Accelerated Aging as a Paradigm to Understand the Late Effects of Cancer Therapies.

Long-term childhood adolescent and young adult (CAYA) cancer survivors may develop health conditions that often coexist at young adulthood or middle age and that normally occur in persons aged 65 years and older, including cardiovascular and musculoskeletal diseases, metabolic syndrome, and secondary malignancies, suggesting that a process of accelerated aging occurs. This chapter summarizes epidemiological evidence and physiological mechanisms of accelerated aging, and possible preventive measures to delay the process of accelerated aging in CAYA cancer survivors. Evidence is mounting that in addition to a high prevalence of specific and multiple aging-related chronic diseases (multimorbidity), CAYA cancer survivors seem to also have a higher risk of other aging phenotypes, including frailty, poor physical performance, and changes in body composition (low muscle and high fat mass). Risk factors for these aging phenotypes include treatment-related factors (cranial-spinal radiotherapy, anthracyclines), sociodemographic factors (higher age, female sex, low socioeconomic status), and unhealthy lifestyle factors (i.e., physical inactivity, obesity, smoking, excess alcohol consumption). The process of accelerated aging may be prevented or delayed by adopting and maintaining a healthy lifestyle, so that CAYA cancer survivors may live a life with optimal quality of life after cancer.

Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the Lifespan of Survivors of Childhood Cancer.

The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.