The premise of this project is that studying immune aging in laboratory mice that areexperiencing a natural burden of major infectious psychological and physical stressors willbetter mirror and inform immune aging in humans. Old age is accompanied by increasedvulnerability to infectious diseases due to the aging of the immune system. Immune aging is in turnsubstantially influenced by the presence of a lifelong persistent infection with the cytomegalovirus(CMV). In the past period of this award we studied mouse CMV (mCMV) in isolation (as a latentpersistent mono-insult). We concluded that mCMV substantially degraded the healthspan of mice butonly in the presence of major stressors such as ionizing radiation or another infection. We propose to advance studies of mCMV and immune aging in mice experiencing a naturalburden of major infectious psychological and physical stressors that are likely to be encountered byhumans repeatedly during the lifespan. We hypothesize that life-long latent mCMV infectioncontributes to the demise of T-cell and global immune function directly proportional to thestress-induced viral reactivation and loss of immune control over mCMV. To test this animals willbe exposed to (i) low dose ionizing radiation; or (ii) low dose stress hormone corticosterone; (iii) non-specific pathogen free (non-SPF) microbiota which has been shown to induce the immune system inSPF mice to become similar to that of humans. We will test how this impacts mCMV reactivation andimmune responses to vaccination and lethal infection. We will ask: SA1. Do repeated individual stressors commonly experienced by humans worsen theimpact of mCMV on immune function with age? SA2. Is the impact of life stressors on immune aging and overall health in mCMV-positivemice caused by CMV DNA replication/reactivation? These experiments will for the first time introduce key physiological variables of importance tohuman immune aging into a well-controlled murine model of mCMV aging and infection. We anticipatethat this poly-insult model will substantially mirror immune aging in humans and provide ground for newdiscoveries that will pave the way for combined antiviral and stress-control therapies to improve T celland overall immunity and healthspan outcomes in aging.