PL1 Nutritional modulation <strong>of</strong> antioxidant and myogenic genes in exercise Jose Vina, Carmen Gomez- Cabrera Departamento de Fisiologia, Facultad de Medicina,Valencia A major aim <strong>of</strong> our laboratory is to identify longevity-associated genes and then to find ways <strong>of</strong> upregulating them by nutritional or physiological manipulations, chiefly physical exercise. It has been known for some years now that training induces the expression <strong>of</strong> antioxidant enzymes such as superoxide dismutase, catalase, or glutathione peroxidase. In fact, we recently proposed that exercise itself can be considered as an antioxidant as it increases the endogenous antioxidant defences (Gomez- Cabrera et al., 2008b). In this regard, exercise may be an even more effective antioxidant than supplementation with antioxidant vitamins. The concept <strong>of</strong> hormesis as applied to exercise was put forward by Radak’s group (Radak et al., 2005) and by our own group (Ji et al., 2006; Vina et al., 2006). We proposed that moderate exercise causes small increases in the level <strong>of</strong> oxidants which result in an up-regulation <strong>of</strong> the antioxidant-related genes. Moreover, treatment <strong>of</strong> animals (or humans) with high doses <strong>of</strong> vitamin C hampers the efficiency <strong>of</strong> training. This is based on the fact that vitamin C lowers the expression <strong>of</strong> critical factors controlling the mitochondriogenic pathway such as PGC-1α, NRF1 and TFAM (Gomez-Cabrera et al., 2008a). Details <strong>of</strong> this work will be discussed. We have recently been concerned with the role <strong>of</strong> the cancer protection pathway <strong>of</strong> p53 and p16/ARF with the promotion <strong>of</strong> longevity (Matheu et al., 2007). Thus our critical finding was that cancer protection and increases in longevity (independent <strong>of</strong> cancer) may be related. The fact that doubletransgenic s-Arf/p53 mice live longer than controls is due to the fact that p53 becomes an antioxidant as it up-regulates a new class <strong>of</strong> antioxidant enzymes, this is sestrins (Sesn)1 and Sesn2 (Matheu et al., 2007). We have recently observed that moderate exercise up-regulates p53 and this results in a significant protection against oxidants like paraquat. Up-regulating p53 by molecular means or by exercise significantly protects against death caused by paraquat. These results will also be discussed. Finally, recent work from our laboratory has shown that animals knocked out for PGC1α (the co-activator <strong>of</strong> PPARγ) respond to exercise in a very similar fashion as that observed in old animals. Experiments will be discussed showing that in fact, the mechanisms to prevent senile sarcopenia may be similar in old animals as those which occur in young ones, but that are knocked-out for PGC1. REFERENCES: Gomez-Cabrera MC, Domenech E, Romagnoli M, Arduini A, Borras C, Pallardo FV, Sastre J & Vina J. (2008a). Oral administration <strong>of</strong> vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr 87, 142-149. Gomez-Cabrera MC, Domenech E & Vina J. (2008b). Moderate exercise is an antioxidant: upregulation <strong>of</strong> antioxidant genes by training. Free Radic Biol Med 44, 126-131. Ji LL, Gomez-Cabrera MC & Vina J. (2006). Exercise and hormesis: activation <strong>of</strong> cellular antioxidant signaling pathway. Ann N Y Acad Sci 1067, 425-435. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA & Serrano M. (2007). Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375-379. Radak Z, Chung HY & Goto S. (2005). Exercise and hormesis: oxidative stress-related adaptation for successful aging. Biogerontology 6, 71-75.
Vina J, Borras C, Gomez-Cabrera MC & Orr WC. (2006). Part <strong>of</strong> the series: from dietary antioxidants to regulators in cellular signalling and gene expression. Role <strong>of</strong> reactive oxygen species and (phyto)oestrogens in the modulation <strong>of</strong> adaptive response to stress. Free Radic Res 40, 111-119.
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