Nutrition and the ageing brain: moving towards clinical applications

The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3 Symposium on "Nutrition for the Ageing Brain: Moving Towards Clinical Applications" held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required

Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID).

Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID). Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range; and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock

The Use of Multivitamin/Multimineral Supplements:A Modified Delphi Consensus Panel Report

PURPOSE: Evidence supporting the use of dietary supplements, in particular, multivitamin/multimineral supplements (MVMS), has been mixed, complicating the ability of health care professionals to recommend their use. To clarify the role that MVMS can play in supporting human health, a series of consensus statements was developed based on expert opinion. METHODS: A panel of 14 international experts in nutritional science and health care was convened to develop consensus statements related to using MVMS in supporting optimal human health. The modified Delphi process included 2 rounds of remote voting and a final round of voting at a roundtable meeting where evidence summaries were presented and discussed. The level of agreement with each of 9 statements was rated on a 5-point Likert scale: agree strongly; agree with reservation; undecided; disagree; or disagree strongly. Consensus was predefined as ≥80% of the panel agreeing strongly or agreeing with reservation to a given statement. FINDINGS: Consensus was reached for all statements. The panel determined that MVMS can broadly improve micronutrient intakes when they contain at least the micronutrients that are consumed insufficiently or have limited bioavailability within a specified population. MVMS formulations may also be individualized according to age, sex, life cycle, and/or other selected characteristics. There are specific biological processes and health outcomes associated with deficient, inadequate, and adequate micronutrient levels. Adequate intake is necessary for normal biological functioning required for good health; in some instances, higher than recommended micronutrient intakes have the potential to provide additional health benefits. Meeting daily intakes established by dietary reference values should be an explicit public health goal for individuals and populations. Use of MVMS is one approach to ensure that adequate micronutrient needs are met in support of biological functions necessary to maintain health. Long-term use of MVMS not exceeding the upper limit of recommended intakes has been determined to be safe in healthy adults. There is insufficient evidence to indicate that MVMS are effective for the primary prevention of chronic medical conditions, including cardiovascular disease and cancer. However, for certain otherwise healthy subpopulations (eg, pregnant women, older adults) and some individuals with existing medical conditions who experience inadequacies in micronutrient intake, addressing inadequacies by using MVMS can provide health benefits. IMPLICATIONS: This consensus panel has described key issues related to the use of MVMS among individuals at risk of or presenting with inadequacies in micronutrient intake or biomarker status

Food overconsumption in healthy adults triggers early and sustained increases in serum branched-chain amino acids and changes in cysteine linked to fat gain

Background: Plasma concentrations of branched-chain amino acids (BCAAs) and the sulfur-containing amino acid cysteine are associated with obesity and insulin resistance. BCAAs predict future diabetes. Objective: We investigated amino acid changes during food overconsumption. Methods: Forty healthy men and women with a body mass index (mean ± SEM) of 25.6 ± 0.6 were overfed by 1250 kcal/d for 28 d, increasing consumption of all macronutrients. Insulin sensitivity and body composition were assessed at baseline (day 0) and day 28. Fasting serum amino acids were measured at days 0, 3, and 28. Linear mixed-effects models evaluated the effect of time in the total group and separately in those with low and high body fat gain (below compared with at or above median fat gain, 1.95 kg). At days 0 and 28, insulin-induced suppression of serum amino acids during a hyperinsulinemic-euglycemic clamp test and, in a subset (n = 20), adipose tissue mRNA expression of selected amino acid metabolizing enzymes were assessed. Results: Weight increased by 2.8 kg. High fat gainers gained 2.6 kg fat mass compared with 1.1 kg in low fat gainers. Valine and isoleucine increased at day 3 (+17% and +22%, respectively; P ≤ 0.002) and remained elevated at day 28, despite a decline in valine (P = 0.019) from day 3 values. Methionine, cystathionine, and taurine were unaffected. Serum total cysteine (tCys) transiently increased at day 3 (+11%; P = 0.022) only in high fat gainers (P-interaction = 0.043), in whom the cysteine catabolic enzyme cysteine dioxygenase (CDO1) was induced (+26%; P = 0.025) in adipose tissue (P-interaction = 0.045). Overconsumption did not alter adipose tissue mRNA expression of the BCAA-metabolizing enzymes branched-chain keto acid dehydrogenase E1α polypeptide (BCKDHA) or branched-chain amino transferase 1 (BCAT1). In the total population at day 0, insulin infusion decreased all serum amino acids (-11% to -47%; P < 0.01), except for homocysteine and tCys, which were unchanged, and glutathione, which was increased by 54%. At day 28, insulin increased tCys (+8%), and the insulin-induced suppression of taurine and phenylalanine observed at day 0, but not that of BCAAs, was significantly impaired. Conclusions: These findings highlight the role of nutrient oversupply in increasing fasting BCAA concentrations in healthy adults. The link between cysteine availability, CDO1 expression, and fat gain deserves investigation.Amany K Elshorbagy, Dorit Samocha-Bonet, Fredrik Jernerén, Cheryl Turner, Helga Refsum and Leonie K Heilbron