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There is large variation in lifespan among different species, and there is evidence that modulation of proteasome function may contribute to longevity determination. Comparative biology provides a powerful tool for identifying genes and pathways that control the rate of aging. Here, we evaluated skin-derived fibroblasts and demonstrate that among primate species, longevity correlated with an elevation in proteasomal activity as well as immunoproteasome expression at both the mRNA and protein levels. Immunoproteasome enhancement occurred with a concurrent increase in other elements involved in MHC class I antigen presentation, including [beta]-2 microglobulin, (TAP1), and TAP2. Fibroblasts from long-lived primates also appeared more responsive to IFN-[gamma] than cells from short-lived primate species, and this increase in IFN-[gamma] responsiveness correlated with elevated expression of the IFN-[gamma] receptor protein IFNGR2. Elevation of immunoproteasome and proteasome activity was also observed in the livers of long-lived Snell dwarf mice and in mice exposed to drugs that have been shown to extend lifespan, including rapamycin, 17-[alpha]-estradiol, and nordihydroguaiaretic acid. This work suggests that augmented immunoproteasome function may contribute to lifespan differences in mice and among primate species., Introduction Within the animal kingdom there is extraordinary variation in lifespan. Members of some species only live a few days or weeks, while others live tens, if not hundreds, of [...]

In mammalian cells, hydrogen peroxide (H2O2)-induced adaptation to oxidative stress is strongly dependent on an Nrf2 transcription factor-mediated increase in the 20S proteasome. Here, we report that both Caenorhabdifis elegans nematode worms and Drosophila melanogaster fruit flies are also capable of adapting to oxidative stress with H202 pre-treatment. As in mammalian cells, this adaptive response in worms and flies involves an increase in proteolytic activity and increased expression of the 20S proteasome, but not of the 26S proteasome. We also found that the increase in 20S proteasome expression in both worms and flies, as in mammalian cells, is important for the adaptive response, and that it is mediated by the SKN-1 and CNC-C orthologs of the mammalian Nrf2 transcription factor, respectively. These studies demonstrate that stress mechanisms operative in cell culture also apply in disparate intact organisms across a wide biological diversity. [ABSTRACT FROM AUTHOR]

Introduction: Behavioral and psychological symptoms in dementia (BPSD) are dynamic phenomena with a high amount of intraindividual variability. We applied a multilevel framework to identify subsyndromes (between-person factors) that represent clinically relevant profiles of BPSD and identify symptom clusters (within-person factors) that represent contextually driven daily symptom experiences., Methods: This study used an intensive longitudinal design in which 68 co-residing family caregivers to persons living with dementia were recruited to proxy report on their care recipient's daily symptom experiences of 23 different BPSD for eight consecutive days (n = 443 diaries). A multilevel exploratory/confirmatory factor analysis was used to account for nested data and separate within-person variances from between-level factor estimates., Results: Exploratory factor analysis identified a 4-between 3-within factor structure based on fit statistics and clinical interpretability., Discussion: This study offers major methodological and conceptual advancements for management of BPSD within Alzheimer's disease and related dementias by introducing two related but distinct concepts of subsyndromes and symptom clusters., Highlights: Because behavioral and psychological symptoms of dementia (BPSD) are dynamic temporal phenomenon, this introduces measurement error into aggregate group-level estimates when trying to create subsyndromes. We propose a multilevel analysis to provide a more valid and reliable estimation by separating out variance due to within-person daily fluctuations. Using a multilevel exploratory factor analysis with intensive longitudinal data, we identified distinct and meaningful groups of BPSD. The four factors at the between-person level represented subsyndromes that are based on how BPSD co-occurred among persons with Alzheimer's disease (AD). These subsyndromes are clinically relevant because they share features of established clinical phenomena and may have similar neurobiological etiologies. We also found three within-person factors representing distinct symptom clusters. They are based on how BPSD clustered together on a given day for an individual with AD and related dementias. These clusters may have shared environmental triggers., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cellular proteins are exposed to oxidative modification and other forms of damage through oxidative stress and disease, and as a consequence of aging. This oxidative damage results in loss and/or modification of protein function, which in turn compromises cell function and may even cause cell death. Therefore, the removal of damaged proteins is extremely important for the maintenance of normal cell function. The 20S proteasome functions primarily as a system for removal of such damaged proteins. Unlike the 26S proteasome, the 20S proteasome exhibits a high degree of selectivity in degrading the oxidized, or otherwise damaged, forms of cell proteins. The 20S proteasome is broadly distributed throughout the cell and has a range of specific functions in different organelles, which are controlled through a number of proteasome regulators. It is also activated, and its synthesis is induced, under conditions of enhanced oxidative stress, thus permitting greater removal of damaged proteins., (Copyright © 2012 Elsevier Inc. All rights reserved.)