Métabolisme du DHA lors du vieillissement

L'acide docosahexaénoïque (DHA) est un acide gras polyinsaturé oméga-3 (AGPI [oméga]3) concentré dans le poisson. Il est l'AGPI [oméga]3 présent en plus grande quantité dans le cerveau. Une étude épidémiologique a démontré que la consommation de deux portions de poisson par semaine peut ralentir le rythme du déclin cognitif qui survient avec le vieillissement. Étude SUPPLÉMENT. Objectif : Évaluer le changement plasmatique en AGPI [oméga]3 chez des sujets jeunes et âgés lors d'une supplémentation en acide eicosapentaénoïque (EPA)/DHA. Résultats : Chez les sujets jeunes et âgés, le DHA (73 « 47% et 117 « 68 %) et l'EPA (133 « 67% et 97 « 52%) plasmatiques ont augmenté significativement (p < 0,05) avec la supplémentation. Le pourcentage de DHA était supérieur chez les sujets âgés par rapport aux sujets jeunes avec la supplémentation. Conclusion : Les différences observées entre les sujets jeunes et âgés suggèrent qu'il existe un changement dans le métabolisme du DHA avec le vieillissement. Étude TRACEUR. Objectif : Évaluer l'incorporation du DHA marqué au carbone 13 (indice supérieur 13]C-DHA) dans les lipides totaux plasmatiques et sa [bêta]-oxydation chez des participants jeunes et âgés en bonne santé. Résultats : Initialement, la concentration de DHA dans les lipides totaux plasmatiques était similaire entre les groupes. Le [indice supérieur 13]C-DHA avait tendance (p = 0,055) à s'incorporer davantage chez les participants âgés (0,80 « 0,35 nmol/ml) comparativement aux jeunes (0,35 « 0,12 nmol/ml) quatre heures après la prise du traceur. Conclusions : Ces résultats suggèrent que l'incorporation du DHA dans les lipides plasmatiques et sa [bêta]-oxydation dans les heures suivant son ingestion sont influencés par l'âge. La faible [bêta]-oxydation du DHA sur un mois montre qu'il est davantage conservé pour des rôles structuraux plutôt qu'à des fins énergétiques. Conclusion générale :L'âge est associé à une augmentation de l'incorporation du DHA dans les lipides plasmatiques qui se reflète par la plus grande augmentation du DHA dans le plasma lors d'une supplémentation chez des personnes âgées. À cause de sa plus grande incorporation, davantage de DHA est disponible pour la [bêta]-oxydation, ce qui explique la plus grande quantité de DHA [bêta]-oxydé chez les personnes âgées. Cependant la [bêta]-oxydation du DHA est trop faible pour entrer en contradiction avec les résultats obtenus lors de la supplémentation.--Résumé abrégé par UMI

Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE ɛ4 but not by the common PPAR-α L162V polymorphism in men

The risk of Alzheimer's disease is increased for carriers of apoE4 (E4) or the PPAR-α L162V polymorphism (L162V), but it is decreased in fish and seafood consumers. The link between high fish intake and reduced risk of cognitive decline in the elderly appears not to hold in carriers of E4, possibly because better cognition is linked to EPA+DHA in the blood, but only in non-carriers of E4. As yet, no such studies exist in carriers of L162V. Our objective was to determine whether the plasma fatty acid response to a dietary supplement of EPA+DHA was altered in carriers of L162V and/or E4. This was an add-on project; in the original study, men were selected based on whether or not they were carriers of L162V (n 14 per group). E4 status was determined afterwards. All subjects received an EPA+DHA supplement for 6 weeks. L162V polymorphism did not interact with the supplement in a way to alter EPA and DHA incorporation into plasma lipids. However, when the groups were separated based on the presence of E4, baseline EPA and DHA in plasma TAG were 67 and 60 % higher, respectively, in E4 carriers. After the supplementation, there were significant gene × diet interactions in which only non-carriers had increased EPA and DHA in plasma NEFA and TAG, respectively

Plasma incorporation, apparent retroconversion and β-oxidation of 13C-docosahexaenoic acid in the elderly

<p>Abstract</p> <p>Background</p> <p>Higher fish or higher docosahexaenoic acid (DHA) intake normally correlates positively with higher plasma DHA level, but recent evidence suggests that the positive relationship between intake and plasma levels of DHA is less clear in the elderly.</p> <p>Methods</p> <p>We compared the metabolism of ¹³C-DHA in six healthy elderly (mean - 77 y old) and six young adults (mean - 27 y old). All participants were given a single oral dose of 50 mg of uniformly labelled ¹³C-DHA. Tracer incorporation into fatty acids of plasma triglycerides, free fatty acids, cholesteryl esters and phospholipids, as well as apparent retroconversion and β-oxidation of ¹³C-DHA were evaluated 4 h, 24 h, 7d and 28d later.</p> <p>Results</p> <p>Plasma incorporation and β-oxidation of ¹³C-DHA reached a maximum within 4 h in both groups, but ¹³C-DHA was transiently higher in all plasma lipids of the elderly 4 h to 28d later. At 4 h post-dose, ¹³C-DHA β-oxidation was 1.9 times higher in the elderly, but over 7d, cumulative β-oxidation of ¹³C-DHA was not different in the two groups (35% in the elderly and 38% in the young). Apparent retroconversion of ¹³C-DHA was well below 10% of ¹³C-DHA recovered in plasma at all time points, and was 2.1 times higher in the elderly 24 h and 7d after tracer intake.</p> <p>Conclusions</p> <p>We conclude that ¹³C-DHA metabolism changes significantly during healthy aging. Since DHA is a potentially important molecule in neuro-protection, these changes may be relevant to the higher vulnerability of the elderly to cognitive decline.</p

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

Interrelation entre déficits métaboliques et neuropathologie associée à la maladie d'Alzheimer chez la souris 3xTg-AD

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2015-2016La maladie d’Alzheimer (MA) est la maladie neurodégénérative qui cause le plus important nombre de cas de démence. On estime que près de 15% des canadiens âgés de plus de 65 ans sont atteints de la MA. Avec le vieillissement de la population, le nombre de cas augmentera de manière substantielle dans les prochaines années. À l’heure actuelle, aucun traitement ne permet de ralentir la progression de la maladie. Pour plus de 99% des cas, ses causes exactes demeurent indéterminées. Toutefois, de nombreux facteurs de risque ont été identifiés. Parmi eux, on retrouve plusieurs facteurs liés au métabolisme énergétique dont l’obésité et le diabète de type 2 (DT2). De manière intéressante, des modifications du métabolisme, telles qu’une résistance à l’insuline centrale et périphérique, sont également observées chez les patients Alzheimer. Afin de mieux comprendre l’interaction entre le DT2 et la MA, nous avons d’abord étudié les altérations métaboliques chez la souris triple transgénique (3xTg-AD), un modèle murin de la MA. Nous avons, en premier lieu, observé une intolérance au glucose qui progresse avec l’âge, qui est plus importante chez les femelles et qui semble liée à l’accumulation du peptide beta-amyloïde (Aβ) humain dans le pancréas. Ensuite, nous avons nourri cette souris avec une diète riche en gras pour vérifier l’impact d’une aggravation des déficits métaboliques sur la pathologie Alzheimer. L’aggravation de l’intolérance au glucose chez les souris 3xTg-AD semblait liée à l’atrophie des îlots de Langerhans et, en conséquence, à une réduction de la production d’insuline en réponse à l’injection de glucose. En plus de l’aggravation des déficits métaboliques, la diète riche en gras a augmenté de manière drastique l’accumulation de la forme soluble du peptide Aβ dans le cortex et a déterioré la mémoire des souris 3xTg-AD. De manière intéressante, l’élévation du peptide Aβ et les troubles de la mémoire ont été rétablis par l’administration d’une seule dose d’insuline. Aussi, nous avons observé une augmentation du peptide Aβ dans le plasma 30 minutes à la suite de l’injection d’insuline, suggérant qu’il est possible que la baisse rapide du peptide soit en partie causée par une élévation de la clairance du peptide au cerveau. Ces résultats renforcent les évidences supportant le potentiel thérapeutique de l’insuline dans le traitement de la MA. Toutefois, les résultats chez les patients mettent en lumière l’inefficacité de l’administration intranasale d’insuline chez les porteurs de l’allèle 4 du gène de l’apolipoprotéine E (APOE4). Afin de comprendre les raisons qui expliquent cette différence de réponse à l’insuline chez les porteurs de l’APOE4, nous avons injecté des souris exprimant l’APOE3 et l’APOE4 humain avec de l’insuline dans le but de vérifier l’effet central et périphérique de l’insuline chez ces animaux. Les souris APOE4 montrent une plus importante élévation de la signalisation de l’insuline au cerveau comparativement aux souris APOE3. Cette plus haute réponse est aussi associée à une élévation plus importante de la phosphorylation de la protéine tau, un marqueur neuropathologique de la MA. En somme, ces résultats suggèrent qu’il existe un cercle vicieux entre la MA et le DT2. L’administration d’insuline a un potentiel thérapeutique intéressant pour la MA, malgré des effets limités chez les patients APOE4 en raison de son impact probable sur la phosphorylation de la protéine tau.Alzheimer’s disease (AD) is the neurodegenerative disorder underlying most dementia cases. About 15% of canadians over 65 years suffer from AD. With the aging of the population, AD cases are expected to increase in years to come. Unfortunately, no treatment is able to slow down the progression of the disease. For more than 99% of the cases, the cause of the disease remain undetermined. However, several risks factors have been identified, including Type 2 Diabetes (T2D) which doubles the risk of developing AD at a later age. Interestingly, metabolic changes such as impaired peripheral and central insulin signaling were also identified in AD patients. To study the interelation between AD and diabetes, we first studied the impact of the induction of AD on peripheral metabolism in an animal model, the 3xTg-AD mouse. We found that the generation of AD neuropathology was associated to glucose intolerance, which progressed with age and was more important in females than in males. Furthermore, glucose intolerance was linked to the accumulation to human beta-amyloid peptide (Aβ) in the pancreas of 3xTg-AD mice. Next, we fed the 3xTg-AD mice a high-fat diet to see the impact of exacerbating metabolic deficits on AD-like neuropathology. The high-fat diet aggravated glucose intolerance and was linked to a reduce pancreatic islets size and impaired insulin production in response to glucose injection. Futhermore, high-fat diet was associated to an increased soluble Aβ accumulation in mice cortex as well as a deteriorated memory function. Interestingly, Aβ accumulation and memory funciton were restored with a single insulin injection. We also observed an increased plasma Aβ 30 min following insulin injection, suggesting that the peptide might be cleared from the brain following insulin administration. Those results strengthen the evidences suggesting that insulin might be an interesting therapeutical tool in AD. However, results in human patients using intranasal insulin suggest that APOE4 carrier do not benefit from insulin. To study the effect of APOE genotype on central insulin response, we injected APOE3 and APOE4 mice with a single insulin injection, five min before sacrifice. We found that APOE4 genotype was linked to a more important cerebral insulin signaling following insulin administration. Also, more increased phosphorylation of tau protein was observe in APOE4 mice injected with insulin. In summary, those results highlight the presence of a vicious circle between AD and T2D. Insulin administration might be an interesting therapeutical tool in AD, although it’s effects are limited in APOE4 patients

In men, plasma omega-3 fatty acid response to an omega-3 fatty acid supplement is modulated by apolipoprotein E 4 but not by the common PPAR-alpha L162V

The risk of Alzheimer’s disease is increased for carriers of apoE4 (E4) or the PPAR-a L162V polymorphism (L162V), but it is decreased in fish and seafood consumers. The link between high fish intake and reduced risk of cognitive decline in the elderly appears not to hold in carriers of E4, possibly because better cognition is linked to EPA þ DHA in the blood, but only in non-carriers of E4. As yet, no such studies exist in carriers of L162V. Our objective was to determine whether the plasma fatty acid response to a dietary supplement of EPA þ DHA was altered in carriers of L162V and/or E4. This was an add-on project; in the original study, men were selected based on whether or not they were carriers of L162V (n 14 per group). E4 status was determined afterwards. All subjects received an EPA þ DHA supplement for 6 weeks. L162V polymorphism did not interact with the supplement in a way to alter EPA and DHA incorporation into plasma lipids. However, when the groups were separated based on the presence of E4, baseline EPA and DHA in plasma TAG were 67 and 60 % higher, respectively, in E4 carriers. After the supplementation, there were significant gene £ diet interactions in which only non-carriers had increased EPA and DHA in plasma NEFA and TAG, respectively

Unresolved issues in the link between docosahexaenoic acid and Alzheimer's disease

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