There is a variety of damage that the DNA molecule can experience and subsequently repair:
Per cell in nuclear DNA:
single strand breaks - most prevalent - estimated rate to be 55,000 per day
depurinations - 10,000 per day
guanine methylation - 3,000 per day
cytosine deaminations - 200 per day
oxidative damage
- 8-hydroxydeoxyguanosine - 140,000 per day
- hydroxymethyluracil - 600 per day
- thymine glycol - 300 per day
- thymidine glycol - 70 per day
Mitochondrial DNA receives about 16-fold more oxidative damage per nucleotide than nuclear DNA.
(Bernstein & Bernstein 1991)Note that this is not an exhaustive treatise on the topic as there are more types of DNA damage. But each of the DNA damage types mentioned above are repairable by enzymes because they only involve one strand. Thus the complementary strand acts as template for the repair. Double stranded breaks are also repairable so long as they only involve ligation of each strand. On the other hand, DNA damage involving the loss of one or more complementary nucleotides from each strand is are far more rare and can only be repaired by physical recombination with another DNA molecule. In humans this is only presently possible with sperm and ova.
One must appreciate that part of the frenetic activity that is occurring in a cell at any one time is associated with ensuring the integrity of the nuclear and mitochondrial genomes as they come under attack by the metabolic by products, toxins or radiation. The balance between spontaneous DNA damage the ability of a cell to repair it will directly influence its lifespan. The premature aging condition, Werner's syndrome, occurs because of DNA repair enzyme impairment. This results in abnormally high level of DNA damage, triggering accelerated aging which in all other respects is similar to normal aging
(Thomson et al 2003).
Consequently, by increasing the rate of DNA repair we should observe an decrease in rate of aging. A recent
study confirms that overexpression of 2 mtDNA repair enzymes reduced oxidative stress in mitochondria.
There are many examples in nature where there are DNA repair systems with greater efficacy, particularly radioresistant bacteria. Some human tumor cell lines also show greater resistance to radiation. Cell division provides a very high quality DNA repair system. In fact cells that are unable to participate in cell division are at a considerable risk as they do not have access to this mechanism of DNA repair. Some of our most important organ cells - neurons and cardiomyocytes (heart muscle cells) tend not to divide at all.
With an increased rate of DNA repair not only is the general rate of aging being slowed but also the likelihood of cancer which is an added benefit (the assumption being that there are no oncogenes active). Admittedly this is not aging panacea since it does not take into account the problem of accumulated debris in old, non-dividing cells. However I am convinced that boosting stem cell production will take care of older cells so long as they can be encouraged to migrate to sites of apoptosis.
It remains a question as to how many years one could add to lifespan once a systemic administration of selected DNA repair enzymes for nuclear and mitochondrial DNA takes place. How cells that have already become senescent would behave. Would the reduced oxidative stress revert gene regulatory mechanisms to pre-stress state? That remains to be experimentally seen. It would be indeed a great day when we can switch senescent regulatory genes in the cell to non-senescent state in-vivo.
I am convinced, however, that as soon as such a treatment of systemic administration of additional DNA repair enzymes is made, the aging process will dramatically slow. Whilst I am not suggesting that one can become more youthful, one would age at a considerably reduced rate proportional to the degree of increase in DNA repair.
You can see why I find Aubrey de Grey's solution of moving the 13 mitochondrial genes into the nucleus so worrying. Aside from all the technical difficulties with accomplishing such a feat, the reward would be very small even if implemented exactly in the way he conceived it without any unforeseen issues with the biology (such as the self-admitted problem of protein hydrophobicity in transferring from nucleus to mitochondria). The obvious reason is that the nucleus is also prone to damage, though not as much, as I have indicated above.
Here is the shock: the treatment of systemic DNA repair enhancement can be available today.
Edited by prometheus, 24 June 2004 - 11:48 AM.