Sex-Dependent End-of-Life Mental and Vascular Scenarios for Compensatory Mechanisms in Mice with Normal and AD-Neurodegenerative Aging

Abstract

Life expectancy decreases with aging, with cardiovascular, mental health, and neurodegenerative disorders strongly contributing to the total disability-adjusted life years. Interestingly, the morbidity/mortality paradox points to females having a worse healthy life expectancy. Since bidirectional interactions between cardiovascular and Alzheimer’s diseases (AD) have been reported, the study of this emerging field is promising. In the present work, we further explored the cardiovascular–brain interactions in mice survivors of two cohorts of non-transgenic and 3xTg-AD mice, including both sexes, to investigate the frailty/survival through their life span. Survival, monitored from birth, showed exceptionally worse mortality rates in females than males, independently of the genotype. This mortality selection provided a “survivors” cohort that could unveil brain–cardiovascular interaction mechanisms relevant for normal and neurodegenerative aging processes restricted to long-lived animals. The results show sex-dependent distinct physical (worse in 3xTg-AD males), neuropsychiatric-like and cognitive phenotypes (worse in 3xTg-AD females), and hypothalamic–pituitary–adrenal (HPA) axis activation (higher in females), with higher cerebral blood flow and improved cardiovascular phenotype in 3xTg-AD female mice survivors. The present study provides an experimental scenario to study the suggested potential compensatory hemodynamic mechanisms in end-of-life dementia, which is sex-dependent and can be a target for pharmacological and non-pharmacological interventions.

Survival Bias and Crosstalk between Chronological and Behavioral Age: Age- and Genotype-Sensitivity Tests Define Behavioral Signatures in Middle-Aged, Old, and Long-Lived Mice with Normal and AD-Associated Aging

“…This is most important when studying the age and disease interaction effects in the expression of phenotypic characteristics of late-onset neurodegenerative processes and the screening for drug discovery [18,29]. However, the number of research works using old (+18 months of age) and very old (+21 months of age) or naturally longlived animals have to overcome the sparsity of studies [30][31][32], to confront methodological difficulties due to the natural constraints of aged animals [33,34] and severe limitations due to mortality bias [35,36]. Since BPSD are highly prevalent also in old people without dementia [6], translational research using AD-models can also provide the benefit of the observation of the age-matched old wildtype specimens as a source of knowledge of the normal aging process, as is presented here.…”

Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway

“…Depression, anxiety and cognitive impairment are the most common symptoms of psychiatric disorders that may concur and/or sway during progression and comorbidity frequently occurs in mental illnesses, which renders the exact diagnosis even more difficult. Scrupulous studies are underway to untangle the thread of pathophysiology of mental disorders and their comorbidities not only in clinical medicine, but also in animal studies [106][107][108][109]. Psychological stress, especially depression has been found to be a risk factor for dementia, a prognostic biomarker for stokes and a therapeutic target for meaning-centered psychotherapy in depression, and animal-assisted and pet-robot interventions in dementia [110][111][112][113].…”

Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway

“…Depression, anxiety, and cognitive impairment are the most common symptoms of psychiatric disorders that may concur and/or sway during progression and comorbidity frequently occurs in mental illnesses, which renders the exact diagnosis even more difficult. Scrupulous studies are underway to untangle the thread of pathophysiology of mental disorders and their comorbidities not only in clinical medicine, but also in animal studies [106][107][108]. Psychological stress, especially depression has been found to be a risk factor for dementia, a prognostic biomarker for stokes, and a therapeutic target for meaning-centered psychotherapy in depression, and animal-assisted and petrobot interventions in dementia [109][110][111][112].…”