Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a ...variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to compare fifteen omics ageing clocks, with correlations of 0.21-0.97 with chronAge, even with substantial sub-setting of biomarkers. These clocks track common aspects of ageing with 95% of the variance in chronAge being shared among clocks. The difference between BA and chronAge - omics clock age acceleration (OCAA) - often associates with health measures. One year's OCAA typically has the same effect on risk factors/10-year disease incidence as 0.09/0.25 years of chronAge. Epigenetic and IgG glycomics clocks appeared to track generalised ageing while others capture specific risks. We conclude BA is measurable and prognostic and that future work should prioritise health outcomes over chronAge.
Regular exercise improves health, modulating the immune system and impacting inflammatory status. Immunoglobulin G (IgG) N-glycosylation reflects changes in inflammatory status; thus, we investigated ...the impact of regular exercise on overall inflammatory status by monitoring IgG N-glycosylation in a previously inactive, middle-aged, overweight and obese population (50.30 ± 9.23 years, BMI 30.57 ± 4.81). Study participants (
= 397) underwent one of three different exercise programs lasting three months with blood samples collected at baseline and at the end of intervention. After chromatographically profiling IgG N-glycans, linear mixed models with age and sex adjustment were used to investigate exercise effects on IgG glycosylation. Exercise intervention induced significant changes in IgG N-glycome composition. We observed an increase in agalactosylated, monogalctosylated, asialylated and core-fucosylated N-glycans (padj = 1.00 × 10
, 2.41 × 10
, 1.51 × 10
and 3.38 × 10
, respectively) and a decrease in digalactosylated, mono- and di-sialylated N-glycans (padj = 4.93 × 10
, 7.61 × 10
and 1.09 × 10
, respectively). We also observed a significant increase in GP9 (glycan structure FA23G1, β = 0.126, padj = 2.05 × 10
), previously reported to have a protective cardiovascular role in women, highlighting the importance of regular exercise for cardiovascular health. Other alterations in IgG N-glycosylation reflect an increased pro-inflammatory IgG potential, expected in a previously inactive and overweight population, where metabolic remodeling is in the early stages due to exercise introduction.
Glycans attached to immunoglobulin G (IgG) directly affect this antibody effector functions and regulate inflammation at several levels. The composition of IgG glycome changes significantly with age. ...In women, the most notable change coincides with the perimenopausal period. Aiming to investigate the effect of estrogen on IgG glycosylation, we analysed IgG and total serum glycomes in 36 healthy premenopausal women enrolled in a randomized controlled trial of the gonadotropin-releasing hormone analogue (GnRH
AG
) leuprolide acetate to lower gonadal steroids to postmenopausal levels and then randomized to transdermal placebo or estradiol (E
2
) patch. The suppression of gonadal hormones induced significant changes in the IgG glycome, while E
2
supplementation was sufficient to prevent changes. The observed glycan changes suggest that depletion of E
2
primarily affects B cell glycosylation, while liver glycosylation stays mostly unchanged. To determine whether previously identified IgG GWAS hits
RUNX1
,
RUNX3
,
SPINK4
, and
ELL2
are involved in downstream signaling mechanisms, linking E
2
with IgG glycosylation, we used the FreeStyle 293-F transient system expressing IgG antibodies with stably integrated CRISPR/dCas9 expression cassettes for gene up- and downregulation.
RUNX3
and
SPINK4
upregulation using dCas9-VPR resulted in a decreased IgG galactosylation and, in the case of
RUNX3
, a concomitant increase in IgG agalactosylation.
Physical inactivity and obesity are growing concerns, negatively impacting the general population. Moderate physical activity is known to have a beneficial anti-inflammatory effect. N-glycosylation ...of immunoglobulin G (IgG) reflects changes in the inflammatory potential of IgG. In this study, GlycanAge index of biological age (GlycanAge), one of the first commercially used biomarkers of aging, was employed to assess effects of exercise intensity in three different groups of athletes: professional competing athletes, regularly moderate active individuals and newly involved recreational individuals, compared to the group of inactive individuals. GlycanAge was significantly lower in the active group compared to the inactive group (β = -7.437, p.adj = 7.85E-03), and nominally significant and increased in professional athletes compared to the active group (β = 7.546,
p
= 3.20E-02). Competing female athletes had significantly higher GlycanAge comparing to active females exercising moderately (β = 20.206, p.adj = 2.71E-02), while the latter had significantly lower GlycanAge when compared with the inactive counterparts (β = -9.762, p.adj = 4.68E-02). Regular, life-long moderate exercise has an anti-inflammatory effect in both female and male population, demonstrated by lower GlycanAge index, and it has great potential to mitigate growing issues related to obesity and a sedentary lifestyle, which are relentlessly increasing world-wide.
A dysregulated postprandial metabolic response is a risk factor for chronic diseases, including type 2 diabetes mellitus (T2DM). The plasma protein N-glycome is implicated in both lipid metabolism ...and T2DM risk. Hence, we first investigate the relationship between the N-glycome and postprandial metabolism and then explore the mediatory role of the plasma N-glycome in the relationship between postprandial lipaemia and T2DM.
We included 995 individuals from the ZOE-PREDICT 1 study with plasma N-glycans measured by ultra-performance liquid chromatography at fasting and triglyceride, insulin, and glucose levels measured at fasting and following a mixed-meal challenge. Linear mixed models were used to investigate the associations between plasma protein N-glycosylation and metabolic response (fasting, postprandial (C
), or change from fasting). A mediation analysis was used to further explore the relationship of the N-glycome in the prediabetes (HbA1c = 39-47 mmol/mol (5.7-6.5%))-postprandial lipaemia association.
We identified 36 out of 55 glycans significantly associated with postprandial triglycerides (C
β ranging from -0.28 for low-branched glycans to 0.30 for GP26) after adjusting for covariates and multiple testing (p
< 0.05). N-glycome composition explained 12.6% of the variance in postprandial triglycerides not already explained by traditional risk factors. Twenty-seven glycans were also associated with postprandial glucose and 12 with postprandial insulin. Additionally, 3 of the postprandial triglyceride-associated glycans (GP9, GP11, and GP32) also correlate with prediabetes and partially mediate the relationship between prediabetes and postprandial triglycerides.
This study provides a comprehensive overview of the interconnections between plasma protein N-glycosylation and postprandial responses, demonstrating the incremental predictive benefit of N-glycans. We also suggest a considerable proportion of the effect of prediabetes on postprandial triglycerides is mediated by some plasma N-glycans.
ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has ...associations with an increased risk of schizophrenia, obesity, Crohn's disease, and reduced blood Mn. Here, we used CRISPR/Cas9-mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn's disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.
Immunoglobulin G is posttranslationally modified by the addition of complex N-glycans affecting its function and mediating inflammation at multiple levels. IgG glycome composition changes with age ...and health in a predictive pattern, presumably due to inflammaging. As a result, a novel biological aging biomarker, glycan clock of age, was developed. Glycan clock of age is the first of biological aging clocks for which multiple studies showed a possibility of clock reversal even with simple lifestyle interventions. However, none of the previous studies determined to which extent the glycan clock can be turned, and how much is fixed by genetic predisposition. To determine the contribution of genetic and environmental factors to phenotypic variation of the glycan clock, we performed heritability analysis on two TwinsUK female cohorts. IgG glycans from monozygotic and dizygotic twin pairs were analyzed by UHPLC and glycan age was calculated using the glycan clock. In order to determine additive genetic, shared, and unique environmental contributions, a classical twin design was applied. Heritability of the glycan clock was calculated for participants of one cross-sectional and one longitudinal cohort with three time points to assess the reliability of measurements. Heritability estimate for the glycan clock was 39% on average, suggesting a moderate contribution of additive genetic factors (A) to glycan clock variation. Remarkably, heritability estimates remained approximately the same in all time points of the longitudinal study, even though IgG glycome composition changed substantially. Most environmental contributions came from shared environmental factors (C), with unique environmental factors (E) having a minor role. Interestingly, heritability estimates nearly doubled, to an average of 71%, when we included age as a covariant. This intervention also inflated the estimates of unique environmental factors contributing to glycan clock variation. A complex interplay between genetic and environmental factors defines alternative IgG glycosylation during aging and, consequently, dictates the glycan clock's ticking. Apparently, environmental factors (including lifestyle choices) have a strong impact on the biological age measured with the glycan clock, which additionally clarifies why this aging clock is one of the most potent biomarkers of biological aging.
Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are ...not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the
IgG expression system. Upregulation of three genes,
and
, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this
expression system.
parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly ...focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist.
in order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as ‘predicted mRNA expression levels’ of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315).
a set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, ‘lifetime smoking status’ and ‘predicted mRNA expression levels’ of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs.
the modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases.
NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH.
People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability ...explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down.
Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids.
Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage.
Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies.
Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".
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