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Molecular epidemiological studies of aging and age-related diseases

The overall aim of my research is to perform molecular epidemiological studies of aging and age-related diseases to better understand the biological mechanisms driving the aging process.

Project leader

Sara Hägg

Senior researcher
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Figure 1. Mesh-terms as a tag cloud from my verified publications.

Towards this aim, samples from the Swedish Twin Registry (STR), the Genomics Aggregation Project in Sweden (GAPS), and the UK Biobank are used. My specific aims are 1) to investigate how different biological age predictors (telomere length, epigenetic clock, frailty index, clinical biomarkers, metabolites and proteins) can be used to explain age-related health outcomes combining genome-wide analyses of omics data, longitudinal modelling, and twin design; and 2) to analyze health and survival effects from geroprotectors – drugs targeting the aging process – by using causal inference methods, such as Mendelian Randomization, and pharmacoepidemiology.

Aim 1 – Biological age predictors

A biological age predictor is a biomarker, clinical measure or composite score which is correlated with chronological age but predicts health outcomes independent of age. Recently, a number of biological age predictors have been developed which we described in a review (Jylhävä et al, EBioMedicine, 2017), and by using markers that are easily accessible, the aging process should be possible to monitor repeatedly. Hence, there are different ways to define a biological age predictor and it can be done by using an overall measure of frailty (e.g., the Rockwood deficit accumulation model, often referred to as the frailty index), by studying biomarkers of aging (e.g., telomeres, epigenetics, metabolomics, and proteomics), or by combining different clinical biomarkers (e.g., C-reactive protein, serum creatinine, systolic blood pressure, serum albumin, total cholesterol etc.). In my studies, I work with many different biological age predictors and I try to understand how they relate to each other and if they can be useful to predict the aging pace.

Aim 2- Geroprotectors

A geroprotector is defined as a drug that is targeting cellular senescence which may then have beneficial effects on overall survival and increase the health span in life. Many possible geroprotectors are proven successful in animal models but translational studies are missing. I propose that a cost-effective approach would instead be to reclassify existing drugs for new purposes, and to investigate their usefulness in large epidemiological data before launching trials. We are currently working on several projects using Mendelian Randomization approaches where genetic variants mimicking a drug target are used to assess unconfounded effects on health outcomes.

Publications

Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study.
Williams DM, Hägg S, Pedersen NL
Am. J. Clin. Nutr. 2019 Jan;109(1):90-98

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
Franceschini N, Giambartolomei C, de Vries PS, Finan C, Bis JC, Huntley RP, et al
Nat Commun 2018 12;9(1):5141

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
Franceschini N, Giambartolomei C, de Vries PS, Finan C, Bis JC, Huntley RP, et al
Nat Commun 2018 12;9(1):5141

Positive bias for European men in peer reviewed applications for faculty position at Karolinska Institutet.
Holst S, Hägg S
F1000Res ;6():2145

A Frailty Index for UK Biobank Participants.
Williams DM, Jylhävä J, Pedersen NL, Hägg S
J. Gerontol. A Biol. Sci. Med. Sci. 2019 Mar;74(4):582-587

A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia.
Chen X, Gustafsson S, Whitington T, Borné Y, Lorentzen E, Sun J, et al
Hum. Mol. Genet. 2018 05;27(10):1809-1818

Apolipoprotein E DNA methylation and late-life disease.
Karlsson IK, Ploner A, Wang Y, Gatz M, Pedersen NL, Hägg S
Int J Epidemiol 2018 Mar;():

Association of telomere length with general cognitive trajectories: a meta-analysis of four prospective cohort studies.
Zhan Y, Clements MS, Roberts RO, Vassilaki M, Druliner BR, Boardman LA, et al
Neurobiol. Aging 2018 09;69():111-116

Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study.
Williams DM, Karlsson IK, Pedersen NL, Hägg S
Neurology 2018 01;90(4):e291-e297

DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins.
Svane AM, Soerensen M, Lund J, Tan Q, Jylhävä J, Wang Y, et al
Genes (Basel) 2018 Feb;9(2):

Genetic and Environmental Contributions to the Covariation Between Cardiometabolic Traits.
Chen X, Kuja-Halkola R, Chang Z, Karlsson R, Hägg S, Svensson P, et al
J Am Heart Assoc 2018 Apr;7(9):

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.
Savage JE, Jansen PR, Stringer S, Watanabe K, Bryois J, de Leeuw CA, et al
Nat. Genet. 2018 07;50(7):912-919

Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to 415,530 participants.
Zhou A, Taylor AE, Karhunen V, Zhan Y, Rovio SP, Lahti J, et al
Sci Rep 2018 May;8(1):7526

Leukocyte Telomere Length and All-Cause Mortality: A Between-Within Twin Study With Time-Dependent Effects Using Generalized Survival Models.
Zhan Y, Liu XR, Reynolds CA, Pedersen NL, Hägg S, Clements MS
Am. J. Epidemiol. 2018 Oct;187(10):2186-2191

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.
Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, et al
Nat Commun 2018 05;9(1):2098

Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data.
Marioni RE, Suderman M, Chen BH, Horvath S, Bandinelli S, Morris T, et al
J. Gerontol. A Biol. Sci. Med. Sci. 2019 Jan;74(1):57-61

An epigenome-wide association study meta-analysis of educational attainment.
Karlsson Linnér R, Marioni RE, Rietveld CA, Simpkin AJ, Davies NM, Watanabe K, et al
Mol. Psychiatry 2017 Dec;22(12):1680-1690

Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study.
Zhan Y, Karlsson IK, Karlsson R, Tillander A, Reynolds CA, Pedersen NL, et al
Circ. Res. 2017 Jul;121(3):214-219

Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort.
Jiang M, Foebel AD, Kuja-Halkola R, Karlsson I, Pedersen NL, Hägg S, et al
Aging (Albany NY) 2017 12;9(12):2629-2646

Genetic susceptibility to cardiovascular disease and risk of dementia.
Karlsson IK, Ploner A, Song C, Gatz M, Pedersen NL, Hägg S
Transl Psychiatry 2017 05;7(5):e1142

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts.
Hägg S, Zhan Y, Karlsson R, Gerritsen L, Ploner A, van der Lee SJ, et al
Transl Psychiatry 2017 04;7(4):e1100

Vitamin D and cognitive function: A Mendelian randomisation study.
Maddock J, Zhou A, Cavadino A, Kuźma E, Bao Y, Smart MC, et al
Sci Rep 2017 10;7(1):13230

Ganna A, Fall T, Salihovic S, Lee W, Broeckling CD, Kumar J, Hagg S, Stenemo M, Magnusson PKE, Prenni JE, Lind L, Pawitan Y, Ingelsson E. Large-scale non-targeted metabolomic profiling in three human population-based studies. Metabolomics 2016 12;1. https://doi.org/10.1007/s11306-015-0893-5

Longitudinal decline of leukocyte telomere length in old age and the association with sex and genetic risk.
Berglund K, Reynolds CA, Ploner A, Gerritsen L, Hovatta I, Pedersen NL, et al
Aging (Albany NY) 2016 07;8(7):1398-415

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.
Hägg S, Fall T, Ploner A, Mägi R, Fischer K, Draisma HH, et al
Int J Epidemiol 2015 Apr;44(2):578-86

Age- and sex-specific causal effects of adiposity on cardiovascular risk factors.
Fall T, Hägg S, Ploner A, Mägi R, Fischer K, Draisma HH, et al
Diabetes 2015 May;64(5):1841-52

Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
Horikoshi M, Mӓgi R, van de Bunt M, Surakka I, Sarin AP, Mahajan A, et al
PLoS Genet. 2015 Jul;11(7):e1005230

Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models.
Chen X, Kuja-Halkola R, Rahman I, Arpegård J, Viktorin A, Karlsson R, et al
Am. J. Hum. Genet. 2015 Nov;97(5):708-14

Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity.
Hägg S, Ganna A, Van Der Laan SW, Esko T, Pers TH, Locke AE, et al
Hum. Mol. Genet. 2015 Dec;24(23):6849-60

Telomere Length Shortening and Alzheimer Disease--A Mendelian Randomization Study.
Zhan Y, Song C, Karlsson R, Tillander A, Reynolds CA, Pedersen NL, et al
JAMA Neurol 2015 Oct;72(10):1202-3

The impact of low-frequency and rare variants on lipid levels.
Surakka I, Horikoshi M, Mägi R, Sarin AP, Mahajan A, Lagou V, et al
Nat. Genet. 2015 Jun;47(6):589-97

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.
Perry JR, Hsu YH, Chasman DI, Johnson AD, Elks C, Albrecht E, et al
Hum. Mol. Genet. 2014 May;23(9):2490-7

Inactivation of the budding yeast cohesin loader Scc2 alters gene expression both globally and in response to a single DNA double strand break.
Lindgren E, Hägg S, Giordano F, Björkegren J, Ström L
Cell Cycle 2014 ;13(23):3645-58

Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers.
Deelen J, Beekman M, Codd V, Trompet S, Broer L, Hägg S, et al
Int J Epidemiol 2014 Jun;43(3):878-86

Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
Björkegren JL, Hägg S, Talukdar HA, Foroughi Asl H, Jain RK, Cedergren C, et al
PLoS Genet. 2014 Feb;10(2):e1004201

Serum selenium in relation to measures of glucose metabolism and incidence of Type 2 diabetes in an older Swedish population.
Gao H, Hägg S, Sjögren P, Lambert PC, Ingelsson E, van Dam RM
Diabet. Med. 2014 Jul;31(7):787-93

Telomere length in circulating leukocytes is associated with lung function and disease.
Albrecht E, Sillanpää E, Karrasch S, Alves AC, Codd V, Hovatta I, et al
Eur. Respir. J. 2014 Apr;43(4):983-92

Evidence of a causal relationship between adiponectin levels and insulin sensitivity: a Mendelian randomization study.
Gao H, Fall T, van Dam RM, Flyvbjerg A, Zethelius B, Ingelsson E, et al
Diabetes 2013 Apr;62(4):1338-44

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.
Rietveld CA, Medland SE, Derringer J, Yang J, Esko T, Martin NW, et al
Science 2013 Jun;340(6139):1467-71

Identification of seven loci affecting mean telomere length and their association with disease.
Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, et al
Nat. Genet. 2013 Apr;45(4):422-7, 427e1-2

The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
Fall T, Hägg S, Mägi R, Ploner A, Fischer K, Horikoshi M, et al
PLoS Med. 2013 ;10(6):e1001474

Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population.
Lind L, Syvänen AC, Axelsson T, Lundmark P, Hägg S, Larsson A
Acta Physiol (Oxf) 2013 May;208(1):88-94

Relative deprivation and mortality--a longitudinal study in a Swedish population of 4.7 million, 1990-2006.
Åberg Yngwe M, Kondo N, Hägg S, Kawachi I
BMC Public Health 2012 Aug;12():664

Blood levels of dual-specificity phosphatase-1 independently predict risk for post-operative morbidities causing prolonged hospitalization after coronary artery bypass grafting.
Hägg S, Alserius T, Noori P, Ruusalepp A, Ivert T, Tegnér J, et al
Int. J. Mol. Med. 2011 Jun;27(6):851-7

Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin.
Hägg S, Salehpour M, Noori P, Lundström J, Possnert G, Takolander R, et al
PLoS ONE 2011 Apr;6(4):e18248

Multi-organ expression profiling uncovers a gene module in coronary artery disease involving transendothelial migration of leukocytes and LIM domain binding 2: the Stockholm Atherosclerosis Gene Expression (STAGE) study.
Hägg S, Skogsberg J, Lundström J, Noori P, Nilsson R, Zhong H, et al
PLoS Genet. 2009 Dec;5(12):e1000754

Biological Age Predictors.
Jylhävä J, Pedersen NL, Hägg S
EBioMedicine 2017 Jul;21():29-36

Telomere Length Shortening in Alzheimer's Disease: Procedures for a Causal Investigation Using Single Nucleotide Polymorphisms in a Mendelian Randomization Study.
Zhan Y, Hägg S
Methods Mol. Biol. 2018 ;1750():293-306

Telomere Length Dynamics and Atherosclerotic Disease.
Hägg S
Circ. Res. 2018 Feb;122(4):546-547