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Highlights: Husbandry homecage behavior and a physical frailty phenotype point to end-point status in mice. Piloerection is the best gross examination hallmark of 16-month-old mice at end-point. Structural kyphosis characterizes end-point mice, while postural kyphosis indicates normal aging. WAT loss and hepatic and splenomegaly indexes can be indirect measures of sarcopenia. Carcass index correlates with piloerection and kyphosis in end-point mice. Simple Summary: This study examines frailty in 16-month-old C57BL/6J mice, revealing physical signs such as kyphosis and alopecia alongside behavioral indicators like poor emotional responses. Unlike typical end-of-life traits, frail mice exhibited unexpected muscle weight changes, hepatomegaly, and splenomegaly. These findings suggest a complex relationship between physical deterioration and emotional distress in frailty, offering insights into mechanisms relevant to aging populations. Recognizing both physical and behavioral signs in preclinical models is crucial for future research on interventions to address frailty-related decline. The state of frailty is a clinical–biological syndrome that affects the older population with a higher risk of functional dependence. Animal models can provide a tool to study this complex scenario. In the present work, we analyzed the physical and behavioral hallmarks of end-point status in 16-month-old mice (C57BL/6J) according to animal welfare regulations compared to age-matched counterparts with normal aging. A group of 6-month-old mice was added to control for age bias. First, we identified 'structural kyphosis' (visible and unmodifiable deformation in locomotion) correlated with piloerection as the hallmarks of the physical frailty phenotype compared to the 'postural kyphosis' (adjustment to counteract increased visceral volume but attenuated during locomotion) of old mice with normal aging. Alopecia (barbering) was presented in both old groups. Normal levels of exploratory activity in the corner test for neophobia and triceps surae muscle weight but an increased latency of rearing indicated the poorest emotional phenotype, with a possible contribution of structural kyphosis. The presence of hepatomegaly and splenomegaly counteracted the significant WAT loss commonly associated with end-of-life traits, which should have a normal body weight but preserved muscle mass. [ABSTRACT FROM AUTHOR]

Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimers disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown. Here, we evaluated the effects of chronic dietary sodium selenate supplementation for 4 months in female 3xTg-AD mice at 12-14 months of age. Chronic sodium selenate treatment efficiently reversed hippocampal-dependent learning and memory impairments, and behavior- and neuropsychiatric-like symptoms in old female 3xTg-AD mice. Selenium significantly decreased the number of aggregated tau-positive neurons and astrogliosis, without globally affecting amyloid plaques, in the hippocampus of 3xTg-AD mice. These results indicate that selenium treatment reverses AD-like memory and neuropsychiatric symptoms by a mechanism involving reduction of aggregated tau and/or reactive astrocytes but not amyloid pathology. These results suggest that sodium selenate could be part of a combined therapeutic approach for the treatment of memory and neuropsychiatric symptoms in advanced AD stages.

The continuously expanding field of Alzheimer's disease (AD) research is now beginning to defocus the brain to take a more systemic approach to the disease, as alterations in the peripheral organs could be related to disease progression. One emerging hypothesis is organ involvement in the process of Aβ clearance. In the present work, we aimed to examine the status and involvement of the kidney as a key organ for waste elimination and the spleen, which is in charge of filtering the blood and producing lymphocytes, and their influence on AD. The results showed morphological and structural changes due to acute amyloidosis in the kidney (glomeruli area) and spleen (red pulp area and red/white pulp ratio) together with reduced antioxidant defense activity (GPx) in 16-month-old male and female 3xTg-AD mice when compared to their age- and sex-matched non-transgenic (NTg) counterparts. All these alterations correlated with the anxious-like behavioral phenotype of this mouse model. In addition, forced isolation, a cause of psychological stress, had a negative effect by intensifying genotype differences and causing differences to appear in NTg animals. This study further supports the relevance of a more integrative view of the complex interplay between systems in aging, especially at advanced stages of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Pre-clinical research in aging is hampered by the scarcity of studies modeling its heterogeneity and complexity forged by pathophysiological conditions throughout the life cycle and under the sex perspective. In the case of Alzheimer's disease, the leading cause of dementia in older adults, we recently described in female wildtype and APP23 mice a survival bias and non-linear chronology of behavioral signatures from middle age to long life. Here, we present a comprehensive and multidimensional (physical, cognitive, and neuropsychiatric-like symptoms) screening and underlying neuropathological signatures in male and female 3xTg-AD mice at 2, 4, 6, 12, and 16 months of age and compared to their non-transgenic counterparts with gold-standard C57BL/6J background. Most variables studied detected age-related differences, whereas the genotype factor was specific to horizontal and vertical activities, thigmotaxis, coping with stress strategies, working memory, and frailty index. A sex effect was predominantly observed in classical emotional variables and physical status. Sixteen-month-old mice exhibited non-linear age- and genotype-dependent behavioral signatures, with higher heterogeneity in females, and worsened in naturalistically isolated males, suggesting distinct compensatory mechanisms and survival bias. The underlying temporal and spatial progression of Aβ and tau pathologies pointed to a relevant cortico-limbic substrate roadmap: premorbid intracellular Aβ immunoreactivity and pSer202/pThr205 tau phosphorylation in the amygdala and ventral hippocampus, and the entorhinal cortex and ventral hippocampus as the areas most affected by Aβ plaques. Therefore, depicting phenotypic signatures and neuropathological correlates can be critical to unveiling preventive/therapeutic research and intervention windows and studying adaptative behaviors and maladaptive responses relevant to psychopathology. [ABSTRACT FROM AUTHOR]