**7. Lifestyle and physical activity**

The ageing process is dynamic and characterized by a continuous remodeling, and it appears evident that the main actors are DNA repair, apoptosis, immune response, oxidative stress and inflammation that these mechanisms are necessary to interact in an efficient way. But life expectancy at birth has been increasing in western societies thanks to the continuous improvement of medical assistance with respect to age-related diseases, especially CVD and cancer, environmental factors and lifestyle.

Among lifestyle factors, having a major impact on the whole organism oxidative stress response, there are impaired nutrition, reduced physical activity, alcohol consumption and cigarette smoking, which are major contributors to the failure of systemic homeostasis, especially if persisting for a long part of the individual's life. For these reasons the effects of physical activity and diet in oxidative stress response in humans have been suggested that both are able to tip the balance of oxidative burden/antioxidant response.

In support of this hypothesis, it has been reported that dietary restricted mice, which live much longer and show a very delayed aging phenotype [93, 94]. Thus, dietary restriction can trigger a molecular genetic response which postpones ageing and age-related phenotypes. Specifically, reduced glucose metabolisms result in an increase in ROS accumulation by stimulating the basal metabolic rate and consequently increase oxidative stress [95]. This has brought to search for drugs or interventions which may act on these mechanisms without the side effects of calorie restriction [96]. Among the most important measures in this context, you may name the protein restriction and the use of drugs involved in the IGF-1 axis and in the FOXO/TOR pathway [97]. As emerged from the analysis of data resulting from studies in geographical areas with exceptional longevity (such as Sardinia and Okinawan), it seems to be important to follow a low-protein diet, such as the Mediterranean diet [98]. In these cases, the traditional diet seems to allow to stimulate molecular mechanisms that increase the lifespan. The Mediterranean diet and red wine consumption, rich in antioxidants like resveratrol, have been shown to have protective effects against oxidative damage. People who consume large amounts of fruits and vegetables have a lower incidence of CVD, stroke and tumors, and it has been proposed that the assumption of micro-nourishments with antioxidant activity could be responsible for the reduction of chronic diseases [99]. Consistently, long-lived individuals seem to prefer a diet rich in vegetables and in natural antioxidants. In addition, lower degree of oxidative stress was found in healthy Okinawan centenarians compared to aged subjects, data obtained by measuring the level of lipid peroxide and tocopherol (Vitamin E) in plasma [100]. Okinawan diet, with its high intake of green leafy and yellow-root vegetables, sweet potatoes as a dietary staple and soy as a principle protein, supplemented by small amounts of fish and meat, may be a significant advantage in achieving their exceptionally long life expectancy, thanks to a particularly high amount of antioxidant vitamins [102]. However, this finding could be due not only to nutritional factors [101] but also to a specific genetic background.

Moderate physical activity attenuates several age-related diseases, reduces blood pressure in hypertensive patients [103] and improves the serum lipid profile with an average reduction of 3.7% in triglyceride and 5% in low-density lipoprotein (LDL)-cholesterol levels and a 4.6% increase of HDL-cholesterol levels [104]. Benefits derived by physical activity in older people, for the maintenance of an optimal health status and the prevention or management of chronic diseases, can derive from exercise-induced adaptations of the cellular antioxidant defence systems [105]. In these subjects indeed, the presence of higher serum levels of antioxidants associated with higher strength and physical performance was demonstrated [106, 107].
