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Protein Folding and Aging


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#1 Mind

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Posted 18 February 2009 - 09:38 PM


Naked Mole Rat Lives Longer With Better Protein Maintenance

One long-standing theory of aging is that it results from the slow degeneration of cells through contact with oxygen, called oxidative stress. But paradoxically, naked mole rats have higher levels of oxidative damage in their cells than do mice, even from a young age. To understand why these animals seem to be resistant to the effects of oxidation, Buffenstein and her colleagues at the Barshop Institute looked at the rodents' proteins, one of the key targets of oxidative damage.

Buffenstein worked with biochemist Asish Chaudhuri to compare the structure of proteins in the liver tissue of old and young naked mole rats to those in mice using high-throughput methods recently developed in Chaudhuri's lab. The analyses showed that proteins in mole-rat cells are more resistant to unfolding, making them more stable than those of mice.

The researchers also found evidence that the cells of mole rats have more efficient mechanisms for getting rid of improperly folded or oxidized proteins. Buffenstein says the results suggest that naked mole rats can withstand oxidative damage better by keeping their proteins stable and quickly removing unfolded proteins before they can accumulate.


Protein crosslinks of course are a major part of the SENS platform as well. All of this is directly related to aging and aging related diseases. All the more reason to support folding@home and TLM (you can of course WIN MONEY folding for TLM, team #32461).

P.S. everyone who reads this should PM Caliban and let him know how important protein folding research is.

#2 brokenportal

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Posted 18 February 2009 - 09:43 PM

This is exactly the kind of inspiration that can and should drive this team to number one. We need more protein data like this to inspire the team, good idea.

#3 Prometheus

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Posted 19 February 2009 - 03:45 AM

I would PM Caliban but firstly take care to distinguish between biological processes that regulate the disposal of improperly folded or damaged proteins and their influence in health versus the prediction of 3-dimensional protein structure from amino acid sequence. These not strictly related matters. If you think they are, then you should take the time to explain how they are related.

#4 caston

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Posted 19 February 2009 - 04:07 AM

Also mis-folded proteins is very different to advanced glycated end-products or AGE's. I think one of the ways SENS deals with mis-folded proteins is to upgrade the lysosome using enzyme replacement therapy or ERT or some other method.
Mis-folded proteins are classified as "intra-cellular junk"

Edited by caston, 19 February 2009 - 04:10 AM.


#5 maestro949

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Posted 19 February 2009 - 09:54 PM

Why does Caliban need to be educated as to the importance of protein folding?

#6 Prometheus

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Posted 20 February 2009 - 05:30 AM

Why does Caliban need to be educated as to the importance of protein folding?


Because his name starts with C

#7 maestro949

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Posted 20 February 2009 - 07:36 PM

Posted Image

#8 Mind

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Posted 20 February 2009 - 11:08 PM

These not strictly related matters. If you think they are, then you should take the time to explain how they are related.


I admit they are only indirectly related, however as folding@home becomes more powerful it has to potential to simulate much more than single protein folding and investigate other related cellular processes.

Pande is preparing to move this multi-peta flop computing platform completely into the cloud (storage and processing) and this could pave the way for more innovative collaborative research into aging processes. I heard a rumor that MF was reaching out to UCLA to start up their own distributive computing project to investigate AGEs and they could probably build upon what has been learned from folding@home and BOINC.

Caliban reminds me every month or so of his opinion that the F@H prize is completely useless. I am of the opposite opinion.

#9 maestro949

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Posted 20 February 2009 - 11:39 PM

Caliban reminds me every month or so of his opinion that the F@H prize is completely useless. I am of the opposite opinion.


The successes (and failures) of f@h will lead to more researchers (including future biogeronotlogists) following in the Pande Groups' footsteps of using large-scale informatics approaches to tackling the biological complexity that is blocking most, if not all significant medical progress. Just about all the low-hanging fruit has been plucked from 20th century scientific methods and tools. New ones are desperately needed and scalable informatics projects are going to be key to just about every aging-related intervention of the future. While the study of misfolded proteins only overlaps with aging related diseases in a relatively small way, f@h does demonstrate a new paradigm and approach to problem solving in this space.

#10 Prometheus

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Posted 21 February 2009 - 12:06 AM

I suppose Caliban's opinion is based on reward vs effort.

#11 stephen_b

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Posted 23 February 2009 - 06:08 PM

Well, that was a fun title. New Scientist has a short article discussing the study "Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat"

Here's the abstract from the study .

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. Surprisingly, data from the longest-living rodent known, naked mole-rats [MRs; mass 35 g; maximum lifespan (MLSP) > 28.3 years], when compared with mice (MLSP 3.5 years) exhibit higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage even at a young age. We hypothesize that age-related changes in protein structural stability, oxidation, and degradation are abrogated over the lifespan of the MR. We performed a comprehensive study of oxidation states of protein cysteines [both reversible (sulfenic, disulfide) and indirectly irreversible (sulfinic/sulfonic acids)] in liver from young and old C57BL/6 mice (6 and 28 months) and MRs (2 and >24 years). Furthermore, we compared interspecific differences in urea-induced protein unfolding and ubiquitination and proteasomal activity. Compared with data from young mice, young MRs have 1.6 times as much free protein thiol groups and similar amounts of reversible oxidative damage to cysteine. In addition, they show less urea-induced protein unfolding, less protein ubiquitination, and higher proteasome activity. Mice show a significant age-related increase in cysteine oxidation and higher levels of ubiquitination. In contrast, none of these parameters were significantly altered over 2 decades in MRs. Clearly MRs have markedly attenuated age-related accrual of oxidation damage to thiol groups and age-associated up-regulation of homeostatic proteolytic activity. These pivotal mechanistic interspecies differences may contribute to the divergent aging profiles and strongly implicate maintenance of protein stability and integrity in successful aging.

It's not clear to me whether the protein damage is due to oxidation or glycation. Any lessons for humans?

StephenB




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