June 07, 2007
Gene Deletion Ages Mice More Rapidly

A genetically engineered hobbling of the ability of mouse stem cells to produce replacement cells caused mice to age more rapidly.

(PHILADELPHIA) – Researchers at the Abramson Family Cancer Research Institute of the University of Pennsylvania have found that deleting a gene important in embryo development leads to premature aging and loss of stem cell reservoirs in adult mice. This gene, ATR, is essential for the body’s response to damaged DNA, and mutations in proteins in the DNA damage response underlie certain types of cancer and other disorders in humans. This work appears in the inaugural issue of Cell Stem Cell.

Signs of aging come fast if an organism can't do tissue repair.

“The reason these mice age prematurely is that we’re exhausting their ability to renew tissues,” says Eric J. Brown, PhD, Assistant Professor of Cancer Biology. “These findings may be helpful to the aging and oncology fields since premature aging syndromes and many cancers involve the loss of DNA repair genes.”

When the researchers deleted ATR in the tissues of adult mice, they noticed that the mice showed signs of premature aging, such as hair graying, hair loss, and osteoporosis, within three to four months.

To be able to renew itself, most tissues have a reservoir of specific adult stem cells. These stem cells don’t divide as frequently as other cell types since they need to maintain the integrity of their DNA, and multiple divisions lead to natural breaks in DNA. But when these stem cells are needed, their progeny can rapidly divide and are able to replenish the tissue with new cells.

As we age our stem cells age right along with the rest of us. Aged stem cells gradually slow down and lose their ability to create replacement cells to repair damage caused by aging. As the repair systems slow down more damage accumulates and we get older.

This study supports the notion that replacement of aged stem cells with youthful stem cells will help slow and even reverse the process of aging. The development of the ability to create the various adult stem cell types is a crucial step in the development of full body rejuvenation therapies. Once we can create such cells on demand then their injection into our blood streams and into specific stem cell reservoirs will give our bodies the resources needed to repair worn out and failing body parts.

Share |      Randall Parker, 2007 June 07 10:56 PM  Aging Mechanisms


Comments
Mats-Erik Pistol said at June 8, 2007 7:52 AM:

This study adds to the mystery of aging. How can DNA damage be the cause of aging if cloning works ? Old cells with their purportedly old damaged DNA nevertheless gives fresh nice young clones.
Aging can be caused by bad methylation of DNA, which can be reset by chemistry, and I guess something like that is rather a cause of aging.
Old mitochondria with bad DNA cannot be the cause of aging either since the mothers egg has old mitochondria. Kurt6 says that the mitochondria are "reset" in the egg, but this is then not a reset of DNA damage, rather a reset of something else analogous to methylation.

Mats-Erik Pistol said at June 8, 2007 7:54 AM:

This study adds to the mystery of aging. How can DNA damage be the cause of aging if cloning works ? Old cells with their purportedly old damaged DNA nevertheless gives fresh nice young clones.
Aging can be caused by bad methylation of DNA, which can be reset by chemistry, and I guess something like that is rather a cause of aging.
Old mitochondria with bad DNA cannot be the cause of aging either since the mothers egg has old mitochondria. Kurt6 says that the mitochondria are "reset" in the egg, but this is then not a reset of DNA damage, rather a reset of something else analogous to methylation.

Kurt9 said at June 8, 2007 2:04 PM:

Mats-Erik Pistol,

The so-called genomic DNA damage that causes aging is very likely to be limited to epigenetics only (there is on-going experimentation to verify this). This would account for why cloning works even though genomic DNA damage increases in somatic cells as we age. The key to reversing all of these damages (epigenetics, methylation reset, mitochondrial DNA reset, and telomere reset) is the nuclear re-programming of regular cells back into stem-cells (sometimes called de-differentiation). There has been significant development in this area in the last couple of days. Nuclear reprogramming will lead to cellular rejuvenation, which is likely within 5 years. Whole-body rejuvenation (that is, us) is going to take a bit more follow on work.

Randall Parker said at June 8, 2007 7:51 PM:

Mats-Erik Pistol,

First off, many attempts are made in order to create a viable clone. My impression is that dozens or hundreds of eggs are needed to clone an adult nucleus into before a viable embryo is created that can go all the way to full term in a pregnancy. Cells with lots of genetic defects get selected out in this process. Though part of the reason the cloning attempts fail is due to epigenetic state problems. The cloning does not fully reset the nucleus into an embryonic state.

Here's what I want to know: What fraction of cells from, say, a 60 year old are genetically abnormal as compared to what a person is born with? 100%? 20%?

With really cheap DNA sequencing technology we can take hundreds or thousands of cells out of different places in the body, get each to divide, and then take one copy and sequence it. The other member of each pair will have about the same DNA sequence. By sorting thru enough cells a great starter cell can get selected to use to convert into a stem cell and then make replacement parts.

Lyle said at June 8, 2007 10:47 PM:

Along these same lines, you may be interested in this release as well: http://www.eurekalert.org/pub_releases/2007-06/uosc-sff060707.php

The fact that a single protein can extend life in an organism is strange. I would have assumed that multiple genetic markers would be needed for anything that extended life by a third.

Additionally, the Comment Submission form gives you the "wait a short time" 'feature' if you preview before posting.

Fly said at June 9, 2007 11:28 AM:

"Old cells with their purportedly old damaged DNA nevertheless gives fresh nice young clones."

Randall addresses the epigenetic factors. I would add that existing nuclear proteins and structures also play a role and are also reset.

I believe Lyle is also right that low success rate for cloning reflects a selection process that eliminates fatal mutations.

Another factor is that different cell lines experience different mutation processes (e.g., environmental, metabolic, or cell division), repair DNA damage with differing reliability, and initiate cell apoptosis under different conditions. I believe the germ cell is much better protected than skin. Most age-related birth defects are traced back to the mother's egg. So the sperm generating cell line seems to be better protected than the egg generating cell line.

Selection also occurs because sperm and eggs must successfully mature and produce a fertilized egg, the embryo must migrate and implant in the uterus, and the fetus must successfully develop.

Harmful mutations are still frequent. On average a child acquires three new harmful mutations. Usually the mutations are recessive, loss-of-function mutations that have little affect on the child. Cloning skin cells might lead to a significant increase in the number of "hidden" defects. Cloning germ line cells might produce better rejuvenation.

"Old mitochondria with bad DNA cannot be the cause of aging either since the mothers egg has old mitochondria."

The story is more complex. Age-related damage of mtDNA does play a role. Experiments have shown that older tissue is less metabolically efficient.

As with nuclear DNA, the damage varies with cell type. Mitochondria are continually dividing and fusing. The numbers change under different metabolic loads. Old mitochondria are recycled.

My speculation: It is possible that different rates of division and destruction act as a selection process that filters mtDNA damage. It is also possible that a stem cell with defective mitochondria may divide less frequently so the least damaged stem cells proliferate the most. The mtDNA passed on to the child may be protected both by less damage occurring in the egg cell line and a selection process that filters most harmful mtDNA mutations.

Randall Parker said at June 9, 2007 12:25 PM:

Fly,

We need an answer to a very practical question: which cell type in which location of the body does the least and accumulates the least amount of damage with age?

Cells that divide a lot will accumulate DNA damage in replication. Cells that burn up more sugar will accumulate more damage due to more metabolic activity. But which cells just sit around doing very little for decades? Whichever cell type that is should be the place we go to to extract cells to turn into stem cells.

Any guesses on which cell types age most slowly?

rsilvetz said at June 9, 2007 1:24 PM:

Cell lifespans? Good question. Best answer I can come up with is something like this:

Neurons
Cardiac myocytes
Rods+Cones?
Memory B-cells

In men: sperm stem cells

Hepatocytes in a class by themselves. Liver turns over frequently over the lifespan and even in elderly patients, can remain highly functional.

Sporadic reports that there are long-lived WBC's.

Memory B-cells give a very interesting possibility as a source. It's not clear to me they die, in a typical course, by any other method than aberrant apoptosis.

Randall Parker said at June 9, 2007 1:33 PM:

Robert Silvetz,

I'm more concerned to know which cells accumulate the least amount of DNA damage. I do not think your list addresses that question. Though neurons might be a good guess - at least if they are in parts of the brain that have lot activity most of the time.

My guess is that post-mitotic cells are going to accumulate DNA damage most slowly. That rules out sperm stem cells or other types of stem cells. I also think it rules out liver cells.

Maybe we have some muscles that don't do much very often which have nuclei that are fairly well preserved.

Bob Badour said at June 9, 2007 3:18 PM:
Most age-related birth defects are traced back to the mother's egg.

I don't see that as any reason to think spermatozoa are any more stable than ova. The only selection process on the ova is whose turn it is that month. Spermatozoa come to the scene by the billion and compete heavily for the opportunity to be the only one to conceive.

Mats-Erik Pistol said at June 9, 2007 4:04 PM:

Thank you all,
Since epigenetics seems to be a key factor, I presume whole body rejuvenation will be a bit tough. Every cell has to be reset to a proper state. Possibly cues from the environment still exist and can be used. In fact, thinking about it, environment cues likely exist in old bodies, since the changes in puberty must involve epigenetic changes and those must be cued from neighboring cells, apart from the brutal force of hormone bathing. Given that the brain also changes in puberty, even the brain, or parts of it, must have the ability to cue cells to get a proper epigenetic setup.

Kurt9 said at June 9, 2007 5:10 PM:

Mats-Erik Pistol,

No, if epigentics is the cause of aging, only the key stem cell reservours and their respective niche cells need to be "reset". The body will regenerate itself on it own once this task is done. Even if aging is cause by damage to the actual genome, it is likely that that damage is not as "stochastic" as its proponents claim. If this was the case, aging people would tend to diverge in appearance and morbitity. This is not what we experience at all. Parts of the genome (particularly parts that code for morphology and what not) are highly conserved. Other parts are not. Stochastic damage to genomic DNA is not a show-stopper. One needs to only replace the cells in the key stem cell reservours with new cells that do not have this damage. In the long run, we will be rebuilding our bodies (in situ, no less) with synthetic biology.

Mats-Erik Pistol said at June 10, 2007 3:41 AM:

Kurt9,

Sorry for demeaning you by calling you Kurt6. This runs contrary to what I learnt in school, where it was claimed that e. g. muscle cells and nerve cells do not get replaced. Are all or most cells in the body replaced from stem cell reservoirs ? You said before, along the same lines, that the brain can rejuvenate itself via stem cells, unfortunately with aging stem cells as we age. Given Yamanakas ability to reset fibroblasts to an embryonic state we are then in a much better shape to contemplate immortality.

Fly said at June 10, 2007 9:45 AM:

Randall: "My guess is that post-mitotic cells are going to accumulate DNA damage most slowly."

Maybe, but it isn't clear to me. Cell lines that rapidly divide don't accumulate cellular waste products or impaired cellular structures. Such accumulated damage might cause more metabolic DNA defects and impair DNA repair.

I've read about mutation rates in bacteria and yeast. I suspect much less is known about human cell lines. With cheap DNA sequencing individual cell lines could be tracked as a mouse ages.

Neurons are high metabolic tissues (especially in the retina) and that might affect the DNA damage rate.

What about white fat cells? They aren't metabolically very active and don't divide rapidly and are readily available.

Fly said at June 10, 2007 10:04 AM:

Bob: "I don't see that as any reason to think spermatozoa are any more stable than ova. The only selection process on the ova is whose turn it is that month. Spermatozoa come to the scene by the billion and compete heavily for the opportunity to be the only one to conceive."

My info came from a genetic counselor who studies risk factors associated with older mothers and fathers. Old fathers seem to slightly increase the risk of schizophrenia. Old mothers have increased risk for many birth defects. I don't know the biological process that creates this outcome. It might be due to non-DNA age related damage. E.g., the cell wall of old eggs is less permeable to sperm which reduces fertility.

It is not clear to me that sperm competition filters DNA damage. The sperm DNA is highly compacted. I don't believe there is much transcription occurring during the gamete phase. There might be some competition occurring in the germ cell lines that generate the sperm.

Randall Parker said at June 10, 2007 10:29 AM:

Fly,

Yes, fat cells are excellent candidates for screening for low levels of mutations. Great suggestion. I should have thought of that.

Neuronal metabolic activity: It is my impression that the neurons are so long that much of the metabolic activity takes place far from the nucleus. So maybe the nucleus doesn't get much of the free radical effect of the mitochondria burning sugar. But if fat cells make a better candidate there's no need to mess with neurons.

Sperm and nuclear DNA mutation: to effectively filter out mutations the damaged genes need to get expressed. We do not appear to have a real checksum process. I'm surprised that old sperm doesn't cause more offspring genetic defects than have been found so far. I wonder why that is.

Fly said at June 10, 2007 10:30 AM:

Mats-Erik Pistol: "This runs contrary to what I learnt in school, where it was claimed that e. g. muscle cells and nerve cells do not get replaced. Are all or most cells in the body replaced from stem cell reservoirs ?"

Muscle cells are unusual. Usually muscle satellite cells fuse with the muscle cell during growth and repair to create a long muscle fiber. So a single muscle cell has many nuclei. Sometime a new muscle fiber will form.

Brain neurons are very long lived. However there is some evidence that damaged neurons can be replaced. Also new neurons seem to play a role in the hippocampus during the formation of new memories. (In order to survive a new neuron needs just the right amount of stimulation...too little and it dies, too much and it dies. I suspect this requirement limits the brain neuron turn-over rate.)

In the last few years stems cells for more and more tissues have been found. (Only .001 to .0001 of the cells in a tissue are stem cells. Also finding cell surface markers that distinguish stem cells from other cells can be difficult.) My guess is that there are stem cells for generating all the body tissues.

Perhaps there is a stem cell reservoir that replenishes the local tissue stem cell reservoirs. Maybe the key is bone marrow. Rejuvenate the bone marrow and from there stem cells will migrate to other stem cell niches and differentiate into specialized tissue stem cells?

Randall Parker said at June 10, 2007 11:01 AM:

Mats-Erik Pistol,

The brain is the hardest organ to rejuvenate because we can't replace it. Replacing old neural stem cells with new neural stem cells will deliver substantial benefits. But we need to fix most of the neurons we have. Therefore we need gene therapies and nano repair devices that can go in and fix neurons.

On the bright side, stem cells can play other rejuvenation roles in the brain aside from neuron replacement. Most notably, we need to send in stem cells to replace aged blood vessel cells. Also, we can devise therapies that will remove accumulated cholesterol plaque and beta amyloid plaque.

Anna Lindgren said at July 25, 2007 10:43 PM:

Mats-Erik Pistol,

Yes, you get fresh nice young clones, but how long will they last? Of course you wouldn't demand the phenotype of the clone to be equal to its body of origin. "the edge" of cloning was that you were not restricted to germ cells, but could use any lousy old soma cell to get new fresh meat. But it was expected to come with same old disadvantages, i.e. that the clone had the same sloppy functions as their cell of origin.

Wikipedia: "Germline cells are immortal, in the sense that they can reproduce indefinitely. This is enabled by a special enzyme called telomerase. This enzyme is dedicated to lengthening the DNA primer of the chromosome, allowing for unending duplication. Somatic cells, by comparison, can only divide around 30-50 times, as they do not contain telomerases.

Dolly was as expected "telomerase-wise" six years older than she seemed to be. So nice and fresh and young, but not for long. I think other clones rather unexpectedly have turned out to have normal or even enhanced telomerase-activity for their age, so maybe I am not up-to-date. Since standard reproductive cloning puts a foreign soma cell nucleus into an oocyte which has been derived of nucleus, maybe this is where the epigenetics may play a role? The "telomerase" or whatever repair/duplication function might depend on the oocyte(female germ cell) environment, and not be inherent to the nucleus as first expected.
Mitocondrias are swimming in the cytoplasm and not coming with the donor nucleus.

Mats-Erik Pistol said at August 1, 2007 1:26 PM:

Anna Lindgren,

From memory I also belive that Dolly was old "telomerase-wise" and died prematurely by being killed. Advanced Cell Technology (ACT) has cloned animals that do not seem to have any reduced lifespan and they have been cloned from old cells. Thus, telomere shortening is not as serious as can be believed. Since most cells in mammals do not divide anyhow, telomere shortening affects only a small, probably very important though, subset of cells. Unfortunately it seems ACT has not published their results but only reported them at a conference talk, which name I forgot (stem cell treatment needed). It could have been a talk at the Edmonton aging conference http://www.edmontonagingsymposium.com/index.php?pagename=eas_archive (Mike West) which I cannot listen to at this internet cafe at the Black Sea.

The mitochondria problem is still present in my mind. Asking people at the local hospital (clinical genetics) in my home town, there seems to be no answer from them. Ova mitochondria are simply not allowed to get old in the sense of being mutated.

So Anna you have raised a third point which is a mystery. Maybe ACT used non-dividing muscle cell nuclei with long telomeres to clone fresh young clones ?

Anna Lindgren said at September 23, 2007 2:45 PM:

Mats-Erik Pistol,

What is the mitochondria problem? If ova mitochondria are young in the sense that they stay non-damaged, maybe this is only because they are better protected than most other cells in the body? Personally, I like the thought of aging as simply a worn out of the organ systems by environmental stress, accumulations over years, gradually effecting the ability for the cells to function or repair. ( This could manifest with or without DNA-damage, "epigenetic" changes and telomerase shortening). Thus finding ways of system detoxification, for me, seems a much more promising approach to stop aging, rather than cell-by-cell-renewal (which might be meaningless if new cells immediately get affected by the ill body).
But detoxification of course does not help if there really also exists an inherent limitation in the cells capacity to divide. Organ transplantations (with your gradual replacement of the brain), might still be a solution though. Maybe it is better with full rather than gradual replacement of organs, considering potential interactions with the environment.

If Dolly came from some dividing cell with short telomeres and ACT used a non-dividing cell with long telomeres, yes, that could make sense? (assuming that non-dividing cells have "long", not "none" telomeres)

Mark Boutilier said at October 24, 2007 11:31 AM:

Might it be possible to take identical twins, at an age where they are showing a difference in expression of aging, and do both differential epigenetic mapping and cDNA analysis on them? Then perhaps working backwards through metabolic pathways, see if guardian proteins (p53 or p21 for example) are being rendered incapable of arresting cell cycle @ G1 or G2 phases. If cell apoptosis (programmed cell death) is not doing its job, then these cells will proliferate and "contaminate" healthy genome.

I think as well the comments on mitochondrial DNA degradation are worthy of note. ROS (reative oxygen species) are going to have greatest effect where metabolism is highest, i.e., in the mitochondria; loss of functional mitochondria leading of course to decreased ATP production.

Mark Boutilier-UCSB

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