Browsing by Subject "Dietary restriction"
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Item Open Access Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction(Pergamon Press, 2010) Adams, Michelle M.; Donohue, H. S.; Linville, M. C.; Iversen, E. A.; Newton, I. G.; Bechtold, J. K. B.Caloric restriction (CR) is a reduction of total caloric intake without a decrease in micronutrients or a disproportionate reduction of any one dietary component. While CR attenuates age-related cognitive deficits in tasks of hippocampal-dependent memory, the cellular mechanisms by which CR improves this cognitive decline are poorly understood. Previously, we have reported age-related decreases in key synaptic proteins in the CA3 region of the hippocampus that are stabilized by lifelong CR. In the present study, we examined possible age-related changes in the functional microcircuitry of the synapses in the stratum lacunosum-moleculare (SL-M) of the CA3 region of the hippocampus, and whether lifelong CR might prevent these age-related alterations. We used serial electron microscopy to reconstruct and classify SL-M synapses and their postsynaptic spines. We analyzed synapse number and size as well as spine surface area and volume in young (10 months) and old (29 months) ad libitum fed rats and in old rats that were calorically restricted from 4 months of age. We limited our analysis to SL-M because previous work demonstrated age-related decreases in synaptophysin confined to this specific layer and region of the hippocampus. The results revealed an age-related decrease in macular axo-spinous synapses that was not reversed by CR that occurred in the absence of changes in the size of synapses or spines. Thus, the benefits of CR for CA3 function and synaptic plasticity may involve other biological effects including the stabilization of synaptic proteins levels in the face of age-related synapse loss. © 2010 IBRO.Item Open Access Caloric restriction eliminates the aging-related decline in NMDA and AMPA receptor subunits in the rat hippocampus and induces homeostasis(Elsevier, 2007) Shi, L.; Adams, Michelle M.; Linville, M.; Newton, I.; Forbes, M.; Long, A.; Riddle, D.; Brunso-Bechtold, J.Caloric restriction (CR) extends life span and ameliorates the aging-related decline in hippocampal-dependent cognitive function. In the present study, we compared subunit levels of NMDA and AMPA types of the glutamate receptor and quantified total synapses and multiple spine bouton (MSB) synapses in hippocampal CA1 from young (10 months), middle-aged (18 months), and old (29 months) Fischer 344×Brown Norway rats that were ad libitum (AL) fed or caloric restricted (CR) from 4 months of age. Each of these parameters has been reported to be a potential contributor to hippocampal function. Western blot analysis revealed that NMDA and AMPA receptor subunits in AL animals decrease between young and middle age to levels that are present at old age. Interestingly, young CR animals have significantly lower levels of glutamate receptor subunits than young AL animals and those lower levels are maintained across life span. In contrast, stereological quantification indicated that total synapses and MSB synapses are stable across life span in both AL and CR rats. These results indicate significant aging-related losses of hippocampal glutamate receptor subunits in AL rats that are consistent with altered synaptic function. CR eliminates that aging-related decline by inducing stable NMDA and AMPA receptor subunit levels.Item Open Access Effects of aging and short-term dietary restriction on neurogenesis and cellular senescence in the zebrafish (Danio Reio) brain(Bilkent University, 2016-09) Erbaba, BegünCurrently we know from rodent and fish studies that adult neuron generation is reduced but still continues in old animals with a dynamic change throughout aging. This process occurs mainly in hippocampal region, which is thought to be analogous to a region in telencephalon of the zebrafish brain. Changes in this neuron turnover are thought to be one contributing factor to cognitive change occuring with advanced age. Since we know that external factors can affect the process of neurogenesis, and as previous studies showed, dietary restriction (DR) extends life span; here, we hypothesized that DR should also alleviate several age associated alterations. In order to test this, we applied a 10-week feeding regimen to young (8-9 months) and old (26-32.5 months) male and female fish. We had two dietary regimen groups, one fed Ad libitum and one fed with a DR that was a pattern of every-other-day feeding, which is a widely accepted method of DR. A total of 124 animals were used in this study. As a result, a significant loss of body weight in both young and old DR groups was observed without an effect on body lengths. To be able to label actively dividing cells we used Bromodeoxyuridine (BrdU), which is a thymidine analog. It is injected into the fish intraperitoneally prior to euthanasia. Four hours later the brains were dissected and fixed for sectioning. We obtained cross-sectional slices of 50 m thickness with a vibratome, performed immunostaining with antibodies against BrdU, NeuN (neuronal marker), HuC (neuronal marker); and visualized the brain sections with confocal microscopy forming 3D reconstructed pictures. We counted the BrdU positive cells in all brain slices, forming a regional map of the telencephalic region of zebrafish brain, in which we documented the specific regions where the adult neurogenesis dominates the most and least. Our results confirmed that there are more BrdU positive cells in young animals than olds, and that age is correlated with an increased senescence associated fi-galactosidase (SA-fi-gal) activity, along with shortened telomere lengths. The 10-week diet was not found to be creating a significant change in cell proliferation rates, cellular senescence, or the differentiation pattern of glial cells. However, it was demonstrated to have a shortening effect on telomere lengths. Our data suggest that the potential effects of DR could be related to telomere regulation. Therefore, in order to detect differentially expressed genes that could be related to this mechanism between the groups, we performed microarray analysis with differing DR regimens. Initial data indicated no significant effects of a 4-week diet on gene expression differences among aged fish. Further analysis of the different periods of DR will be performed. Taken together, the effects of age are more robust than a short-term DR.Item Open Access Short-term dietary restriction in old zebrafish changes cell senescence mechanisms(Elsevier, 2016-10) Arslan-Ergul, Ayca; Erbaba, Begun; Karoglu, Elif Tugce; Halim, Dilara Ozge; Adams, Michelle M.Brain aging is marked by a decline in cognitive abilities and associated with neurodegenerative disorders. Recent studies have shown, neurogenesis continues into adulthood but is known to be decreasing during advancing age and these changes may contribute to cognitive alterations. Advances, which aim to promote better aging are of paramount importance. Dietary restriction (DR) is the only non-genetic intervention that reliably extends life- and health-span. Mechanisms of how and why DR and age affect neurogenesis are not well-understood, and have not been utilized much in the zebrafish, which has become a popular model to study brain aging and neurodegenerative disease due to widely available genetic tools. In this study we used young (8–8.5 months) and old (26–32.5 months) zebrafish as the model to investigate the effects of a short-term DR on actively proliferating cells. We successfully applied a 10-week DR to young and old fish, which resulted in a significant loss of body weight in both groups with no effect on normal age-related changes in body growth. We found that age decreased cell proliferation and increased senescence associated β-galactosidase, as well as shortened telomere lengths. In contrast, DR shortened telomere lengths only in young animals. Neither age nor DR changed the differentiation patterns of glial cells. Our results suggest that the potential effects of DR could be mediated by telomere regulation and whether these are beneficial or negative remains to be determined.Item Open Access Short-term dietary restriction maintains synaptic plasticity whereas short-term overfeeding alters cellular dynamics in the aged brain: evidence from the zebrafish model organism(Elsevier, 2021-06-19) Karoğlu-Eravşar, Elif Tuğçe; Tüz Şaşik, Melek Umay; Adams, MichelleIncreased caloric intake (OF) impairs quality of life causing comorbidities with other diseases and cognitive deficits, whereas dietary restriction (DR) increases healthspan by preventing age-related deteriorations. To understand the effects of these opposing dietary regimens on the cellular and synaptic dynamics during brain aging, the zebrafish model, which shows gradual aging like mammals, was utilized. Global changes in cellular and synaptic markers with respect to age and a 12 week dietary regimen of OF and DR demonstrated that aging reduces the levels of the glutamate receptor subunits, GLUR2/3, inhibitory synaptic clustering protein, GEP, synaptic vesicle protein, SYP, and early-differentiated neuronal marker, HuC. DR significantly elevates levels of glutamate receptor subunits, GLUR2/3, and NMDA clustering protein, PSD95, levels, while OF subtly increases the level of the neuronal protein, DCAMKL1. These data suggest that decreased caloric intake within the context of aging has more robust effects on synapses than cellular proteins, whereas OF alters cellular dynamics. Thus, patterns like these should be taken into account for possible translation to human subjects.Item Open Access Zebrafish-A model organism for studying the neurobiological mechanisms underlying cognitive brain aging and use of potential interventions(Frontiers Media S.A., 2018) Adams, Michelle M.; Kafalıgönül, HulusiClassically, the zebrafish model organism has been used to elucidate the genetic and cellular mechanisms related to development since the embryo forms and grows externally following fertilization. This provides insight into the genetic control of developmental processes in humans because their genomes are similar. Also, unlike other animal models, the genes of zebrafish can be manipulated quite easily by using reverse genetic screens tools such as morpholinos, which transiently silence target genes of interest or systems such as the transposon-mediated insertional mutagenesis or CRISPR-Cas9. Moreover, one pair of fish will provide up to 300 offspring, which means that if there is a gene of interest that is manipulated, then it can be transmitted to a large population of fish. What is beginning to emerge is that similar to other mammals, adult zebrafish have an integrated nervous system, which is proposed to contain homologous brain structures to those found in humans, as well as equivalent cellular and synaptic structure and function. Moreover, like humans, zebrafish exhibit age-related declines in cognitive functions, and a convergence of evidence has indicated that subtle changes in cellular and synaptic integrity underlie these changes. Therefore, the zebrafish is a powerful model organism for studying the neurobiological consequences of aging-related behavioral and biological changes, which offers the potential to identify possible interventions that would promote healthy aging. In what follows, we present and discuss recent findings and advances along these directions.