Professor of Molecular Genetics at Erasmus University Rotterdam (The Netherlands)
Using DNA repair-deficient mouse mutants and human syndromes we discovered that DNA damage-induced transcription stress is a main cause of systemic aging, and that nutritional interventions delay aging and transcription stress and extend healthspan.
Previously, we generated a world-wide unique collection of mouse models with DNA damage repair defects, which proved to be excellent paradigms for very severe human repair disorders. We discovered that these conditions are actually accelerated aging diseases, linking DNA repair not only to cancer but also aging. Our subsequent findings identified DNA damage as main cause of aging and recently also elucidated how: DNA lesions physically block transcription causing genome-wide transcription stress preferentially of long genes, as DNA damage is stochastic. Since gene expression initiates all cellular processes, lowered and particularly dysbalanced transcriptional output with aging affects numerous cellular pathways, explaining multimorbidity and other aging hallmarks as secondary consequences. This includes frailty, neurodegeneration (resembling Alzheimer disease), hepato-, nephro-, and hematological aging, cardiovascular disease, osteoporosis, etc. — addressing a massive unmet medical need and identifying DNA damage as main cause of aging.
Additionally, we discovered that reducing calorie intake triples lifespan and enormously delays accelerated aging in our repair-deficient mice. Translating reduced caloric intake to progeroid DNA repair-deficient children with Cockayne syndrome and trichothiodystrophy, disorders with a life expectancy often limited to childhood and no cure, strongly improved all disease parameters, most impressively neurofunction and significantly extends lifespan. This has led to a complete reversal of nutritional guidelines: counterintuitively these growth-retarded patients should have low instead of high calorie intake and it constitutes the first very effective treatment of any DNA repair disorder. Moreover, we discovered that calorie restriction reduces genome-wide transcription stress by lowering DNA damage, explaining its universal anti-aging, lifespan-extending activity, which has been elusive for almost a century.
By understanding the main cause of aging and the underlying mechanisms of aging-associated diseases we hope to find ways to effectively delay/prevent aging pathologies and promote healthy aging — improving quality of life of a significant fraction of the human population.
The overall goal of the Hoeijmakers lab is to fully understand how accumulating DNA damage contributes to systemic aging and to various age-related processes like stem cell exhaustion, cell death, cellular senescence and functional decline. Detailed gene expression analysis of progeroid DNA repair-deficient mouse mutants revealed close similarity to natural aging but also to a highly conserved anti-aging ‘survival’ response, which resembles the response to calorie restriction. Hence, DNA damage-driven premature aging links with both aging and longevity.
Specific questions we would like to explore are:
To obtain answers to the above questions we aim for an integral, multi-omics approach in multiple organs and tissues of normal and accelerated aging models and after interventions influencing aging. This insight is indispensable to design rational-based strategies, which effectively prevent or delay major aging-associated diseases, most notably neurodegeneration, to promote healthy aging.
Professor of Molecular Genetics at Erasmus University Rotterdam (The Netherlands)