Infertility is a disease of nearly endemic proportions, affecting up to 15% of couples of reproductive ages. Overall, a pure male factor infertility underlies the problem in at least 30% of cases. General health status in infertile men is gaining increasing clinical attention throughout the last decades. Indeed, infertile men were shown to be at increased risk of nononcologic and oncologic morbidity and mortality compared to age-comparable fertile ones. Despite emerging and solid epidemiological studies, the common ground fostering overall health status and male infertility is still far from being understood. Notwithstanding the numerous hypotheses that have been considered to explain the potential link overall men's health status and male infertility - e.g., including genetic, endocrinological, and metabolic abnormalities - the exact nature of these associations remains unclear. Recent clinical findings showed evidence of onset of age-related comorbidities 10-15 years earlier in infertile compared to fertile men. Single-cell transcriptome profiling of testes of men with idiopathic germ cell aplasia revealed an immature testis with a somatic environment stuck at puberty with immaturity of Leydig cells associated with chronic tissue inflammation, fibrosis, and senescence phenotype of the somatic cells, as well markers of chronic inflammation in the blood. Compelling evidence indicate that defects in the regulatory arms of the immune system and metabolic status can be associated with the risk of developing numerous oncological and non-oncological diseases. Thus far, limited reliable data on the immunological status of infertile men are available. Preliminary data from the coordinating group of the project revealed increased pro-inflammatory cells and reduced T cells in peripheral blood of infertile men. Moreover, the few T cells observed in infertile men displayed an exhausted phenotype. The investigators proposed an innovative multidisciplinary approach to identify causal links between infertility as a disease and chronic inflammation and comorbidities. Moreover, the investigators aim at identifying novel prognostic biomarkers/tools toward the development of tailored prevention strategies of severe comorbidities in infertile men. They will combine extensive clinical data of a unique and homogenous cohort of infertile men and controls with state-of-the art transcriptomic approaches, a comprehensive monitoring and functional characterization of adaptive and innate immune cells, and the endocrine-metabolomic signature of men with primary infertility. The success of our strategy will be instrumental for defining novel molecular causes of male infertility, along with the pathophysiological mechanism behind the higher burden of comorbid conditions. Results will provide information on cell compartments, and the senescent and endocrine status, mostly in men with primary idiopathic infertility, and new insights into the etiology responsible for the early onset of comorbidities in infertile men. This will represent a breakthrough in the infertility field and a major advancement towards better caring of male patients and healthy ageing in the real-life setting and will set the stage for the development of more tailored clinical approaches to prevent malignant and nonmalignant comorbidities in infertile men. Thereof, the findings of the research project will have a significant rebound in terms of cost-effectiveness on the national health system.