ACTLIFE: is Active Life-style Enough?

The first aim of this projects will be to identify the bioactive molecules and functional mechanisms that are candidates for exercise-induced health benefits through biological pathways that are largely different from those targeted by common drugs. In the view of more reliable, ecological and tailored approaches to counteract the pandemic problem of sedentary lifestyle in elderly population, the second aim of this project will be to evaluate the effectiveness of an ecological exercise intervention (EEI) in comparison to traditional exercise intervention (TEI) in sedentary older adults.

Introduction: Despite our society has developed several advances in technology and medicine, the human genetic framework is largely tailored to support the physical activity (PA) patterns of hunter-gatherer societies living 2.5 million years ago, for which food finding was obligatorily associated to PA. The energy expenditure of hunter-gatherers (1,500 kcal/day) is similar to 3h/day of moderate-to-vigorous PA (MVPA). Contrarily, technological improvements have influenced the dramatic drop in human PA levels: 1/3 of adults worldwide are currently inactive, and the endemic inactivity trend starts in early life. Indeed, sedentary behaviors in contemporary obesogenic environments trigger dysfunctions that cause chronic diseases and this phenomenon is becoming a major public health problem. Interestingly, regular PA has a profound effect on the expression of the potentials of human resilience, resulting in numerous positive adaptations and decreased risk of chronic diseases.

Protective role of exercise on cardiovascular disease risk factors: There is strong epidemiological evidence indicating that regular PA is associated with reduced rates of cardiovascular disease (CVD), hypertension, stroke, metabolic syndrome and Type 2 diabetes. Moreover, a dose-response of PA is usually observed in the general population. It is important to note, that exercise training has an improving effect on endothelial function.

The polypill-like effect of Exercise: Despite, in the last 40 years the pandemic increase of cardio-metabolic diseases has paralleled the advances in medicine, CVD remains the leading cause of death worldwide. In this complicated scenario, Wald and Law first described a combination pill for CVD prevention, which they called a "polypill". These authors claimed that CVD could be reduced by 88% and strokes by 80% if all those over 55 years of age were given a polypill containing statin, low-dose aspirin, and folic acid. This controversial and provocative approach of "medicalizing" the population is not possible and not ethical, but polypill-like benefits are achievable with a drug-free intervention, regular PA. It is worth of mention that the identification of the bioactive molecules and biological mechanisms that are candidates for exercise-induced health benefits through biological pathways that are largely different from those targeted by common drugs, is highly relevant, since it might help to improve our knowledge of the pathophysiology of the chronic diseases in the sedentary eldely population as well as to maximize the efficacy of PA interventions by implementing the best possible exercise dosage, resulting in optimal circulating levels of "health" molecules.

The exercise polypill: Skeletal-muscle fibers can produce a plethora of secreted factors, including proteins, growth factors, cytokines, with such secretory capacity increasing during active exercise, myogenesis and muscle remodeling. Muscle-derived molecules exerting either paracrine or endocrine effects are termed "myokines" and can be consider the exercise polypill.

Since regular exercise has protective effects on cardiovascular diseases and, interestingly, it is more protective than expected based on the improvement of traditional risk factors (blood lipids, hypertension, diabetes) it is easy to speculate that additional positive effects could be mediated by myokines on targets such as adipose tissue or liver.

For example, IL-6 is probably the myokine prototype because its level increases with exercise intensity and duration. Systemic low-level inflammation is a cardinal feature of cardio-metabolic diseases, and it can be attenuated by the cumulative effect of regular exercise bouts, during which the muscle releases IL-6 which creates a healthy milieu by inducing the production of other anti-inflammatory cytokines. Another prototype of contraction-induced myokine is IL-15, with resistance exercise stimulating its secretion. Muscle-derived IL-15 is one of the mediators of the anti-obesity effects of exercise. Recent research identified a novel PGC-1 -induced myokine called iriscin. Iriscin is associated with improved aerobic fitness in cardiac patients, muscle mass, and metabolic factors in healthy people, and neurogenesis in animal models. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein released into the bloodstream by skeletal muscle in response to aerobic exercise plays a pivotal role in adipocyte differentiation and adipose tissue turnover.

Myostatin, is a potent muscle-growth inhibitor, endurance or resistance exercise downgrade myostatin expression.

Another class of molecules which are potentially up-regulated with regular exercise and could have additional effects on the protective effects of regular exercise are neurotrophins. Among them, brain-derived neurotrophic factor (BDNF) is the most affected by exercise. Increased levels of BDNF are well documented, providing mechanistic support for a beneficial exercise effect in cognitive function. Furthermore, BDNF increases phosphorylation enhancing fatty acid oxidation and glucose utilization in skeletal muscle.The emerging general feature is that During physical inactivity, adipose tissue secretes pro-inflammatory cytokines, which can lead to development of metabolic and cardiovascular diseases, such as T2DM and atherosclerosis (Iyer et al., 2010). The study of myokines as potential biomarkers for effectiveness of exercise is an attractive approach to develop better physical protocols to apply to the elderly population.

Intervention approaches: Sedentary behaviors in older adults are strongly associated with systemic dysfunctions that cause chronic diseases and this phenomenon is becoming a major public health problem. Moreover, the recognized polypill-like effect of exercise, needs further research in order to identify the biological mechanisms that are candidates for exercise-induced health benefits. Furthermore, it is necessary to maximize the efficacy of PA interventions by implementing the best possible exercise dosage. In this complicated scenario, Owen and colleagues explain in their scientific contribution "Adults' Sedentary Behavior Determinants and Interventions" the relevant phases of the behavioral epidemiology research strategy on sedentary behavior for children and adults, highlighting several strengths of the evidence relevant to interventions and public health initiatives.

Ecological-Exercise-Intervention: One of the goals of public health interventions would be to reduce total sedentary time and also to increase the number of breaks in sedentary time. A starting point for this 'Ecological-Exercise-Intervention'(EEI), would be to limit sitting time to no more than 2 hours/day, and to stand up and move after 30 minutes of continuous sitting. In accordance with several epidemiologic evidences light-intensity activities would be encouraged to substitute sedentary time (e.g., standing up while talking on the telephone, ironing while watching TV). Taking into consideration the guidance provided by ecologic models of health behavior evidences about specific constructs to guide EEI may be derived from behavioral research on physical activity. However, further studies are needed to clarify the feasibility, acceptability, and effectiveness of EEI in young and adult populations. On this matter, promising results have been observed in studies targeting increases in daily walking. Moreover, systematic evaluations of these "natural approaches" could be highly informative, especially through assessing whether changes in sedentary time actually do result.