**4. Discussion**

The present work investigated the interaction between mental health and cardiovascular disease under a translational gender-medicine perspective. We used two strains of mice modeling normal (NTg) and neurodegenerative (3xTg-AD) aging, where first evidence of compromised small peripheral mesenteric resistance artery (MRA) properties was recently shown [21]. Worse physiologically relevant MRA structural and functional alterations of 3xTg-AD females suggested sex-dependent dysfunctions. We hypothesize that those findings would also extend to other cardiovascular health measures. Since the aging process is very heterogeneous [7], here, we studied two cohorts where females exhibited worse mortality rates than males since birth. We were interested in exploring brain–cardiovascular interaction mechanisms relevant for long-lived animals. Eight functional aspects were successively studied from middle age to natural death or euthanasia at 16 months. First, we determined the physical (including frailty) and behavioral (neuropsychiatric-like and cognitive) phenotypes of animals. Once the "mental health" of each animal was characterized, we determined their "cardiovascular phenotype" through systolic blood pressure, rCBF, angiogenesis, and arterial function. Survival was continuously monitored. Glucocorticoid levels, an indicator of HPA axis function, were analyzed from blood samples collected during the euthanasia. In the results, the analysis includes the sample size at each time point; so that the results of a certain functional analysis are those taking into account the highest sample available. The results agreed with those from the analysis performed only using the final sample size of survivors (censored data).
