Cancer and Longevity Answers by Howes Randolph

Author:Howes, Randolph
Language: eng
Format: epub
Published: 2015-06-14T16:00:00+00:00

Over expression of Antioxidant Enzymes

An alternative approach to studying the impact of antioxidants on longevity is to genetically overexpress antioxidant genes with the intention of extending lifespan. In mice, only a handful of studies examining lifespan in response to overexpression of antioxidant enzymes have been published.

A key question in these studies is whether or not an increase of activity in one antioxidant enzyme will in fact reduce endogenous oxidative stress, cause down-regulations of other antioxidants or even upset the balance of oxidant removal leading ultimately to a counter-intuitive increase in oxidative damage.

A large cohort study showed that overexpression of CuZnSOD did not increase lifespan. (Huang et al, 2000)

High overexpression of both CuZnSOD and MnSOD leads to harmful phenotypes such as muscular dystrophy, neuronal degeneration and infertility, with at least the muscular dystrophy correlated ironically with higher levels of oxidative damage such as lipid peroxidation. (Rando et al, 1998) (Jasrsma et al, 2000) (Raineri et al, 2001)

Furthermore, although overexpression of CAT showed protection in a cell culture model, at the whole organism level it actually led to an increase in gamma irradiation sensitivity. Mice overexpressing CAT (2- to 4-fold) in the peroxisome did not show a significant extension of maximal lifespan, although median lifespan showed a modest 10% increase. (Chen et al, 2004)

Transgenic mice that overexpress human CAT in mitochondria (MCAT) showed a statistically significant extension of both median and maximum lifespan of approximately 20% and equivocal changes in lifespan when expressed in other organelles.

No increases in lifespan was evident with overexpression of MnSOD. (Perez et al, 2008)

Thioredoxin (Trx) facilitates the reduction of other proteins by cysteine thiol-disulfide exchange. Overexpression of human thioredoxin (Hs Trx1) in mice reportedly leads to a 20% increase in lifespan, as well as increased resistance to cerebral ischemia and to UV-induced oxidative stress. In these animals HsTrx1 was three to six times more prevalent in tissues than endogenous Trx1. Metallothionein (MT), a scavenger of metal ions OH− is also highly induced by oxidative stress.

Transgenic mice overexpressing metallothionein (MT-TG) showed a 15% increase in mean lifespan relative to control mice. Furthermore, their cardiomyocytes have attenuated age-related increases in superoxide generation, cytochrome c release, p47phox (Neutrophil cytosol factor-1) expression and higher aconitase activity In contrast, knockout mouse models of MT show enhanced toxicity from ROS (EMODs) especially in cardiomyocytes. However, a lifespan study of MT null mice has not been conducted.

The Mastushima group reported that overexpression of Prx3 protects the heart against post-mycardial infarction remodeling and failure in mice. Prx3 overexpression reduced left ventricular dilatation and dysfunction and attenuated myocyte hypertrophy, interstitial fibrosis and apoptosis of the non-infarcted myocardium. These beneficial effects of the Prx3 gene overexpression were also associated with attenuation in oxidative stress and mtDNA decline and dysfunction.

Clearly, overexpression of the antioxidants discussed above enhance protective mechanisms that could contribute to extended healthspan and lifespan. While lifespan studies have not been conducted on every antioxidant gene that is overexpressed, despite the many signs of enhanced protection, the available data show that the impact on lifespan is modest.

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