Periodic Reporting for period 1 - EpiMetAgeing (Epitranscriptomics at the crossroads of metabolism and cellular ageing)
Reporting period: 2020-09-15 to 2022-09-14
Due to the continuous increase in life expectancy in western societies, ageing has become the greatest risk factor for most human diseases such as cardiovascular and metabolic disorders, cancer and neurodegenerative processes. In turn, although obesity can affect an individual´s health at all stages of life, risk arising from metabolic disfunctions increases with age. In Europe the increasing prevalence of obesity and associated pathologies during ageing will translate in an Economic, Health and Social burden for the upcoming generations. Importantly, emerging evidence indicates that metabolism plays an important role in regulating epigenetic modifications that dramatically affect cellular function with age. It is widely known that ageing promotes the progressive loss of fitness of living organisms, but the causes of ageing remain one of the main open questions in Biology. Among the different approaches to erase cellular ageing hallmarks, somatic cell reprogramming with the Yamanaka factors has proven itself the best suited to rejuvenate cells, restoring a young phenotype. The EpiMetAgeing proposal aimed at dissecting novel molecular mechanisms whose deregulation contributed to ageing in an obesity context, and which could be reset to a youthful state through somatic cell reprogramming. In particular, we focused in dissecting the contribution of the epigenetic (i.e. acting on DNA) and epitranscriptomic (i.e. acting on RNA) regulator TET2, to cellular loss of fitness during ageing due to obesity. The EpiMetAgeing project aimed at scrutinizing the status quo and the dynamics of 5hmC in RNA in ageing and cellular rejuvenation, and dissecting TET2 interacting network which mediates this epitranscriptomic modification during ageing and rejuvenation in an obesity context. The appointment of the ER as a principal investigator in the Spanish R&D system has led to the early termination of the EpiMetAgeing proposal, but the exciting preliminary results obtained will be further explored in her new position as an independent researcher. For this reason, in the long run, the EpiMetAgeing project will contribute to expand the understanding of the molecular underpinnings of ageing, which is ultimately necessary to finally develop better strategies for alleviating or stopping age-related diseases in an obesity context.
During the 7-months period of the project, we have derived somatic cells from young and old mice fed with either a standard diet or a high-fat diet (HFD). We have characterized transcriptional differences influenced by diet-induced obesity during ageing, identifying both protein-coding and long non-coding RNAs whose expression was significantly altered with age in presence of high-fat diet. Furthermore, we are in the process of characterizing transcripts with altered RNA chemical modifications due to fluctuations in metabolite levels and enzyme cofactors influencing the deposition and removal of epitranscriptomic modifications, as well as the protein mediators involved in such regulation. Finally, we have started characterizing the impact of HFD in cellular rejuvenation through somatic cell reprogramming.
EpiMetAgeing will provide a better understanding about how in vivo alterations of cellular metabolism during ageing contributes to loss of cellular fitness, and the identification of novel players which could be used to explore new perspectives for cellular rejuvenation strategies and treatment of age-related metabolic pathologies.