June 01, 2003
Brain Protein Tangles Cause Memory Loss With Age

The tangled up pieces of protein fragments (known as neurofibrillary tangles) seen in Alzheimer's Disease patients also occur to a lesser extent in aging brains in people who do not develop Alzheimer's.

The researchers found tangles in all of the brains. However, the number of tangles was higher in those with mild cognitive impairment.

The researchers also found a direct link between the number of tangles and scores from memory tests carried out on the eight people before they died.

You might see this as bad news. Our brains are accumulating protein tangles that are causing cognitive decline as we age. Well, the cognitive decline is already happening regardless of its cause. But if you look at this latest research in the right light it is good news. Why? A lot of money and effort are going into discovering the causes of Alzheimer's and how to treat it. These latest results suggest that those future treatments developed for Alzheimer's which work by ridding the brain of neurofibrillary tangles will probably be of benefit to us all regardless of whether we are going to develop Alzheimer's.

Neurofibrillary tangles are far from the only harmful compounds that accumulate in the body as we age. One key class of therapies designed to repair and reverse the effects of aging throughout the body will be the development of techniques for the removal of assorted classes of junk that accumulate within cells. One place in cells where junk or waste accumulates as cells age are the lysosomes. Lysosomes are intracellular organelles that specialize in breaking down cellular waste. But some forms of waste (notably lipofuscin - which is actually an assortment of different kinds of compounds) can not be broken down by lysosomal enzymes and hence these forms of waste accumulate. Lipofuscin and other accumulating forms of waste are suspected of contributing to the formation of a number of degenerative diseases of old age.

University of Cambridge biogeronotologist Aubrey de Grey has proposed the development of cellular rejuvenation therapies using gene therapy to transfer bacterial or fungal enzymes into cells to break down lipofuscin and other accumulated cellular waste products. (PDF file)

Here I consider the feasibility of a hitherto unexplored approach to this problem: augmentation of the lysosomal catabolic machinery with “xenohydrolases”, enzymes identified in other organisms that can degrade material that our existing apparatus cannot. Such enzymes should only need to break down a small minority of the molecular structures present in these aggregates to have a substantial effect because by doing so they will create and/or expose previously inaccessible substrates for enzymes we already have. Lysosomal function seems to be impaired by such aggregates [7], but not abolished, indicating that new hydrolases are continually (albeit ineffectively) targeted to aggregate-laden lysosomes.

The neurofibrillary tangles which are linked to cognitive impairment may also be accumulating in lysosomes. Therefore therapies aimed at introducing “xenohydrolases” (xeno in this context referring to enzymes whose genes are transferred from other species) may also be able to be adapted to work against neurofibrillary tangles.

The development of gene therapies that give cells the ability to synthesize enzymes that can "throw out the trash" promises to extend longevity, make cells throughout the body to perform in more youthful ways, and to contribute to the eventual ability to reverse aging and make aging humans young again. Gene therapies to break down toxic accumulated waste in cells will play an essential part in efforts to achieve Engineered Negligible Senescence. If you want to read more about Engineered Negligible Senescence and the coming ability to make aged humans young again then check out the FuturePundit Aging Reversal archive. Also, see the Strategies for Engineered Negligible Senescence (SENS) web site.

Share |      Randall Parker, 2003 June 01 02:53 PM  Aging Reversal

Charlie said at June 1, 2003 8:26 PM:

You made mention of some of the problems that the accumulation of lipofuscin causes- Is there any truth to the speculation that centrophenoxine use reduces lipofuscin levels in skin and other tissues?

Randall Parker said at June 1, 2003 8:48 PM:

Charlie, The answer is a bit subtle. Lipofuscin is not really a single compound. Effectively it is the name for a class of compounds that absorb light at a certain frequency (I forget which). Well, the lipofuscin compounds that are most harmful are probably not decreased by centrophenoxine.

There has been some knowledgeable discussion on this question in the Usenet group sci.life-extension and if you click on my link to that group (look down the right hand column of my main page for the link) and then search on centrophenoxine lipofuscin restricted to that group you will come up with a relevant thread on the subject.

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