Does a senescene-like phenotype in neurons contribute to brain ageing and neurodegeneration?

PhD ThesisSenescent cells accumulate in the body with age, and drive organismal ageing and tissue dysfunction. Senescence is not a simple growth arrest, but is accompanied by a host of phenotypic changes, including the generation of pro-inflammatory molecules, and is maintained by a network of auto- and paracrine reinforcement. Senescence is now also understood to occur in post-mitotic cells, including neurons – contrary to the former definition of senescence occurring exclusively in proliferating cells. This is called the senescent-like phenotype. While senescent cells can be seen to increase with age, little is known about their relation to cognitive function with age or pathological states such neuro-inflammation. Using a model of chronic inflammation, the nfkb1-/- mouse, I investigated neuro-inflammation, cognitive function and the frequency of senescent-like neurons with age and treatment with the COX-2 inhibitor ibuprofen. Increasing microglial proliferation and neuro-inflammation could be observed, together with deficits in spatial memory. This was accompanied by an increase in the numbers of senescent-like neurons. Increased accumulation of persistent DNA damage in pyramidal neurons, and a deficit in the generation and propagation of Carbachol induced gamma frequency oscillations, could be seen in the CA3. COX-2 appears to have a role in mediating these effects, as treatment with ibuprofen was effective in ameliorating levels of neuro-inflammation, cognitive dysfunction and senescent-like neurons. Ageing INK-ATTAC mice were given pharmacogenetic and pharmacological treatments to investigate if these could clear senescent-like neurons. Pharmacological clearance (Dasatinib and Quercetin) was effective in reducing the numbers of senescent like neurons, and these mice showed an improvement in cognitive function, while pharmacogenetic treatment had a lesser effect. The data presented in this thesis implicate the senescence and the senescent-like phenotype in neuro-inflammation and ageing, and in driving the accompanying declines in cognitive function

Angler‐Caught Piscivore Diets Reflect Fish Community Changes in Lake Huron

Examination of angler‐caught piscivore stomachs revealed that Lake Trout Salvelinus namaycush, Chinook Salmon Oncorhynchus tshawytscha, and Walleyes Sander vitreus altered their diets in response to unprecedented declines in Lake Huron’s main‐basin prey fish community. Diets varied by predator species, season, and location but were nearly always dominated numerically by some combination of Alewife Alosa pseudoharengus, Rainbow Smelt Osmerus mordax, Emerald Shiner Notropis atherinoides, Round Goby Neogobius melanostomus, or terrestrial insects. Rainbow Trout Oncorhynchus mykiss (steelhead), Coho Salmon Oncorhynchus kisutch, and Atlantic Salmon Salmo salar had varied diets that reflected higher contributions of insects. Compared with an earlier (1983–1986) examination of angler‐caught predator fishes from Lake Huron, the contemporary results showed an increase in consumption of nontraditional prey (including conspecifics), use of smaller prey, and an increase in insects in the diet, suggesting that piscivores were faced with chronic prey limitation during this study. The management of all piscivores in Lake Huron will likely require consideration of the pervasive effects of changes in food webs, especially if prey fish remain at low levels.Received December 19, 2013; accepted June 30, 2014Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141251/1/tafs1419.pd

Spawning Habitat Unsuitability: An Impediment to Cisco Rehabilitation in Lake Michigan?

The cisco Coregonus artedi was one of the most important native prey fishes in Lake Michigan and in the other four Laurentian Great Lakes. Most of the cisco spawning in Lake Michigan was believed to have occurred in Green Bay. The cisco population in Lake Michigan collapsed during the 1950s, and the collapse was attributed in part to habitat degradation within Green Bay. Winter water quality surveys of lower Green Bay during the 1950s and 1960s indicated that the bottom dissolved oxygen (DO) concentration was less than 2 mg/L throughout much of the lower bay, and most cisco eggs would not successfully hatch at such low DO concentrations. To determine present‐day spawning habitat suitability in lower Green Bay, we compared cisco egg survival in lower Green Bay with survival at a reference site (St. Marys River, Michigan–Ontario) during 2009. We also conducted winter water quality surveys in lower Green Bay and the St. Marys River during 2009 and 2010. Cisco egg survival in lower Green Bay averaged 65.3%, which was remarkably similar to and not significantly different from the mean at the St. Marys River site (64.0%). Moreover, the lowest bottom DO concentrations recorded during the winter surveys were 11.2 mg/L in lower Green Bay and 12.7 mg/L in the St. Marys River. These relatively high DO concentrations would not be expected to have any negative effect on cisco egg survival. We conclude that winter water quality conditions in lower Green Bay were suitable for successful hatching of cisco eggs and that water quality during the egg incubation period did not represent an impediment to cisco rehabilitation in Lake Michigan. Our approach to determining spawning habitat suitability for coregonids would be applicable to other aquatic systems.Received May 14, 2011; accepted July 6, 2011Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142025/1/nafm0905.pd

Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

Abstract: Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially

Using time-varying asymptotic length and body condition of top piscivores to indicate ecosystem regime shift in the main basin of Lake Huron: a Bayesian hierarchical modeling approach

We evaluated the ecosystem regime shift in the main basin of Lake Huron that was indicated by the 2003 collapse of alewives, and dramatic declines in Chinook salmon abundance thereafter. We found that the period of 1995-2002 should be considered as the early phase of the final regime shift. We developed two Bayesian hierarchical models to describe time-varying growth based on the von Bertalanffy growth function and the length-mass relationship. We used asymptotic length as an index of growth potential, and predicted body mass at a given length as an index of body condition. Modeling fits to length and body mass at age of lake trout, Chinook salmon, and walleye were excellent. Based on posterior distributions, we evaluated the shifts in among-year geometric means of the growth potential and body condition. For a given top piscivore, one of the two indices responded to the regime shift much earlier than the 2003 collapse of alewives, the other corresponded to the 2003 changes, and which index provided the early signal differed among the three top piscivores.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Improved Growth Kinetics of Enteric Adenovirus Type 40 in a Modified Cell Line that Can No Longer Respond to Interferon Stimulation

Human enteric adenoviruses propagate poorly in conventional human cell lines used to grow other adenovirus serotypes. As human enteric adenoviruses have a defect in counteracting the cellular interferon (IFN) response in cell culture, to aid in growth of the virus, a 293-based cell line defective in its ability to respond to IFN was constructed. This cell line (293-SV5/V) constitutively expresses V-protein of the paramyxovirus Simian virus 5, which degrades the signal transducer and activator of transcription 1 (STAT1) and thereby prevents the STAT1-mediated IFN response. Analysis of human enteric adenovirus type 40 (HAdV-40)-infected 293-SV5/V cells compared with parental 293 cells shows that the recombinant line allows more rapid production of virus and results in higher titres. These results suggest that the defect in HAdV-40 in counteracting the IFN response can be overcome at least partially through the use of 293-SV5/V cell lines.</p