11 replies to this topic

[Lazarus Long]

While some of this is not new I think this article helps focus recent findings and suggests to me another approach for SENS. How much of the mole rat's genome is mapped?

The reason is that they appear to have much of what is desired to genetically engineer a mouse to win the MMP. They appear to have a significantly better mechanism for coping with oxidative stress that mice and I wonder if that could be transgenically scripted into the normal mouse genome, and better yet, passed on?

Naked Mole-rats Hold Clues to Human Aging

Jeanna Bryner
LiveScience Staff Writer
LiveScience.com
Mon Oct 9, 1:00 PM ET

VIRGINIA BEACH, VA—They wouldn't win any beauty contests, but naked mole-rats would take home the crown for longevity. And research into human aging might draw from knowledge of the wrinkly subterranean creatures.

No bigger than a stick of butter, mole-rats [image] long outlive similar-sized rodents. They're known to approach age 30. Now scientists have gained some insight into this longevity: Mole-rats simply deal with the kind of cellular damage that life normally brings about.

"The naked mole-rat, with its surprisingly long life span and remarkably delayed aging, seems like the perfect model to provide answers about how we age and how to retard the aging process," said Rochelle Buffenstein of the City College of New York. "This animal may one day provide the clues to how we can significantly extend life."

Mole-rat Oddities
They almost never go above ground and are nearly blind.
They dig out burrows with oversized buckteeth.
They live in colonies of up to 300 individuals, with one breeding female similar to a queen bee.
Within their tunneling burrows, they delineate a separate toilet area, where feces and urine get stored.
They farm underground tubers by feeding from one end, plugging the end with soil and then feeding from the tuber’s other end.

Buffenstein presented her team's research here at a meeting of the American Physiological Society.


Aging cells

Humans and other animals are constant victims to oxidative stress. In the body, oxygen splits into single oxygen atoms, known as free radicals due to their unpaired electrons. They scavenge the body to nab or donate an electron, causing damage to cells, proteins and genetic material. Antioxidants produced by the body help to neutralize the free-radical attack.

Since mole-rats live several times longer than other rodents their size, scientists would expect them to exhibit either lower oxidative stress or a greater ability to defend against the attack by free radicals, perhaps by employing more antioxidants.

Buffenstein's team compared two-year-old naked mole-rats to four-month-old mice, selecting ages that were equivalent relative to the animals’ maximum life spans. Turns out the mole-rats had more oxidative damage to biological molecules, including more DNA and protein damage in the kidney and liver. Plus, the mole-rats had lower levels of oxidative neutralizers.

Yet somehow they live on.

Unknown mechanism

Buffenstein suspects the mole-rat is able to fend off acute bouts of oxidative stress, and that may be more important than dealing with routine injury caused by daily levels of oxidative stress.

“It’s like saying if something really unexpected came along and instead of having a nervous breakdown, I just fixed it," Buffenstein told LiveScience.

Further research is needed to figure out exactly how the mole-rats live with the damage caused by oxidative stress.



Aging Cause Found in Mice, Could Help Humans

SPECIAL REPORT: Toward Immortality

[treonsverdery]

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Edited by treonsverdery, 01 November 2006 - 01:43 AM.

[jaydfox]

[Lazarus Long]

Jay I guest that makes him a "Rat Star".

[John Schloendorn]

I wonder if that could be transgenically scripted into the normal mouse genome

Check out the SENS1 presentation by Mario Capecchi ;-) Nice dream, I have no idea if/how this has progressed.

[Mind]

Well, this sure seems strange. It certainly seems to challenge the oxidative stres theory of aging. Or this mouse has a tremendous defense and repair mechanism. We must find out.

What does everyone else think. I am very interested.

Do you think oxidative stress is not really a big factor in aging, at leats less a factor than what is commonly believed?

or

Does this mouse have better repair/protection mechanisms?

[Lazarus Long]

IMHO probably a little of both Mind.

[jaydfox]

I would guess the latter. For example, one could look at DNA mutations in mice and in men, in relation to cancer, and conclude that they must not be that big a deal, because the rate of accumulation of unrepaired DNA damage in humans is not sufficiently low relative to mice to explain why humans live longer.

The key difference, of course, is that we have additional layers of cancer defense, such that we can withstand a significantly higher amount of DNA damage before getting cancer. Not per cell, but when you consider that we have about 10,000 times as many cells as mice (within an order of magnitude), we should have a much lower rate of unrepaired DNA damage than we do, to explain the low cancer incidence prior to reaching our 40's (or age 2, for that matter).

But like I said, it's just a guess based on an analogy.

[Lazarus Long]

I think we are seeing both aspects at work because this rodent does exhibit a better repair mechanism (albeit still unknown) and a way of continuing without cancerous mutations or apoptosis even though it shows a high level of oxidative stress.

I suspect that we will find a gene sequence that controls a mechanism for doing so that provides either a higher tolerance or a repair mechanism but I also suspect we can xenotransplant that ability to a normal mouse and test that assumption. Regardless once we see that mechanism at work and can study the proteins involved and we may even be able to synthesize something that can help the body resist mutation even with higher levels of oxidative stress such as we find in elderly cells.

If that suspicion is correct then it could be a whole new class of drugs that do for oxidative damage in the cell what statins do for cholesterol in the blood.

However I also think it implies that there is more going on than is provided by the oxidative stress model in aging. That doesn't mean oxidative stress is unimportant it just means that I think we need to look for more related (and perhaps unrelated) problems that also contribute to aging.

So in a way that makes oxidative stress less of a factor because it is only a part of a larger picture, hence I answered "a little bit of both". Obviously this is all speculation but it is worth speculating or better yet investigating and testing.

[Lazarus Long]

Thanks John, I recommend that everyone listen to the discussion he references as they touch on many aspects of this subject.

It appears after listening to the talk John that there is a confusion of two somewhat different objectives. The intent of the presented study has much more to do with genetic systems mapping than actual results from the xenotransplantation of homologous genes.

This is not a contradiction though because both aspects are important and IMHO simply highlight the need for more attention to be paid to the subject. In fact I offer that the same kind of study should be done between bats AND the naked mole rat to help map them and the difference between them and the mouse.

For example if we see similar mechanisms at work providing longevity to both the naked mole rat and the bat then we might consider this a real candidate for use in higher mammals. If we see very different mechanisms at work then we might develop parallel avenues of study into how these mechanisms synergize or contradict in the real world (if at all).

Or how one of these could be useful and the other perhaps a dead end for our purposes. Clearly the comparative mapping of the genomes of multiple species, in this case these three are essential to the ability to manipulate their genomes and isolate the critical sequence(s) that might be transplanted to more complex species for testing.

[John2009]

I had read here http://en.wikipedia.org/wiki/Vitamin_D that "The naked mole rat appears to be naturally cholecalciferol deficient as serum 25-OH vitamin D levels are undetectable.[13] Interestingly, the naked mole rat is resistant to aging, maintains healthy vascular function[14] and is the longest lived of all rodents.[15]"

I thought this was a little interesting with all the publicity today regarding the health benefits of vitamin D and recommendations that most people should supplement with 1000 to 2000 IU of vitamin D per day. Then again, humans are not naked mole rats and the rats appear to have evolved without a need for as much vitamin D as us (if any). On the other hand, perhaps giving the rats vitamin D would be good for them, who knows :-)

http://en.wikipedia..../Naked_mole_rat