key: cord-0938875-j75kd4ok authors: Bartolomucci, Alessandro; Sapolsky, Robert M. title: Psychosocial risk factors, non-communicable diseases and animal models for COVID-19 date: 2020-12-19 journal: Biol Psychiatry DOI: 10.1016/j.biopsych.2020.12.014 sha: f6cb6772e04d2c78676501636f9ea708185b60d1 doc_id: 938875 cord_uid: j75kd4ok nan endocrine stress response is among the benefits of short term DEX treatment in patients affected by COVID- Overall, emergence of diseases exacerbating the Covid-19 prognosis appears highly sensitive to psychosocial risk factors. In particular, psychosocial stress mediates much of the link between low SES and high prevalence of NCDs (7, 15) ; commensurate with that, NCDs and life-threatening COVID-19 outcomes disproportionately impact low SES communities and disadvantaged minorities (5, 16) . Chronic social stress animal models recapitulate the multi co-morbidities increasing risk for severe These risk factors suggest that the conventional approach of cross breeding humanized models of COVID-19 with monogenetic models of human disease, using pharmacological or surgical models ( Table 1) , or injecting viruses in mice expressing the hACE2 in the same disease models, should not be the preferred approach as it is unlikely to model the complexity of human risk factors. Consistent with this idea, SARS-CoV-2 injection in even health young mice engineered to express a (h)ACE2 rapidly resulted in death (2) . Such risk factors suggest the importance of alternative approaches and the need to combine humanized mouse models of COVID-19 with models of multiple comorbid NCDs. Here we provide a rationale for the use of social and behavioral laboratory models of multi co-morbidities including obesity, hypertension, cardiovascular disease and accelerated senescence in the study of COVID-19. Extensive research, including our own, has focused on models of chronic social stress that are contingent upon negative social relationships built around uncontrollable and perceived potential life-threatening conditions (9, 17, 18) . Such stress-based models can be ideal for studying the interactions between COVID-19 and NCDs. These models, are arguably the most potent and reliable (non-genetic and non-pharmacological) models to induce multiple comorbid disease observed in severe cases of COVID-19 such as obesity, T2D, hypertension, a proinflammatory state, neurological and neuropsychiatric diseases and even accelerated aging, overall resulting in shorten lifespan (19) ( Table 1) . Thus, we advocate for a research focus on, a) studies of humanized COVID-19 mice undergoing classic psychosocial stress models for worsening NCDs relevant to COVID-19 risk; b) use of hACE2 viral vectors coupled with such psychosocial stress models in wildtype animals, particularly old subjects. An interesting new opportunity provided by the selection of mutant SARS-CoV-2 viruses capable of infecting common laboratory strains of mice (20), is to pair the use of these viruses with chronic psychosocial stress paradigms in order to optimally model the human condition. Mental stress has been advocated as a consequence of COVID-19 pandemic leading to negative long-term risk for psychopathologies (21). Here we suggest that the reverse should also be considered. 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Authors declare no biomedical financial interests or potential conflicts of interest. Severe Obesity (BMI ≥ 40 kg/m2) Cohort Study (53) , Cross-Sectional Study (54) , Meta Analysis (55) No morbid obesity has been reported. . html. ** Only the most common models are described. "Strongest and most consistent evidence" = Consistent evidence from multiple small studies or a strong association from a large study (CDC classification). Mixed evidence = Multiple studies that reached different conclusions about risk associated with a condition (CDC classification). The "Limited evidence category" from CDC website was omitted from this