Reforging the Brain, One Small Piece at a Time
Permalink | View Comments (3) | Post Comment | | Posted by Reason

The repair of aging in the human brain will have to proceed one small step at a time. Either the rejuvenation biotechnologies of the SENS program will prove sufficient to remove every aggregate and process that stops an old brain maintaining itself like a young brain does, or there must be an even more patchwork quilt of therapies, each one fixing some form of damage. The former is a much more efficient path towards meaningful healthy life extension than the latter, but the vast majority of laboratory research and related funding goes towards progress on the harder, slower road.

So reforging the brain: if we're not thinking about picking out the fundamental forms of cellular and molecular damage that cause aging and then letting the body repair itself, then the list of repairs is a long one. There is myelin to be restored where it wears away; the matter of diminished stem cell activity and so ever fewer new neurons created to replace losses; the failure of structures like the choroid plexus that remove unwanted metabolic byproducts from cerebral fluids; the malfunctioning of the brain's complex complement of immune cells; and so on for many, many more items.

Here are a couple of research releases, each looking at one small aspect of the brain's fine structure, and giving some insight into means of repair.

Cells Forged from Human Skin Show Promise in Treating Multiple Sclerosis, Myelin Disorders

The source of the myelin cells in the brain and spinal cord is cell type called the oligodendrocyte. Oligodendrocytes are, in turn, the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Myelin disorders have long been considered a potential target for cell-based therapies. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.

It took [researchers] four years to establish the exact chemical signaling required to [transform human induced pluripotent stem cells, or hiPSCs, into] OPCs in sufficient quantities for transplantation and each preparation required almost six months to go from skin cell to a transplantable population of myelin-producing cells.

They found that the OPCs spread throughout the brain and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice. "The new population of OPCs and oligodendrocytes was dense, abundant, and complete. In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."

Dickkopf makes fountain of youth in the brain run dry

Cognitive decline in old age is linked to decreasing production of new neurons. [Scientists] have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals.

Neural stem cells in the hippocampus are responsible for continuous supply of new neurons. Specific molecules in the immediate environment of these stem cells determine their fate: They may remain dormant, renew themselves, or differentiate into one of two types of specialized brain cells, astrocytes or neurons. One of these factors is the Wnt signaling molecule, which promotes the formation of young neurons. However, its molecular counterpart, called Dickkopf-1, can prevent this.

Stem cells in the hippocampus of Dickkopf knockout mice renew themselves more often and generate significantly more young neurons. The difference was particularly obvious in two-year old mice: In the knockout mice of this age, the researchers counted 80 percent more young neurons than in control animals of the same age. Moreover, the newly formed cells in the adult Dickkopf-1 mutant mice matured into potent neurons with multiple branches. In contrast, neurons in control animals of the same age were found to be more rudimentary already.

Comments

I think you are too pessimistic regarding how this sort of research fits with the SENS agenda. One of the stated parts of SENS therapy (one of 7) is the supplementation via cell therapy of cell populations that have undergone gradual attrition. Furthermore, AdG and others have acknowledged that this will require teasing out the determinants of cell fate so that all the relevant cell types can be generated for renewal. AdG has stated that the number of cell types involved makes this one of the most intrinsically difficult and time-consuming parts of SENS.

So what do we have here? Researchers have found the determinants of cell fate relevant to oligodendrocytes, they have generated the requisite precursor cells and actually demonstrated renewal of the myelin! In fact this progress is exactly in accordance with the SENS research program and it's effectively SENS research and rejuvenation biotechnology in progress.

Where is the strategic mistake in these research priorities? I'm not really following you this time.

Posted by: José at February 8, 2013 6:30 AM

@José: The question I'm asking here is whether these and many similar approaches are necessary, or whether they are poor substitutes for SENS, just patches on the underlying problem that will suffer from the same issues as near-all present medicine for age-related conditions, in that they are expensive short-term pseudo-fixes. If aggregates, senescent cells, and mitochondrial damage are removed, and the immune system pruned back to healthy programming, will the brain then sort out its own neurogenesis rate and myelination, as it did when young?

This sort of question is an important one, but it seems to me that the cheapest way to answer it is to implement SENS and see what happens.

Posted by: Reason at February 8, 2013 7:43 AM

Yes, but I don't understand why you would think that replacing cells that fail to self-renew is a "poor substitute for SENS." It's a part of SENS:

http://www.sens.org/research/introduction-to-sens-research/repleni

If cells are missing, how is their replacement a "pseudo-fix?" I would think of it as damage repair and restoration of underlying structure to rescue function.

You seem to be pondering whether some paths of SENS therapy may obviate the need for others. That's possible, but I think we should research all paths just in case (and especially should start on those paths that are likely to require the most effort). After all, what if the rate of ongoing myelin repair is not adequate even in youth and this only becomes exacerbated and evident later in life?

Posted by: José at February 8, 2013 10:01 AM
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