Testosterone (T) has anti-inflammatory properties, and has been shown to play a role in the pathogenesis of infectious and autoimmune diseases. Disease pathology from influenza A virus (IAV) infection is caused by an excessive pro-inflammatory response, and severe disease is especially common among elderly men, who have lower T levels. We tested the hypothesis that T will protect against IAV pathogenesis in young adult (8-10 weeks) and old (17-18 months) male mice. To study the effects of T in young adult male mice, the mice were gonadectomized, treated with T or placebo capsules, infected with a sub-lethal dose of H1N1, and monitored for morbidity and mortality. In old male mice, serum T is naturally low, therefore gonadectomies are not required before the subsequent steps. In addition, we attempted to elevate testosterone levels endogenously in old male mice through steroidogenic drugs called TSPO ligands. However, two different drugs tested did not significantly raise serum testosterone levels. T-treated young adult males experienced lower morbidity, and had lower IgG antibody titers compared to placebo-treated young adult males. In old males, while the same dose of T was not protective against morbidity from IAV infection, treatment with a higher dose of T resulted in improved recovery from influenza disease. Protection from morbidity by testosterone treatment is not reflected in the expression of Ki67, which is a marker for proliferation, in the lungs at 21 days after infection. This suggests that either the improved recovery from disease is not associated with improved repair, or day 21, which is after peak disease and viral clearance, is too late a time point to detect any difference. We hypothesize that old males require a higher dose of T in order to mitigate the chronic pro-inflammatory state brought about by aging
