Monday, May 23, 2011

Are You Stressed Enough for a Longer Life? Reactive Oxygen Specimen and Oxidative Stress May Contribute to Longevity

In June 2010 my fellow countrymen Michael Ristow from the Department of Human Nutrition at the University of Leipzig formed an interesting hypothesis (Ristow. 2010) stating that the dreaded reactive oxygen species [ROS], most scientists associate with accelerated cell-aging and degenerative diseases were in fact "essential signaling molecules which are required to promote health and longevity". In a more recent paper he picks this hypothesis up and, in cooperation with Sebastian Schmeisser from the Department of Clinical Nutrition at the German Institute of Human Nutrition in Nuthetal, Germany, reviews the current literature on selected longevity-promoting intervention.
Figure 1: Health and longevity as a function of mitochondrial reactive oxygen species (ROS) formation.
Both too much and too little ROS are detrimental, due to either insufficient stimulus for or overtaxing of hormetic processes (this graph is a mere illustration and is not based on any existing experimental data)
Ristow and Schmeisser conclude that, as different as they may at first appear, calorie restriction, the reduction of specific macronutrients (esp. low-carb diets), life-extension related to insulin and IGF-1 modulation and physical exercise, have one common denominator, which is
enhanced mitochondrial activity and subsequently increased ROS formation that ultimately induce an adaptive response (increased defense mechanisms and improved stress resistance) which culminates in metabolic health and extended longevity.
For someone, who has been told for years, to avoid the formation of radical oxygen species at all cost, and, for that purpose, to supplement with as much anti-oxidants as possible, this proposition may sound absurd. It also goes against the free radical hypothesis of aging (FRTA) and the hitherto accepted hypothesis that calorie restriction, the one and only relatively established means of life-extension in several animal models (I just want to remind you that the results still await direct confirmation in human beings), would work, because it would reduce the metabolic rate of the fasting critter and thus reduce the amount of potentially harmful reactive oxygen specimen (ROS) which are produced by the down-regulated mitochondria. The authors' response to this hypothesis is that
[...] more recent findings regarding the question whether CR [calorie restriction] actually decreases metabolic rate are, at least in part, inconsistent with FRTA [the free radical theory of aging]. Hence, it has been reported that CR increases metabolic rate (quantified by both oxygen consumption and heat production) in the nematode and well-established model organisms for aging research,  Caenorhabditis elegans. Furthermore, a positive correlation between low metabolic rate and enhanced lifespan could also not be observed in the fruitfly Drosophila melanogaster.
As a diligent student of the SuppVersity you will also be familiar with the lack of effect of antioxidant supplementation in human intervention studies to increase lifespan, promote health or prevent cancer, of which Ristow and Schmeisser write:
[...] in contrast to some of the above-mentioned work in lower organisms, several prospective clinical intervention studies were unable to found a positive association between the supplementation of antioxidants and health beneficial effects. Whereas most studies found a lack of effect in regards to health promotion in humans, other reports even suggest that antioxidants may promote cancer growth. Moreover, supplementation with antioxidants has been linked to increased incidence of a number of diseases to adverse effects of human longevity
These observations stand in line with the previously reported findings of Ristow et al. (Ristow. 2009) on the detrimental effect of antioxidant supplementation on exercise induced health promotion, which caused quite a stir in the world of supplement addicted exercise junkies. In all these cases, the German researchers suspect that the inhibition of the formation of an adequate amount of reactive oxygen species (ROS) blocks the initiation of hormetic physiological responses - just like using the 0.5 pound dumbbells for biceps curls to avoid injury would, at the same time, forestall muscular adaptations in form of muscle growth.

Ristow and Schmeisser also point out that, just as it is the case for resistance training, where using too heavy weights may easily lead to injury, the same "so-called adaptive response processes [which] may explain how increased ROS formation culminates in promotion of health and lifespan" may eventually turn against you, if the rate of ROS formation exceeds certain limits:
Interestingly, low doses of ROS seem to exert such effects [promotion of health and lifespan], while higher doses are unquestionably detrimental. Such biphasic responses to a potentially harmful compound are commonly named hormesis, a concept which was initially postulated in 1943 by Southam and Ehrlich and which was shown to have significant impact on aging with a variety of stressors described.
It is this concept of "mitochondrial hormesis or mitohormesis" you should thus keep in mind, when you read about the latest and greatest antioxidant supplement that just hit the market. As an athlete on a two-a-day intensive training regimen, you may well find yourself deep within the red zone on the right of the "optimal health" window in my little graph in figure 1 and thus need additional antioxidants to reduce the amount of ROS and return into the 'hormetic window' of optimal health and longevity. As a couch potato lounging in the red zone to the left of the hormetic window, you better get your metabolism going in order to produce some reactive oxygen specimen and to reap the health and longevity benefits of ROS-triggered hormetic adaptations.