In this study we tested the hypothesis that the immunosenescence profile could account for the disproportional susceptibility of the elderly to severe forms of COVID-19. The immunological profiles of volunteers residing in endemic and non-endemic areas for chronic infectious diseases were analyzed at early stage of SARS-CoV-2 infection. A unique signature of inflammatory plasma mediators was identified in COVID-19 volunteers when compared to individuals with other flu-like syndromes. COVID-19 severity correlated with high levels of inflammatory mediators; among them, CXCL9, a serum marker of aging. Patients who progressed to hospitalization displayed high frequencies of CD8+ and CD4+ T cells expressing exhaustion and senescence markers and showed reduced and more mature B cell repertoires, which are typical of senescence. They also had an acceleration of epigenetic age measured by DNA methylation. Therefore, severe COVID-19 correlated with phenotypic, functional, and epigenetic features of accelerated immunosenescence at onset of infection.

The authors do not have any conflicts of interest regarding this manuscript, its preparation, or the research that went into it.

This study was supported by grants from Merck Dohme & Sharp (MISP100795), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil, 407363/2021-1), Coordenacao de Aperfeicoamento de Pessoal do Ensino Superior (CAPES, Brazil) and Pro-reitoria de Pesquisa da Universidade Federal de Minas Gerais (PRPq-UFMG). A.M.C.F., A.T-C., D.M.F., T.U.C., O.A.M.F., G.C.C., M.M.C., M.A.O., M.F.O., V.D.M. are recipients of esearch fellowships and scholarships from CNPq, L.H.A.V., L.T., L.N. are recipients of scholarships and fellowships from CAPES, Brazil,F.C.M. is recipient of a scholarship from Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG, Brazil), M.A. and C.L. are recipients of a scholarships from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Brazil).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Comissao Nacional de Etica em Pesquisa/CONEP Comite de Etica em Pesquisa da Universidade Federal de Minas Gerais/CEP-UFMG Comite de Etica em Pesquisa do Instituto de Infectologia Emilio Ribas/CEP-IIER

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No unique code was generated in this study. Data are available upon request to the corresponding author.