Molecular and Cellular Biology of Aging

Dr. Judith Campisi strives to understand several fundamental aspects of the aging process. The Campisi laboratory works primarily with human and other mammalian cell cultures and mouse models to study the evolutionary, cellular and molecular relationships between aging, tumor suppressor mechanisms and the development of cancer. The laboratory also studies nuclear structures such as telomeres, and nuclear processes such as DNA repair and transcription, to understand how genetic and epigenetic damage leads to aging and cancer phenotypes. A recent focus of the Campisi lab is to identify links between mitochondrial function and cellular responses that can affect the development of aging phenotypes and age-related diseases in tissues and organisms.

Internationally known for her work on the role of cellular senescence in aging and cancer, Campisi considers the cellular responses of senescence and apoptosis as possible examples of an evolutionary trade-off between tumor suppression and aging (antagonistic pleiotropy). Her laboratory's current research interests include the regulation and function of the p53 and pRB tumor suppressor pathways, the structure and function of telomeres (chromosome stabilizing "caps"), and the role of DNA repair mechanisms in suppressing genomic instability and assuring organismal longevity. The Campisi laboratory also studies human premature aging and cancer-prone disorders such as the Werner and Bloom syndromes, and the role of adaptive responses in protecting cells and organisms from genotoxic and other stresses, including mitochondrially-derived oxidative stress.

Recent important discoveries made by the Campisi laboratory include the deleterious of senescent cells, including their ability to disrupt normal tissue structure and function and drive cancer progression; the striking difference between human and mouse cells in sensitivity to oxidative stress, which may explain the higher rate of aging and increased frequency of cancer in mice; the reversal of the senescent state in cultured cells (long thought to be impossible); the dualistic nature of telomeres, which can protect against senescence and cell death under certain stressful conditions but sensitize cells to oxidative and other stresses under other conditions.

Many projects in the Campisi laboratory are interdisciplinary and carried out in collaboration with other groups at the Buck Institute. The Campisi and Lithgow laboratories have a joint grant to study conserved mechanisms by which cell cycle checkpoint functions impact aging in nematodes and mammalian cells. In this project, the two laboratories combine classic and molecular genetics with organismal physiology and cell biology approaches. The Campisi laboratory is also part of a newly funded Program Project Grant directed by Dr. Julie Andersen. Within this grant, the laboratory collaborates with Drs. Chris Benz, Simon Melov and Brad Gibson to understand how mitochondrially-generated oxidative stress alters p53 structure and function. In addition, the grant supports collaborations with Dr. David Nicholls to understand how mitochondrial bioenergetics affects p53 function and cell fate decisions, and with Dr. Andersen to understand how post-mitotic neurons respond to genotoxic and oxidative stress. The Campisi laboratory is also part of an ongoing Program Project Grant directed by Dr. Jan Vijg . Vijg and Campisi have a longstanding collaboration in which they use human and mouse cultures and mouse models to understand how genome maintenance and repair systems postpone the development of aging and cancer. Vijg and Campisi recently initiated a new collaboration to explore species-specific differences and the molecular basis for stochastic fluctuations in gene expression (transcriptional noise). The Campisi laboratory also has new collaborations with Dr. Pankaj Kapahi's laboratory to explore links between TOR signaling, translational control and cellular senescence, and with Dr. Xianmin Zeng's laboratory to understand stem cell aging.