September 10, 2011
Low Lon Protease Lets Cells Accumulate Damage

If you've got cells low on Lon they will accumulate garbage proteins that cause trouble.

When the body fights oxidative damage, it calls up a reservist enzyme that protects cells but only if those cells are relatively young, a study has found.

Biologists at USC discovered major declines in the availability of an enzyme, known as the Lon protease, as human cells grow older.

A protease is an enzyme that breaks down peptides (pieces of protein). So this enzyme does not neutralize free radicals. It breaks down proteins damaged by chemicals that rampage thru the cell doing damage. Without enough Lon (and other proteases as well) damaged pieces will accumulate in a cell. This has a number of undesirable consequences such as taking up space that would get used by functional proteins. Also, the damaged proteins will in some cases do wrong things such as generate reactive species that do even more damage. Aging is a vicious cycle where damage causes even more damage.

Would a drug be capable of boosting Lon activity? Is that even the right response to the problem found by these researchers?

The finding may help explain why humans lose energy with age and could point medicine toward new diets or pharmaceuticals to slow the aging process.

The researchers showed that when oxidative agents attack the power centers of young cells, the cells respond by calling up reinforcements of the enzyme, which breaks up and removes damaged proteins.

As the cells age, they lose the ability to mobilize large numbers of Lon, the researchers reported in The Journals of Gerontology.

A cell that does not have enough Lon protease has likely accumulated a lot of damage. The low Lon protease might even be the result of damage to mitochondria where the cell loses the ability to generate enough energy. It would not surprise me if the cell basically turns off optional systems like Lon when energy levels drop too lo. So just trying to boost Lon might not work.

If boosting Lon is either not practical or useful then what? I see two options: Fix the root cause of low Lon. If the root cause is damaged mitochondrial DNA then send in gene therapy to fix the mitochondria. Another option: Try to kill cells that do not make enough Lon. Then neighboring cells or stem cells could divide to replace them. That's an approach that would need selective control so that you don't die due to an organ suddenly failing due to excessive cell loss. Also, cell therapies would be needed to replace cells in organs that have limited repair capability (e.g. the heart).

Share |      Randall Parker, 2011 September 10 08:59 AM  Aging Mechanisms


Comments
Brett Bellmore said at September 11, 2011 7:16 AM:

Maybe we should find a way to 'kill' defective mitochondria; After all, they do have their own genetics, they reproduce within the cell. This means that a cell probably has genetic diversity in it's mitochondrial population. Kill off the bad ones, and they could be replaced with functional ones.

Presumably there's some mechanism for keeping a good population of mitochondria, and the presence of non-functional ones is spoofing it into maintaining too low a population of functional ones.

In said at September 11, 2011 11:55 AM:

I wonder how this relates to autophagy. Autophagy can be upregulated through fasting.

Lou Pagnucco said at September 12, 2011 8:02 AM:

After a quick web search, the only approach I can find that appears to slow the decline in Lon activity is caloric restriction. I'm not sure whether it can restore Lon function once it is lost.

Randall Parker said at September 15, 2011 7:14 PM:

Brett Bellmore,

I think it'll be easier to kill defective whole cells than mitochondria because cells provide a lot more ways to combine characteristics to trigger a kill.

The other option with mitochondria is to send genes into the nucleus that replace damaged mitochondrial genes. Aubrey de Grey has advocated this approach. The 15k of DNA in a genome of a mitochondrion is a lot more susceptible to damage than nuclear DNA.

In, Lou,

It would be good to be able to put one's body into a high repair state where it does lots of chopping up of junk, autophagy, and apoptosis. Plan some number of days where you will feel very tired because your body is doing deep repair. Then eventually augment this with gene therapies, immune therapies (programmed to clean up junk), and other therapies that enhance the process of throwing out the junk.

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