The oxidation of energy substrates during healthy aging

Glucose and ketones are important energy substrates in the human body and brain. Their use is highly regulated depending on energy status which can vary according to multiple factors such as type of cell, fed or fasted state, type of diet, or health state. Use of either substrate is also subject to multiple homeostatic feedback loops. Energy substrate availability has implications in several disorders including declining cognitive function in the elderly. While glucose availability is known to decrease in elderly with cognitive deficits, it is unclear whether this also occurs in healthy elderly, either in the body or brain. Also unknown is whether, in healthy elderly, the use of ketones as energy substrates is affected, and whether ketones could be used as an alternative energy substrate in situations of a decline in glucose availability. A clearer understanding of the use of glucose and ketones in aging is necessary to determine whether declining energy substrate availability that may occur in the elderly is a contributing factor to cognitive deficits, a result of cognitive pathology, or simply a feature of the physiological aging process. Objective. The overall goal of the laboratory where this research was carried out is to ascertain whether alternate energy sources to glucose, i.e. ketones, may help alleviate the risk of declining cognitive function during aging. The specific objective of the research project presented in this thesis was to evaluate the metabolism of glucose and ketones in the healthy elderly compared to young or middle age subjects during mild, short-term ketosis induced by a ketogenic breakfast. Results. Elderly people in relatively good health have a similar capacity to produce ketones and to oxidize [superscript 13]C-glucose and [superscript 13]C-β-hydroxybutyrate as middle-aged or young adults. Discussion. The results of this project encourage further exploration of whether ketones could be used as and alternative energy substrate to glucose as, at least in healthy elderly, there is no impedance of raising plasma ketones in response to a ketogenic intervention. // Résumé : Introduction. Le glucose et les cétones sont des substrats énergétiques importants pour le corps et le cerveau humain. Leur utilisation est spécifiquement régulée selon I'état énergétique qui varie en fonction du type de cellule, de I'état nourrie ou à jeun, du type de diète, de I'état de la santé. L'utilisation est également régulée par des voies de rétrocontrôle homéostatique. La disponibilité des substrats énergétiques est impliquée dans plusieurs désordres, dont le déclin des fonctions cognitives, chez les personnes âgées où une diminution de la disponibilité du glucose est démontrée. Cependant, il n'est pas encore connu si cette diminution est présente chez les personnes âgées en bonne santé ; soit dans le corps ou le cerveau. La capacité d'utiliser les cétones comme substrats énergétiques chez les personnes âgées saines et la possibilité d'utiliser les cétones comme substrat énergétique alternatif dans le cas d'un déclin de la disponibilité de glucose sont inconnues. Une meilleure compréhension de I'utilisation du glucose et des cétones sera nécessaire pour clarifier si une diminution de la disponibilité des substrats énergétique contribue au déclin cognitif, se manifeste à la suite des pathologies cognitives, ou encore est simplement une caractéristique du processus physiologique du vieillissement. Objectif. L'objectif principal du laboratoire est de déterminer si les sources d'énergie alternatives au glucose, c'est-à-dire les cétones, pourraient ralentir le déclin cognitif chez les personnes âgées. L'objectif du projet de recherche de ce mémoire était d'évaluer le métabolisme du glucose et des cétones chez les sujets âgés, d'âge moyen, et jeune après la prise d'un déjeuner induisant une faible cétogénèse de courte durée. Résultats. Les personnes âgées en santé ont une capacité similaire au sujet d'âge moyen et jeune à produire des cétones et à oxyder le [indice supérieur 13]C-glucose et le [indice supérieur 13]C-β- hydroxybutyrate. Perspectives. Les résultats de ce projet incitent à continuer à explorer si les cétones pourraient être utilisés comme substrats énergétiques afin de contourner le problème d'un déclin de I'utilisation du glucose, car il n'y a aucun obstacle dans la production des cétones suite a une intervention cétonique chez des sujets âgées en bonne santé

Linking low docosahexaenoic acid intake to Alzheimer's disease : caution recommended

Prospective cohort studies and animal models support the concept that low docosahexaenoic acid intake is implicated in the etiology or progression of Alzheimer’s disease. However, other studies crucial to this relationship are less encouraging. To date, the few trials using docosahexaenoic acid to treat declining cognition in the elderly have either been very small or, in the largest trial, the beneficial effect was mild and limited to a sub-group of patients. The supplements used in each of these clinical trials contained at least one polyunsaturated fatty acid other than docosahexaenoic acid, so the active ingredient remains unclear. One widely cited study reported markedly lower brain docosahexaenoic acid in Alzheimer’s disease but at least five other much less commonly cited reports have not corroborated this effect. There are numerous inconsistencies or confounders in the data and several challenges to overcome before definitively attributing a specific role to docosahexaenoic acid in the protection of cognitive function in the elderl

Plasma n-3 fatty acids in the elderly

The elderly reportedly have a significantly higher % of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in plasma and red cell lipids. However, these observations are from a few small studies and the health status of the elderly in these studies is for the most part unclear. Since the elderly are susceptible to cardiovascular and neurological illnesses that seem to be related in part to lower intake of n-3 fatty acids it seems paradoxical that their blood levels of EPA and DHA would be higher than in young adults. We report here plasma fatty acid profiles and their response to supplementation with two types of fish oils from several of our recent studies in the moderately healthy elderly. We define the moderately healthy elderly as those who were in good physical condition, had no cognitive decline and, if present, in whom hypothyroidism, hyperlipidemia and/or hypertension were well-controlled. As shown previously, we confirm the higher % EPA and % total n-3 fatty acids (but not DHA) in fasting plasma and extend these findings to include higher plasma concentrations (mg/L) of n-3 fatty acids as well. The EPA-predominant supplement raised DHA only in the young, whereas the DHA-predominant supplement raised EPA more in the young than in the elderly. The moderately healthy elderly clearly have higher plasma n-3 fatty acids but whether this reflects differences in intake versus aging-related changes in n-3 fatty acid metabolism remains to be elucidated

Plasma response to fish oil in the elderly

Little information is available concerning whether incorporation of dietary omega-3 fatty acids into plasma lipids changes during healthy aging. Elderly (74 ± 4 years old) and young (24 ± 2 years old) adults were given a fish oil supplement for 3 weeks that provided 680 mg/day of docosahexaenoic acid and 320 mg/day of eicosapentaenoic acid, followed by a 2 week wash-out period. Compliance was monitored by spiking the capsules with carbon-13 glucose, the excretion of which was measured in breath CO2. In response to the supplement, plasma docosahexaenoic acid rose 42% more in the elderly but eicosapentaenoic responded similarly in both groups. Despite raising docosahexaenoic acid intake by five to tenfold, the supplement did not raise plasma free docosahexaenoic acid (% or mg/dL) in either group. We conclude that healthy aging is accompanied by subtle but significant changes in DHA incorporation into plasma lipids

JNK1 controls dendritic field size in L2/3 and L5 of the motor cortex, constrains soma size, and influences fine motor coordination

Peer reviewe

Brain lipids and cholesterol in neuropsychiatric disorders

Neuropsychiatric disorders and suicidal behaviour represent major contributions to mortality in Canada. Among the many factors associated with psychiatric disorders and suicide, alterations in lipids and cholesterol have been demonstrated both peripherally and centrally, supporting their roles as mediating variables in the underlying neuropathology. Cholesterol (CHL) regulation is a complex and dynamic system, and while animal studies also support a mediating role of CHL on brain function, efforts to determine a biological association in humans have achieved only modest gains. While mechanisms governing cholesterol regulation are not entirely understood, cholesterol is well accepted to have important impacts on a variety of brain functions from neurotransmission to synaptic plasticity and neurodegeneration, with unique contributions from neurons, astrocytes, and oligodendrocytes. Given the extensive regulatory feedback mechanisms and the implications in neurological function, determining a biological basis for the association of cholesterol with neuropsychiatric disorders remains an important area of research. This research aimed to explore the neurobiological mechanism whereby alterations in CHL may relate to neuropsychiatric phenotypes. The results presented in chapter 3 suggest, while no clear differences were found in suicide completers with major depressive disorder, expression of several CHL related genes associate more strongly with white matter CHL levels compared to grey matter, suggesting a potential contribution of SORT1, LPL, and ABCA2, in the regulation of white matter CHL. The results of chapter 4 suggest altered phospholipid levels and expression of lysosomal acid lipase A gene in violent suicides in the prefrontal cortex, which would have important consequences for inhibitory neurotransmission. The results of chapter 4 suggest an increase in 24-hydroxycholesterol in the prefrontal cortex of suicide completers and this could have implications for synapse maintenance and loss in the neuropathology of suicide. In regards to CHL levels, however, little evidence in support of alterations in CNS CHL in neuropsychiatric disorders and suicidal behaviour was noted.Les troubles neuropsychiatriques et les comportements suicidaires contribuent de façon importante au taux de mortalité au Canada. Parmi les facteurs associés aux troubles neuropsychiatriques, on retrouve des altérations lipidiques autant périphériques que centrales, ce qui supporte une implication lipidique dans les mécanismes neuropathologiques. Étant donné la complexité des mécanismes régissant le cholestérol, et malgré les études animales qui soutiennent un rôle fonctionnel dans le cerveau, les déterminants biologiques sous-jacents à une telle association chez les humains demeurent incertains. Alors que les mécanismes impliqués dans la régulation du cholestérol ne sont pas entièrement compris, on attribue au cholestérol un rôle important dans la régulation de plusieurs fonctions cérébrales telles que la neurotransmission, les modifications synaptiques, et la neurodégénération avec des contributions uniques aux neurones, astrocytes et oligodendrocytes. Compte tenu de l'étendue de ces mécanismes, de leur relation entre les différents types cellulaires et de leur implication dans les troubles neuropsychiatriques, déterminer une association biologique demeure d'une importance majeure afin de comprendre l'implication du cholestérol dans les troubles psychiatriques. Ce projet de recherche vise à explorer les mécanismes neurobiologiques et génétiques supportant une relation entre le cholestérol et différents phénotypes psychiatriques. Les résultats présentées aux chapitre 3 suggère, tandis que pas de différences distinctes ont été remarqués dans les suicidés, l'expression de plusieurs gènes liés à la CHL associer plus fortement avec les niveaux de CHL dans la substance blanche par rapport à la substance grise, ce qui suggère une contribution potentielle des SORT1 , LPL, et ABCA2, dans la régulation de CHL dans la substance blanche. Les résultats du chapitre 4 indiquent une altération des niveaux de phospholipides et l'expression du gène lipase acide lysosomale A chez le cortex préfrontal des suicides violent, qui aurait des conséquences importantes pour la neurotransmission inhibitrice. Les résultats du chapitre 4 suggèrent une augmentation de 24-hydroxycholestérol dans le cortex préfrontal des suicidés, ce qui pourrait avoir des implications pour l'entretien et la perte des synapses dans la neuropathologie de suicide. En ce qui concerne les niveaux de CHL, cependant, peu de preuves ont été constatées à l'appui des altérations de cholestérol du système nerveux central aux troubles neuropsychiatriques et aux comportements suicidaire

Age and Haplotype Variations within FADS1 Interact and Associate with Alterations in Fatty Acid Composition in Human Male Cortical Brain Tissue

<div><p>Fatty acids (FA) play an integral role in brain function and alterations have been implicated in a variety of complex neurological disorders. Several recent genomic studies have highlighted genetic variability in the fatty acid desaturase (FADS1/2/3) gene cluster as an important contributor to FA alterations in serum lipids as well as measures of FA desaturase index estimated by ratios of relevant FAs. The contribution to alterations of FAs within the brain by local synthesis is still a matter of debate. Thus, the impact of genetic variants in FADS genes on gene expression and brain FA levels is an important avenue to investigate.</p> <h3>Methods</h3><p>Analyses were performed on brain tissue from prefrontal cortex Brodmann area 47 (BA47) of 61 male subjects of French Canadian ancestry ranging in age from young adulthood to middle age (18–58 years old), with the exception of one teenager (15 years old). Haplotype tagging SNPs were selected using the publicly available HapMap genotyping dataset in conjunction with Haploview. DNA sequencing was performed by the Sanger method and gene expression was measured by quantitative real-time PCR. FAs in brain tissue were analysed by gas chromatography. Variants in the FADS1 gene region were sequenced and analyzed for their influence on both FADS gene expression and FAs in brain tissue.</p> <h3>Results</h3><p>Our results suggest an association of the minor haplotype with alteration in estimated fatty acid desaturase activity. Analysis of the impact of DNA variants on expression and alternative transcripts of FADS1 and FADS2, however, showed no differences. Furthermore, there was a significant interaction between haplotype and age on certain brain FA levels.</p> <h3>Discussion</h3><p>This study suggests that genetic variability in the FADS genes cluster, previously shown to be implicated in alterations in peripheral FA levels, may also affect FA composition in brain tissue, but not likely by local synthesis.</p> </div

Haplotype characteristics.

<p>The haplotype frequencies were comparable to those specified in the CEU HapMap dataset. Subjects did not differ in terms of age, post-mortem interval, RNA integrity number, or brain tissue pH. Values represent mean ± standard deviation. Haplotypes reconstructed based on rs174548, rs174549, and rs174555. As only 2 subjects had the CGC haplotype, they were excluded from the subsequent analyses.</p