process by causing disarray in the processes of cells where it occurs, although this point is debated. It may be that beyond cancer incidence the level of nuclear DNA damage suffered over the present human life span is not large enough to provide a significant contribution to age-related disease, frailty, and death.

Here is a review of the literature that confirms the correlation between nuclear DNA damage and age. It is necessary in the scientific process to continually anchor every concept with ever more evidence, especially when the matter at hand is a complex system only partially understood:

Although DNA is not the only target changed with aging, taking account of the major role of this macromolecule in the regulation of all cellular structures and its own cell cycle, DNA damage has been studied with particular attention. The alterations could have several consequences for genome stability with repercussions on cellular component synthesis, cell cycle machinery and signaling pathways that control cell cycle arrest, and programmed cell death or apoptosis. The consequences of DNA damage will depend on the type of damage, genes affected and type of cell and tissue damaged.

The prevailing view is that there is a tendency for an age-related DNA damage accumulation. However, on examination, results of studies show inconsistency; it is possible that confounding factors influence this relation and explain some of the inconsistency. Factors such as diet, lifestyle, exposure to radiation and genotoxic chemicals seem to have a significant influence on the relationship between cumulative DNA damage and age. Methodological factors might have also influenced the observed results. Indeed, different assays may be used to measure DNA damage. Furthermore, the measured DNA damage could reflect changes in the causative factors, and/or changes in DNA protection and/or changes in DNA repair capacity. It must also be noted that the type of cell and tissue used could reflect different aging rates within the organism.

Although there are several excellent narrative reviews on age-related nuclear DNA damage, they usually refer to individual animal and humans studies and, as far as we know, no meta-analytic technique has been used to estimate the extent of effect of potential moderators on age-related DNA damage in humans. Thus, the overall goal of this paper is to address this important gap in the literature.

Electronic databases and bibliographies for studies published since 2004 were searched. A total of 76 correlations from 36 studies with 4676 participants were included. Based on our analysis, a correlation between age and DNA damage was found. The test for heterogeneity of variance indicates that the study's results are significantly high. Moderator variables such as smoking habits, technique used, and the tissue/sample analyzed, are shown to influence age-related DNA damage. Nevertheless, sex did not show any influence on this relation.

In conclusion, this meta-analysis showed an association between age and DNA damage in humans. It was also found that smoking habits, the technique used, and tissue/sample analyzed, are important moderator variables in age-related DNA damage.



So this is evidence for the DNA damage hypothesis of aging, and hence evidence against the 'SENS hypothesis' that there are only seven classes of damage, and that DNA damage only matters when it causes cancer?

Posted by: Jim at June 9th, 2014 8:44 AM

So if aging is caused by DNA damage, how do we fix it? I guess we can't. Maybe aging is inevitable and irreversible after all. I'm interested to see future developments in this research.

Posted by: CoolGenius at June 9th, 2014 1:29 PM

@Jim: No, it isn't evidence for causation of any sort. It is an assessment of the robustness of the evidence for an association that suggests we should be suspicious of studies that dispute this association between nuclear DNA damage and aging. But that association doesn't tell us about causes and consequences.

Posted by: Reason at June 9th, 2014 3:57 PM

Some clarification is in order here, as a result of a most unfortunate accident of terminology: whereas in SENS we use the term "damage" to refer to things that accumulate throughout life because there is no mechanism to repair them, the DNA damage field uses that same word for something completely different, namely pre-mutagenic lesions like 8OHdG. The things that (putatively) in fact accumulate, namely mutations and epimutations, are not classed as damage at all in the DNA community, because they are not chemically distinct from undamaged DNA. Because the "damage" discussed in this paper is these intermediates, what the increase with age means is not that there is any accumulation, but rather that there is a shift in the equilibrium between creation and elimination of those intermediates. That shift presumably means that there is a corresponding acceleration in the rate at which the elimination is done in the undesirable direction, i.e. at which the lesion matures into a mutation or an epimutation rather than being repaired - but that only implies a problem in aging if the rate becomes sufficient to translate into pathology, or even to be detectable - which I have argued (in my "protagonistic pleiotropy" paper) that it should not, and which those who have studied actual mutations (notably Vijg's group) have indeed shown it does not, at least in most tissues (most importantly the cerebral cortex).

Posted by: Aubrey de Grey at June 19th, 2014 9:49 AM

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