A couple of the regulars were discussing recent advances in the scientific understanding of the aging process on the Extropy-Chat mailing list, and an interesting exchange it was too. I've reproduced it here, with permission. The two principles are Robert Bradbury - who maintains the Aeiveos Research Library and has a very interesting history of work on healthy life extension - and Joao Magalhaes, author of one of the Longevity Meme articles and currently involved in biogerontological studies.
Well, we finally have some real progress on understanding aging.
It looks like SIRT1 (homologue of yeast Sir2), regulates FOXO3 which in turn regulates the enzymes that resist oxidative stress.
Now *before* everyone gets all excited please note that the gene regulation goes against apoptosis (programmed cell death) and for stress resistance (particularly from free radicals). That is probably a reasonable strategy in short lived animals (which include most that scientists work on in labs).
However in long lived larger organisms one does not want to suppress apoptosis (because it will probably lead to an increase in cancer). In long lived species one needs to allow apoptosis or improve the ability of the immune system to recognize and eliminate cancer cells (which people are working on). One also needs to promote stem cell replacement of lost cells (which we have some of but it probably isn't as finely tuned as one would like).
But it is clear that this provides a key piece of the puzzle as to how cells manage the repair/replicate/die decision processes. Now whether the actions of FOXO3 on apoptosis and stress resistance have been split in longer lived organisms (so one has 2 genetic programs under individual controls rather than just a combined genetic program with only 1 control factor) remains to be seen.
I don't want to be the skeptic around here but I should remind you that there is NO evidence SIRT1 is in anyway involved in human aging. Yes, in yeast sir2 is involved in cell cycle regulation--which is not the same as aging. Maybe sir2 is involved in aging of C. elegans but results from Drosophila and mice do not suggest any involvement of SIRT1 in aging. Since drosophila and mice are biologically closer to humans than c. elegans and yeast, I'm skeptical that SIRT1 plays a role in human aging.
As for the Forkhead family, these transcription factors are very much involved in development, so it is normal that they affect redox potential and apoptosis. Nevertheless, I wouldn't be surprised if they were involved in mammalian aging since p66 has been associated with the forkhead family. Yet the connection to human aging is not clear because of cancer. After all, yeast, drosophila and c. elegans don't have cancer and mice have much higher cancer incidences. So we must be very careful in extrapolating this sort of data into humans.
Joao (Hi!), I have no problem with your comments regarding the involvement of SIRT1/sir2 in higher organisms (because I know of no evidence for such involvement as you point out).
But I would offer the idea that it is very very difficult for Nature/evolution to change course. So *if* theapoptosis/stress response pathways were linked to each other very early on in evolution I would propose that it would be difficult for them to become separated. Not impossible mind you -- which is why I'm slowly pushing behind the scenes to get a number of long-lived genomes sequenced -- so we can have the data to figure this out. What I strongly suspect is that there are "patches" on the apoptosis program that may decouple it from the stress response program.
With respect to the cancer incidences -- one has to have an organism that can actually get cancer. Yeast clearly can't and probably C. elegans and Drosophila as well. Cancer is a direct result of a failure of the program of the regulatory processes of cell replication in organisms that have enough cells for this to be important. This probably involves a delicate balance -- in organisms with enough cells you want to kill off those that are replicating out of control. In that case you want to replace those cells so there is presumably a pool of cells biased towards replication (when necessary). In my opinion, it doesn't take too much for that situation to get out of control (which is why cancer causes ~30% of deaths). (IMO)
But good comments. If you would care to expand on the p66 involvement I'd be interested in reading them on/off list. (I know what it is but don't have current knowledge with respect to where it fits into the big picture.)
I would guess the short summary of my previous message is that they now have a strong candidate for the regulation of at least the stress response -- it isn't going to take that long to confirm that or blow it out of the water (even for higher mammals). That is why I called it "real progress". Ultimately, it may not prove to be progress from a biochemical standpoint -- but it is going to open the door somewhat wider towards nailing these pathways down.
Isn't it amazing that we live in an age when we can have these sorts of detailed conversations about the way in which aging works? Not to mention the likelihood that many of the questions brought up in this exchange will be answered within a few years at the current rate of progress. Like many observers, I find the newfound pace of scientific research, powered by bioinformatics and new tools, to be exhilarating.
As Robert Bradbury notes, nailing the biochemical mechanisms of aging, one by one, is the quickest way to move forward. Understanding, rather than blind testing (even massive, parallel blind testing powered by bioinformatics that is reaping so many benefits in modern research) is what will lead us directly to therapies for the aging process.