More on Aging, Cancer, Stem Cells and p16INK4a

A fair amount of chatter is taking place over recent research into the protein p16INK4a and the gene producing it. The name indicates it is an INhibitor of cyclin-dependent Kinase 4A; romantic, slipstreamed naming schemes are the first casualty of complexity in science - and it doesn't get much more complex than biochemistry. I noted the EurekAlert! release at the Longevity Meme, but the HHMI News article is an easier read and more to the point as to what folk are thinking could be done with the research. See what you think:

A single molecular switch plays a central role in inducing stem cells in the brain, pancreas, and blood to lose function as they age, researchers have found. Mice lacking that switch show considerably reduced aging-related decline in stem cell function and tissue regeneration.

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People tend to think that old tissues have less regenerative capacity because they are wearing out. This work shows that they are not just wearing out; they are actively shutting themselves down.

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While the finding could ultimately lead to drugs to slow or reverse degeneration in the brain and other tissues, the researchers cautioned such treatments would have to be balanced against the chance of increasing cancer risk in patients.

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I think if you asked before these studies whether you could delete a single gene and rescue stem cell function in multiple tissues, and neurogenesis in an old brain, many people would have said that aging is such a complex phenomenon that you would not get a significant effect.

This last quote aptly illustrates why there is great interest in this research - it's always exciting to find a common trigger for many different aspects of aging biochemistry.

Much of the discussion presently taking place relates to evolutionary explanations for this mechanism: the well known trade-off between aging and cancer that are seen in many cellular mechanisms:

Morrison theorized that p16INK4a is a suppressor of stem cell function that evolved as part of the regulatory machinery that also includes proto-oncogenes that encourage cell proliferation. "We are all evolutionarily selected to, on the one hand, maintain regenerative capacity of our tissues through adult life so that we can repair our cells and survive injuries - while on the other hand, limit proliferation in our tissues with age, so cells don't divide out of control, causing cancers," he said. "And the way that we achieve that balance is by having proto-oncogenes that promote proliferation come into balance with tumor suppressor genes that inhibit proliferation. This work shows one way that this balance changes with age.

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While these tumor suppressor mechanisms don't even exist during fetal development, where cells must divide rapidly, it makes sense that they become stronger in old age, when we are more at risk of getting a cancer. So, the benefit is that genes like p16 allow us to get older before we get cancer, but the bad news is that they make us lose function with age.

Beyond the whys and wherefores, the temptation is, as always, to latch onto the latest idea and what-if your way forward. What if this all works much the same way in humans? What if reliable cancer therapies pan out by 2015? Wouldn't that make therapies directed at p16 worth exploring as a path towards healthy life extension?

From where I sit on the sidelines, it seems that tinkering with the structure of the engine - building better components for hot-swapping on the go - is not as utilitarian a path forward as developing the means to repair accumulated age-related damage to the present engine. Improving components is a matter of slowing aging; repairing damage is a matter of preventing and reversing aging.

Look at it this way: you might gain as much in the first decade of full-on commercialization from the results of either of these two different philosophies of development, but replacing a component of your biochemistry in order to slow aging is a one-time deal per component. You change your biochemistry, and there you go, running on the same old timer with a few extra ticks of the second hand. With a working repair technology, you can keep coming back again and again until something else becomes the limiting factor to your health and life span.

That said, there's no such thing as useless knowledge in biochemistry; it's all grist for the mill of the next few decades. We'll be hearing more about p16INK4a, I'm sure, as research into aging, cancer and stem cells continues to overlap and reinforce mutual progress.

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Comments

I think it may be too soon to just accept that there's only a biochemical choice between aging and cancer. From what I've read of the work of Cynthia Kenyon with C. Elegans and the article regarding the study of the Smk-1 gene published recently at news-medical.net, it seems like there must be a third way, or a way to optimally balance between the two. My guess is that the gene which codes for the p16INK4a protein isn't the 'master gene' for longevity, but simply one which responds to signaling generated by some other gene or (more likely) combination of genes. The real trick will be identifying, in humans, the gene(s) that act as the conductor of the whole biochemical orchestra and getting them to play an 'extended set' if not the song that never ends.

http://www.news-medical.net/?id=16569

Posted by: Elenion at September 7th, 2006 9:56 AM

I think if a person could have a healthy immune system they wouldn't be in so much risk of cancer. Just as the young person doesn't need to restrict stem cell division so much. Of course there is more factors then that, but the immune system's capability seems to be the main factor from what I have seen.

Posted by: aa2 at September 8th, 2006 12:26 AM

What about linking research on the p16 gene with the Wake Forest research with mice that have the ability to suppress cancer? A two-pronged approach to restoring healthy stem cell function and suppressing incipient cancer formation may well be the way forward to healthy longevity. Maybe this is the light at the end of the tunnel!
Practical anti-agathic drugs re:Cities in Flight by James Blish.
We need a lot more young scientists heading to the lab benches, and now!

Posted by: John Fahey at September 9th, 2006 10:58 AM

What about 'replication errors?'
If proofreading and repairs fails to correct the DNA, it is senecence and PCD (programmed cell death, apoptosis, etc) or it is cancer.

Posted by: stevo at September 15th, 2006 7:10 AM

I was thinking that ther could be other ways to aproach this. It seems that p16INK4a recognizez the age of the cell. (the study shows that if you insert an older cell into a younger body p16INK4a stops it from multiplication). What about figuring out why is an older cell diferent from an younger one (it could be mitochondrion related). The cell simply emits diferent readings after it has multiplicated for a number of times and p16 stops it so that it woldnt multiply in other cells that wold have the same energy readings.
How i wold aproach this: Study which cells p16 stops and after that inhibit p16 and see what cells turned concerous and wich didnt.
After these design a replacement for p16 that wold only stop the cells that are about to copy themselvs rong..not all of them just becouse they have a certayn age.

Posted by: T. Andrei at September 19th, 2006 8:03 AM

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