TXNIP as a Target to Protect Against Oxidative Stress and Slightly Slow Aging

Researchers here overstate the potential relevance of an approach demonstrated to improve defenses against molecular damage caused by oxidation in flies. Looking over the diagrams in the paper, reduced levels of TXNIP don't in fact increase life span all that much in flies - and consider that fly life span is far more plastic in response to this sort of manipulation than is the case in humans. A range of approaches that greatly increase fly life span, or nematodes, or mice, are known to do no such thing in our species, even though some may help to improve the quality of health along the way. This is the nature of aging and metabolism in short-lived versus long-lived species.

The researchers also lean heavily on oxidative theories of aging, which are showing their age these days. Oxidative stress certainly increases in later life, and that increase causes downstream issues, but it is entirely possible to argue based on the evidence that it isn't as important as other aspects of aging. It is also secondary to issues such as mitochondrial dysfunction and chronic inflammation. Removing excessive oxidative molecules or improving defenses against them can evidently produce some degree of benefits, but the details of the biochemistry are very important. Few of the approaches illustrated to date have sizable, unambiguous results that are worthy of further interest - perhaps mitochondrially targeted antioxidants, for example. Even those don't seem capable of significant rejuvenation, however, versus a slight slowing of aging.

Oxidative stress causes cells and entire organisms to age. If reactive oxygen species accumulate, this causes damage to the DNA as well as changes in the protein molecules and lipids in the cell. The cell ultimately loses its functionality and dies. Over time, the tissue suffers and the body ages. Researchers have now discovered the key regulator that is responsible for shifting the sensitive balance from vital to harmful amounts of reactive oxygen molecules and thus accelerating the aging process: A protein molecule called TXNIP (thioredoxin-interacting protein).

One way in which the body disposes of harmful reactive oxygen species is their conversion by the enzyme thioredoxin-1 (TRX-1). TRX-1 has been proven to play a role in protecting DNA from oxidative stress and slowing down aging processes. Its antagonist TXNIP inhibits thioredoxin-1 and thus ensures that the reactive oxygen molecules are retained. The researchers wanted to know whether more TXNIP is formed in the body with increasing age, thereby undermining the protective mechanism against oxidative stress. To this end, they first compared T cells from the blood of a group of over 55-year-old volunteers with the T cells of younger blood donors, who were between 20 and 25 years old. It turned out that the cells of older subjects produce significantly more TXNIP. The scientists have also observed similar findings in other human cell and tissue types.

The researchers also found that more TXNIP is produced in the fly Drosophila with increasing age. In order to test whether TXNIP is actually responsible for aging, they bred flies that produce significantly more TXNIP than their relatives as well as flies in which TXNIP synthesis is greatly reduced. "Flies that produced more TXNIP lived on average much shorter, while flies with less TXNIP had a longer average life. TRX-1 and its opponent TXNIP are highly conserved in the course of evolution; they hardly differ between flies and humans." It can therefore be assumed that the two proteins perform similar functions in flies and humans. If more TXNIP is produced with increasing age, this means that TRX is gradually switched off with its protection function. This leads to more oxidative stress, which damages cells and tissue and eventually causes them to die.

Link: https://www.dkfz.de/en/presse/pressemitteilungen/2018/dkfz-pm-18-38-Key-molecule-of-aging-discovered.php


If researchers could only upregulate/over express the TRX-1 gene and downregulate/excise TXNIP we might have a very valuable and effective antiaging strategy. It doesn't seem so difficult to at least conceptualize this scenario, but may be more difficult to implement, as all these anti-aging strategies seem to develop slowly in the labs of the World.

Posted by: Biotechy Marcks at June 21st, 2018 9:04 AM

United States Patent Application 20170252376 Kind Code: A1

One attempt to do that is the use of a TXNIP promoter-liked Trx1 gene construct. Transfection of this construct lowers TXNIP and increases Trx1 level. Proof of concept of gene and cell therapy for diabetes and aging-related neurodegenerative diseases may be established with such an experiment in animal models including fruitflies, zebra fish and mouce......

Posted by: Lalit Singh Pukhrambam at July 5th, 2018 1:32 PM

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