Robert Bradbury of the Aeiveos Research Library has been working on a grand unified theory of aging of late. He was kind enough to post a summary to the extropy-chat list, which is reproduced here with permission:
I've been working on this theory for the past year or so and thought I would present it to the list so it gets into general circulation. You could call this either "A Grand Unified Theory of Aging" or "The Mutation-Energy Catastrophe Theory of Aging." In it, I try to bring together a number of elements from a number of other aging theories to see if we can begin to reach a greater understanding.
First, lets assume the Free Radical theory of Aging which involves various aspects of Mitochondrial damage and aging are correct. This explains why caloric restriction works.
Second, lets assume you can't do too much about them because radicals and/or other pro-oxidants (e.g. nitric oxide) are being used as signal molecules. This assumption may be somewhat controversial.
Third, lets assume that the free radicals lead to DNA mutations (which is one way cancer develops) or worse leads to DNA double strand breaks. Radiation and perhaps toxic substances in food or the environment might contribute to this as well.
DNA double strand breaks are bad. There are 3 possible results:
(a) Repair the break via the homologus recombination pathway. This can lead to "gene conversion" where a masked defective gene gets copied such that it becomes dominant. So for example you may have a cell that can function well with one good and one bad p53 gene, if the bad p53 gene gets copied to where the good p53 gene once was you are in big trouble. The net result is an increased risk of cancer.
(b) Repair the break via the non-homologus end-joining pathway. This appears to involve perhaps the Artemis protein and/or the Werner's Syndrome protein both of which seem to be exonucleases. Bottom line your DNA gets chewed up and you get a microdeletion during the repair. Alternatively if you happen to have two double strand breaks at the same time the two chromosomes can get mispaired with the wrong chromosome. This leads to several types of cancer.
(a) and (b) are aspects of various "mutation" theories of aging.
(c) Avoid repair by the cell committing apoptosis. In this case you lose cells and if the cells are not replaced by stem cells - which may themselves have damage from (a) or (b) - then you suffer a gradual loss of function.
The above seems to explain much of aging and cancer, but now the problem gets worse. If (b) goes on for long enough you will gradually accumulate mutations in various (most probably different) genes in *ALL* cells. i.e. the genomic "program" that the cells require to operate properly is gradually corrupted in random ways.
So gene expression may become defective in many various ways in many cells. This incorporates the dysdifferentiation theory of aging and perhaps aspects of the neuroendocrine theory of aging. However if the mutations occur within genes rather than say regulatory regions now you will probably have a protein that will not fold properly. This will probably be detected and the protein will be degraded. But the lack of a sufficient quantity of these proteins will probably result in cellular signals to make more of them. But they or at least half of them will not fold properly either. Now both protein manufacture and many types of protein degradation require energy (ATP). So when the cells detect a decline in ATP (due to futile synthesis and degradation of proteins) they may attempt to increase energy production. This might be through making the mitochondria work harder or making more mitochondria. In either case the result of this will most probably be more free radicals which feeds back into the start of this whole process. So over time cells will "age" increasingly faster.
The net result is that you get an exponential decline in function (i.e. aging). So far I've only managed to imagine two solutions for this.
1. Develop better DNA repair processes that do not allow the genome to become corrupted.
2. Shift things to allow more apoptosis when DNA double strand breaks are detected but also increase the replacement rate by stem cells.
(1) is a reason to support the sequencing of the genomes of other long lived species -- to see if they have figured out better solutions to the problems outlined. (For example we know that Deinococcus radiodurans has better double strand break repair but we do not fully understand this yet or know if it can be applied to humans).
(2) is a reason to be very supportive of stem cell research.
As Robert Bradbury mentioned to me, there is a lot of background information behind this summary, unfortunately still in the rough notes stage. His attempt to shift genome sequencing priorities is related to this theory and its implications for research.