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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

Telefon:08-524 822 36

E-post:Sara.Hagg@ki.se

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.

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

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

Williams DM, Hägg S, Pedersen NL. Circulating antioxidants and Alzheimer's disease prevention: a Mendelian randomization study. The American Journal of Clinical Nutrition, accepted for publication.

Franceschini N, Giambartolomei C, de Vries PS,…, Hägg S, … et al. Genome-wide association study and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. Nature Communications, accepted for publication.

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Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study.

Williams D, Karlsson I, Pedersen N, Hägg S

Neurology 2018 Jan;90(4):e291-e297

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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

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