Biology subjects

Kolbe, D.

Publications and source records attributed to Kolbe, D..

6 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↗

bioRxiv2024

Neolithic introgression of IL23R-related protection against chronic inflammatory bowel diseases in modern Europeans

BackgroundThe hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel disease (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe. MethodsThis study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture informed analyses and selection scans of rs11209026-A and its haplotypes. Findingsrs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%) where it was likely under weak positive selection. AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe. InterpretationGiven the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralization therapies for chronic inflammatory diseases. This study highlights how evolutionary informed research can provide promising targets for new therapeutic strategies. FundingDeutsche Forschungsgemeinschaft (DFG German Research Foundation) under Germanys Excellence Strategy - EXC 2167 390884018 and EXC 2150 390870439.

evolutionary biology↗

bioRxiv2023

Admixture as a source for HLA variation in Neolithic European farming communities

The northern European Neolithic is characterized by two major demographic events: immigration of early farmers (EF) from Anatolia (5500 BCE) and their admixture (from [~]4200 BCE) with western hunter-gatherers (WHG) forming late farmers (LF). The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is understudied. Here, we conducted population and immunogenetic analyses on 83 individuals from six EF and LF sites located in present-day Germany. We observed significant shifts in HLA allele frequencies from EF to LF. The HLA diversity increased from EF to LF, likely due to admixture with WHG. However, it was considerably lower than in modern populations. Both EF and LF exhibited a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time. We additionally noted that LF resulted from sex-biased admixture from male WHG. TEASERMore restricted HLA allele spectrum and lower diversity in Neolithic farmers than in modern populations

genetics↗

bioRxiv2023

The effect of parental age on the quantity and quality of offspring in Syngnathus typhle, a species with male pregnancy.

Offspring quantity and quality are known to vary according to parental age, with most studies focusing on the mothers age, who produces costly eggs and often carries out pregnancy, hampering to distinction between trans-generational age effects due to egg quality or physiological deterioration. We investigated the ramification of parental age on the offspring in the broad-nosed pipefish Syngnathus typhle, a fish species with male pregnancy, allowing us to separate these two female traits. By mating parents of different sizes we examined the impact of parental age on offspring number, size and gene expression. Our results show that older parents produced more and larger-sized offspring. However, we revealed intriguing insights into the differential gene expression patterns in offspring, strongly influenced by the paternal lineage but minimally affected by maternal age. Offspring from old fathers exhibited notable changes in gene expression profiles, particularly related to cell cycle regulation, metabolism, protein synthesis, stress response, DNA repair and neurogenesis. Our findings provide valuable insights into the role of pregnancy in shaping offspring physiology. Moreover, we recognize the value of assessing a broader range of species that have evolved with sex-specific differences in parental investment vs. gamete provisioning, as the age of either the mother or father may hold greater significance than the other in influencing offspring fitness.

evolutionary biology↗

bioRxiv2019

Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous Tor1a gene

In patients with the brain disorder dystonia, body movement is severely affected - with involuntary muscle contractions and abnormal postures, causing extensive deterioration of the patients quality of life. The most common inherited form of this disorder is DYT1 dystonia, which is caused by a mutation in TOR1A gene and autosomal dominant. The molecular mechanisms that underlie the effects of the TOR1A mutation on brain function remain unclear. To understand these, we examined the gene expression profiles (transcriptome) in four brain regions (cerebral cortex, hippocampus, striatum and cerebellum) in a mouse model, the heterozygous {Delta}E-torsinA knock-in mice which genetically reproduce the mutation in DYT1 dystonia. The samples were obtained at 2 to 3 weeks of age, a period during which synaptic abnormalities have been reported. Pairwise comparisons of brain regions revealed differential gene expression irrespective of genotype. A comparison of heterozygous to wild-type mice failed to reveal genotype-dependent differences in gene expression in any of the four brain regions when examined individually. However, genotype-dependent differences became apparent when the information for all brain regions was combined. These results suggest that any changes in the transcriptome within a brain region were subtle at this developmental stage, but that statistically significant changes occur across all brain regions. Such changes in the transcriptome, although subtle in degree, could underlie the processes that give rise to DYT1 dystonia.

neuroscience↗