In this NIH Program Project a consortium of 6 investigators under the leadership of Dr. Jan Vijg, Chairman of the Department of Genetics, addresses the question of DNA damage as the main driver of the process of aging. Based on previous observations that genetic defects in genome maintenance are associated with multiple symptoms of premature aging, the consortium studies the mechanistic basis of the possible causal role of genotoxic stress in aging. Extensive characterization at the phenotypic level showed that only mutations in select genome maintenance pathways, e.g., nucleotide excision repair, double-strand break repair, lead to premature aging. Other pathways, most notably DNA mismatch repair, are associated with cancer but do not elevate the frequency of non-cancer, degenerative symptoms of aging. It was found that both cellular responses to DNA damage, i.e., p53-mediated apoptosis and cellular senescence, and increased levels of genome rearrangements (in contrast to point mutations, which were mainly important for cancer) were critical in the etiology of the observed premature aging phenotypes. Surprisingly, the increased genotoxic stress caused by the DNA repair defects also elicited a protective response in the form of a dampening of the growth hormone (GH)/Insulin-like growth factor (IGF) axis. The current main topics of study are the relationship between segmental premature aging and normative aging, the balance between stochastic and regulated aspects of aging and to extend the concept of genome maintenance to healthy human aging using Einstein's cohort of Ashkenazi Jewish centenarians. This should lead to new rationales for intervention strategies aimed at improving late-life health and reducing mortality rates.
The following investigators are leading the 5 different research projects:
Dr. Jan Hoeijmakers (Erasmus University, Rotterdam, The Netherlands): Project 1 - Genetic and Environmental Manipulation of Aging
Dr. Jan Vijg (Albert Einstein College of Medicine, New York, NY, USA): Project 2 - Genome Dynamics in Aging
Dr. Judy Campisi (Buck Institute for Age Research, Novato, CA, USA: Project 3 – Genome maintenance, cellular phenotypes and Aging
Dr. Paul Hasty (University of Texas Health Science Center, San Antonio, TX, USA): Project 4 – The impact of cellular defense on the role of Ku80 in genome maintenance and longevity assurance
Dr. Yousin Suh (Albert Einstein College of Medicine, New York, NY, USA): Project 5 – Genome Maintenance and Human Longevity
Core Leader of the Animal and Pathology Core is Dr. Harry van Steeg (National Institute for Public Health and the Environment, Bilthoven, The Netherlands)
Selected publications:
Holcomb VB, Rodier F, Choi Y, Busuttil RA, Vogel H, Vijg J, Campisi J, Hasty P. Ku80 deletion suppresses spontaneous tumors and induces a p53-mediated DNA damage response. Cancer Res. 2008;68:9497-9502.
Garinis GA, van der Horst GT, Vijg J, Hoeijmakers JH. DNA damage and ageing: new-age ideas for an age-old problem. Nat Cell Biol. 2008;10:1241-1247.
Busuttil RA, Muñoz DP, Garcia AM, Rodier F, Kim WH, Suh Y, Hasty P, Campisi J, Vijg J. Effect of Ku80 deficiency on mutation frequencies and spectra at a LacZ reporter locus in mouse tissues and cells. PLoS One. 2008;3:e3458.
Vijg J, Campisi J. Puzzles, promises and a cure for ageing. Nature. 2008;454:1065-1071.
Park JY, Cho MO, Leonard S, Calder B, Mian IS, Kim WH, Wijnhoven S, van Steeg H, Mitchell J, van der Horst GT, Hoeijmakers J, Cohen P, Vijg J, Suh Y. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice. PLoS One. 2008;3:e2346.
Melis JP, Wijnhoven SW, Beems RB, Roodbergen M, van den Berg J, Moon H, Friedberg E, van der Horst GT, Hoeijmakers JH, Vijg J, van Steeg H. Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes. Cancer Res. 2008;68:1347-1353.
Calder RB, Beems RB, van Steeg H, Mian IS, Lohman PH, Vijg J. MPHASYS: a mouse phenotype analysis system. BMC Bioinformatics. 2007;8:183.
Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, van Leeuwen W, Theil AF, Vermeulen W, van der Horst GT, Meinecke P, Kleijer WJ, Vijg J, Jaspers NG, Hoeijmakers JH. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature. 2006;444:1038-1043.
Dollé ME, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E, Niedernhofer LJ, van der Horst G, Hoeijmakers JH, van Steeg H, Vijg J. Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat Res. 2006;596:22-35.
Wijnhoven SW, Beems RB, Roodbergen M, van den Berg J, Lohman PH, Diderich K, van der Horst GT, Vijg J, Hoeijmakers JH, van Steeg H. Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric restriction. DNA Repair (Amst). 2005;4:1314-1324.
Hasty P, Vijg J. Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity. Aging Cell. 2004;3:55-65.
Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J. Aging and genome maintenance: lessons from the mouse? Science. 2003;299:1355-1359.
Other Special Projects in the Department of Genetics: