Nuno Mendonça

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

Significance This study provides insights into the physiological role of Sel1L, an adaptor protein for the ubiquitin ligase Hrd1 in endoplasmic reticulum-associated degradation (ERAD). Using both animal and cell models, this study provides unequivocal evidence for an indispensable role of Sel1L in Hrd1 stabilization, mammalian ERAD, endoplasmic reticulum homeostasis, protein translation, and cellular and organismal survival. Moreover, generation of inducible knockout mouse and cell models deficient in both Sel1L and Hrd1 provides an unprecedented opportunity to elucidate the functional importance of this key branch of ERAD in vivo and to identify its physiological substrates. Suppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L’s physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is indispensable for Hrd1 stability, ER homeostasis, and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 wk with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation, and promotes cell death. Serendipitously, using a biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of the mammalian Hrd1 ERAD complex and ER homeostasis, which is essential for protein translation, pancreatic function, and cellular and organismal survival.

Macronutrient intake and food sources in the very old: analysis of the Newcastle 85+ Study.

Food and nutrient intake data are scarce in very old adults (85 years and older) - one of the fastest growing age segments of Western societies, including the UK. Our primary objective was to assess energy and macronutrient intakes and respective food sources in 793 85-year-olds (302 men and 491 women) living in North-East England and participating in the Newcastle 85+ cohort Study. Dietary information was collected using a repeated multiple-pass recall (2×24 h recalls). Energy, macronutrient and NSP intakes were estimated, and the contribution (%) of food groups to nutrient intake was calculated. The median energy intake was 6·65 (interquartile ranges (IQR) 5·49-8·16) MJ/d - 46·8 % was from carbohydrates, 36·8 % from fats and 15·7 % from proteins. NSP intake was 10·2 g/d (IQR 7·3-13·7). NSP intake was higher in non-institutionalised, more educated, from higher social class and more physically active 85-year-olds. Cereals and cereal products were the top contributors to intakes of energy and most macronutrients (carbohydrates, non-milk extrinsic sugars, NSP and fat), followed by meat and meat products. The median intakes of energy and NSP were much lower than the estimated average requirement for energy (9·6 MJ/d for men and 7·7 MJ/d for women) and the dietary reference value (DRV) for NSP (≥18 g/d). The median SFA intake was higher than the DRV (≤11 % of dietary energy). This study highlights the paucity of data on dietary intake and the uncertainties about DRV for this age group.

Intakes of Folate and Vitamin B12 and Biomarkers of Status in the Very Old: The Newcastle 85+ Study

Very old adults are at increased risk of folate and vitamin B12 deficiencies due to reduced food intake and gastrointestinal absorption. The main aim was to determine the association between folate and vitamin B12 intake from total diets and food groups, and status. Folate or vitamin B12 intakes (2 × 24 h multiple pass recalls) and red blood cell (RBC) folate or plasma vitamin B12 (chemiluminescence immunoassays) concentrations were available at baseline for 731 participants aged 85 from the Newcastle 85+ Study (North-East England). Generalized additive and binary logistic models estimated the associations between folate and vitamin B12 intakes from total diets and food groups, and RBC folate and plasma B12. Folate intake from total diets and cereal and cereal products was strongly associated with RBC folate (p < 0.001). Total vitamin B12 intake was weakly associated with plasma vitamin B12 (p = 0.054) but those with higher intakes from total diets or meat and meat products were less likely to have deficient status. Women homozygous for the FUT2 G allele had higher concentrations of plasma vitamin B12. Cereals and cereal products are a very important source of folate in the very old. Higher intakes of folate and vitamin B12 lower the risk of “inadequate” status.

Nutrition in the Very Old

The population of older adults aged 85 years and over (the very old) is growing rapidly in many societies because of increases in life expectancy and reduced mortality at older ages. In 2016, 27.3 million very old adults were living in the European Union, and in the UK, 2.4% of the population (1.6 million) were aged 85 and over. Very old age is associated with increased risks of malnutrition, multimorbidity, and disability. Diet (nutrition) is a modifiable risk factor for multiple age-related conditions, including sarcopenia and functional decline. Dietary characteristics and nutrient intakes of the very old have been investigated in several European studies of ageing to better understand their nutritional requirements, which may differ from those in the young-old. However, there is a major gap in regard to evidence for the role of dietary patterns, protein, vitamin D and other nutrients for the maintenance of physical and cognitive functioning in later life. The Newcastle 85+ Study, UK and the Life and Living in Advanced Age, New Zealand are unique studies involving single birth cohorts which aim to assess health trajectories in very old adults and their biological, social and environmental influences, including nutrition. In this review, we have updated the latest findings in nutritional epidemiology with results from these studies, concentrating on the diet–physical functioning relationship.

One-Carbon Metabolism Biomarkers and Cognitive Decline in the Very Old: The Newcastle 85+ Study

Objectives Although the biological rationale for the association between folate, vitamin B12, and homocysteine with cognitive function seems plausible, conflicting results have been reported. This study aimed to determine the associations between 1-carbon (1-C) metabolism biomarkers (folate, vitamin B12, and homocysteine), and cognitive impairment at baseline and the rate of cognitive decline over 5 years in the very old. Design The Newcastle 85+ Study was a prospective longitudinal study of people 85 years old and followed over 5 years in Northeast England. Setting Community-dwelling and institutionalized. Participants The analytical sample included 765 very old participants with 1-C metabolism biomarkers and cognitive measures. Measurements Global cognition was measured by the Standardized Mini-Mental State Examination (SMMSE) at baseline, and at 3 and 5 years of follow-up and, attention-specific cognition with the Cognitive Drug Research (CDR) System at baseline, and at 1.5 and 3.0 years of follow-up. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were determined by immunoassay. Linear mixed models were used to estimate the associations between quartiles of 1-C metabolism biomarkers and cognition over 3 (CDR) and 5 years (SMMSE). Results Compared with participants in the lowest quartile of RBC folate concentrations (<612 nmol/L), those in the highest quartile of RBC folate concentrations (>1280 nmol/L) had 1 more point on the SMMSE at baseline (β = +1.02, SE = 0.43, P = .02). Those in quartile 4 of tHcy (>21.4 μmol/L) had 1 point less in the SMMSE at baseline than those in the lowest quartile (<13.5 μmol/L) (β = −1.05, SE = 0.46, P = .02). Plasma vitamin B12 was not predictive of global or attention-specific cognition at baseline and at follow-up. None of the 1-C metabolism biomarkers except tHcy was associated with the rate of decline in attention scores over 3 years. Conclusion RBC folate and tHcy, but not plasma vitamin B12, were associated with better global cognition in the very old at baseline but were not predictive of rate of decline over 5 years.

Low protein intake, muscle strength and physical performance in the very old: the Newcastle 85+ Study

Summary Background Low protein intake has been linked to reduced muscle strength and physical performance in older adults but little is known about how it may affect muscle health and subsequent functional decline in the very old (aged 85+), who are at enhanced risk of malnutrition and loss of muscle mass and strength. Aims To investigate the associations between low protein intake, defined as the intake of <1 g protein/kg adjusted body weight/day (<1 g/kg aBW/d) and decline in muscle strength and physical performance in the very old. Methods The analytic sample consisted of 722 community-dwelling participants (60% women) from the Newcastle 85+ Study who had protein intake at baseline. Participants were followed-up for change in grip strength (GS) and Timed Up-and-Go (TUG) test over 5 years (baseline, 18, 36, and 60 months). We used mixed models to determine the effects of low protein intake on muscle strength and physical performance in all participants, and also stratified by sex. Results At baseline, 390 (54%) participants (261 women, p < 0.001) reported low protein intake, and these differed from participants with good intake (≥1 g/kg aBW/d) on several measures of health and function. In the model adjusted for protein intake, consuming <1 g/kg aBW/d of protein was associated with a 1.62 kg lower GS (p = 0.008) in all participants, and especially in women (β (SE) = −0.83 (0.41), p = 0.05) after adjusting for key baseline covariates (anthropometry, multimorbidity, arthritis in hands, cognitive status and physical activity). The rate of decline in GS over 5 years was not associated with protein intake. Women, but not men, with low protein intake had worse baseline TUG (β (SE) = 0.04 (0.02), p = 0.03) compared with those with good protein intake in the fully adjusted model, but the rate of decline in TUG was not affected by daily protein status. Conclusions Intake of <1 g protein/kg aBW/d may negatively affect muscle strength and physical performance in late life, especially in older women, independently of important covariates. More research is needed in the very old to define the optimal protein intake for maintenance of muscle health and function.

What do we know about the nutritional status of the very old? Insights from three cohorts of advanced age from the UK and New Zealand

Very old people (referred to as those aged 85 years and over) are the fastest growing age segment of many Western societies owing to the steady rise of life expectancy and decrease in later life mortality. In the UK, there are now more than 1·5 million very old people (2·5 % of total population) and the number is projected to rise to 3·3 million or 5 % over the next 20 years. Reduced mobility and independence, financial constraints, higher rates of hospitalisation, chronic diseases and disabilities, changes in body composition, taste perception, digestion and absorption of food all potentially influence either nutrient intake or needs at this stage of life. The nutritional needs of the very old have been identified as a research priority by the British Nutrition Foundations Task Force report, Healthy Ageing: The Role of Nutrition and Lifestyle. However, very little is known about the dietary habits and nutritional status of the very old. The Newcastle 85+ study, a cohort of more than 1000 85-year olds from the North East of England and the Life and Living in Advanced Age study (New Zealand), a bicultural cohort study of advanced ageing of more than 900 participants from the Bay of Plenty and Rotorua regions of New Zealand are two unique cohort studies of ageing, which aim to assess the spectrum of health in the very old as well as examine the associations of health trajectories and outcomes with biological, clinical and social factors as each cohort ages. The nutrition domain included in both studies will help to fill the evidence gap by identifying eating patterns, and measures of nutritional status associated with better, or worse, health and wellbeing. This review will explore some of this ongoing work.