Age related metabolic adaptation of mesechymal stem cells and the development of obesity

• Applicant: Dr. Juliane-Susanne Jung
• Subject Area: Biogerontology and Geriatric Medicine
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446925227

The UN estimates that the number of people older than 65 years will grow from 7% in 2000 to 16% in 2050 worldwide. Research on aging mechanisms and aged-related disease is one major issue of our ageing world. Mesenchymal stem cells (MSCs) provide a suitable in vitro model because MSCs are affected by molecular and cellular aging mechanisms. MSCs generate and regenerate the vast majority of tissues of the humane body including fat, muscle, bones, and cartilage. Generation and regeneration capacity depends on stem cell plasticity, which is necessary for maintenance of organ functions. Reduced stem cell plasticity is a causative for the development of aged-related diseases. However, little is known about metabolic changes of MSCs during aging. The project will analyze the metabolism of MSCs during aging and how MSCs adapt to the aged body.Apoliprotein (APOE) is the key regulator of the cholesterol metabolism expressed in adipocytes and many other cell types. Certain isoforms of the APOE have a reduced functionality such as APOE4, which is strongly associated with age-related diseases including Alzheimer’s disease and Type-2-diabetes. APOE knock out rabbits showed elevated triglyceride values and a strong induction of the cholesterol level. There was also arteriosclerosis and hyperlipidemia. APOE knock out rabbits are a model for studying onset of cardiovascular diseases. Together, APOE acts in an age-dependent manner recommending the analysis of APOE4 and APOE knock outs in the context of aging.The rabbit is a valuable animal model for a variety of biomedical research areas including embryology, organogenesis, and modeling of diabetes, obesity, or cardiovascular diseases. MSCs can be generated from different tissues of adult rabbits and they have the capability to self-renew and can differentiate into several mesodermal cell types. We successfully established rabbit MSC cultures representing an in vitro model for the analysis of stem cell aging mechanisms, especially in the context of metabolic changes.Rabbit MSCs will be generated from visceral adipose tissue of young (>15 weeks), old (>108 weeks) and APOE knock out (>15 weeks) female rabbits. MSCs will be differentiated into adipocytes. Permanent rabbit induced pluripotent stem cell lines (RiPSCs) will be generated for the establishing of an in vitro model suitable for the differentiation into MSCs and adipocytes. Analysis will include state of the art molecular and cellular techniques including flow cytometry, cellular bioenergetics analytical instruments, and metabolomics. The focus is on key regulators of stem cell plasticity, cellular metabolism, and regulators of aging. Data from metabolomics will be evaluated using appropriate statistics and bioinformatics for characterization of key regulator pathways. Data will be compared with the data sets from the CARLA cohort in Halle.Altogether, the project will reveal new insights in the onset, progression, and treatment of age-related diseases.

• DFG Programme: Research Grants