Chemotherapy and radiotherapy remain the presently dominant forms of cancer treatment. Immunotherapies are making slow inroads, but remain a minority of all treatments. Both chemotherapy and radiotherapy kill cells and force cells into senescence, cancerous cells and otherwise. They are a balance struck between killing the cancer and killing healthy tissue, and are are not pleasant at all for the patient. Cancer survivors have a significantly reduced life expectancy, as large as that resulting from life-long smoking, and evidence strongly suggests that this is due to a significantly increased burden of >senescent cells left behind following treatment.
Cells become senescent for many reasons, including the DNA damage and environmental toxicity produced by chemotherapies and radiotherapies. Senescence is a state of growth arrest in which cells bloat, cease to replicate, and begin to secrete an inflammatory mix of signals intended to attract immune cells. In a youthful, healthy metabolism, senescent cells are created constantly and quickly destroyed. In older people, more senescent cells are created and the processes of destruction become less efficient. Senescent cells accumulate, and their inflammatory signaling degrades tissue and organ function. This accumulation is one of the causes of degenerative aging.
In this sense, chemotherapy and radiotherapy cause accelerated aging. That is a considerably better option than death by cancer, but it may soon be reversible, rather than a fact of life than one must accept. Senolytic therapies capable of selectively destroying some fraction of the senescent cells present in tissue are now a reality, under active development, while some of the early senolytic drugs are readily available on the global market. These have not yet been applied to cancer patients in human trials of their senolytic effects, but that is only a matter of time. The cancer research community is most interested in finding ways to reduce the long-term impact of cancer treatment.
Strategies to Prevent or Remediate Cancer and Treatment-Related Aging
The rapidly aging U.S. population coupled with improved cancer survival rates has led to predictions of unprecedented growth in the number of cancer survivors over the next decade. Unfortunately, many modalities used to cure or control cancer damage healthy tissue, leading rate of functional decline) or accentuate the aging process (e.g., paralleled “normal” aging trajectory with weakened reserve). Data suggests that cancer survivors treated with adjuvant therapies are at risk for early onset of multimorbidity commonly seen in older patients. Estimates indicate that up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with cancer- and treatment-related comorbidities, including frailty, sarcopenia, cognitive impairment, and/or subsequent neoplasms. Adult cancer survivors report engaging in healthy behaviors at levels similar to adults with no history of cancer, and are more likely to adhere to physical activity recommendations. However, there are limited data on how physical activity and other strategies mitigate age-related conditions for cancer survivors.
Aging involves multifaceted, interdependent biological processes that can be altered by cancer and its treatments. The Geroscience Hypothesis postulates that many age-related conditions can be slowed or delayed by targeting hallmarks of aging (e.g., genomic instability, stem cell exhaustion, cellular senescence, inflammation, mitochondrial dysfunction, and epigenetic alterations). Given the complementarity of hallmarks that undergird aging, cancer, and cancer treatments, geroscience-guided interventions might delay or avert the age-related conditions observed in cancer survivors.
To consider emerging strategies that might prevent, mitigate or reverse cancer- and treatment-related aging consequences, the National Cancer Institute (NCI) convened the second of two think tanks under the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Emphasis was placed on therapies linked to age-related conditions or underlying aging processes (hallmarks of aging) that could be potential targets for interventions. Although several age-related processes provide potential targets for interventions, meeting discussions focused on cellular senescence. Cellular senescence is a cell fate that includes an irreversible proliferative arrest. Senescent cells accumulate in multiple tissues, and interestingly, transplanting small numbers of senescent cells into young animals induces frailty and age-related disease. Senescent cells also develop a pro-inflammatory senescence-associated secretory phenotype (SASP) that can disrupt tissue and immune function and create a permissive microenvironment for cancer growth.
Senescent cells are a promising target for aging interventions since these cells do not divide and can be eliminated by intermittent dosing using drugs with short half-lives. The SASP is also modifiable: it can be up- or down-regulated by hormones, pathogens, and drugs. Rapamycin, a mTOR inhibitor, is a promising agent that has been implicated in both aging and senescence. Rapamycin fed to older mice was shown to delay aging and extend lifespan. Senolytics have also achieved success in recent pre-clinical studies; notably, several senolytics are repurposed cancer drugs. The first trial in humans, a pilot, open-label study of dasatinib plus quercetin for idiopathic pulmonary fibrosis, a progressive, fatal, senescence-driven disease, was recently published. After nine doses over three weeks, participants showed improved physical function one-week later. If shown to be safe and effective in larger trials, the hope is that mTOR inhibitors and senolytics can be tested as preventatives of age-related conditions in cancer populations. Research is needed to determine the safety and efficacy of dosing intervals, and systemic, as opposed to local, administration.