Cellular aging and cancer

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Abstract

Aging is manifest in a variety of changes over time, including changes at the cellular level. Cellular aging acts primarily as a tumor suppressor mechanism, but also may enhance cancer development under certain circumstances. One important process of cellular aging is oncogene-induced senescence, which acts as a significant anti-cancer mechanism. Cellular senescence resulting from damage caused by activated oncogenes prevents the growth of potentially neoplastic cells. Moreover, cells that have entered senescence appear to be targets for elimination by the innate immune system. In another aspect of cellular aging, the absence of telomerase activity in normal tissues results in such cells lacking a telomere maintenance mechanism. One consequence is that in aging there is an increase in cells with shortened telomeres. In the presence of active oncogenes that cause expansion of a neoplastic clone, shortening of telomeres, leading to telomere dysfunction, prevents the indefinite expansion of the clone, because the cells enter crisis. Crisis results from chromosome fusions and other defects caused by dysfunctional telomeres and is a terminal state of the neoplastic clone. In this way the absence of telomerase in human cells, while one cause of cellular aging, also acts as an anti-cancer mechanism.

Introduction

It is often stated that, because cancer incidence is strongly age-related, cancer must be a disease of aging. In the past, this has not been a universally accepted view [1]. If cancer is not related to aging, then the age-related increase in cancer is explained by the facts that cancer takes several molecular steps for full development, and each step takes time; however, those steps are neither more nor less likely in an old individual than a young one. Although there is some validity to this view, it has also become clear over the past decade or so that aging impacts cancer initiation and progression in many ways. Aging comprises many time-dependent changes in organs and tissues; a variety of age-dependent changes occur at the cellular level in tissues. Collectively these changes are termed cellular aging. In this review the basic science of cellular aging and its impact on cancer are reviewed.

While the emphasis in this review is on specific aspects of cellular aging and their impact on cancer, it is important to place this in context. A very large variety of time-dependent events take place in the human body and to varying extents cause the changes in the body that we term aging. While the aspects of cellular aging reviewed here are important, they no doubt form only a very small aspect of the total set of processes that comprise the aging process as a whole.

Section snippets

Telomere shortening in culture

The earliest described form of cellular aging comprised the phenomenon often associated with the name of its discoverer, Leonard Hayflick [2]. In the 1960s Hayflick showed that normal human cells could not divide indefinitely in culture. Decades later it was shown that this limit results from progressive cell division-dependent shortening of telomeres [3], [4]. Telomeres shorten in most dividing human somatic cells because they lack activity of the enzyme complex telomerase, which is required

Senescence resulting from the action of oncogenes rather than telomere shortening

Although senescence was first described as the result of telomere shortening, it was later recognized that many cellular events can drive cells into senescence. Although these events are often described as premature stress-induced senescence, the term premature does not have any real meaning here – senescence as an end-point can be attained by many stresses, one of which is telomere dysfunction. Among these stresses, as a cause of senescence, is the action of activated forms of oncogenes [49],

Conclusion

This review has emphasized the role of telomere biology as a major factor in the anti-cancer action of cellular aging. Continued research in this area will yield more insights into the role of this aspect of aging at the cell level in preventing human cancer. Additionally, oncogene-induced senescence forms an important barrier to cancer development. Recent progress in understanding the consequences of senescence in tissues has emphasized the role of the innate immune system. For both forms of

Reviewers

Tamas Fulop, M.D., Ph.D., Department of Medicine, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, IUGS, Pavillon Argyll, 375, rue Argyll, Sherbrooke, Quebec J1J 3H5, Canada.

Irmgard Irminger-Finger, Ph.D., Head Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, University Hospitals Geneva, 30 Blvd de la Cluse, CH-1211 Geneva, Switzerland.

Conflict of interest statement

The author has no conflict of interest.

Dr. Peter Hornsby obtained a Ph.D. in Cell Biology at the Institute of Cancer Research of the University of London. He has held faculty positions at the University of California San Diego, the Medical College of Georgia, and Baylor College of Medicine. Currently he is professor in Department of Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio.

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    Dr. Peter Hornsby obtained a Ph.D. in Cell Biology at the Institute of Cancer Research of the University of London. He has held faculty positions at the University of California San Diego, the Medical College of Georgia, and Baylor College of Medicine. Currently he is professor in Department of Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio.

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