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Background: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aβ) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia., Methods: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aβ42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis., Results: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (β 0.11; 95% CI: 0.05-0.17)., Conclusions: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms., Competing Interests: DISCLOSURES No disclosures to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Major hallmarks of functional loss, loss of metabolic and musculoskeletal health and (multi)morbidity with aging are associated with sleep disturbances. With poor sleep shifts in gut microbial composition commonly manifest, which could mediate the pro-inflammatory state between sleep disturbances and sarcopenia. This systematic review presents the recent evidence on how sleep disturbances throughout the lifespan associate with and contribute to gut microbial composition changes, proposing a mechanism to understand the etiology of sarcopenia through sleep disturbances. The relationship between disturbed sleep and clinically relevant gut microbiota composition on health aspects of aging is discussed. A search was performed in PubMed, Cochrane Library, Scopus, Web of Science using keywords including (microbio* OR microflora) AND (sleep OR sleep disorder). Six cross-sectional population-based studies and five experimental clinical trials investigating healthy individuals with ages ranging from 4 to 71 were included. The cross-sectional studies reported similarities in associations with sleep disturbance and gut microbial diversity. In older adults, shorter sleep duration is associated with an increase in pro-inflammatory bacteria whereas increasing sleep quality is positively associated with an increase of beneficial Verrucomicrobia and Lentisphaerae phyla. In young adults, the effect of sleep disruption on gut microbiome composition, specifically the ratio of beneficial Firmicutes over Bacteroidetes phyla, remains contradictory and unclear. The findings of this review warrant further research in the modulation of the gut microbiome linking poor sleep with muscle-catabolic consequences throughout the lifespan., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10 -6 ), methionine (p-value = 9.2 × 10 -5 ), tyrosine (p-value = 2.1 × 10 -4 ), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10 -4 ), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10 -4 ), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10 -4 ). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

Human ageing is an extremely personal process leading across the life course of individuals to large population heterogeneity in the decline of functional capacity, health and lifespan. The extremes of this process are witnessed by the healthy vital 100-year-olds on one end and the 60-year-olds suffering from multiple morbid conditions on the other end of the spectrum. Molecular studies into the basis of this heterogeneity have focused on a range of endpoints and methodological approaches. The phenotype definitions most prominently investigated in these studies are either lifespan-related or biomarker based indices of the biological ageing rate of individuals and their tissues. Unlike for many complex, age-related diseases, consensus on the ultimate set of multi-biomarker ageing or lifespan-related phenotypes for genetic and genomic studies has not been reached yet. Comparable to animal models, hallmarks of age-related disease risk, healthy ageing and longevity include immune and metabolic pathways. Potentially novel genomic regions and pathways have been identified among many (epi)genomic studies into chronological age and studies into human lifespan regulation, with APOE and FOXO3A representing yet the most robust loci. Functional analysis of a handful of genes in cell-based and animal models is ongoing. The way forward in human ageing and longevity studies seems through improvements in the interpretation of the biology of the genome, in application of computational and systems biology, integration with animal models and by harmonization of repeated phenotypic and omics measures in longitudinal and intervention studies. This article is part of a Special Issue entitled: Model Systems of Aging - edited by "Houtkooper Riekelt"., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.

To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes., (© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Subtelomeres are patchworks of evolutionary conserved sequence blocks and harbor the transcriptional start sites for telomere repeat containing RNAs (TERRA). Recent studies suggest that the interplay between telomeres and subtelomeric chromatin is required for maintaining telomere function. To further characterize chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, we systematically quantified histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres were characterized by a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation. However, we did not find increased levels of markers of euchromatin or derepression of the 7q VIPR2 gene. The repressed state of the subtelomeres was maintained upon senescence, which could be attributed to a rise in levels of facultative heterochromatin markers at both subtelomeres. While senescence-induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns. At the 7q TERRA promoter, chromatin structure was co-regulated with the more proximal subtelomere. In contrast, the 11q TERRA promoter, which was previously shown to be bound by CCCTC-binding factor CTCF, displayed lower levels of markers of constitutive heterochromatin that did not change upon senescence, whereas levels of markers of facultative heterochromatin decreased upon senescence. In line with the chromatin state data, transcription of 11q TERRA but not 7q TERRA was detected. Our study provides a detailed description of human subtelomeric chromatin dynamics and shows distinct regulation of the TERRA promoters of 7q and 11q upon cellular senescence.

The offspring of nonagenarian siblings suffer less from age related conditions and have a lower risk of mortality compared to their partners. Fibroblast strains derived from such offspring in middle age show different in vitro responses to stress, more stress-induced apoptosis and less senescence when compared to strains of their partners. Aiming to find differences in cellular metabolism in vitro between these fibroblast strains, cell culture supernatants collected at 24 hours and five days were analysed using (1)H nuclear magnetic resonance (NMR)-based metabolic footprinting. Between 24 hours and five days of incubation, supernatants of all fibroblast strains showed decreased levels of glucose, pyruvate, alanine-glutamine (ala-gln), valine, leucine, isoleucine, serine and lysine and increased levels of glutamine, alanine, lactate and pyroglutamic acid. Strains from offspring and their partners were compared using a partial least squares-discriminant analysis (PLS-DA) model based on the data of the five-day time point. The ala-gln and glucose consumption were higher for fibroblast strains derived from offspring when compared to strains of their partners. Also, production of glutamine, alanine, lactate and pyroglutamic acid was found to be higher for fibroblast strains derived from offspring. In conclusion, differences in NMR-based metabolic profiles of human cells in vitro reflect the propensity for human longevity of the subjects from whom these were derived.

Objectives: To assess whether familial longevity can be attributed to sustained hematopoietic capacity., Design: Prospective follow-up study of two independent population-based cohorts., Setting: The Leiden Longevity Study and the Leiden 85-plus Study., Participants: From the Leiden Longevity Study, 1,001 nonagenarians with familial longevity were included. As age-matched controls, 260 nonagenarians without familial longevity were used from the Leiden 85-plus Study., Measurements: Hemoglobin, leukocytes, and thrombocytes were measured for all subjects with and without familial longevity. Standardized mortality ratios, linear regression, and left-censored Cox regression were used for statistical analysis., Results: Mortality in nonagenarians with familial longevity was 28% lower than in nonagenarians from the general population (standardized mortality ratio=0.72, 95% confidence interval (CI)=0.65-0.79, P<.001). No differences were found between hemoglobin, leukocyte, and thrombocyte count in nonagenarians with and without familial longevity (all P>.30). Nonagenarians with familial longevity had greater mortality risk when anemia was present (sex-adjusted hazard ratio=1.71, 95% CI 1.41-2.07, P<.001). No relationship was found between leukocytes, thrombocytes, and mortality in either study group (all P>.20)., Conclusion: Hematopoietic capacity cannot explain the significantly better survival of nonagenarians with familial longevity, but in those with familial longevity, anemia may contribute to mortality.

The heritability of age at first cigarette was estimated in 5883 Dutch twins and siblings registered with the Netherlands Twin Register. Heritability was 60% for males and 39% for females. Shared environmental influences were found in females only (30%). Linkage analyses were performed on data of 422 DZ twins and siblings from 175 families, forming 368 sibling pairs. Genomic regions that may harbor susceptibility loci for age at first cigarette with LOD score greater than 2 were detected on chromosomes 5, 14 and 22. A simultaneous analysis of these three genomic regions showed that most of the variance was explained by the linkage effect on chromosome 5 (205 cM). This peak encloses the D1A dopamine receptor gene which is a functional candidate gene for smoking behavior.

Mice in which the p66(SHC) specific region of the SHC gene is deleted live 30% longer without apparent disease. These mice have lower levels of oxidative stress and apoptosis, both of which have been linked to old age survival in man. This makes SHC1 an important candidate gene for longevity in humans. We found no variations in the p66 specific region of the SHC1 gene in 30 young and 30 extreme long-lived subjects. Thus in man, no common sequence variations occur in p66 specific region of the SHC1 gene. In two independent cohorts of respectively 730 and 563 subjects aged 85 and over, we tested the only known non-synonymous polymorphism, Met(410)Val, for association with longevity using a prospective follow-up design. In the first cohort, we found increasing valine allele frequency in three strata of increasing age at death (2.8-5.2%). Moreover, compared to Met/Met carriers, mortality rate was a factor of 0.71 (95% CI 0.45-1.13) reduced for Met/Val carriers in the combined cohorts, with similar risk estimates in both cohorts. Low valine allele frequency resulted, however, in low power to detect statistical significance. These data suggest that an association between the Met(410)Val polymorphism and longevity in humans may exist.