HEBE - Healthy Aging Versus Inflamm-aging: the Role of Physical Exercise in Modulating the Biomarkers of Age-associated and Environmentally Determined Chronic Diseases. Research Line 1. Proof of Concept

Non-communicable diseases (NCDs) are the cause of premature aging and death of 41 million people each year, accounting for 71% of all deaths globally. NCDs are closely linked to rapid urbanization and globalization. In this context, unsustainable lifestyles, characterized by a lack of physical activity, trigger the progression of NCDs. To date, it is estimated that around 41% of Europeans (and as many as 60% of Italians) do not engage in any type of physical activity (even light) during the week and this increases the risk of chronic diseases: 86% of deaths are attributable to cardiovascular disease, cancer, chronic respiratory disease and type 2 diabetes, a disease from which approximately 52 million people suffer in Europe (8.4% of men and 7.8% of women among 20 and 79 years of age).

Over the years, the progressive increase in the number of senescent cells can lead to tissue/organ dysfunction. In an attempt to respond to this process, senescent cells undergo metabolic modifications leading to increased secretion of soluble factors (e.g. cytokines, chemokines, growth factors, metalloproteases), which thus modulate their microenvironment through the removal of damaged cells by the recruitment of phagocytes and stimulating cell differentiation and proliferation for tissue renewal. The secretion of pro-inflammatory molecules and the activation of immune cells contributes to the generation of a low-grade chronic pro-inflammatory state known as "inflammaging", which is at the root of most age-related diseases. Furthermore, upregulation of mitogenic and pro-angiogenic pathways dangerously increases the risk of oncogenic transformation. The modulation of the complex of alterations that make up inflammaging could therefore be the key to guaranteeing healthy aging and reducing the risk of developing early NCD. A very promising approach to controlling inflammaging involves focusing on reducing the risk factors associated with these diseases by proposing alternative development models.

The main challenge of the HEBE project as a whole therefore consists in addressing three fundamental questions:

1. What primary prevention approaches can we develop, considering all phases of the individual's life, to ensure an improvement in the quality of life and health status of the population, with a positive impact on the socio-economic system of the area?
2. What intervention protocols based on physical exercise, combined with diet and any pharmacological/pharmaceutical approach, can we propose to frail subjects, in order to intervene on "inflammaging", to increase life expectancy and healthy ageing?
3. Which inflammaging markers (biomarkers and other clinical indicators) can we measure and integrate to define the risk of developing NCD, especially in frail subjects, to guide integrated personalized preventive interventions (precision/personalized healthcare)?

General objectives of the trial