At 08:35 AM 27/08/99 +1000, Patrick reposted a wonderful press release:
>University of Wisconsin-Madison
>Study details genetic basis of aging -- and how it might be delayed
>In the process of metabolism, some toxic byproducts are produced, damaging
>proteins and triggering a stress response that acts to repair damaged
>and that seems to be governed by a few select genes. But with age, the body's
>ability to repair damaged proteins declines, possibly as a result of
>cellular energy levels.
I'll be interested to see how this fits in with Aubrey de Grey's theory of mitochondrial damage (which is highly salient to cellular energy availability).
Here's a bit from my recent book THE LAST MORTAL GENERATION:
More than forty years ago, Denham Harman proposed that ageing is principally an accumulation of damage to key parts of the body's cells wrought by free radicals. In 1972, he suggested that mitochondria might be most at risk, since these chemical powerhouses are a prime source of oxygen free radicals. Certainly some mitochondria fall prey to ROS impacts that delete or rewrite genes, compromising the specialised function of the cell. But it turns out that less than one tenth of one percent of mitochondria in mammalian tissues show such damage. Could such a modest effect interfere drastically enough with the cell's - indeed, the body's - metabolism to bring about the tragic cascade of ruin we call ageing? Despite Harman's advocacy, and research continuing through the decades, it seemed that the cellular mechanism responsible for ageing must be found elsewhere - in telomere shortening, as we saw earlier, in changed patterns of gene expression, and so forth.
In the inaugural number of the Journal of Anti-Aging Medicine, in 1998, its editor declared that this estimate was due for review. The mitochondrial camp, the editor observed, had `lacked any coherent rationale for the preferential accumulation of damaged mitochondria in aging; the battle appeared to have been won by the senescent gene expression camp not for reasons of data, but rather by intellectual default.' In one stroke, however, in February, 1997, a paper by Cambridge University theorist Aubrey D. N. J. de Grey had shifted opinion sharply, providing an elegant mitochondrial explanation for ageing, and suggesting bold implications for clinical treatment.13
de Grey noted that even cells which do not divide - muscles and nerves, for example - nonetheless produce a continuing turnover in the generations of their mitochondria. Why do cells bother with the energy-expensive business of breaking down old mitochondria and making new ones? de Grey offered a startlingly counter-intuitive explanation: the housekeeping machinery of the cell preferred, by a kind of bungle, to destroy healthy mitochondria while leaving the mutant, damaged units alone - so that some cells ended up choked with poisoned, useless mitochondria. How could this be explained in a system that had evolved by natural selection? Isn't it supposed to be `survival of the fittest'?
The argument is enticing, however. Suppose everything is functioning happily, and mitochondria are doing their job of providing ATP, the chemical that powers cells. This process releases a lot of reactive oxygen species, which attack the membranes of the mitochondria. `In due course,' de Grey argued in his original paper, `the membrane will become unable to perform its main function, which is the maintenance of the proton gradient created by the respiratory chain. This will not affect the operation of the respiratory chain itself, however, only the production of ATP, so damage will continue.' A suitable strategy to ensure a cell its supply of ATP is to destroy mitochondria that have become damaged in this way, and to prompt the remaining less damaged mitochondria to divide, thereby maintaining the number of mitochondria in the cell as a whole. But suppose a mutation strikes that impairs a mitochondrion's respiration, lowering its production of harmful free radicals? Suddenly the mutant organelles are damaging themselves with their own free radical production *less* than healthy ones are - so they survive better than their optimised kin, which are being digested by mistake!
In rapidly dividing cells, this is not a problem, since membrane damage is cancelled out by fresh membrane creation. Brain cells and muscle tissue, alas, do not replace themselves - although their mitochondria do, providing opportunities for mutation and `an accumulation of ATP-deficient cells leading to aging at the organismal level.' If de Grey's argument is correct, mutated mtDNA can thus be very damaging even though there is so little of it in the body. Cells with mutant mtDNA seem to survive indefinitely, despite having lost the ability to use oxygen. These cells may be highly toxic, releasing ROS molecules into the blood stream and thence into other, mitochondrially healthy, cells. It's this increased load of oxidative stress that wrecks lipids and proteins, with those ill effects multiplied to other, healthier tissues: a classic example of throwing a single spanner into a complicated machine and watching all the gears seize up.
The new approach suggested by Aubrey de Grey hints at means to improve mitochondrial health, and thus repair the energy systems of the body. de Grey has offered several suggestions, some more extreme than others and all of them too technical to discuss here in detail. One path would maintain or restore oxidative phosphorylation, which accounts for nine-tenths of synthesised ATP. How? Using a suitable vector, engineered or normal `wild-type' mtDNA could be imported into ailing cells, to augment damaged genes. Or residual wild-type mtDNA (if there is any left in a given cell) could be encouraged to replicate. Or the thirteen protein-coding genes that the organelle carries could be reverse-engineered into the nuclear DNA itself, using tailored transgenes. Protein products expressed by normal mtDNA (now safeguarded in the nucleus by its superior proof-reading machinery and its lowered incidence of ROS damage) could be built in the cell's cytoplasm and moved through the mitochondrial membrane. This would also require new apparatuses to force the expression of needed proteins, chaperone them into the mitochondria, and fold them up neatly after they have unkinked for their passage through the pores of the outer and inner membranes. There are formidable obstacles in the way of each of these bold proposals, but de Grey argues that at least one method - importing proteins - can perhaps be solved, possibly by learning from the equivalent genes in plants (which employ the `universal' nuclear DNA code, instead of the variant version used by animal mtDNA).
But why not just eliminate the guilty party, the less than one percent of low-efficiency or anaerobic mitochondria? If de Grey's analysis is right, cells harbouring these organelles have certain distinctive features - technically, a very high level of plasma membrane oxidoreductase, or PMOR - that could serve as a well-defined target. What's more, a reagent called pCMBS selectively inhibits PMOR and thus kills cells relying on it. If the progressive enfeeblement of mitochondrial defences against antioxidant attack can be retarded or halted by such means, then very plausibly, as de Grey claims, it `would profoundly alter our view of the inevitability of old age'.