Carmen Martin-Ruiz

Objective Telomere length is an indicator of cellular ageing, with patients with severe mental disorders tending to have shorter telomeres than the general population. Coffee consumption may reduce oxidative stress, helping prevent biological ageing processes like telomeric shortening. The British National Health Service (NHS) advises limiting caffeine intake to 400 mg/day (4 cups of coffee). However, the role of coffee consumption and telomere length in psychiatric populations remains unclear. Methods This cross-sectional study included 436 participants (schizophrenia spectrum [n = 259] and affective disorders [n = 177]) from the Norwegian TOP study. Leukocyte telomere length (TL) was measured via blood using quantitative real-time Polymerase Chain Reaction (qPCR). Patients self-reported coffee consumption, quantified as cups per day (no coffee, 1-2, 3-4, 5+). Results An inverted J-shape was found between TL and coffee intake, peaking at 3-4 cups/day before declining after 4 cups (F = 3.29, p = .02). The largest TL difference was between those drinking the highest recommended dose and non-drinkers (F = 6.13, p = .01). Coffee drinkers within the recommended dose had longer TL, comparable to five years younger biological age, adjusted for confounders. Conclusion Coffee intake within the recommended dose is linked to longer telomeres in severe mental disorders, comparable to five years younger biological age. What is already known on this topic? Patients with severe mental disorders tend to have shorter telomere lengths, an indicator of accelerated cellular ageing. Coffee consumption has been noted to possess health benefits, which may help prevent telomere shortening. The relationship between coffee consumption and telomere length in psychiatric populations remains unclear. What this study adds? Coffee consumption up to 3-4 cups per day, but not exceeding this amount, was associated with longer telomeres in patients with severe mental disorders. Patients consuming up to 4 cups of coffee per day had telomere lengths comparable to a biological age five years younger than non-coffee drinkers. How this study might affect research, practice or policy? Our study suggests the importance of further research investigating the role of coffee consumption in biological ageing.

The demographics of Western populations are changing, with an increase in the proportion of older adults. There is evidence to suggest that genetic factors may influence the aging process: studying these may lead to interventions to help individuals live a longer and healthier life. Evidence from several groups indicates that Klotho (KL), a gene encoding a single-pass transmembrane protein that acts as an FGF23 co-receptor, may be associated with longevity and healthy aging. We aimed to explore this area further by comparing the genotype counts in 642 long-lived individuals from the Newcastle 85+ Study with 18 295 middle-aged Newcastle-based controls from the UK Biobank to test whether variants at the KL gene locus are over- or under-represented in older individuals. If KL is associated with longevity, then we would expect the genotype counts to differ between the 2 cohorts. We found that the rs2283368 CC genotype and the rs9536338 C allele, but not the KL-VS haplotype, were associated with reaching very old age. However, these associations did not replicate in the remainder of the UK Biobank cohort. Thus, our results do not reliably support the role of KL as a longevity factor.

(1) Introduction: vitamin D may maintain the telomere length, either directly or via the inflammation effect and/or modulating the rate of cell proliferation. Whilst results from cross-sectional studies investigating the association between 25(OH)D concentration and telomere length have been mixed, there is a dearth of data from prospective studies which have assessed these associations. This study aimed to examine the association between 25(OH)D concentration in plasma and telomere length in blood cells in very-old adults (≥85 years old) at baseline, 18 months and 36 months by controlling for related lifestyle factors. (2) Methodology: our prospective cohort study comprised 775 participants from the Newcastle 85+ Study who had 25(OH)D measurements at baseline. Plasma 25(OH)D was stratified as 50 nmol/L (high). Peripheral blood mononuclear cell telomere length was measured by quantitative real-time polymerase chain reaction at baseline, 18 and 36 months from baseline. (3) Results: a positive significant association was found between 25(OH)D concentration and telomere length amongst very-old participants at baseline (95% CI = 12.0–110.3, B = 61.2 ± 5.0, p = 0.015). This association was negative at 18 months (95% CI = −59.9–−7.5, B = −33.7 ± 13.3, p = 0.012) but was non-significant at 36 months. (4) Conclusion: Circulating 25(OH)D concentration shows inconsistent relationships with telomere length over time in very-old (85+ year old) adults.

Aims: Tay–Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay–Sachs and Sandhoff diseases. Results: Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. Innovation: Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. Conclusions: We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22613-2

Background: Low vitamin D status is common in very old adults which may have adverse consequences for muscle function, a major predictor of disability. Aims: To explore the association between 25-hydroxyvitamin D [25(OH)D] concentrations and disability trajectories in very old adults and to determine whether there is an ‘adequate’ 25(OH)D concentration which might protect against a faster disability trajectory. Methodology: A total of 775 participants from the Newcastle 85+ Study for who 25(OH)D concentration at baseline was available. Serum 25(OH)D concentrations of 50 nmol/L were used as cut-offs to define low, moderate and high vitamin D status, respectively. Disability was defined as difficulty in performing 17 activities of daily living, at baseline, after 18, 36 and 60 months. Results: A three-trajectory model was derived (low-to-mild, mild-to-moderate and moderate-to-severe). In partially adjusted models, participants with 25(OH)D concentrations Conclusions: Vitamin D status does not appear to influence the trajectories of disability in very old adults.

Objectives: We conducted a prospective longitudinal study of plasma cytokines during the Mild Cognitive Impairment (MCI) stage of Lewy body disease and Alzheimer's disease, hypothesizing that cytokine levels would decrease over time and that this would be correlated with decline in cognition.Methods: Older (≥60) people with MCI were recruited from memory services in healthcare trusts in North East England, UK. MCI was diagnosed as due to Alzheimer's disease (MCI‐AD) or Lewy body disease (MCI‐LB). Baseline and repeat annual clinical and cognitive assessments were undertaken and plasma samples were obtained at the same time. Cytokine assays were performed on all samples using the Meso Scale Discovery V‐Plex Plus Proinflammatory Panel 1, which included IFNγ, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13 and TNFα.Results: Fifty‐six patients (21 MCI‐AD, 35 MCI‐LB) completed prospective evaluations and provided samples up to 3 years after baseline. Six cytokines (IFNγ, IL‐1β, IL‐2, IL‐4, IL‐6 and IL‐10) showed highly significant (P < .002) decreases over time. AD and LB did not differ in rate of decrease nor were there any effects related to age or general morbidity. Decrease in five of these cytokines (IFNγ, IL‐1β, IL‐2, IL‐4, and IL‐10) was highly correlated with decrease in cognition (P < .003).Conclusions: Peripheral inflammation decreased in both disease groups during MCI suggesting this may be a therapeutic window for future anti‐inflammatory agents.

Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27−CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51–0.86). In addition, CD27−CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.

Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care. Older patients undergoing invasive management for NSTEACS were recruited to the ICON-1 biomarker study (NCT01933581). Peripheral blood mononuclear cells (PBMC) were recovered on 153 patients. DNA was isolated and mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio (T/S ratio), and a telomere repeat amplification assay was used to assess TA during index presentation with NSTEACS. Primary clinical outcomes consisted of death, myocardial infarction (MI), unplanned revascularisation, stroke and significant bleeding recorded at 1 year. TL and TA were divided into tertile groups for analysis. Cox proportional hazards regression was performed. Ordinal regression was performed to evaluate the relationship between TL and TA and traditional cardiovascular risk factors at baseline. 298 patients were recruited in the ICON-1 study of which 153 had PBMC recovered. The mean age was 81.0 ± 4.0 years (64% male). Mean telomere length T/S ratio was 0.47 ± 0.25 and mean TA was 1.52 ± 0.61 units. The primary composite outcome occurred in 44 (28.8%) patients. There was no association between short TL or low TA and incidence of the primary composite outcome (Hazard Ratio [HR] 1.50, 95% Confidence Interval [CI] 0.68–3.34, p = 0.32 and HR 1.33, 95% CI 0.52–3.36, p = 0.51 respectively). TL and TA are not found to be associated with the incidence of adverse outcomes in older patients presenting with NSTEACS undergoing invasive care. URL: https://www.clinicaltrials.gov Unique identifier: NCT01933581