Is Nuclear DNA Damage a Cause of Aging?
When people say "DNA" they usually mean nuclear DNA. Our nuclear DNA resides, as you might guess, in the nucleus of cells. It is the packaged blueprint for the proteins and biochemical processes that give rise to our physical structure, protected, repaired, and manipulated by a dazzlingly complex array of attendant biological machinery. Our cells are constantly assaulted by reactive molecules created as a byproduct of metabolic processes, and despite the very efficient DNA repair mechanisms we have evolved, damage to nuclear DNA accumulates slowly over time and results in mutations - changes to the information coded in the DNA strands - or other forms of outright impairment of cellular operations.
It is well settled that the level of nuclear DNA damage and mutation exhibited by an organism rises over time. It is also well settled that higher levels of nuclear DNA damage and mutation mean a greater cancer risk - this is one of the reasons why cancer is predominantly a disease of the old. The more cells that suffer DNA damage, the more likely it is that one or more cells experience exactly the type of damage needed to run amok as the self-replicating seeds to a cancer. But is nuclear DNA damage and mutation a cause of aging?
That increasing instability of the genome contributes to age-related degeneration is the present working assumption for much of the aging research community, but this hypothesis is not unchallenged. The lack of a definitive proof is one problem: there is no good experiment to show that reduction in nuclear DNA damage levels - and only nuclear DNA damage levels - extends life. We can point to, for example, the fact that calorie restriction results in lower nuclear DNA damage levels, but this is only correlation. Calorie restriction slows the progression of every measure of biological aging, and produces significant changes in all of the master controls of metabolism and their subsystems, which makes it very hard to tease out any one dominant first cause. (And where work is proceeding on that front, boosted autophagy is the leading candidate in any case).
Biomedical gerontologist Aubrey de Grey has argued for the irrelevance of nuclear DNA damage to aging - beyond the issues of cancer risk, and over the present human life span, that is:
Since Szilard's seminal 1959 article, the role of accumulating nuclear DNA (nDNA) damage - whether as mutations, i.e. changes to sequence, or as epimutations, i.e. adventitious but persistent alterations to methylation and other decorations of nDNA and histones - has been widely touted as likely to contribute substantially to the aging process throughout the animal kingdom. Such damage certainly accumulates with age and is central to one of the most prevalent age-related causes of death in mammals, namely cancer. However, its role in contributing to the rates of other aspects of aging is less clear. Here I argue that, in animals prone to cancer, evolutionary pressure to postpone cancer will drive the fidelity of nDNA maintenance and repair to a level greatly exceeding that needed to prevent nDNA damage from reaching levels during a normal lifetime that are pathogenic other than via cancer or, possibly, apoptosis resistance.
The high-level goal of de Grey's SENS program is to develop the biotechnologies needed to repair and reverse all of the identified biochemical differences between a young person and an old person. That remit obviously includes nuclear DNA damage and mutation, but de Grey's position above is essentially an efficiency argument - other forms of difference are far more important, so the research community should deal with those first.
This is far from the last word in the ongoing debate over aging and nuclear DNA damage, of course, and until someone designs an experiment to show extended life in mice achieved through nothing more than better DNA repair, it will remain a debate. If you look back into the Fight Aging! archives, you'll find more on this topic:
- Arguing for Nuclear DNA Damage as a Cause of Aging
- Another Way to Look at DNA Damage and Aging
- Fuel for the Debate Over DNA Damage and Aging
- More DNA Damage Research, In Mice This Time
There are good arguments and supporting evidence on either side; sometimes in the life sciences you have to accept that a good answer beyond mere hypothesis remains elusive, and more work must be done in order to change that fact.
Learn about Mr. Stolyarov's novel, Eden against the Colossus, here.