I have puzzled over this ever since reading Hart and Setlow’s famous PNAS paper. Ultimately, a person dies because each and every one of his cells senesces.
Unrepaired DNA damage could accelerate aging in at least two ways – by increasing the mutation rate in replicating cells and by reducing transcription in all cells. The former seems not to be true (it does not even pass the correlation tests) and the latter seems pretty trivial. At most when a gene is damaged, one would expect no more than a twofold decrease in the gene’s protein content. In general, metabolism seems flexible enough to work around this tiny change. A person does not die from this.
ON THE OTHER HAND, as I have argued, the instantaneous probability of death is the product of 7 factors, the 7 factors that work together to keep us alive, and each of these systems declines only a little bit by the time of death. A little decline taken to the 7th power makes a big decline. So perhaps the twofold change in transcription of a small number of genes in each cell in all 7 of the systems keeping us alive is enough to eventually kill us.
YET, nothing makes more sense than to say that death is “programmed” into our DNA – I do not mean programmed by a programmer. I mean that we die because we have the genome of a human and not that of some immortal being. I mean that in a species like man with a finite lifespan and an appropriately matched reproductive rate will over vast stretches of time outcompete a rival species of similar strength, abilities, and competitiveness with a much longer lifespan (particularly if this involves much more stable DNA) and a very low reproductive rate. The latter species will not be evolving rapidly enough to survive the inevitable major changes in the environmental selective pressures. Such long-lived species, if they ever existed, have for the most part already joined the ranks of the 99+% of extinct species.
Lastly, is there a metabolic workaround for the genetic defects behind aging and mortality? Or do we have to become superhuman to become immortal?