Biology subjects

Deelen, J.

Publications and source records attributed to Deelen, J..

10 recordsLinked to original sources

bioRxiv2026

Rare genetic variants in the IIS/mTOR signalling pathway identified in exceptionally long-lived individuals show shared in vitro effects associated with lifespan across species

BackgroundThe increase in human lifespan without a proportional increase in healthspan imposes a substantial burden on individuals and society. Exceptionally long-lived individuals and members of long-lived families exhibit compression of multi-morbidity. Genetics, and in particular rare protein-altering variants, appear to play an important role in their longevity. MethodsIn this study, we employed a targeted pathway approach to provide functional evidence of the significance of rare variants in the insulin/insulin-like growth factor 1 signalling - mechanistic target of rapamycin (IIS/mTOR) signalling pathway identified in long-lived individuals. To this end, we used CRISPR/Cas9 to introduce these rare genetic variants into mouse embryonic stem cells (mESCs). We subsequently assessed several functional readouts that have previously been associated with lifespan regulation in model organisms and/or IIS/mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathway activity. ResultsFunctional characterisation revealed that the variants exhibit both shared and distinct effects on the signalling pathways. Principal component analysis of omics-based datasets showed that the variants clustered into two groups, a distribution that corresponds with the grouping observed for a subset of functional readouts. All variant mESC lines exhibited a downregulation in IIS/mTOR and MAPK/ERK signalling pathway activity as well as an increase in Foxo3 expression and FOXO3 binding activity. We identified alterations in lipid and mitochondrial metabolism, including a reduction in mitochondrial DNA levels, which were mostly shared among all variants. All variant mESC lines exhibited a signature implying increased pluripotency. The effects on stress resistance and growth rate diverged between the two variant groups, with partially opposing effects. Group 1 demonstrated a reduced growth rate and increased resistance to a subset of stressors, while Group 2 demonstrated an increased growth rate and reduced resistance to a subset of stressors. ConclusionsHere, we provide evidence that rare genetic variants in the IIS/mTOR and MAPK/ERK signalling pathways identified in long-lived human individuals result in shared functional effects associated with longevity in model organisms. These insights can serve as a foundation to better understand the role of rare variants in the insulin signalling network in the regulation of human longevity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/728260v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1ef36c3org.highwire.dtl.DTLVardef@1f44c96org.highwire.dtl.DTLVardef@1d0150forg.highwire.dtl.DTLVardef@16ab7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2025

Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families

Life expectancy has steadily increased in the last two centuries, while healthspan has been lagging behind. Survival into extreme ages strongly clusters within families which often exhibit a delayed onset of (multi)morbidity, yet the underlying protective genetic mechanisms are still largely undefined. We performed affected sib-pair linkage analysis in 212 sibships enriched for ancestral longevity and identified four genomic regions (LODmax [≥]3.0) at 1q21.1, 6p24.3, 6q14.3, and 19p13.3. Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes (NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2, and SH2D3A) located in longevity-associated loci. Notably, a missense variant in CGAS (rs200818241), was present in two sibships. Using human- and mouse-based cell models, we showed that rs200818241 reduced protein stability and attenuated activation of the canonical cGAS-STING pathway in a cell-type specific manner. This dampened signalling mitigated inflammation and delayed cellular senescence, mechanisms that may contribute to the survival advantage of CGAS variant carriers. Our findings indicate novel rare variants and candidate genes linked to familial longevity and highlight the cGAS-STING pathway as a potential contributor to the protective mechanisms underlying human longevity.

genetics↗

bioRxiv2025

Heritability of human lifespan is about 50% when confounding factors are addressed

The heritability of human lifespan is a fundamental question in biology. Current estimates of heritability are low - twin studies show that about 20-25% of the variation in lifespan is explained by genetics, and some large family pedigree studies suggest it is as low as 7%. However, these studies do not distinguish between deaths driven by intrinsic biological processes and deaths caused by extrinsic factors such as accidents or infections. Here we use mathematical modeling and analyses of twin cohorts raised together and apart to show that extrinsic mortality skews heritability estimates by driving down measured lifespan correlations among twin pairs. We also identify a nonlinear effect of the cutoff age--the minimum age of death included in each study -- on estimates of heritability. Correcting for these factors more than doubles previous estimates, revealing that intrinsic heritability of human lifespan is above 50%. Such high heritability is similar to most other complex human traits. We thus challenge the consensus that genetics has only a minor effect on lifespan and show that genes explain the majority of lifespan variation. Since genes are important, understanding the genetics of longevity can reveal aging mechanisms and inform medicine and public health.

genetics↗

bioRxiv2023

Functional characterisation of rare variants in genes encoding the MAPK/ERK signalling pathway identified in long-lived Leiden Longevity Study participants

Human longevity, which is coupled to a compression of age-related disease, has been shown to be heritable. However, the number of identified common genetic variants linked to this trait remains small. This may indicate that longevity is, at least to some extent, determined by rare genetic variants that are potentially family-specific. We therefore investigated whole-genome sequencing data of long-lived families from the Leiden Longevity Study for family-specific variants. We identified variants residing in genes involved in the mitogen-activated protein kinase (MAPK) cascade, a lifespan-associated and evolutionarily conserved pathway emerging from studies in model organisms. We subsequently generated mouse embryonic stem cells (mESCs) harbouring these variants and conducted in vitro functional characterisation. Two variants, located in NF1 (Phe1112Leu) and RAF1 (Asp633Tyr), reduce MAPK/extracellular signal-regulated kinase (ERK) signalling pathway activity in mESCs. At the proteomic and transcriptomic level, we observed prominent changes that were shared (e.g. up-regulation of the ribosome) and opposing between the variants (e.g. down-regulation of mTORC1 signalling in the RAF1Asp633Tyr variant cell line versus up-regulation in the NF1Phe1112Leu variant cell lines). These metabolic changes were accompanied by an opposing effect of the variants on proliferation. Moreover, the RAF1Asp633Tyr variant improved resistance to replication stress, while this was not the case for the NF1Phe1112Leu variant. In conclusion, we identified two rare genetic variants in long-lived families that influence MAPK/ERK signalling in a manner that has previously been linked to increased lifespan in model organisms. Interestingly, we also observe some opposing and diverging effects between the variants, which indicates that they may either have some pleiotropic effects that are not relevant to longevity or that they target slightly different mechanisms to elicit their effects in mESCs. Our findings suggest that mESCs offer a good starting point for in vitro characterisation of rare genetic variants linked to human longevity and can be used to assess which of these variants to take forward to in vivo studies in model organisms.

genetics↗

bioRxiv2022

Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis

Energy homeostasis is disrupted with age, which then fuels multiple age-related pathologies. The AMP-activated protein kinase (AMPK) is the primary sensor of cellular energy in eukaryotes. However, the genetic regulation of vertebrate aging by AMPK remains poorly understood. Here, we manipulate energy levels in the turquoise killifish by mutating APRT, a key enzyme in AMP biosynthesis. These manipulations produced a male-specific lifespan extension and restored metabolic plasticity. Exploring the observed sex differences using an integrated omics approach implicated the mitochondria as an important player. Mechanistically, APRT regulated mitochondrial functions and AMPK activity, mimicking energy starvation in heterozygous cells. A fasting-like state was also detected, particularly in heterozygous males, which leads to resistance to high-fat diet. Finally, life-long intermittent fasting eliminated the male-specific longevity benefits mediated by the APRT mutation. These observations identify the AMP/AMPK axis as a sex-specific regulator of vertebrate longevity and metabolic health.

genetics↗

bioRxiv2021

A combined lifestyle intervention induces a sensitization of the blood transcriptomic response to a nutrient challenge

The global population is growing older. As age is a primary risk factor of (multi)morbidity, there is a need for novel indicators to predict, track, treat and prevent the development of disease. Lifestyle interventions have shown promising results in improving the health of participants and reducing the risk for disease, but in the elderly population, such interventions often show less reliable or subtle effects on health outcomes. This is further complicated by a poor understanding of the homeodynamics and the molecular effects of lifestyle interventions, by which their effects of a lifestyle intervention remain obscured. In the Growing Old Together (GOTO) study, we examined the responses of 164 healthy, elderly men and women to a 13-week combined physical and dietary lifestyle intervention. In addition to collecting blood samples at a fasted state, we sampled blood also 30 minutes following a standardized meal. This allows us to investigate an intervention response not only in the traditional fasted state, but also in the blood metabolic and cellular responses to a nutrient challenge. We investigated the transcriptomic and metabolomic responses to this nutrient challenge, how these responses relate to each other, and how this response is affected by the lifestyle intervention. We find that the intervention has very little effect on the fasted blood transcriptome, but that the nutrient challenge induces a large translational inhibition, and an innate immune activation, which together comprise a cellular stress response that is stimulated by the intervention. A sex-specific analysis reveals that although the same set of genes respond in the same direction in both males and females, the magnitude of these effects differ, and are modulated differently by the intervention. On the other hand, the metabolomic response to the nutrient challenge is largely unaffected by the intervention, and the correlation between the metabolomic nutrient response and transcriptomic modules indicates that the change in transcriptomic response to the nutrient challenge is independent from a change in cellular metabolomic environment. This work constitutes a glance at the acute transcriptomic stress response to nutrient intake in blood, and how a lifestyle intervention affects this response in healthy elderly, and may lead to the development of novel biomarkers to capture the phenotypic flexibility of health.

molecular biology↗

bioRxiv2021

Genetically independent phenotype analysis identifies LPA and VCAM1 as drug targets for human ageing

The length and quality of life is important to us all, yet identification of promising drug targets for human ageing using genetics has had limited success. Here, we combine six large European-ancestry genome-wide association studies (GWAS) of human ageing traits--healthspan, father and mother lifespan, exceptional longevity, frailty index, and self-rated health--in a principal component framework that maximises their shared genetic architecture. The first principal component (GIP1) is more heritable than the original studies and shows strong genetic correlations with length of life as well as multiple indices of mental and physical wellbeing. We identify 27 genomic regions associated with GIP1, and provide additional, independent evidence for an effect on human ageing for loci near HTT and MAML3 using a study of Finnish and Japanese subject survival. Across the genome, GIP1 associations are enriched in genes involved in haem metabolism and pathways related to transcription, neurogenesis, homeostasis, proteolysis, intracellular signalling, immunity, and the muscle system. Finally, using proteome-wide two-sample Mendelian randomisation and colocalisation, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) (LPA) and vascular cell adhesion molecule 1 (VCAM1) on GIP1. Together, our results demonstrate that combining multiple ageing traits using genetic principal components enhances power to detect biological targets for human ageing.

genomics↗

bioRxiv2019

Lifestyle-intervention-induced reduction of abdominal fat is reflected by a decreased circulating glycerol level and an increased HDL diameter

SCOPEAbdominal obesity is one of the main modifiable risk factors of age-related cardiometabolic disease. Cardiometabolic disease risk and its associated high abdominal fat mass, high cholesterol and glucose concentrations can be reduced by a healthier lifestyle. Hence, our aim is to understand the relation between lifestyle-induced changes in body composition, and specifically abdominal fat, and accompanying changes in circulating metabolic biomarkers.\n\nMethods and resultsWe used the data from the Growing Old Together (GOTO) study, in which 164 older adults (mean age 63 years, BMI 23-35 kg/m2) changed their lifestyle during 13 weeks by 12.5% caloric restriction plus 12.5% increase in energy expenditure. We show that levels of circulating metabolic biomarkers, even after adjustment for body mass index, specifically associate with abdominal fat mass. Next, we show that the applied lifestyle intervention mainly reduces abdominal fat mass (-2.6%, SD=3.0) and that this reduction, when adjusted for general weight loss, is highly associated with decreased circulating glycerol concentrations and increased HDL diameter.\n\nConclusionsThe lifestyle-induced reduction of abdominal fat mass is particularly associated, independent of body mass index or general weight loss, with associated with decreased circulating glycerol concentrations and increased HDL diameter.

molecular biology↗

bioRxiv2019

Predicting biological age based on the BBMRI-NL 1H-NMR metabolomics repository

The blood metabolome incorporates cues from the environment as well as the hosts genetic background, potentially offering a holistic view of an individuals health status. We have compiled a vast resource of 1H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts. Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individuals biological age. Exploration in independent cohorts demonstrates that being judged older by ones metabolome, as compared to ones chronological age, confers an increased risk on future cardiovascular disease, mortality and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardio-metabolic health.

epidemiology↗

bioRxiv2019

Genome-wide association study of plasma lipids

There is continuous interest in the genetic determinants of plasma triglycerides (TGs) and phospholipids and their role in the etiology of cardiovascular disease (CVD). Here, we report the results of a Dutch genome wide association study (GWAS) of an in-house developed lipidomics platform, focusing on 90 plasma lipids. Lipids were assessed by liquid chromatography mass spectrometry in participants from the Leiden Longevity Study, the Netherlands Twin Register and the Erasmus Rucphen Family (ERF) study and meta-analysed, resulting in a sample size of 5537 participants. In addition, we performed genetic correlation analyses between the 90 plasma lipids and markers of metabolic health, as well as vascular pathology and CVD combining our GWAS results with publicly available GWAS outputs. We replicated previously known associations between 34 lipids and 10 lipid quantitative trait loci (lipQTL) (GCKR, APOA1, FADS1, SGPP1,TMEM229B, LIPC, PDXDC1, CETP, CERS4 and SPTLC3) with metabolome-wide (P < 1.61 x 10-9) significance. Moreover, we report 6 novel phospholipid-related and 5 triglyceride (TG)-related loci: SGGP1 (SM21:0), SPTLC3 (SM21:0 and SM25:1), FADS1 (LPCO16:1, PC38:2, PEO36:5, PEO38:5, TG56:5, TG56:6, and TG56:7), TMEM229 (LPCO16:1), GCKR (TG50:2), and APOA1 (TG54:4). In addition, we report suggestively significant (P < 5 x 10-8) associations mapping to eleven novel lipid quantitative trait loci (lipQTLs), three of which are supported by mining previous GWAS data: MAU (PC34:4), LDLR (SM16:0), and MLXIPL (TG48:1 and TG50:1)). Genetic correlation analysis indicates that one specific specific sphingomyelin, SM22:0, shares common genetic background with CVD. Levels of SM22:0 also positively associate with carotid artery intima-media thickness in the ERF study, and this observation is independent of LDL-C level. Our findings yield higher resolution of plasma lipid species and new insights in the biology of circulating phosholipids and their relation to CVD risk.

epidemiology↗