Epigenetic reprogramming of cellular ageing
Description: Ageing is one of the major risk factors for most human diseases including cancer, neurodegeneration, and cardiovascular diseases, and therefore has been identified as one of the major challenges for modern societies. Ageing can be defined as the progressive decline in the ability of a cell or an organism to resist damage, stress and disease, ultimately leading to death. Unfortunately, despite decades of research, the process of ageing remains poorly understood at both cellular and physiological level. Importantly, although alterations in a broad range of cellular processes, known as the hallmarks of ageing, are observed during life, their causative role in longevity is not clear. In this line, analysis of samples from model organisms at different age has revealed alterations at multiple levels of the epigenetic regulation of the genome. Consequently, epigenetic clocks based on changes on DNA methylation occurring during life have been recently established allowing the determination of the biological age of tissues and organs from multiple organisms. Lastly, I have recently demonstrated that cellular reprogramming induced by epigenetic remodelling through forced expression of a set of transcription factors including Oct4, Sox2, Klf4 and c-Myc allows the amelioration of age-associated phenotypes at the cellular and organismal level. These observations highlight the potential role of epigenetic alterations as drivers of ageing and open the door for the development of novel anti-ageing strategies based on epigenetic reprogramming. This proposal will investigate the role of epigenetic changes occurring during life as drivers of cellular ageing and study the epigenetic mechanisms leading to the amelioration of age-associated phenotypes by cellular reprogramming. I hypothesize that epigenetic dysregulation as consequence of the interaction with the environment drives cellular and organismal ageing, therefore epigenetic reprograming might have the capacity to slow down or reverse cellular ageing. To test this hypothesis, I propose the following specific aims:Aim 1: To identify genome-wide epigenetic changes driving cellular ageing.Under this aim I will analyse by next generation sequencing (NGS) mouse and human dermal fibroblasts of different age to identify biologically relevant epigenetic changes driving ageing. Aim 2: To establish novel epigenetic clocks based on chromatin accessibility.For this purpose, I will use the assay for transposase-accessible chromatin sequencing (ATAC-seq) to establish novel epigenetic clocks for the analysis of biological age in mouse and human fibroblasts.Aim 3: To investigate the amelioration of ageing by cellular reprogramming.Lastly, I will use cellular biology, NGS, and metabolomics to study the mechanisms leading to the amelioration of age-associated phenotypes by cellular reprogramming in vitro and in vivo.Results arising from this proposal will allow for a better understanding of the epigenetic mechanisms driving cellular ageing and lead to the development of novel therapeutic interventions based on epigenetic reprogramming for the amelioration of age-associated diseases and improvement of healthspan.
Amount: CHF 1,500,000
Funding type: fellowship
Funder scheme: Eccellenza grant
Start date: 2020-02-01
End date: 2025-01-31
Investigator: Ocampo, Alejandro
Institution: University of Lausanne – LA
Funded outputs count: 3
Funder award ID: 186969
OpenAlex ID: G3746248716