Background: COVID-19 pandemic poses a heavy burden on public health and accounts for substantial mortality and morbidity. Proteins are building blocks of life, but specific proteins causally related to COVID-19, healthspan and lifespan have not been systematically examined.

Methods: We conducted a Mendelian randomization study to assess the effects of 1,361 plasma proteins on COVID-19, healthspan and lifespan, using large GWAS of severe COVID-19 (up to 13,769 cases and 1,072,442 controls), COVID-19 hospitalization (32,519 cases and 2,062,805 controls) and SARS-COV2 infection (122,616 cases and 2,475,240 controls), healthspan (n = 300,477) and parental lifespan (~0.8 million of European ancestry).

Results: We identified 35, 43, and 63 proteins for severe COVID, COVID-19 hospitalization, and SARS-COV2 infection, and 4, 32, and 19 proteins for healthspan, father’s attained age, and mother’s attained age. In addition to some proteins reported previously, such as SFTPD related to severe COVID-19, we identified novel proteins involved in inflammation and immunity (such as ICAM-2 and ICAM-5 which affect COVID-19 risk, CXCL9, HLA-DRA and LILRB4 for healthspan and lifespan), apoptosis (such as FGFR2 and ERBB4 which affect COVID-19 risk and FOXO3 which affect lifespan) and metabolism (such as PCSK9 which lowers lifespan). We found 2, 2 and 3 proteins shared between COVID-19 and healthspan/lifespan, such as CXADR and LEFTY2, shared between severe COVID-19 and healthspan/lifespan. Three proteins affecting COVID-19 and seven proteins affecting healthspan/lifespan are targeted by existing drugs.

Conclusions: Our study provided novel insights into protein targets affecting COVID-19, healthspan and lifespan, with implications for developing new treatment and drug repurposing.