Understanding the genetic basis of healthy ageing and metabolic diseases
In the World Health Organization (WHO) European Region diabetes affects around 60 million people. This results in associated health expenditure amounting to billions of euros. The prevalence of metabolic disorders is rapidly rising among all age groups, further straining European health economies and affecting the quality of life and life expectancy of European citizens. About 4 000 single nucleotide polymorphisms have been associated with over 200 traits/diseases. However, the functional role and the clinical impact of genetic variants and the associated pathways are yet to be determined. Under the aegis of the HUMAN (Health and the understanding of metabolism, aging and nutrition) project, researchers will address gaps in knowledge and develop new therapeutic and research tools. The HUMAN team aims to carry out large-scale multi-centre metabolic phenotyping of humanised animal and cellular models. They have access to collections of cryopreserved human cells from cohorts such as the semi-supercentenarians from Bologna and from the Leiden longevity study. Based on genotype profile, metabolic phenotype and healthy longevity phenotype, fibroblasts from donors were selected. These cells will be induced into pluripotent stem cell for further differentiation to hepatocytes or pancreatic β-cells for humanisation of mice. Researchers made significant progress towards generating the mouse models with humanised liver or pancreatic β-cells in the first project period. After obtaining ethical approval as well as completing material transfer agreements and generating new standard operating procedures, fibroblast cell lines required for induced pluripotent stem cell production were shipped to partner laboratories and induction started. Scientists also genotyped several liver cell samples to identify donors with the highest number of risk or protective alleles. Also, they determined that FRGN mice with humanised liver are a better model for studies of human metabolism than the FRG mice with humanised liver. In terms of novel pharmaceutical approaches, HUMAN focused on druggable gene targets such as thyroid hormone (TH) and liver X receptors (LXRs). These nuclear receptors are transcription factors involved in lipogenesis, a key process in fat metabolism. The synthetic LXR agonist GW3965 has been tested in liver-humanised mice. Analysis of their lipoprotein profiles, messenger RNA and blood glucose levels revealed changes in the lipid metabolism pathway as well as blood glucose levels. HUMAN researchers will work on testing the impact of different nutritional regimes and pharmaceuticals on organs and hormone regulation in the humanised mouse models under development. Besides providing novel therapeutic targets, this should boost European health-related industries and businesses while improving human health and life quality.
Keywords
Metabolic diseases, ageing, health, diabetes, genetic variants, metabolism, nutrition
