January 22, 2009
Neuron Nuclear Membranes Decay With Age

Some important types of cells (e.g. neurons, muscle cells) do not divide. Cells that divide dilute junk that accumulates inside of them and the newly divided cells can manufacture new internal structures (e.g. proteins in membranes). The non-dividing (aka post-mitotic) cells do not do this dilution and do not create as much internal structure. Some researchers at the Salk Institute find that key proteins in nuclear membranes (which enclose and protect our DNA) do not get replaced as we age. These components of our membranes deteriorate with age and make the nuclei of cells basically spring leaks. Not good.

As parts of us age, even the membrane bound nuclei , which house the genetic instructions for life that are "written" in our DNA, begin to show considerable wear and tear, suggests a new report in the January 23rd issue of the journal Cell, a Cell Press publication. The nuclear pore complexes that normally act as gatekeepers--selectively importing and exporting the molecular ingredients for life to and from the nucleus--begin to break down and spring leaks.

That's because some of the 30 or so nucleoporin proteins that make up those complexes can't be replaced once cells stop dividing, they found.

We need to develop the means to create replacements and somehow tear down old nucleoporin proteins. That will not be easy to do.

" These proteins are unusually stable," said Martin Hetzer of the Salk Institute for Biological Studies. "Most proteins turnover within minutes or hours. These last the entire life span of the cell," a period that can in some cases be decades. In fact, he said, many cells in the body do not actively divide most of the time, and that lack of cell division is particularly dramatic for cells such as muscle and neurons.

Earlier studies had shown that some components of the nuclear pore complexes are very dynamic while others hang around throughout the cell cycle, getting replaced only when cells split into two daughter cells, Hetzer explained. His team wondered what that meant for cells that had stopped dividing.

As long time readers know, I see the brain as the most difficult part of the body to rejuvenate. Some parts of the body will get rejuvenated by replacement. Got an old and failing liver or kidneys? Grow new parts using future advances in tissue engineering and transplant in the new parts. Or find a way to grow new organs inside of our bodies. But neurons with leaking nuclear membranes are especially problematic because the neurons must be repaired rather than replaced.

They now report that the scaffold nucleoporins are extremely stable and do not exchange once they are incorporated into the nuclear membrane, persisting for the entire life span of a differentiated cell. In those cells, the nuclear pore complexes deteriorate with time, eventually losing nucleoporins that are critical for maintaining the pore diffusion barrier. Strikingly, they found that nuclei of old rat neurons containing deteriorated nuclear pore complexes become increasingly permeable.

The proteins in the nuclear membranes that serve as pores also serve as structure to maintain the membrane's three dimensional structure. To replace these proteins is akin to replacing structural beams in a building without letting the building collapse. This is far harder to do at microscopic levels and in hundreds of millions of cells.

Cells are usually very efficient at getting rid of old or damaged proteins and replacing them with new copies, Hetzer said, but it seems they have no way to replace the most stable components of the nuclear pore complexes. He suspects that's because the pores are not only essential for molecular transport, but they are also structural components of the double lipid layer that is the nuclear membrane. If those gated holes are lost, the membrane collapses, he said.

" How do you replace a bridge while transport is happening?" he asked. "It's not possible."

I disagree with the "It's not possible" claim. But development of techniques for doing this will be very difficult and I fear this problem won't be solved for decades.

Share |      Randall Parker, 2009 January 22 11:33 PM  Aging Mechanisms

Mthson said at January 23, 2009 2:00 AM:

If we had a means to replace the brain one quarter inch at a time, wouldn't the degree of lost identity/continuity be acceptable? It seems like the rest of the brain could simply re-train the new part.

The costs of that incremental method would be somewhat localized to that area of cognitive function, which would certainly be preferable to the systemic loss of cognitive function associated with old age.

Brett Bellmore said at January 23, 2009 4:20 AM:

You'd probably lose infrequently accessed memories, and lose resolution for frequently accessed ones. (You'd be remembering remembering, instead of remembering the original event.) An acceptable price to pay, if there were no other way to keep the brain running, though.

Possible solutions:

1. Replace the whole nucleus. "Just" do a hot swap for a fresh one, with the added advantage of it being an opportunity for genetic error correction and upgrades.

2. Create a new nuclear membrane around/within the old one, then destroy the old one.

3. Develop even more stable nuclear membrane proteins, that last longer.

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