Project Details
Projekt
The impact of chronic genome instability on tissue homeostasis and how reduced diet alleviates DNA damage-driven functional deterioration
Applicant
Professor Jan Hoeijmakers, Ph.D.
Subject Area
Cell Biology
Toxicology, Laboratory Medicine
Toxicology, Laboratory Medicine
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 496650118
To properly maintain cell functioning and homeostasis and respond to different environmental stimuli, cells require intact genome and proficient chromatin maintenance. Gene expression profiling has identified numerous processes, which are altered in aging, but how these changes arise is largely unknown. We combined nascent RNA sequencing and RNA polymerase II ChIP-seq to explore underlying mechanisms influencing gene expression changes in wildtype aged mice. We found that in 2-year-old livers, 40% of elongating RNApolII complexes are stalled, drastically lowering productive transcription at a rate of 0,35%/kb and skewing transcriptional output in a gene-length-dependent fashion. This ‘transcription stress’ (TS) is directly caused by endogenous DNA damage and explains the majority of gene expression changes in aging in many organs, affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience and is evolutionary conserved from nematodes to man. These findings disclose how DNA damage functionally underlies major aspects of normal aging. Although aging is universal, not every tissue and cell type ages the same rate. Understanding the key mechanisms responsible for tissue-specific aging could help finding effective anti-aging strategies. Currently, dietary restriction (DR), is the most robust intervention delaying age-associated pathologies in numerous tissues and species, but how it works is still largely unknown. Here, we propose a comprehensive multidisciplinary (in vivo, in vitro and in silico) approach to investigate how age-related accumulating DNA damage influences homeostasis in 4 key organs (heart, muscle, brain and kidney) and how DR counteracts aging. We aim to 1. characterizing the genomic, transcriptional and metabolic burden of increasing DNA damage and TS in the above postmitotic tissues in progeroid repair mutants and wt mice. 2. Examine the effect of DR-induced metabolic redesign on TS, DNA damage and organismal health. 3. Identify key mechanisms and signaling pathways responsible for DR-based metabolic redesign.
DFG Programme
Research Units
