The age of cancer Advancing age ranks as the most potent of all “carcinogens” 7 an asso-ciation so strong that we often fail to acknowledge its prominence. In humans, cancer incidence rises expo-nentially in the final decades of life, culminating in a lifetime risk ofone in two for men and one in three for women This link between aging and cancer portends a formidable problem as the ever—increasing number of aged individuals in our society promises to strain already limited health resources in the decades ahead. By 2030, more than 20% ofthe US pop-ulation will be 65 years or older and the number ofindividuals over the age of 85 years will double to 9 million The aggregate number of cancer cases is expected to rise sharply with these graying demographics, and in the com—ing decades, cancer will likely replace heart disease as the leading cause of death in this country. Thus, as we enter this “Age of Cancer,” any mechanistic insights into the aging—cancer connec—tion carry with it opportunities for new preventive and therapeutic strategies to reduce the anticipated high cancer but—den in our aging society. What underlies the intimate link between aging and cancer? This relationship is not a simple one, as reflect—ed by the simple fact that the age-relat—ed increase in cancer incidence is not equivalent across all cancer types. The dramatic escalation in cancer risk that occurs from ages 40 to 80 is fueled largely by a marked increase in epithe—lial malignancies, particularly carcino—mas of the breast, lung, colon, and prostate (Figure 1). In contrast, tumors originating from mesenchymal (sarco—ma) or hematopoietic (leukemia/lymphoma) lineages, so common in pedi—atric patients, exhibit only modest increases in the adult years (Figure 1).

Equally intriguing and perplexing is that the laboratory mice do not follow the same distinctive cancer spectra and kinetics of aging humans (3, 4). More—over, the cancers that do emerge in mice show modest levels of chromosomal aberrations—in sharp contrast to the complex genomes of adult epithelial cancers, which are typified by chromo—somal gains and losses (aneuploidy), complex rearrangements (nonrecipro-cal translocations), and regional ampli—fications and deletions (reviewed in ref. 5). Dissection of the molecular mecha—nisms underlying these cancer-associat-ed chromosomal structural aberrations has emerged as an important focus in the cancer field—a focus driven largely by the view that elucidation of genome instability would lead to fundamental insights into the pathogenesis of the major cancer types affecting humans: epithelial cancers in the aged. The data reviewed in this report lend support to the thesis that telomere dysfunction and resultant breakage—bridge-fusion cycles represent one such mechanism fueling genome instability in nascent