Abstract Stress Reduction, telomere length, and COVID infection and severity: A randomized trial The COVID-19 pandemic has led to unprecedented challenges in the daily lives of all Americans. Further, in the San Francisco Bay Area, residents are under additional stress, as in addition to COVID fear and restrictions (social distancing, school closures, food insecurity) the area is at the epicenter of climate crises in the US--rampant wildfires, evacuations, and smoke exposure--that contribute to economic impact and poor mental health. This confluence of stressors creates the ideal circumstances for testing an emotional resilience intervention remotely. We have a large pre-existing cohort where we can examine the impact of stress on mental health and infections (including COVID infection) over the next year, and test a digital mindfulness intervention, delivered at distance, to enhance management of COVID related stressors, fitting the mission of NOSI-AT-20-011. We propose to study 1500 UCSF employees, 30% low income. We have pre-pandemic measures of stress and health on the majority of this sample (1200) so we can prospectively quantify the effect of the COVID-19 epidemic on stress, anxiety, and depression (and secondary outcomes of financial and social impact) compared to their pre-COVID baseline (Aim 1). We will quantify COVID and climate related stressors and responses to assess their impact. In addition, we will test the additional value of knowing a baseline measure of immune system age, telomere length, in predicting susceptibility to infection, and if this interacts with stress (Aim 3). To test this, dried blood spots will be obtained to quantify telomere length at baseline and antibodies to SARS-CoV-2 at baseline and 6-months. To test the buffering effect of the stress reduction intervention, this Fall, we will randomize half of our sample to engage in an 8-week digital meditation intervention program (n = 750) and compare them to those in the control group (n = 750) (Aim 2). Measures will be obtained at baseline, post-intervention (8-weeks), 6 and 12 months (11/01/20 to 10/31/2021). Monthly measures of symptoms of infections and illness, and 3 days of daily diary measures each month on mental and physical health as well as putative psychological mechanisms of mindfulness (daily stress resilience, tolerance of uncertainty), will be obtained. This is a high impact study – on a well-tested Stage 3 intervention to examine real world efficacy and mechanisms of change on a highly vulnerable pre-existing cohort. By following our sample for 12 months, given the common severe stressor exposures of COVID and climate crises, we are likely to see the long-term buffering effect of a mindfulness intervention and discover important biobehavioral findings about vulnerability and resilience to infection.