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Mitochondria Aging


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#31

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Posted 15 December 2004 - 12:10 AM

I don't care about helping my germ-line and distant descendants hang onto what I have. They can sweat it out for themselves. I want to know about how I can hang onto what I already got at birth. Manofsan

I share your sentiments. These mechanisms are all very, very interesting, but their relevance in an adult organism insofar as lifespan extension is concerned may be questionable.

#32 kevin

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Posted 06 January 2005 - 02:36 PM

Link: http://www.discover....ns-spark-aging/

Another article about Larsson's discovery.. in Discovery


39: Cell Mutations Spark Aging
By Jocelyn Selim
DISCOVER Vol. 26 No. 01 | January 2005 | Biology & Medicine

Posted Image
These two young mice were born on the same day. The one on the right carries a faulty enzyme.

Molecular biologists may be on the brink of unleashing a cellular fountain of youth. In May Nils-Goran Larsson of the Karolinska Institute in Sweden pinpointed where the process of aging begins in a cell—the mitochondria—and thus where it may be slowed.

Mitochondria are tiny organelles that harness energy and turn it into a usable form. They are also the only structures outside a cell’s nucleus that contain their own DNA, and that turns out to be important. While DNA in the nucleus has an extensive system of proofreading and repairing enzymes, mitochondria depend mostly on a single protein to patch up mutations. When Larsson engineered mice with a defective, error-prone version of the protein, mice accumulated mutations unchecked. The results were startling. At young adulthood, Larsson’s mice resembled those three times their age, with bone and muscle loss, heart disease—even baldness.

The study is the first hard evidence that these mutations are a cause of aging rather than just a sign, like wrinkles. When mitochondria begin to break down, they run less efficiently, creating more toxic free radicals. The process resembles an inefficient engine producing more smoke. Larsson’s research suggests that the damage from these free radicals—either to the mitochondria or other parts of a cell—is what triggers the aging process.

Mitochondrial mutations may also underlie Alzheimer’s, Parkinson’s, and other diseases that are common among senior citizens, says Doug Wallace, director of the University of California at Irvine’s new Center for Molecular and Mitochondrial Medicine and Genetics. “If we could find a way to protect mitochondrial DNA, either with drugs or by using gene therapy to transplant it to the nucleus, it could not only extend our life spans but prevent many of the diseases we associate with aging as well."

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#33 John Schloendorn

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Posted 07 January 2005 - 12:22 AM

Kev, the orignial study that this article tries to summarize is quite fascinating. These guys used a proofreading defective DNA polymerase to mimic the mutator phenotype of aging mitochondria. The phenotype of these mice was intriguingly similar to aging.

When trying to extend life spans, I hope we will get around the mitochondria problem by a cellular replacement strategy. In an approach where replacement (stem-) cells are generated from embryonic stem (ES) cells and made histocompatible by therapeutic cloning, the replacement cells will have fresh mitochondria and thats all there is to it. The same would be true for whole tissues engineered from ES cells.
However, as for the neurons of the brain, the prospects of replacement both on the cellular and the tissue level seem slim to me. Thus, we will want to keep an eye on gene-therapy based re-engineering of neuronal mitos. I would have loved to see more phenotypical characterization of the brain in these mice.

And still, all the data obtained by Larsson is negative. In my opinion, one would have to selectively slow, or fix mitochondrial mutations before one could speak of a causal relationship to aging.

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#34 olaf.larsson

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Posted 07 January 2005 - 12:36 AM

How about delete mitochondria and feed cells with pure ATP? That could give a good image of the importance of mitos.

#35 John Schloendorn

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Posted 07 January 2005 - 12:43 AM

To be specific, I would say the experiment suggests that mitochondrial mutations are a contributing cause to aging, or one limiting factor to staying young. Now other factors, say hormone levels, gene expression changes, stem cell depletion, cancer, may also exist. As long as they do, there is no selective pressure to improve on any single factor beyond the given level. Thus it is conceivable that fixing mitochondiral mutations will be necessary, but not sufficient to extend life span.

#36 John Schloendorn

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Posted 07 January 2005 - 12:50 AM

Wolf, a good way is to feed them with glucose and deprive them of oxygen, so that they do cytoplasmic glycolysis. This indeed extends cellular life span in culture.
The thing is that in cell culture you can't do much of the phenotypical characterization. When we say some creature is aging slower, we want to see things like less wrinkles, thicker fir, more muscle mass etc. In vivo, reduction in respiratory activity may be part of what's happening during CR, but other things may be happening as well, so we don't know.

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#37 kevin

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Posted 07 January 2005 - 01:54 AM

And still, all the data obtained by Larsson is negative. - John S

Yep.. I was thinking the same thing... correlation is not causation. mtDNA damage is likely only one lever. I think proteosomal function might be as important. It seems to me that the trigger for the synthesis of new proteins is often a signal given by specific fragments of the proteosomal digest. The quality of intercellular matrixes play an important role in stem cell progenitor differentiation. If the protesomal machinery is bunged up the matrix does not get regenerated properly and thus stem cell fate dependent on proper signals from the environment is changed to something else, fat cells for instance, upsetting hormonal and metabolic balances which of course are not going to be that healthy.

Progenitor stem cell exhaustion plays a role in regenerative capacity as well and I don't think enough is known about that yet either. We might be able to manipulate aging by accelerating it as in the Larsson study or slow it slightly with CR and perhaps enhancing mtDNA protection might eke out a bit more, but I don't think that if mtDNA was perfectly replicated we would achieve anything like the extended lifespans we really want because of other non-energetics related problems.

#38 olaf.larsson

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Posted 07 January 2005 - 02:32 AM

I would indeed make more sence if the mitos came from the father. Then the sperm race would infact be a quality control of mitos. The arangement would make sence to 100%.

#39 John Schloendorn

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Posted 07 January 2005 - 02:55 AM

The race could also be wasting the sperm mitos due to "win at all costs" selection on the nuclear gene level.

#40 olaf.larsson

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Posted 10 January 2005 - 04:35 PM

"The race could also be wasting the sperm mitos due to "win at all costs" selection on the nuclear gene level". Yeah thats right.. better to live the mitos outside with the spem flagella as its done in real life.

Idea for experiment that could establish the importance of mitos for aging (Im not really sure this is possible in real life though) :

Take an fertilized diploid oocyte from a long lived spieces and take out the nucleus.
Put the long lived diploid nucleus in a oocyte from a short lived spieces.
Now you have a hybrid with a long lived nucleus and short lived mitos.
If everything works the proteins of the short lived spieces will be diluted becouse of breakdown, and newsythesis of long lived spieces proteins.
The cells could be implanted in a surrogate mother and hopefully a hybrid animal would soon be born, whos mitos come from the short live spieces.

#41 John Schloendorn

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Posted 11 January 2005 - 06:08 AM

Good stuff Wolfram. I don't see why it should not work. These guys here would rather ablate the mitos from the Zygote and inject the xeno ones, as to account for cytoplasmic incompatibility. No attempt was made to assess any life span effects.
They found only minor metabolic abnormalities in the progeny that could largely be controlled for in your experiment.

The mitos could be taken from a creature called the naked mole rat, which lives 15-20 years and may or may not be sufficiently related to mus musculus. Now the transmitochondrial mice we're getting should be used as a starting material to implement further SENS, so that the limiting factors can be conquered one by one.

Let's do it! How's in your garage?

#42 Mind

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Posted 15 December 2008 - 11:13 PM

Another good read from Reason about autophagy, mitos, and aging.

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#43 advancedatheist

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Posted 01 March 2009 - 01:09 AM

http://www.box.net/s.../upevgz2qu0.pdf




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