Caloric restriction and exercise can both have what might be described in broad terms as anti-aging properties. Resveratrol, a polyphenol found most notably in red wine, can affect the deacetylase SIRT1 pathway and can mimic the positive effects of caloric restriction on inflammation, vascular function and metabolic regulation. Resveratrol is also a potent anti-oxidant and in some models anti-oxidants also slow age related declines in physiological function. Exercise training can have many of these same effects and one idea is that at least some of the positive effects of exercise, shared with caloric restriction, operate via its effects on SIRT pathways or by more generally countering the negative effects of ‘oxidative stress’ on a number of biological systems. In this issue of The Journal of Physiology, Gliemann et al. (2013) show that resveratrol feeding in older men blunts many of the positive effects of exercise training on markers of inflation, vascular function and even exercise capacity. Is this surprising and if so how surprising is it? Obviously, these are big issues that could each be tackled with a major review. That having been said, perhaps a five course selection of ‘intellectual appetizers’ can at least provide some food for thought that needs to be more widely considered and digested before the main course. First, the effects of caloric restriction on longevity are not as uniform as generally thought. When a variety of inbred mice strains are exposed to ∼40% caloric restriction some strains show marked life extension others show a reduced lifespan with some differences noted between sexes (Liao et al. 2010). The effects of caloric restriction on longevity of the grandchildren of truly ‘wild mice’ were also limited, perhaps because the wilder animals ate less when given access to an ad lib diet. So clearly the caloric restriction story is not entirely straightforward. Second, like resveratrol, statin drugs have powerful effects on vascular function and inflammation and the hope is these effects would be amplified by exercise training. However, in overweight or obese subjects at risk of the metabolic syndrome they too limit the effects of exercise training on cardiorespiratory function and markers of mitochondrial biogenesis (Mikus et al. 2013). Statins also have anti-oxidant effects and the observations that both resveratrol and statins can blunt responses to exercise training are consistent with the idea that reactive oxygen species trigger at least some of the adaptive responses to training. Third, recent data from a set of comprehensive studies in rodents and cultured myotubes question the role of the SIRT1 pathway in mitochondrial biogenesis (Higashida et al. 2013). This paper also raises fundamental questions about the idea the mitochondrial biogenesis is always a ‘good thing’ in the context of caloric restriction. As the authors noted: “Adaptive responses were selected for because they enhance an organism's chances of surviving environmental changes. Increases in energy expenditure and substrate oxidation resulting in more rapid depletion of energy stores, such as were reported to occur with SIRT1 activation, would be seriously maladaptive responses to fasting, starvation, or CR.” Fourth, the translatability of data from animal models to humans is not always linear. In animal models, resveratrol can amplify the positive effects of exercise training, and clearly this was not seen in the human study featured in this Perspectives article. On a larger scale, the search for drugs and therapies to treat life-threatening sepsis has perhaps been slowed by an overreliance on rodent models (Leist & Hartung, 2013). Fifth, while epidemiology studies show that diets rich in anti-oxidants are generally associated with better health and longer life, large trials of anti-oxidant supplements in both healthy humans and patients with various diseases have failed to show much benefit across trials and pathology. In some cases the outcomes have even been negative (Tinkel et al. 2012). These observations raise questions about other dietary components influencing the effects of anti-oxidants, and perhaps there is a ‘sweet spot’ for anti-oxidant consumption with the possibility of too much of an otherwise good thing. Now that the appetizers have been served, what is the main course? The epidemiologists tell us that, beginning in middle age, accelerated loss of physiological function ultimately leading to frailty is a powerful predictor of both mortality and disability-free life expectancy. So far only physical activity and exercise training appear to offer effective counter measures to slow this decline and in some circumstances the results can be truly impressive. While drug companies and others look for an ‘exercise pill’, perhaps the better strategy is to take a walk, go for a bike ride, hit the gym and generally find a way to become more active.
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Dec 1, 2018
K N Nilaweera + 1
