The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence
Shameel Shafqat, … , Areez Shafqat, Shahrukh K. Hashmi
Shameel Shafqat, … , Areez Shafqat, Shahrukh K. Hashmi
Published July 1, 2022
Citation Information: J Clin Invest. 2022;132(13):e158452. https://doi.org/10.1172/JCI158452.
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Review Series

The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence

Abstract

Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment–induced early aging accounts for significant morbidity, mortality, and health expenditures among cancer survivors. One major mechanism driving this accelerated aging is cellular senescence; cancer treatments induce cellular senescence in tumor cells and in normal, nontumor tissue, thereby helping mediate the onset of several chronic diseases. Studies on clinical monitoring and therapeutic targeting of cellular senescence have made considerable progress in recent years. Large-scale clinical trials are currently evaluating senotherapeutic drugs, which inhibit or eliminate senescent cells to ameliorate cancer treatment–related aging. In this article, we survey the recent literature on phenotypes and mechanisms of aging in cancer survivors and provide an up-to-date review of the major preclinical and translational evidence on cellular senescence as a mechanism of accelerated aging in cancer survivors, as well as insight into the potential of senotherapeutic drugs. However, only with time will the clinical effect of senotherapies on cancer survivors be visible.

Authors

Shameel Shafqat, Evelyn Arana Chicas, Areez Shafqat, Shahrukh K. Hashmi

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Figure 1

Cancer therapies can induce senescence via two pathways.

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Cancer therapies can induce senescence via two pathways. The replicative...
The replicative senescence pathway is initiated by a DDR that triggers the p53/p21CIP1 axis and inhibits CDK2. Alternatively, oncogene-induced senescence is triggered by activation of the CDNK2A gene locus encoding p16INK4, which inhibits CDK4/6. Both senescence-mediating pathways converge by inhibiting phosphorylation of the Rb protein, which, in turn, causes senescence. Senescent cells release a characteristic secretome termed the SASP, components of which reinforce senescence in an autocrine fashion, termed cell-autonomous effects. Moreover, SASP factors exert non-cell-autonomous effects on neighboring and distant cells. In this regard, they can also mediate ECM degradation, chronic sterile inflammation, and immunosenescence. The resulting tissue dysfunction manifests clinically as accelerated aging phenotypes and a higher burden of chronic diseases, including cancer. Indeed, a higher senescent cell burden may be responsible for these aging phenotypes being observed in higher frequencies in cancer survivors, as compared with healthy controls without a history of cancer.