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Late-life depression is a prevalent and debilitating disorder. It differs significantly from depression in younger adults and often co-occurs with cognitive decline and increased physical frailty. This narrative review explores the role of accelerated biological ageing in late-life depression. We examine evidence linking three interconnected processes, namely telomere attrition, mitochondrial dysfunction and cellular senescence, to the pathophysiology of late-life depression. Excessive attrition of telomeres may serve as a biomarker of accumulated stress and cellular ageing. Mitochondrial dysfunction not only reduces energy production but also promotes oxidative stress and inflammation that increase neuroinflammatory pathways and synaptic loss. Increased cellular senescence further induces senescence-associated secretory phenotype factors that drive chronic inflammation and neuronal loss. Together, these processes create a cycle of cellular stress, persistent inflammation and damage to brain circuits involved in late-life depression. We additionally highlight potential limitations in current findings and propose a roadmap for future research to better elucidate the mechanistic dysfunction of late-life depression. These include the need for evaluation in long-term prospective cohort studies, improved tools to better correlate blood-based markers with changes in disease-relevant brain tissues and regions, and trials that test treatment and lifestyle modifications that are targeted at ageing biomarkers.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci ( P  < 5 × 10 −8 ). Several of these contain candidate genes ( TINF2 , PARP1 , TERF1 , ATM and POT1 ) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6 , NKX2-3 and TYMS . We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804–0.906), P  = 1.88 × 10 −7 ] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections ( P  = 7.44 × 10 −4 ) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence. Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

Although humans contain the same genes, the sequence within these DNA sites can vary from person to person. These small variations, also known as genetic variants, can increase the risk of developing certain diseases. While each variant will only have a weak effect, if multiple variations are present the odds of developing the disease becomes significantly higher. To determine which variants are linked to a disease, researchers carry out genome-wide association studies which involve analyzing the genomes of individuals with and without the condition and comparing their genetic codes. This data is then used to calculate how different combinations of variants impact a person’s chance of getting the disease, also known as a polygenic risk score . Currently, most genome-wide association studies only incorporate genetic data from people with European ancestry. Consequently, polygenic risk scores performed using this information may not accurately predict the risk of developing the disease for individuals with other ethnicities, such as people with Asian ancestry. Here, Ho et al. evaluated how well previously calculated polygenic risk scores for the four most common cancers (breast, colorectal, prostate and lung) worked on individuals of East Asian descent. The scores were tested on a dataset containing the genetic sequence, medical history, diet and activity levels of over 21,000 people living in Singapore in the 1990s. Ho et al. found that the polygenic risk scores for breast, prostate and colorectal cancer were able to predict disease risk. However, the score for lung cancer did not perform as well. The polygenic risk score for breast cancer was the most accurate, and was able to stratify individuals into distinct risk bands at an earlier age than other scores. These findings shed light on which existing polygenic risk scores will be effective at assessing cancer risk in individuals with East Asian ancestry. Indeed, Ho et al. have already incorporated the polygenic risk score for breast cancer into a pilot study screening individuals in a comparable population in Singapore. However, the polygenic risk scores tested still performed better on individuals with European ancestry, highlighting the need to address the lack of Asian representation in genome-wide association studies.

Aging is an inevitable biological process that contributes to the onset of age-related diseases, often as a result of mitochondrial dysfunction. Understanding the mechanisms behind aging is crucial for developing therapeutic interventions. This study investigates the effects of curcumin on postmitotic cellular lifespan (PoMiCL) during chronological aging in yeast, a widely used model for human postmitotic cellular aging. Our findings reveal that curcumin significantly prolongs the PoMiCL of wildtype yeast cells, with the most pronounced effects observed at lower concentrations, indicating a hormetic response. Importantly, curcumin also extends the lifespan of postmitotic cells with mitochondrial deficiencies, although the hormetic effect is absent in these defective cells. Mechanistically, curcumin inhibits TORC1 activity, enhances ATP levels, and induces oxidative stress. These results suggest that curcumin has the potential to modulate aging and offer therapeutic insights into age-related diseases, highlighting the importance of context in its effects.

Background Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established. Methods A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling. Results Higher n6:n3 ratio was significantly associated with shorter LTL ( p  = 0.018) and increased CAD risk ( p  = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ( p  < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold ( p  < 5 ×  10 − 8 ). Mediation analysis showed that PUFA and LTL affected CAD risk independently. Conclusions Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

BackgroundA breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants.MethodsGenome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p < 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium.ResultsBreast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p < 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time.ConclusionsConsistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer.

FTO Variants Are Associated With Obesity in the Chinese and Malay Populations in Singapore Jonathan T. Tan 1 , Rajkumar Dorajoo 2 , Mark Seielstad 2 , Xue Ling Sim 1 , Rick Twee-Hee Ong 2 , Kee Seng Chia 1 , Tien Yin Wong 3 4 , Seang Mei Saw 3 5 , Suok Kai Chew 6 , Tin Aung 3 and E-Shyong Tai 1 7 1 Center for Molecular Epidemiology, National University of Singapore, Singapore, Singapore 2 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore 3 Singapore Eye Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 4 Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia 5 Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 6 Ministry of Health, Singapore, Singapore 7 Department of Endocrinology, Singapore General Hospital, Singapore, Singapore Corresponding author: Tai E. Shyong, eshyong{at}pacific.net.sg Abstract OBJECTIVE— Association between genetic variants at the FTO locus and obesity has been consistently observed in populations of European ancestry and inconsistently in non-Europeans. The aim of this study was to examine the effects of FTO variants on obesity and type 2 diabetes in Southeast Asian populations. RESEARCH DESIGN AND METHODS— We examined associations between nine previously reported FTO single nucleotide polymorphisms (SNPs) with obesity, type 2 diabetes, and related traits in 4,298 participants (2,919 Chinese, 785 Malays, and 594 Asian Indians) from the 1998 Singapore National Health Survey (NHS98) and 2,996 Malays from the Singapore Malay Eye Study (SiMES). RESULTS— All nine SNPs exhibited strong linkage disequilibrium ( r 2 = 0.6–0.99), and minor alleles were associated with obesity in the same direction as previous studies with effect sizes ranging from 0.42 to 0.68 kg/m 2 ( P < 0.0001) in NHS98 Chinese, 0.65 to 0.91 kg/m 2 ( P < 0.02) in NHS98 Malays, and 0.52 to 0.64 kg/m 2 ( P < 0.0001) in SiMES Malays after adjustment for age, sex, smoking, alcohol consumption, and exercise. The variants were also associated with type 2 diabetes, though not after adjustment for BMI (with the exception of the SiMES Malays: odds ratio 1.17–1.22; P ≤ 0.026). CONCLUSIONS— FTO variants common among European populations are associated with obesity in ethnic Chinese and Malays in Singapore. Our data do not support the hypothesis that differences in allele frequency or genetic architecture underlie the lack of association observed in some populations of Asian ancestry. Examination of gene-environment interactions involving variants at this locus may provide further insights into the role of FTO in the pathogenesis of human obesity and diabetes. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 3 July 2008. J.T.T. and R.D. contributed equally to this study. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 19, 2008. Received February 15, 2008. DIABETES

Aging is a multifaceted biological process marked by the decline in both mitotic and postmitotic cellular function, often central to the development of age-related diseases. In the pursuit of slowing or even reversing the aging process, a prominent strategy of significant interest is calorie restriction (CR), also known as dietary restriction, and the potential influence of a drug called rapamycin (RM). Both CR and RM have demonstrated the capacity to extend healthspan and lifespan across a diverse array of species, including yeast, worms, flies, and mice. Nevertheless, their individual and combined effects on mitotic and postmitotic cells, as well as their comparative analysis, remain areas that demand a thorough investigation. In this study, we employ RNA-sequencing methodologies to comprehensively analyze the impact of CR, RM, and their combination (CR + RM) on gene expression in yeast cells. Our analysis uncovers distinctive, overlapping, and even contrasting patterns of gene regulation, illuminating the unique and shared effects of CR and RM. Furthermore, the transcriptional synergistic interaction of CR + RM is validated in extending the lifespan of both yeast and human cells. Systematic transcriptomics analysis reveals the synergistic interaction of calorie restriction and rapamycin in extending cellular lifespan, identifying unique and overlapping gene regulation patterns in both yeast and human cells.

This study aims to evaluate differences between Infinium MethylationEPIC (EPICv1) and Infinium MethylationEPICv2 (EPICv2) arrays in estimating DNAm age with eleven DNAm clocks using buffy coat, peripheral blood mononuclear cell (PBMC), and saliva from 16 healthy middle-aged individuals. DNAm ages were estimated using six principal component-based (PC) clocks (PCHorvath1, PCHorvath2, PCHannum, PCPhenoAge, PCGrimAge, and PCDNAmTL) and five non-PC clocks (DunedinPACE, DNAmFit, YingCausAge, YingAdaptAge, and YingDamAge) across all biological samples. Agreement between arrays was assessed using Spearman correlation, Bland-Altman plots, and Wilcoxon Signed-Rank test. The 16 individuals with median age of 48 [43.5;53.8] years, were predominantly female, Chinese and non-smokers. High correlations (ρ > 0.8) were observed between EPICv1 and EPICv2 except for DunedinPACE, YingDamAge and YingAdaptAge. PC-based clocks showed lower systematic bias (MAPE:0.118-8.98%) compared to non-PC-based clocks (MAPE:5.31-21.2%). Saliva samples demonstrated greatest variability between arrays. EPICv2 introduces systematic biases especially in non-PC-based clocks and between different biological samples. Assessment of DNAm varies across platforms, especially in non-PC-based clocks and between buffy coat, peripheral blood mononuclear cell and saliva in 16 healthy middle-aged individuals.

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta =  − 1.167, P Adj  = 2.75 × 10 −4 ). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.