Discussing the Accelerated Aging of Cancer Survivors

It is well known that cancer survivors who underwent chemotherapy or radiotherapy exhibit a shorter life expectancy, greater chance of unrelated cancer incidence, and greater risk of age-related disease. The most reasonable hypothesis at present is that these undesirable outcomes are the result of an increased burden of senescent cells. Historically, cancer treatments have been in large part designed to force cancerous cells into senescence, those that are not killed outright by the therapy. Since these cancer therapies are toxic to cells, they also tend to cause off-target cell death and senescence. It is possible that similar issues can arise from the more aggressive cancer immunotherapies, but the mechanisms by which the burden of cellular senescence is increased would be very different and more indirect.

Today's open access paper presents a broad discussion of the ways in which cancer therapies may provoke accelerated aging. It is centered on an increased burden of cellular senescence, but also touches on other hallmarks of aging. Cancer patients should hope that cellular senescence is the primary mechanism by which accelerated aging manifests following treatment, as senolytic treatments capable of selectively destroying lingering senescent cells are under development. Clinical trials to assess whether first generation senolytics (such as the dasatinib and quercetin combination) prevent the increased risk of age-related conditions in cancer survivors would take years to run though to a robust conclusion. It may be possible to get a good idea as to the efficacy of senolytics more rapidly, however, by looking at whether or not they can meaningfully reduce some of the side-effects of chemotherapy or radiotherapy in the first few months after treatment.

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

Cancer survivors are at a significantly higher risk of age-related diseases than non-cancer controls, comparable to incident rates in the elderly population. Cellular senescence is a biologic aging hallmark and plays a causative role in numerous age-related diseases, many of which affect cancer survivors. Furthermore, many cancer therapies induce senescence, suggesting that therapy induced senescence (TIS) may be responsible for cancer survivors' various side effects.

A seminal study showed that treating fibroblasts with the chemotherapeutic doxorubicin induces senescence, as indicated by higher SA-β-gal, p16INK4, p21CIP1, and DNA damage response expression. Notably, doxorubicin induces senescence systemically and not only in tumor cells. In addition, doxorubicin significantly impairs hematopoietic stem cell function by reducing the number of colony-forming units, an effect rescued by ganciclovir-mediated (GCV-mediated) clearance of senescent cells (SCs). Furthermore, cardiomyopathy, a well-known side effect of doxorubicin, was almost entirely prevented by GCV treatment. Treating mouse breast cancer models with doxorubicin arrests tumor growth, with later cancer relapse, but combining doxorubicin with GCV significantly improves the survival of mice, reduces the incidence of metastasis, and reduces the number of metastatic foci in mice that developed metastasis. Lastly, the nocturnal running time of mice was significantly impaired after doxorubicin treatment, and GCV treatment almost entirely rescued this effect.

Eliminating SCs alleviates many acute effects (elevated inflammatory markers and cardiotoxicity) and chronic effects (fatigue, cancer relapse, metastasis) of doxorubicin, suggesting TIS-dependent pathogenesis of cancer therapy-related adverse effects in survivors, at least those treated with doxorubicin.

Focusing on cellular senescence over other mechanisms assumes that senescence drives accelerated aging processes in cancer survivors while conferring a relatively limited role to other biologic aging hallmarks. This, however, has not been proven; but since transformative preclinical advancements in alleviating age-related health conditions have been achieved by elimination of SCs, we feel it appropriate to focus on cellular senescence and advocate that considering cellular senescence as the driver of early aging in survivors could have great benefits in advancing the implementation of potential cutting-edge interventions to mitigate premature aging.

Undoubtedly, there is a concerted effort from the scientific community to address the phenotypes, mechanisms, biomarkers, and interventions of early aging in cancer survivors. Knowledge about cellular senescence has exponentially increased in recent years on the basis of preclinical studies, but only the outcomes of well-designed, robust clinical studies can prove whether senotherapies will be beneficial in decreasing morbidity, increasing longevity, and improving quality of life in survivors. Thus, the scientific community must go through the rigorous process of translating bench work into clinical trials with a well-defined outcome. Only after completion of randomized trials, if senolytics and other anti-aging drugs show excellent short- and long-term safety and efficacy, should these drugs be used in the clinic.