Volume 1, 2020

Neutrophil Response to Cyclophosphamide Predicts Resilience to Age-related Learning Impairment

Marianne Bjorner, Lida Zhu, Warren Ladiges

Abstract: Ability to respond to stress, defined as resilience, was measured by white blood cell counts in various age C57BL/6 mice receiving a nonlethal dose of cyclophosphamide (CYP). Neutrophil counts dipped and then rebounded in a consistent and age-dependent manner. Low neutrophil rebound correlated with improved learning in middle age mice suggesting CYP-induced neutrophil response may predict resilience to aging.

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Short Term Sleep Deprivation Predicts Pharmcological Resilience Response to Aging

Juan Wang, Clarice Forbes, Neva Hahn, Warren Ladiges

Abstract: The ability of an organism to respond to physical stress with increasing age, defined as physical resilience, was measured by the effect of short term sleep deprivation (SD) in 17 month old CB6F1 male mice. Sleep loss induces histone deacetylation (HDAC), resulting in cognitive dysfunction.  These mice were treated with phenylbuterate (PBA), an HDAC inhibitor, and then put through two physiological assessments. SD resistant mice had a weaker grip strength, but higher running distances than SD sensitive mice, suggesting these two physiological assessments have different pathway connections with PBA targeted hippocampal learning.

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GHK Peptide Prevents Sleep Deprived Learning Impairment in Mice

Katie Nickel, Warren Ladiges, Lida Zhu

Abstract: Sleep deprivation is known to cause memory impairment and is associated with inflammation and cell damage linked to neurodegenerative diseases. GHK (glycyl-L-histidyl-L-lysine) is a naturally occurring tripeptide found in mammalian plasma. GHK has anti-inflammatory activity and can pass through the blood brain barrier suggesting the potential to prevent neuroinflammation associated with sleep deprivation. In this study, mice were injected with 15mg/kg GHK per day for five days and sleep deprived on the last two days of treatment. Sleep deprived mice treated with GHK did not show the acute learning impairment seen in sleep deprived mice treated with saline. GHK prevented an increase in MCP-1 and nitric oxide levels in the hippocampus of sleep deprived mice suggesting that anti-inflammatory and anti-reactive nitrogen species activity could be a therapeutic target for learning impairment associated with short term sleep deprivation.

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Volume 1, 2022

A Unique Drug Cocktail Slows Aging in Mice

Jackson Wezeman, Zhou Jiang, Kavita Sharma, Warren Ladiges

Abstract: The process of aging as a physical process is due to a decrease of function in multiple interconnected biological pathways. It thus follows that in order to increase resilience to aging, several pathways must be targeted. Acarbose, as comparative enzyme was proven to delay glucose absorption and lower postprandial hyperglycemia, as well as increase lifespan in HET3 mice in previous NIA intervention testing programs. Rapamycin inhibits mTOR1 function through binding with its immunophilin which is regulated by upstream pathways responsive to nutrient intake therefore suppress autophagy impairment.  PBA is a broad-spectrum inhibitor and an active ER stress chaperone that inhibits histone deacetylation and decreases ER stress. This study was designed to determine whether the effects of a drug combination would create an increase in resilience to aging through relative senescence quantification. The drug cocktail was given to a cohort of mice via oral delivery in their feed starting at age 21 months and ending at the age of 24 months when many of the chronic and histological lesions associated with aging are quite apparent. Another group of mice of the same number were fed regular feed for control comparison. P53 and P16 are the two most common senescence pathways and were examined for the purpose of this study though 2 step RT-qPCR on their respective primers. Preliminary data from liver samples showed that cocktail treated mice had less P16 expression than control mice but similar levels of P21. Senescence expression will be evaluated and relatively quantified on major organs to further investigate the cellular mechanism of testing the drug cocktail.  These observations are important as these drugs are prescribed commonly for humans, and their potential in increasing resistance to aging in mice. could provide a method for increasing resilience to aging in humans as well as developing poly-pharmaceutical therapies against age related diseases.
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Confirmation of Alzheimer’s Disease Neuropathology in Old Pet Cats

Jackson Wezeman, Zhou Jiang, Warren Ladiges

Abstract: Alzheimer’s disease (AD) is complex and a common neurodegenerative disease in humans. Disease-modifying treatments have proven difficult as there are not yet ways to evaluate early signs and risk factors associated with early AD as well as not having a predictable animal model. AD is diagnosed by the presence of amyloid plaques and tau tangles during brain autopsy, decades after the pathology in the brain has appeared. Preliminary data shows amyloid plaques and tau tangles have been discovered to develop spontaneously in aging domestic cats in similar fashion to humans. One additional benefit is house cats share the same environment as their owners which validates the results further. Pet cats have the potential to provide a competitive and unique animal model for studies of AD. The purpose of this study is to validate the naturally occurring aging lesion pathology of AD in old pet cats is comparable to human AD patients. Immunohistochemistry (IHC) will then be done on formalin-fixed paraffin embedded slides from old pet cat brains with Amyloid Beta-42 and phosphorylated tau antibodies to examine location and severity of lesions. Additional IHC staining with microglia and astrocyte targeted antibodies will be performed to validate the expression of glial cells around AD associated histology lesions. Finally, a landmark correspondence software package will be used to merge slide images with different staining for comparing the heat map intensity level of each antibody expression around certain lesions of interest. The observations made during this experiment are important and far-reaching as having a reliable animal model for AD would significantly help researchers to develop interventions as well as develop clinical tests for early signs of AD.
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