Skip to Content

Aging and Lifespan

When Natural Selection’s Through With You – Part II

Another useful paper (Science 296, 1276) has come out on the mechanisms of aging. Ever since the 1950s, the idea of accumulating free radical damage has been a strong contender, to the point that it’s been absorbed into popular culture. All the free radicals needed for this damage to take place are produced by our own metabolism: oxygen is pretty fierce stuff to handle.

There’s a good amount of evidence that this theory is at least partially correct (such as the existence of enzymes like superoxide dismutase, SOD, whose only function in life is to get rid of one of those reactive oxygen-derived species.) And now there’s more. The latest work involves mice with a mutated form of a particular helicase protein called Xpd. This is an important part of the DNA-RNA transcription machinery, and it’s also important for a variety of DNA repair, nucleotide excision. The dual function makes sense; both processes involve unwinding the double helix so enzymes can bind to it directly.

There’s a human genetic disease, trichothiodystrophy (TTD) that involves alterations in Xpd function, and the research group was trying to come up with a mouse syndrome that would mimic it. They got it, but the mice also shown signs of accelerating aging (gray hair, osteoporosis, loss of appetite, shorter life span.)

That would seem to be the end of the story: if you can’t repair DNA damage, you age quicker. But another experiment has already been done to completely knock out a closely related protein called Xpa, and that knockout completely wipes out the ability to do nucleotide-excision repair. But those knockout mice don’t show signs of premature aging! So what’s going on?

One way to find out would be to take those Xpa-knockout mice and introduce the Xpd mutation into them. This group tried that experiment, and got the same premature aging, but in much more severe form. What might be happening, then, is that the total effect of DNA damage on gene transcription might be the aging factor. If you can still read off the DNA, damaged or not, then cell activity can still muddle on (as in the Xpa knockouts that don’t show premature aging.) If your gene transcription keeps getting stalled out, as in the Xpd mutants, then you’re in trouble. The cells involved end up dying (by programmed cellular suicide, apoptosis) or damaged. If you have both mutations at once, the defective DNA that accumulates is unwound and exposed for even longer periods, setting both those processes in motion even faster.

We’re getting closer to making a coherent picture out of this – other knockout experiments shed some light on it, and others are no doubt in progress. As for what to do about it, that’s a different question. The close association of aging with DNA damage means that there may well be a tradeoff between oncogenesis and aging – you can keep your cells alive for a long time, at the risk of developing cancer, or you can have them kill themselves off at the first sign of trouble, which helps to cause aging. We’ll have to tread carefully, but there would still seem to be some wiggle room in there.