Identifying and Implementing Endpoints for Geriatric Mice

Toth, Linda A

doi:10.30802/aalas-cm-18-000022

Cited by 17 publications

(7 citation statements)

References 95 publications

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“…Furthermore, we recommend environmental enrichment and mass housing/socializing to optimize animal welfare. The predefined humane endpoints should be designed for aged rodents (Toth, 2018 ). The animal caretakers must have special focus on periodic observations of age-related defects, such as unkept fur, reduced apathy and mobility, over-growing teeth and eye problems (Wilkinson et al, 2020 ).…”

Section: Challengesmentioning

confidence: 99%

Impact of aging on animal models of Parkinson's disease

Klæstrup

Just

Holm

et al. 2022

Front. Aging Neurosci.

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Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models.

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Section: Challengesmentioning

confidence: 99%

Impact of aging on animal models of Parkinson's disease

Klæstrup

Just

Holm

et al. 2022

Front. Aging Neurosci.

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“…Rap1 KI/KI mice displayed deficits in behavioral tests of locomotor and chemosensory function. Decline in these functions are well-documented during the normal aging process of mice and humans alike [ 49 , 50 ]. Immune-response transcripts were most upregulated in the Rap1 KI/KI brain, in agreement with increased pro-inflammatory cytokine production in this tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Lifespan was determined using the Kaplan-Meier survival analysis. Mice died naturally (the animals were found dead in the cage) or euthanized prior to any noticeable distress according to NIA-ACUC Policy 005 humane endpoint criteria, as described alike [ 49 , 50 ]. Following euthanasia, whole bodies or organs with gross abnormalities and masses were submitted to the NIH Division of Veterinary Resource for histopathological analysis.…”

Section: Methodsmentioning

confidence: 99%

Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes

et al. 2022

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Short telomeres induce a DNA damage response (DDR) that evokes apoptosis and senescence in human cells. An extant question is the contribution of telomere dysfunction-induced DDR to the phenotypes observed in aging and telomere biology disorders. One candidate is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knockin mouse carrying a mutated Rap1, which was incapable of binding telomeres and did not result in eroded telomeres or a DDR. Primary Rap1 knockin embryonic fibroblasts showed decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in human fibroblasts undergoing telomere erosion. Rap1 knockin mice were viable, but exhibited transcriptomic alterations, proinflammatory cytokine/chemokine signaling, reduced lifespan, and decreased healthspan with increased body weight/fasting blood glucose levels, spontaneous tumor incidence, and behavioral deficits. Taken together, our data present mechanisms distinct from telomere-induced DDR that underlie age-related phenotypes.

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“…Aging mice normally develop a ruffled fur [ 31 ]. Macroscopically, the fur of the treated mice looked smoother than the fur of controls.…”

Section: Discussionmentioning

confidence: 99%

Long-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism

Doeppner

Coman²,

Burdusel

et al. 2022

Aging

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Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. Since spermidine increases autophagy, we asked if treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Recently, chloroquine has intensively been discussed as a treatment option for COVID-19 patients. To rule out unfavorable long-term effects on longevity, we examined the effect of chronic treatment with chloroquine given in the drinking water on the lifespan and organ pathology of male middle-aged NMRI mice. We report that, surprisingly, daily treatment with chloroquine extended the median life span by 11.4% and the maximum life span of the middle-aged male NMRI mice by 11.8%. Subsequent experiments show that the chloroquine-induced lifespan elevation is associated with dose-dependent increase in LC3B-II, a marker of autophagosomes, in the liver and heart that was confirmed by transmission electron microscopy. Quite intriguingly, chloroquine treatment was also associated with a decrease in glycogenolysis in the liver suggesting a compensatory mechanism to provide energy to the cell. Accumulation of autophagosomes was paralleled by an inhibition of proteasome-dependent proteolysis in the liver and the heart as well as with decreased serum levels of insulin growth factor binding protein-3 (IGFBP3), a protein associated with longevity. We propose that inhibition of proteasome activity in conjunction with an increased number of autophagosomes and decreased levels of IGFBP3 might play a central role in lifespan extension by chloroquine in male NMRI mice.

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Identifying and Implementing Endpoints for Geriatric Mice

Cited by 17 publications

References 95 publications

Impact of aging on animal models of Parkinson's disease

Impact of aging on animal models of Parkinson's disease

Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes

Long-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism

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