In the1900s, the primary cause of death was infection. and its role in the immune system A deeper understanding of the thymus is critical in combating COVID-19. Immune changes that occur with thymic aging (immune senescence) lead to an inflammatory environment that underlies the pathogenesis of diseases of aging (i.e. cardiovascular disease, hypertension, chronic obstructive lung disease and arthritis),1C4 and people who develop these comorbidities are known to be at higher risk for severe COVID-19 infection and death.5,6 Although knowledge of the thymus has existed since the time of the CDX4 ancient Greeks (130C200 AD), who called the thymus expression due to 22q11.2del may modulate the expression of hundreds of micro RNAs (miRNAs). MicroRNAs are a family of approximately 2000 evolutionarily conserved small noncoding RNAs (18C22 nucleotides) found in many body fluids such as serum, plasma, saliva and amniotic fluid. These molecules bind to diverse mRNA transcripts that play a role in SCH58261 cell function and target mRNA transcripts for degradation.20,21 MiRNAs play an important role in thymic organogenesis, maturation and involution,22 and conversely, aging influences miRNA levels.23 Interestingly, miRNAs not only regulate host cellular responses but also responses to infectious agents like viruses.24 There is a decrease in T cell number and increased susceptibility to infection observed in DiGeorge syndrome;16 miRNA dysfunction seen in this disease may be a contributor. Environmental factors regulate thymic development both pre- and postnatally. Gestational diabetes has the potential to cause birth defects, and newborns born to women with gestational diabetes have congenital features overlapping with 22q11.2del.17 Approximately 1 out of 5 infants with thymic aplasia with deletions on chromosome 22q11.2 and requiring a thymic tissue transplant were born to mothers with a clinical history of gestational diabetes.17 Retinoic acid treatment SCH58261 of pregnant women (tretinoin, isotretinoin) for acne also leads to 22q11.2-like congenital malformations in their infants.17 Postnatally, acute stress such as emotional distress,25 malnutrition,26 and infections27 may induce transient thymic involution characterized by a reduction in thymus size. This is postulated to be caused by an acute loss of cortical thymocytes and reduced output of na?ve T cells to the periphery.28 Soluble factors released from lymphocytes and from nonlymphoid cells in the thymus, lymph nodes and at sites of inflammation regulate thymic function and T lymphocyte proliferation.29 Interleukin (IL)-6 (previously called B cell-stimulating factor, BSF-2) is a costimulant for human thymocytes and T lymphocytes and plays a role in B lymphocyte differentiation.29 At physiologic levels, IL-6 SCH58261 may promote thymocyte proliferation. However, during acute stress, elevated IL-6 levels may lead to thymic suppression.30 One IL-6 family protein, leukemia inhibitory factor (LIF), has been shown to induce thymic suppression and is dependent both on intra-thymic and systemic cortisol levels.30 Physical trauma to the chest is common among children, especially males, and may lead to thymic injury. Thymic injury during youth may lead to a chronic inflammatory state and premature immune-senescence and may increase the risk for obesity, insulin resistance and metabolic syndrome.31 Research has shown that participation in American football may increase the risk for cardiovascular disease later in life, and repetitive blunt trauma to the chest may be a cause.32 Defensive lineman football players endure repeated chest insults, this may explain the higher rates of obesity and metabolic syndrome even among collegiate lineman.33 Long term, regular, strenuous exercise (-approximately 2?hours of daily swimming, running and cycling plus weight, interval or skills training) has also been shown to decrease thymic function among healthy young people.34 These observations may explain COVID-19 deaths observed in some healthy, athletic young.