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The immune response is remodeled with aging in a process called immunosenescence. Some immunologists conceive immunosenescence as an adaptation of immunity to the aged immune-environment rather than a merely collapsed reactivity of immune cells against microbes and tumor cells. Others believe on an uninterrupted activation of the innate immune system with aging, leading to a low grade, sterile and chronic proinflammatory state called inflammaging. For instance, it is possible that chronic infection by cytomegalovirus leads to persistent production of viral load. This phenomenon offers periodic stimuli to the immune system that ultimately contribute to the remodeling of the immune response. If investigating immunosenescence at the cellular level is already a difficult task, considering the population level is much more complex. However, by studying immunosenescence at the population level, we can extract valuable results with viable applications. While studies with animal models allow scientists to deepen their understanding of the mechanisms of immunosenescence, studying large populations can bring practical innovations to medicine and the health system. Many researchers and funders have dedicated themselves to producing methods for the evaluation of immunosenescence on a large scale, aiming to elucidate new mechanisms by which diseases are established in the elderly. The description of how the immune response is remodeled with aging emerges as a new tool to identify the subset of subjects in which unhealthy aging is a matter of time, to help better individualize clinical management and select patients who may benefit. of early interventions. This review focuses on functional assays as valuable methods for measuring the remodeling of the immune response with aging and discuss their clinical impact. We also recall fundamental concepts for understanding the aging process of the immune response. In addition, we highlight future prospects for immunosenescence research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cunha, Valsecchi and Ward.)

Elderly individuals are the most susceptible to an aggressive form of coronavirus disease (COVID-19), caused by SARS-CoV-2. The remodeling of immune response that is observed among the elderly could explain, at least in part, the age gradient in lethality of COVID-19. In this review, we will discuss the phenomenon of immunosenescence, which entails changes that occur in both innate and adaptive immunity with aging. Furthermore, we will discuss inflamm-aging, a low-grade inflammatory state triggered by continuous antigenic stimulation, which may ultimately increase all-cause mortality. In general, the elderly are less capable of responding to neo-antigens, because of lower naïve T cell frequency. Furthermore, they have an expansion of memory T cells with a shrinkage of the T cell diversity repertoire. When infected by SARS-CoV-2, young people present with a milder disease as they frequently clear the virus through an efficient adaptive immune response. Indeed, antibody-secreting cells and follicular helper T cells are thought to be effectively activated in young patients that present a favorable prognosis. In contrast, the elderly are more prone to an uncontrolled activation of innate immune response that leads to cytokine release syndrome and tissue damage. The failure to trigger an effective adaptive immune response in combination with a higher pro-inflammatory tonus may explain why the elderly do not appropriately control viral replication and the potential clinical consequences triggered by a cytokine storm, endothelial injury, and disseminated organ injury. Enhancing the efficacy of the adaptive immune response may be an important issue both for infection resolution as well as for the appropriate generation of immunity upon vaccination, while inhibiting inflamm-aging will likely emerge as a potential complementary therapeutic approach in the management of patients with severe COVID-19., (Copyright © 2020 Cunha, Perazzio, Azzi, Cravedi and Riella.)