Aging, tumor suppression and cancer: high wire-act!
Introduction
There have been extraordinary advances in the last decade in understanding the evolution of genomes and the genetic basis for aging. The idea that aging is under genetic control may now seem obvious, especially considering the sometimes large differences in life span among organisms with comparatively similar genomes (Williams, 1957). Recent discoveries, however, have explicitly identified evolutionarily conserved genes that are important regulators of life span, as well as early life fitness, among diverse species (Guarente and Kenyon, 2000, Kirkwood and Austad, 2000, Walker et al., 2000, Finch and Ruvkun, 2001). In general, these recent findings support modern evolutionary theories of aging. They have uncovered candidate genes on which evolution likely acted to produce species-specific life spans, and elucidated conserved pathways within organisms that link metabolism, reproduction and life span. At present, we still know remarkably little about the cellular and molecular bases for longevity differences among species. However, owing in large measure to our recent understanding of the genetic similarities in longevity pathways among species, we are gaining important insights into the mechanisms that control aging within species.
Here, we review the evolutionary theory of antagonistic pleiotropy, and emerging evidence that aging in complex multicellular organisms is caused in part by the antagonistically pleiotropic effects of tumor suppressive mechanisms—mechanisms that evolved to prevent the development of cancer in young organisms.
Section snippets
Environment and the evolution of genomes
An obvious tenet of any evolutionary theory is that hereditable traits, including species-specific life spans, are controlled by genes, and that these genes in turn evolved in response to environmental pressures. In addition, the environments in which genomes evolve are typically fraught with natural hazards—predators, infection, food scarcity, harsh climatic conditions, etc., which generally kill organisms long before they reach “old age”. That is, the environments in which genomes evolve
Tumor suppressor mechanisms
Because cell division can lead to mutations and hence cancer, organisms with renewable tissues had to evolve strategies to prevent the cancer. Collectively, these strategies are termed tumor suppressor mechanisms. Tumor suppressor mechanisms can, in general, be broadly classified into two major categories—caretakers and gatekeepers (Kinzler and Vogelstein, 1997).
Caretaker tumor suppressors act on the genome, generally by preventing or repairing DNA damage. Thus, caretaker tumor suppressors
Antagonistic pleiotropy
Because aging is a consequence of the declining force of natural selection with age, traits that benefit young organisms—suppressing cancer, for example—can have unselected deleterious effects—driving aging phenotypes, for example—later in the life span. This is the concept of evolutionary antagonistic pleiotropy (Williams, 1957, Rose, 1991, Kirkwood and Austad, 2000, Finch and Ruvkun, 2001). In simple terms, antagonistic pleiotropy holds that what is good for an organism when it is young can
Causes of senescence
The senescence response was first formally described as the process that limits the proliferation of human cells in culture (Hayflick, 1965). We now know that this limit is due in large measure to the loss of telomeric DNA that occurs when cells that do not express telomerase undergo DNA replication (Levy et al., 1992, Wright and Shay, 2001). Telomeres, the DNA sequence and proteins that cap the ends of linear chromosomes, are essential chromosomal elements, loss of which causes genomic
Testing the hypothesis that gatekeeper tumor suppressors, specifically the senescence response, is antagonistically pleiotropic
The hypothesis that gatekeeper tumor suppressors, and particularly the senescence response, is antagonistically pleiotropic makes a number of predictions, not all of which have been tested experimentally. Here, we review the major predictions and, where applicable, the pertinent experimental results.
Summary, conclusions and challenges
We hypothesize that mechanisms that protect complex organisms from cancer (gatekeeper tumor suppressors) do so in balance against the mechanisms that promote longevity (Fig. 1). These cancer protection mechanisms engage the cellular processes of apoptosis and senescence. Both apoptosis and senescence are crucial for suppressing malignant tumorigenesis, yet both have the potential to contribute to aging and age-related pathology. The senescence response is notable in that the senescent phenotype
Acknowledgements
As always, thanks to past and present lab members for their refreshing ideas and hard work, colleagues for stimulating discussions and valuable reagents, and the National Institute on Aging, Department of Defense and University of California Breast Cancer Research Programs, Ellison Medical Foundation and Department of Energy for research support.
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