1. Research Background:

Advancing age is the major risk factor for many chronic diseases. Instead of tackling each of these diseases one by one, we should focus on the identification of shared mechanisms that compress multimorbidity and thereby contribute to healthy ageing.

In our group, we use two different approaches to find out why some people age more healthily than others. The first approach is aimed at elucidating the genetic mechanisms underlying healthy ageing and extended lifespan in humans. The second approach is the identification of biomarkers of ageing that can subsequently be used as surrogate endpoints in clinical trials or intervention studies that are aimed at improving general health.

2. Research questions addresses by the group:

One of the main aims of our research group is to study the functional effect of common genetic variants (identified using large-scale genetic association studies of healthy ageing) (Timmers et al. Nature Communications 2020) and rare protein- altering genetic variants (identified using sequencing data of long-lived individuals). To this end, we make use of the CRISPR/Cas9 system to generate transgenic cell lines and animals harbouring the variants in question. We subsequently measure the in vitro (mouse embryonic stem cells) and in vivo (mice) effects of the genetic variants on the functioning of the genes (Baghdadi, Hinterding et al. Brief Funct Genomics 2021). This work is supported by both an ERC Starting Grant and a Longevity Impetus Grant.

Another main aim of our research group is to establish novel human ageing studies in Cologne to determine the efficacy of previously reported biomarkers of ageing in clinical studies. The main focus is on biomarkers that have been identified in large- scale international collaborations of human studies using omics-based approaches, such as metabolomics (Deelen et al. Nature Communications 2019). In addition, we include biomarkers originating from studies in model organisms to determine their translatability.

3. Possible projects:

The possible project will most likely be based on the first aim of our group; functional characterisation of genetic variants. The focus of the project will be on studying the functional effect of either (1) commongenetic variants identified through genomewide association studies of healthy ageing-related phenotypes or (2) rare genetic variants in candidate-gene pathways identified using sequencing data of long-lived individuals.

The exact content of the PhD project is open for discussion to match the candidate’s interests and skills. The PhD project can be made bioinformatic- or wet-lab-based (or a combination of those).

4. Applied Methods and model organisms:

For our research on the functional effects of genetic variants, we currently use both cellular models and mice. We use a wide variety of methodologies to generate and characterise the transgenic cell lines/mice harbouring our genetic variants of interest, including:

• CRISPR/Cas9-based gene editing
• Mammalian cell culture
• FACS
• State-of-the-art molecular biology and biochemistry
• Viability assays
• Mouse metabolic phenotyping
• Bioinformatics

5. Desirable skills and qualifications:

We seek a creative and highly motivated young scientist to join our small, enthusiastic, and collaborative research group. Experience in mouse metabolic phenotyping, CRISPR/Cas9-based gene editing, mammalian cell culture, and/or bioinformatics are desirable, but not required.

6. References:

• Baghdadi M, Hinterding HM, Partridge L, Deelen J. From mutation to mechanism: deciphering the molecular function of genetic variants linked to human ageing. Brief Funct Genomics 21:13-23, doi: 10.1093/bfgp/elab005 (2022).
• Deelen J, Kettunen J, Fischer K, van der Spek A, Trompet S, Kastenmüller G, Boyd A, Zierer J, van denAkker EB, Ala-Korpela M, Amin N, Demirkan A, Ghanbari M, van Heemst D, Ikram MA, van Klinken JB, Mooijaart SP, Peters A, Salomaa V, Sattar N, Spector TD, Tiemeier H, Verhoeven A, Waldenberger M, Würtz P, Davey Smith G, Metspalu A, Perola M, Menni C, Geleijnse JM, Drenos F, Beekman M, Jukema JW, van Duijn CM, Slagboom PE. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. Nat Commun 10:3346, doi: 10.1038/s41467-019-11311-9 (2019).
• Timmers PRHJ, Wilson JF, Joshi PK, Deelen J. Multivariate genomic scan implicates novel loci and haem metabolism in human ageing. Nat Commun 11:3570, doi: 10.1038/s41467-020-17312-3 (2020).