During aging, the immune system (IS) undergoes remarkable changes known as immunosenescence, a multifactorial and dynamic phenomenon that affects both natural and acquired immunity and plays an important role in most chronic diseases in older people. Among the determinants of immunosenescence, we find a low-grade sterile chronic inflammation, known as “inflamm-aging”. This condition of chronic inflammation causes a progressive reduction in the ability to trigger antibody and cellular responses effective against infections and vaccinations. In this review, we wanted to explore the role of immunosenescence and inflamm-aging as determinants of the immunological aging process and predisposing viral infections phenomena, with a particular reference to cytomegalovirus (CMV), varicella zoster virus (VZV), influenza virus (IFV) diseases and SARS-CoV2. IS aging is also reflected in a reduction in the antibody response to vaccinations, hence there is a need to expand trials to elderly patients, in order to identify the most appropriate methods for developing effective and safe vaccination and preventive strategies.