Fight Aging!

The trouble with trying to slow down aging by manipulating metabolism is that the interaction of day to day metabolism and the processes driving aging is fantastically complex. So much so that the investigation of even tiny little slices of it by multiple research teams can span a decade or more, consume millions of dollars, and yet produce no great advance in understanding of the big picture over that time. This is the story for the role of p66shc in aging and mitochondrial metabolism: data is gathered and scientists are at work, but the high level explanation of what is known remains much the same as it was ten years ago. Reducing or removing the protein p66shc may or may not extend life in mice, and may or may not be a meaningful target for age-slowing drugs in humans.

The researchers quoted below, like other teams, investigate p66shc in the context of mitochondria and aging. As in past research, the fact that p66shc has an influence on reactive oxygen species production in mitochondria makes it plausible that it might have some role in the pace of aging. Numerous genetic alterations that extend life in lower animals are accompanied by either an increase or reduction in the production of reactive oxygen species. The theory here is that a reduction means less oxidative damage to cellular components and an increase means that cellular housekeeping mechanisms are spurred into greater action, with the same end result of a net lowering of oxidative damage. (This is to be compared with other alterations that reduce life span while either lowering or raising generation of reactive oxygen species. Nothing is ever simple). The reality under the hood is probably more complicated than present theories in many of these cases, and there is plenty of room for new data, new interpretations, and new arguments as to how these established means of life extension via slowing aging actually work.

Again, it comes back to the fact that this is all enormously complex. Adjusting metabolism in a desired way is very hard at our present level of technology and understanding. Consider, for example, that we have calorie restriction and exercise as examples of ways to reliably reproduce desirable alterations in metabolism. They are right in front of us to study whenever we want, in as much detail as we want, and yet despite that fact, some fifteen years of work and billions of dollars have so far failed to find ways to safely and reliably recreate even a fraction of these altered metabolic states.

In any case, this paper is more grist for the mill of plausibility when it comes to p66shc levels influencing the course of aging. The researchers also make some interesting comments on the differences between mice and humans in the discussion:

Prooxidant Properties of p66shc Are Mediated by Mitochondria in Human Cells

p66shc is a protein product of an mRNA isoform of SHC1 gene that has a pro-oxidant and pro-apoptotic activity and is implicated in the aging process. Mitochondria were suggested as a major source of the p66shc-mediated production of reactive oxygen species (ROS), although the underlying mechanisms are poorly understood.

We studied effects of p66shc on oxidative stress induced by hydrogen peroxide or by serum deprivation in human diploid human dermal fibroblasts (HDFs). An shRNA-mediated knockdown of p66shc suppressed and an overexpression of a recombinant p66shc stimulated the production of ROS in the both models. This effect was not detected in the mitochondrial DNA-depleted ρ0-RKO cells that do not have the mitochondrial electron transport chain (ETC). Mitochondria-targeted antioxidants SkQ1 and SkQR1 also decreased the oxidative stress induced by hydrogen peroxide or by serum deprivation. Together the data indicate that the p66shc-dependant ROS production during oxidative stress has mitochondrial origin in human normal and cancer cells.

Noteworthy, most studies challenging functions of p66shc in mitochondria were performed in mouse models. However, the impact of oxidative stress that hypothetically may serve as a rheostat for the lifespan regulation differs substantially in the mouse and the human models. Human cells are more resistant to oxidative stresses and have at least two-fold lower mitochondria ROS production rate. Therefore, some mechanisms related to p66shc and their significance could also differ in human cells. More focused studies on p66shc mechanisms in human cells would provide valuable clues for treatment and prevention of accelerated aging and numerous diseases associated with elevated ROS.