September 07, 2006
Aging Is Product Of Genetic Anti-Cancer Program

Why do we age? Why don't our stem cells continue to divide to produce cells needed to repair and maintain the body? Three research groups at Harvard, University of North Carolina at Chapel Hill, and at University of Michican have found very strong evidence that as cells age they make more of a protein that slows down cells in order to reduce the risk of cancer.

ANN ARBOR, Mich.—The natural consequences of growing old include slower wound-healing and a brain that makes fewer new neurons because old tissues have less regenerative capacity. What has not been clear is why. A trio of papers published on-line Sept. 6 in the journal Nature shows that old stem cells don’t simply wear out, they actively shut themselves down, probably as a defense against becoming cancerous from genetic defects that accumulate with age.

"The good news is that we can get older before we get cancer," said Sean Morrison, director of the Center for Stem Cell Biology at the University of Michigan, and lead author on one of the three papers. "The bad news is that our tissues can’t repair themselves as well."

Though science has long known about the reduced regenerative capacity in aging tissues, the actual mechanisms are only now coming to light. What Morrison and his colleagues at Harvard University and the University of North Carolina have found is that a gene called Ink4a actively interferes with the ability of stem cells to divide in several different types of tissue, including the brain, the pancreas, and the blood-forming system of the bone marrow.

This important discovery came as a result of the development of a mouse with a gene knockout for Ink4a.

Though mice with Ink4a deleted had more regenerative capacity in tissues like the brain and the pancreas as they aged, they started dying of a wide variety of cancers at one year of age. So it can’t really be said that losing the gene helped them live longer.

"If you had a drug that could inhibit Ink4a function, you’d potentially have a therapy against degenerative diseases," Morrison said. "But you’d have to watch patients carefully for cancers. By the same token, drugs that mimic Ink4a function could be used to fight cancer." Ink4a was known to be a tumor suppressor gene that becomes more highly expressed with age, eventually triggering the cell to shut down replication. Sharpless was investigating cancer genes when he developed a mouse without Ink4a six years ago, while working at Harvard, but he also became intrigued by its 10- to 100-fold increase in expression with age.

I find these results thoroughly unsurprising. Biogerontologists have speculated that natural selection has selected for a trade-off where cells in older bodies become less able to divide in order to reduce the risk of cancer. The reduced cancer risk comes at the expensive of gradually losing the ability to do repairs. These results show a mechanism for how this works.

Reducing the accumulation of the protein product of the INK4a gene reduces cell death and increases cell division of blood stem cells.

The researchers found that reducing the accumulation of p16INK4a in haematopoietic stem cells (blood stem cells) reduces cell death as well as defects in the ability of the cells to repopulate.

"There are two things about this that are important," Scadden said. "It shows that specific properties of aging stem cells directly contribute to the reduced healing that occurs with aging; and it indicates that one might be able to modify a single gene product and improve the function of aging stem cells and repair of aging tissue - and that is very encouraging. This may mean that there are opportunities to target this gene product with medication and potentially decrease the impact of aging.

"However," Scadden noted, "p16INK4a is also known to suppress tumor formation, so a judicious balance must be struck between reduced p16INK4a when needed for repair and sufficient p16INK4a to prevent emergence of malignant stem cells."

One obstacle to the use of stem cells as rejuvenation therapies is that the stem cells could become cancerous.

The UNC Chapel Hill group also developed a mouse strain that produced too much product of the INK4a gene and that caused accelerated aging.

The UNC study focused on p16INK4a effects on the function of pancreatic islet cells. Islet cells are responsible for insulin production and secretion. Because p16INK4a stops cancer cells from dividing and demonstrates increased expression with age, the scientists suspected the gene played a similar role in aging. The researchers developed strains of mice that were either deficient in p16INK4a (the gene was deleted, or 'knocked out") or genetically altered to have an excess of the protein to a degree seen in aging.

According to Sharpless, islet proliferation persisted in p16INK4a -deficient animals as they aged, "almost as if they were younger animals." In mice with an excess of p16INK4a, "islet cells aged prematurely; they stopped dividing early."

"This suggests that if we could attenuate p16INK4a expression in some way in humans, it could lead to enhanced islet re-growth in adults and a possible new treatment for diabetes," Sharpless said.

Similar results were found in the other studies, which focused on brain stem cells and blood stem cells.

Diabetics experience accelerated aging. So use of a drug to temporarily suppress the INK4a gene that allowed pancreatic islet cells to repopulate would probably good trade-off on risks and benefits.

Sharpless cautions that any promise of a potential new aging treatment based on p16INK4a should include two important caveats. "First, even though old mice lacking p16INK4a show enhanced stem cell function, they do not live longer. This is because p16INK4a is an important cancer-suppressor gene, and mice lacking p16INK4a develop more cancers than old, normal mice," he said.

"Secondly, in all three studies, p16INK4a loss was associated with an improvement in some but not all of the consequences of aging. There are clearly things in addition to p16INK4a that contribute to aging. We don't yet know what they are."

However, the gene may prove immediately useful as a biomarker for studies of aging, Sharpless said. "If you were going to calorically restrict yourself or take green tea or resveratrol every day for years in an effort to prevent aging, wouldn't you like some evidence that these not entirely benign things were having a beneficial effect? Now we have a biomarker that can directly test the effects of such things," he said.

One really big question: Is the INK4a gene upregulated in older cells due to factors floating around in entire old bodies? Or is the gene upregulated by changes that happen in each cell? If the answer is the former possibility then even introduction of youthful stem cells into an old body will not help the old body rejuvenate very much. If compounds in circulation in old bodies can cause injected youthful stem cells to slow down and do less repair work then that makes rejuvenation much harder. I'm pessimistic on that score and my pessimism predates this latest report. See my previous post Young Mice Blood Turns On Regenerative Ability Of Old Mice Muscle.

Once we have highly effective and low general toxicity cures for cancer (i.e. cancer cures that only damage cancer cells) then drugs that turn down the activity of INK4a could be developed and used to safely make stem cells do more repair work. We need cures for cancer in any case. But cancer cures will also make possible more aggressive and risky uses of stem cell therapies.

Even without great cancer cures drugs that block INK4a would still be useful for people who are at very high risk of death from heart disease. Someone who has a great risk of death from heart disease probably would reduce their total risk of death even if they took an INK4a suppressor that increased their risk of cancer.

We need stem cells that do not have any mutations that increase the risk of cancer. We also need to prevent those stem cells from being suppressed by the INK4a gene. We also need gene therapies that will repair cells in the body so that their accumulated damage will not cause them or other cells to make INK4a.

Stem cell therapies are not the only method possible for replacing aged and damaged cells. Stem cells will also be used to grow replacement organs outside the human body for transplant. Those transplant organs will replace much larger chunks of aged cells. But replacement organs are not practical for all parts of the body - especially not for the central and peripheral nervous systems.

Update: Some types of neural stem cells slow down even without exposure to p16INK4a.

Morrison and his colleagues also found evidence that the gene does not play the same role in other neural tissues. “There are different kinds of stem cells in different regions of the brain, and some of those stem cells are more sensitive to factors like p16INK4a than others,” said Morrison. p16INK4a deficiency did not prevent the atrophy of the cortex that normally occurs with aging, they found. Nor did the deficiency prevent loss of function in another brain region, the hippocampus, that is also a center for neurogenesis in adults. The researchers also analyzed peripheral nerve cells in the gut and found that p16INK4a did not prevent loss of stem cell function there. “There are probably other factors that are important for aging of the hippocampus and the peripheral nervous system,” Morrison noted.

Nevertheless, he said, the discovery of the central role of p16INK4a is highly significant. “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,” he said.

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.

What causes these other stem cells to slow down with age?

Stem cells that slow down due to internal damage or due to genetic clocks internal to each stem cell do not pose much of a problem for the development of rejuvenation therapies. Once scientists develop the ability to create replacement stem cells of each desired type then existing stem cell reservoirs in the body can be reseeded with younger and more vigorous stem cells

More systemic body-wide signals that tell cells throughout the body to slow down strike me as much more problematic for the development of rejuvenating stem cell therapies. I see two strategies for dealing with these signals. First, develop such great cancer treatments that it becomes very low risk to neutralize the hormones or other compounds that travel through the bloodstream to tell cells throughout the body to slow with age. A second approach would be to genetically program replacement stem cells to be less sensitive to the body-wide stem cell suppressor signals. The genetic programming of youthful stem cells could be done in a way that allowed those cells to ignore suppressor signals for a few decades. Basically give them a genetic clock that allowed them to divide even though the body has stem cell suppressor chemicals circulating in it that are the result of aging.

Share |      Randall Parker, 2006 September 07 10:49 PM  Aging Mechanisms

Lou Pagnucco said at September 8, 2006 10:13 AM:

Apparently caloric restriction does reduce expression of both P16INK4a and ARF gene expression in calorically restricted aging animals. See: "Ink4a/Arf expression is biomarker of aging" at URL:

The article reports that caloric restriction reduces the dramatic increase in p16INK4a and ARF expression in many aging tissues. Since it was not stated, I assume the animals were life-long CR. It would interesting to find whether adult-onset CR reverses expression of these genes. If so, their activity may be centrally or systemically orchestrated, rather than intrinsic to tissue.

Experiments using parabiosis or tissue transplantion could determine whether the upregulation is tissue intrinsic or not. Maybe upregulation is a response to a cancer promoting factor in the local environment, like inflammation or disruption of cell-to-cell gap junctions. Are old-to-young tissue transplants (between immune compatible animals) more cancer prone?

Also comparison between species could be revealing. For example, nonhuman primates have lower cancer rates and age faster than humans. Is their p16INKa and ARF expression higher?

Fly said at September 8, 2006 12:24 PM:

From the article: “old stem cells don’t simply wear out, they actively shut themselves down”

They showed that increased Ink4a levels decrease stem cell division and increase apoptosis. And they showed that Ink4a levels increase with age. I don’t believe that they showed that Inka4a actively shuts down stem cell division. I see these possibilities:

There may be a selection process that removes stem cells with lower levels of the Ink4a protein as we age. Suppose stochastic development generates cells with a wide range of the Ink4a protein levels. Further suppose that each time a cell divides there is a slight chance that apoptosis will be triggered. Then faster dividing cell lines might die out sooner. As we age the percentage of fast dividing cells decreases. (The interplay between apoptosis and cell division could be complex.) The selection process would have to account for the 10-100 fold difference seen between young and old stem cells.

Ink4a is responding to environmental signals. The aging body itself triggers increased levels of Ink4a. (FuturePundit discusses this possibility.)

Ink4a is responding to internal cell degradation. The DNA damage and degrading gene-silencing results in higher Ink4a levels. (The connection between Ink4a and apoptosis is interesting.)

A developmental clock such as number of cell divisions controls Ink4a levels.

Only the last two possibilities represent old stem cells actively shutting themselves down.

“If compounds in circulation in old bodies can cause injected youthful stem cells to slow down and do less repair work then that makes rejuvenation much harder.”

Now that Ink4a has been identified it shouldn’t be hard to identify compounds that affect Ink4a levels in stem cell cultures. (Related note: Breathing air with increased oxygen levels increases stem cell levels in the blood.)

Note that having more stem cells is not sufficient to regenerate tissue. In the brain, the new neurons require the right environment for proper integration; otherwise they die. Scars in heart tissue prevent regeneration.

Tj Green said at September 10, 2006 7:28 AM:

Living with high levels of radiation seem to activate cancer fighting genes. This makes sense when you think of genes as answers to questions asked in the past. I think the main reason for aging is the mitochondria (the DNA of each human cell receives 10,000 oxidative hits per day,not all are repaired). The body therefore ages at different rates,so you get a domino effect. We have evolved in to something amazing,the problem is our mitochondria hasn`t.

Rob said at September 10, 2006 3:21 PM:

Tj, hormesis is the process where an environmental insult like radiation or a toxin increases the mechanisms that reduce the damage or eliminate the toxin. The hormetic response overcompensates, and improves health. I worked out a couple of half-assed evolutionary mechanism for it.

Some chemical(s) in cigarretes (I don't think it's nicotine) ups the liver enzymes that detoxify it. Those same liver enzymes also metabolize caffeine. Smokers clear caffiene about twice as fast as nonsmokers. Let's play pretend and say that caffeine is worse than smoking. We would see coffee-drinking smokers living longer than coffee drinking nonsmokers.

The problem with hormesis is that it's dose-dependent, very poorly understood, different for different insults, and typically touted by polluters.

here's the wiki:

Lou Pagnucco said at September 11, 2006 10:09 PM:

According to the article, "Studies find general mechanism of cellular aging" at URL:
upregulation of p16ink4A is irreversible.

To quote the article:
"The researchers found increasing concentration, or expression, of the gene p16INK4a in older cells; these aging cells worked poorly compared to young cells and remembered their "age" even when transferred from old mice to young mice."

BTW, this news item made me recall an older story on the p66 tumor suppressor gene.
See "Scientists Link a Single Gene to Longer Life in Mice" at URL:

Unlike the case of p16ink4A, bioengineered mice lacking p66 live 30% longer.

The possible reason is stated in the article -
"In a commentary in Nature on the Italian team's work, Dr. Guarente suggested that the p66 protein had a ''hair trigger setting'' that vigilantly prevented the buildup of damaged cells during development. But older animals start to run out of cells, even though many of the cells destroyed by p66 are viable enough.
Evolution has not corrected the excesses of p66, Dr. Guarente surmised, because the power of natural selection wanes sharply for genetic effects that appear after reproductive age."

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