Thioredoxin Reductase Correlates with Species Longevity

Researchers here summarize current data on thioredoxin reductase and longevity across a range of species, finding a correlation for the mitochondrial variant of this protein. There are numerous proteins for which one can point to correlations with species life span, and some of them relate to mitochondria and oxidative metabolism, as is the case here. What we should take away from this, and related research, is that there is a great deal of evidence pointing towards the importance of mitochondria in the way in which the operation of cellular metabolism determines the pace of aging. That in turn means that greater emphasis should be placed on research such as the SENS rejuvenation research programs that offer the prospect of protecting mitochondria from damage, preventing their age-related decline and hopefully minimizing the role they play in causing aging.

The rate at which aging leads to physiological decline, late-life disease, and death varies greatly among species of birds, rodents, and primates. Maximum lifespan varies from 2 years to over 100 years among species of mammals. This variation is thought to represent adaptation, across evolutionary timescales, to niches that reward either rapid reproduction or slower, more sustained patterns of development and reproductive investment. This variation in lifespan can be seen not just across the animal kingdom but within individual animal clades. Maximum lifespan among nonhuman primate species varies from 15 to 60 years. Maximum lifespan among rodent species varies from 4 to 32 years, and maximum lifespan among bird species varies from 5 to 70 years. This implies that a long lifespan has evolved multiple times in different clades. What strategies have been employed by these different groups to extend lifespan and whether these strategies are conserved or divergent among animal clades forms an interesting topic for research. Understanding the mechanisms that different species have employed to extend their lifespan has both medical implications for developing treatments to age-associated diseases.

Comparative analysis of cultured cells from species that vary in lifespan provides a powerful tool to identify factors which may regulate the rate of aging. Much circumstantial evidence links cellular resistance to oxidative stress and organismal lifespan. Genetic, dietary, or drug manipulations that extend lifespan in mice, flies, and worms often increase oxidative stress resistance. Cells from longer-lived species are often more resistant to oxidative stress than cells derived from shorter-lived species of the same clade. Increased resistance to oxidative injury seems often to accompany increased longevity, but to be insufficient to increase lifespan on its own, as demonstrated by the catalase overexpression is targeted to mitochondria, hinting that mitochondrial antioxidant defenses might be of particular importance, rather than oxidation elsewhere in the cell.

Thioredoxin (TXN) is a small redox protein which both removes oxidants and free radicals from the cellular environment and reduces protein disulfide bonds once these are formed. Thioredoxin reductase (TXNRD) reduces oxidized TXN thioredoxin while simultaneously catalyzing conversion of NADPH into NADP+. Thus, TXNRD controls the availability of reduced TXN. The TXN/TXNRD pathway also represses apoptosis through inhibition of ASK-1 signaling. In mammals, there are three forms of thioredoxin reductase: cytosolic TXNRD1, mitochondrial TXNRD2, and TXNRD3, whose function is poorly defined. In Drosophila, there are two forms of thioredoxin reductase: cytosolic Trxr-1, an orthologue of TXNRD1, and mitochondrial Trxr-2, an orthologue of TXNRD2.

In this report, we show a correlation between TXNRD enzyme activity and species lifespan using fibroblasts from birds, rodents, and primates. In some clades, we found similar associations with glutathione reductase activity, but did not see a correlation for any of the other redox enzymes evaluated. The increase in TXNRD activity in the longer-lived species is due to enhanced mitochondrial TXNRD2 with no change in cytosolic TXNRD1 or TXNRD3. A similar increase in TXNRD2 is seen in tissues of several models of enhanced longevity in mice, and in an analysis of mRNA levels from multiple tissues of primate species. Lastly, we demonstrate that overexpression of mitochondrial TXNRD2, but not cytosolic TXNRD1, can extend median (but not maximum) lifespan in female flies with a small lifespan extension in male flies in Drosophila melanogaster.

These data demonstrate that augmentation of mitochondrial thioredoxin reductase 2 is a conserved approach utilized by species from a range of animal clades under selection for a long lifespan. Furthermore, we demonstrate directly that augmentation of this enzyme is able to extend organismal lifespan in Drosophila melanogaster. Our approach shows the power of combining comparative biology cross-species approaches with direct interventions in model organisms as a means of discovering regulators of aging and lifespan. In addition, we identify mitochondrial Thioredoxin reductase 2 as a new target, for basic and applied research in aging.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12596/full