Helga Refsum

University of Oslo · Department of Nutrition

Vitamin B12 deficiency is usually simple to diagnose. However, our patient demonstrates that in difficult cases, the ordinary clinician may need a transdisciplinary approach. The finding of a double haploinsufficiency as a possible cause of vitamin B12 deficiency in our patient, illustrates the usefulness of performing large panel clinical exome se...

Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the relationship between tHcy and epigenetic age in older adults with mild cognitive impairment from the VITACOG study. Epigenetic age and rate of aging (ROA) were assessed using various epigeneti...

Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6–7 individuals per dose...

Background In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue. Aim To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and ob...

Background Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in humans with overweight or obesity. Meth...

Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals, but in humans, SAAR has not been investigated in translational clinical trials. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensiv...

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels...

Background and objectives Growing evidence links air pollution with dementia risk, but the biological mechanisms are largely unknown. We investigated the role played by homocysteine (tHcy) and methionine in this association and explored whether this could be explained by cardiovascular diseases (CVDs). Methods Data were extracted from the ongoing...

Aim: To investigate whether mesna-sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. Methods: C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body compositi...

Background: Plasma sulfur amino acids (SAAs, i.e., methionine, total cysteine (tCys), total homocysteine (tHcy), cystathionine, total glutathione (tGSH) and taurine) are potential risk factors of obesity and cardiometabolic disorders. However, except for plasma tHcy, little is known about how dietary intake modifies the concentrations of plasma SA...

People with high plasma total cysteine (tCys) have higher fat mass and higher concentrations of the atherogenic apolipo-protein B (apoB). The disulfide form, cystine, enhanced human adipogenesis and correlated with total fat mass in a Middle-Eastern cohort. In 35 European adults with overweight (88.6% women) and with dual-X-ray absorptiometry measu...

Vitamin B 12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B 12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shif...

Decreasing the dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur a...

Purpose Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. Methods We examined cross-sectional subsets from the CODAM cohort (n = 470,...

Aim Plasma total cysteine (tCys) is associated with fat mass and insulin resistance, whereas taurine is inversely related to diabetes risk. We investigated the association of serum sulfur amino acids (SAAs) and related amino acids (AAs) with incident diabetes. Methods Serum AAs were measured at baseline in 2997 subjects aged ≥ 65 years. Diabetes w...

Amino acids (AAs) and dietary inflammatory potential play essential roles in muscle health. We examined the associations of dietary inflammatory index (DII) of habitual diet with serum AA profile, and ascertained if the associations between DII and muscle outcomes were mediated by serum AAs using general linear models, in 2994 older Chinese communi...

Decreasing dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), i.e., sulfur amino ac...

Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, have been shifting towards a higher consumption of plant-based food. There is growing evidence that vitamin B12 deficiency is associated with incr...

Background and Objectives A randomized placebo-controlled trial found a significant negative interaction between aspirin and B vitamins in cognitive functioning in older people with mild cognitive impairment (MCI). To validate this finding, we pooled data of this trial with that of a similar B-vitamin trial (VITACOG) to examine the effectiveness of...

Background Higher serum homocysteine is associated with cognitive decline in older people. But homocysteine-lowering trials including folic acid (FA) show inconsistent results on cognitive decline. The reduction of FA to dihydrofolate by dihydrofolate reductase (DHFR) is slow in humans. Objective We examined the effects of the DHFR 19-bp deletion/...

Plasma cysteine is associated with human obesity, but it is unknown whether this is mediated by reduced, disulfide (cystine and mixed-disulfides) or protein-bound (bCys) fractions. We investigated which cysteine fractions are associated with adiposity in vivo and if a relevant fraction influences human adipogenesis in vitro. In the current study, p...

Background: Metals, silicon, and homocysteine are linked to Alzheimer’s disease. B vitamin therapy lowers homocysteine and slows brain atrophy and cognitive decline in mild cognitive impairment (MCI). Objective: Examine metals and silicon as predictors of cognition/brain atrophy in MCI, their interaction with homocysteine and cysteine, and how B vi...

Objective To study the timescale of plasma fatty acid changes during transition to an exclusively plant- and fish-based diet in healthy humans and determine whether there are associated alterations in arachidonic acid (ARA)-derived inflammatory mediators, estimated stearoyl coenzyme A desaturase (SCD) activity and blood pressure. Methods In pursui...

Background: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer's disease. Objective: We tested...

Background Dietary sulfur amino acid (SAA) restriction is an established animal model for increasing lifespan and improving metabolic health. Data from human studies are limited. In the study outlined in this protocol, we will evaluate if dietary SAA restriction can reduce body weight and improve resting energy expenditure (REE) and parameters rela...

Introduction: Elevated homocysteine (Hcy) and related metabolites accelerate Alzheimer's disease. Hcy-lowering B vitamins slow brain atrophy/cognitive decline in mild cognitive impairment (MCI). Modification with Hcy-thiolactone generates auto-immunogenic N-Hcy-protein. We tested a hypothesis that anti-N-Hcy-protein autoantibodies predict cognitio...

We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine. The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age‐related conditions are also associat...

Objective In this 7-day pilot study we randomized healthy, normal-weight men and women to either a dietary intervention with methionine and cysteine restriction enriched in PUFA (Met/Cys low + PUFA, n = 7) or with high contents of methionine, cysteine and SFA (Met/Cys high + SFA, n = 7). The objective was to describe the short-term responses in ora...

Aims/hypothesis Obesity and insulin resistance may be associated with elevated plasma concentration of branched-chain amino acids (BCAAs) and impaired BCAA metabolism. However, it is unknown whether the insulin-sensitising effect of long-term exercise can be explained by concomitant change in BCAAs and their metabolism. Methods We included 26 sede...

Exercise influences epigenetic regulation of gene expression by modulating tissue methyltransferase activity, whereas effects on methyltransferases with other crucial biological functions have not been elucidated. We performed RNA sequencing of skeletal muscle (SkM) and white adipose tissue (WAT) obtained from 26 sedentary men undergoing acute exer...

Background and Purpose B-vitamin supplements lower circulating concentrations of homocysteine and may reduce stroke incidence. Homocysteine concentrations are associated with the incidence of stroke but other sulfur-containing compounds in the related metabolic pathway have not yet been investigated for an association with incident cerebrovascular...

Plasma and tissue sulfur amino acid (SAA) availability are crucial for intracellular methylation reactions and cellular antioxidant defense, which are important processes during exercise and in recovery. In this randomized, controlled crossover trial among eight elite male cyclists, we explored the effect of exhaustive exercise and post-exercise su...

Background Impairment of methylation status and raised values of homocysteine and cysteine may be modifiable risk factors for cognitive decline. We aimed to investigate the association of vitamin B12, folate, and sulfur amino‐acids with cognitive decline in a large sample of community dwelling older adults. Method From the Swedish National Study o...

Plasma and tissue sulfur amino acid (SAA) availability are crucial for intracellular methylation reactions and cellular antioxidant defense, which are important processes during exercise and in recovery. In this randomized, controlled crossover trial among eight elite male cyclists, we explored the effect of exhaustive exercise and post-exercise su...

Objective In this 7-day pilot study we randomized healthy, normal-weight men and women to either a dietary intervention with methionine and cysteine restriction enriched in PUFA (Met/Cys low +PUFA, n = 7) or with high contents of methionine, cysteine and SFA (Met/Cys high +SFA, n = 7). The objective was to describe the short-term responses in the o...

Purpose We hypothesized that biomarkers and dietary factors related to cardiovascular disease risk were associated with serum retinol and evaluated these potential associations in patients with suspected coronary artery disease (CAD). Methods We used cross-sectional data from 4116 patients hospitalised for suspected CAD. Dietary data were obtained...

Objective The sulfur amino acid (SAA) cysteine is positively related, whereas polyunsaturated fatty acids (PUFAs) are inversely related to activity of the lipogenic enzyme stearoyl-CoA desaturase (SCD). High SCD activity promotes obesity in animals, and plasma activity indices positively associates with fat mass in humans. SCD may thus be a target...

Importance Strong evidence links high total serum homocysteine (tHcy) and low methionine (Met) levels with higher risk of ischemic disease, but other cardiovascular (CV) diseases may also be associated with their pleiotropic effects. Objectives To investigate the association of serum concentrations of tHcy and Met with the rate of CV multimorbidit...

Background Dietary restriction of methionine and cysteine is a well-described model that improves metabolic health in rodents. To investigate the translational potential in humans, we evaluated the effects of dietary methionine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profile, serum fibroblast growth...

Evidence from human, animal and cellular studies suggests that high plasma total cysteine (tCys) is causally linked to human obesity, but determinants of population tCys variability are unknown. We hypothesized that tCys elevation in obesity may be mediated by an altered tCys response to intake of its precursor, methionine. We investigated whether...

Background Human milk vitamin B12 (B12) concentrations depend on maternal status and intake; only few data are available in high-income countries. Objective We assessed human milk B12 concentrations during the first 6 months postpartum in Norwegian women and its association with maternal dietary B12 intake and maternal urinary methylmalonic acid (...

Background Weight regain after bariatric surgery often starts after 1–2 y, but studies evaluating strategies to prevent weight regain are lacking. The aim of this intervention was to evaluate the efficacy of a 2-y-group-based lifestyle intervention starting approximately 2 y after Roux-en-Y gastric bypass (RYGB) compared with usual care on weight r...

With aging, poor bone mineral density (BMD) and accelerated decrease in BMD are strong risk factors for fracture. Reports of the associations of dietary protein intake with bone strength are inconsistent, possibly owing to differences in protein sources and amino acid (AA) composition. We examined the associations of serum AA with 4-year hip BMD lo...

Importance Impairment of methylation status (ie, methionine to homocysteine ratio) may be a modifiable risk factor for structural brain changes and incident dementia. Objective To investigate the association of serum markers of methylation status and sulfur amino acids with risk of incident dementia, Alzheimer disease (AD), and the rate of total b...

To the Editor In a recent Viewpoint,¹ Dr Hellmuth and colleagues stated that “no known dietary supplement prevents cognitive decline or dementia.” We agree that there is no evidence that dietary supplements can prevent dementia, but that is partly because there have been few well-designed trials to test this idea. In trials of nutrients, a basic re...

We aimed to investigate the association between baseline levels of total serum glutathione (tGSH) and rate of chronic disease accumulation over time. The study population (n=2596) was derived from a population-based longitudinal study on ≥60-year-olds living in Stockholm. Participants were clinically assessed at baseline, three- and six-year follow...

Background: Trials of supplementation with omega-3 fatty acids (ω3-FAs) in patients with mild cognitive impairment or Alzheimer's disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and ω3-FAs in relation to brain atrophy and cognitive decline. Objective: We investiga...

Plasma sulphur-containing amino acids and related metabolites are associated with insulin sensitivity, although the mechanisms are unclear. We examined the effect of exercise on this relationship. Dysglycemic (n = 13) and normoglycemic (n = 13) men underwent 45 min cycling before and after 12 weeks exercise intervention. We performed hyperinsulinem...

This report on vitamin B-12 (B12) is part of the Biomarkers of Nutrition for Development (BOND) Project, which provides state-of-the art information and advice on the selection, use, and interpretation of biomarkers of nutrient exposure, status, and function. As with the other 5 reports in this series, which focused on iodine, folate, zinc, iron, a...

Dietary and plasma total cysteine (tCys) have been associated with adiposity, possibly through interaction with stearoyl-CoA desaturase (SCD), which is an enzyme that is involved in fatty acid and energy metabolism. We evaluated the effect of a dietary intervention with low cysteine and methionine and high polyunsaturated fatty acids (PUFAs) on pla...

PurposePlasma concentrations of several amino acids (AAs) are positively correlated with obesity. The aim of this study was to examine if selected plasma AAs are associated with weight regain from 2 to 4 years after Roux-en-Y gastric bypass (RYGB). Methods In a prospective study with 165 patients, we examined the relationship between plasma aromati...

Introduction: Tryptophan, its downstream metabolites in the kynurenine pathway and neopterin have been associated with inflammation and dementia. We aimed to study the associations between plasma levels of these metabolites and cognitive function in community-dwelling, older adults. Methods: This cross-sectional study included 2174 participants...

Background: The acute effects of high-intensity endurance exercise involve altered amino acid metabolism, oxidative stress and alterations in DNA methylation. Sulfur-containing amino acids (SAAs) including methionine and cysteine, are essential for protein integrity, antioxidant capacity and methylation reactions. Maintenance of plasma concentratio...

Background Plasma total homocysteine (tHcy) has been implicated in the development of cardiovascular disease, but the mechanisms remain unclear. Vitamin A (Vit-A) is involved in homocysteine metabolism and we therefore explored the potential interaction between plasma tHcy and serum Vit-A in relation to incident acute myocardial infarction. Method...

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 ± S...

Studies suggest a role for BCAA in decreased IS and type 2 diabetes. Exercise improves IS, but the relationship with BCAA metabolism is unclear. We studied the effects of a 12 w exercise intervention on IS, liver fat and BCAA metabolism in prediabetic (n=13) and normoglycemic men (n=13). We estimated IS by hyperinsulinemic-euglycemic clamp, transcr...

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocys...

The biosynthesis of B12, involving up to 30 different enzyme-mediated steps, only occurs in bacteria. Thus, most eukaryotes require an external source of B12, and yet the vitamin appears to have only two functions in eukaryotes: as a cofactor for the enzymes methionine synthase and methylmalonylCoA mutase. These two functions are crucial for normal...

Aims: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Methods: Cross-sectional analyses were...

A 19-year-old male with 22q11.2 deletion syndrome presented with a 4-year history of cognitive decline and symptoms suggestive of atypical psychosis. Potential for elevated homocysteine and NMDA-receptor antibodies in the pathogenesis of his symptoms was investigated. He had elevated blood homocysteine level (18.7 μmol/l), low-normal vitamin B12 an...

Objective We compared Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) and body mass index (BMI) as correlates of body fat percent (BF%) and the association with future risk of cardiovascular disease (CVD) and type 2 diabetes in a Caucasian population. Methods We used data from 6796 individuals (born 1925–27 and 1950–52) from the...

Recruitment in the Hordaland Homocysteine Study and Hordaland Health Study. Notes: The figure shows the numbers of individuals at each stage of the study, and number of individuals used in the analyses in the present study. Abbreviations: CVD, cardiovascular disease; DXA, dual-energy X-ray absorptiometry; HHS, Hordaland Homocysteine Study; HUSK, Ho...