Should young cancer survivors be preemptively treated with senolytics or other antiaging drugs?
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Radiotherapy and chemotherapy not only kill tumor cells, but they also induce senescence in tumor and niche cells. This fosters tumor relapse. An antisenescence intervention can, therefore, improve the efficiency of adjuvant tumor therapy.
Therapy-induced senescence spreads throughout the body, causing accelerated, premature aging. This involves multimorbidity including secondary tumors, cardiovascular disease, metabolic diseases and cognitive decline — all major age-associated diseases — as well as premature frailty and enhanced mortality. The only intervention that can be offered at present is lifestyle counseling.
In mice experiments, antisenescence interventions are effective. Data from Short and colleagues show these interventions postpone the incidence of a wide range of age-associated diseases and functional losses and, if given to mice after sublethal irradiation even for only a very short while, appear to normalize rates of frailty development, loss of neuromuscular coordination, cognitive decline and incidence of secondary tumors. Efficacy in humans is not yet known, but first results from small human trials appear promising. For instance, Hickson and colleagues showed a 3-day oral course of dasatinib (Sprycel, Bristol-Myers Squibb) plus quercetin decreased senescent cell abundance — demonstrated by decreases in p16INK4A- and p21CIP1-expressing cells, cells with senescence-associated beta-galactosidase activity and adipocyte progenitors — among adults with diabetic kidney disease. Also, Justice and colleagues showed the same drug combination conferred significant improvements in physical function, as measured by a 6-minute walk distance, 4-minute gait speed and chair-stand times (P < .05), among adults with idiopathic pulmonary fibrosis.
First-generation senolytics have several side effects. However, these should be tolerable if in humans, like in irradiated mice, a very short course is sufficient to provide lifetime benefits. Moreover, an intense search is going on in many labs for more potent, less toxic senolytics.
Toxicity problems of senolytics might also be overcome by using senostatics, also termed senomorphics, instead. These drugs do not kill senescent cells but block the signals they secrete to spread senescence. For instance, the antidiabetes drug metformin has an excellent safety profile and blocks spread of senescence and premature aging in mice, and has demonstrated efficacy similar to that of senolytics.
Hickson LJ, et al. EBioMedicine. 2019;doi:10.1016/j.ebiom.2019.08.069.
Justice JN, et al. EBioMedicine. 2019;doi:10.1016/j.ebiom.2018.12.052.
Short S, et al. EBioMedicine. 2019;doi:10.1016/j.ebiom.2019.01.056.
Thomas von Zglinicki, PhD, is professor of cellular gerontology at Newcastle University. He can be reached at Newcastle University, Center for Aging and Vitality, Newcastle upon Tyne, NE4 5PL, UK; email: email@example.com. Disclosure: von Zglinicki reports research grants from Innovate UK and Nuchido Ltd to develop novel senolytics and from Biotechnology and Biological Sciences Research Council and Procter & Gamble to test use of senolytics on skin.
Although senolytic agents may have promise as a future intervention for premature aging in childhood cancer survivors, there is not nearly enough data to support the use of these agents at this time. We are very early in our research on senolytic agents. Our understanding of the mechanisms of premature aging in young survivors of childhood cancer is relatively incomplete.
We are still investigating whether certain treatments are causing this premature senescence, and why some patients are and some are not at risk for premature aging. Until we have a better understanding of the biological and molecular drivers of premature aging in this population, I don’t believe we should be preemptively treating patients with senolytic agents. It is possible that changes in treatment regimens may be sufficient to control premature aging in this population.
Additionally, there are potential safety concerns regarding preemptive use of these treatments. First-generation senolytics have been associated with side effects, and this warrants further study before they are routinely used. Because this population is already facing numerous increased risks, we need to be cautious about preemptively introducing a drug that could lead to further risks.
These agents are being studied and, ideally, we will soon have a better understanding of their potential role in preventing premature aging in childhood cancer survivors. However, I don’t think senolytic drugs should be used for that purpose until we have data that conclusively proves their efficacy and ensures their safety.
Smita Bhatia, MD, MPH, is Gay and Bew White endowed chair in pediatric oncology and professor of pediatric oncology at University of Alabama Birmingham School of Medicine and professor/director of the Institute for Cancer Outcomes and Survivorship at UAB School of Medicine and Children’s of Alabama. She also is a HemOnc Today Editorial Board Member. She can be reached at Children’s of Alabama, 1600 7th Ave. South, Birmingham, AL 35233; email: firstname.lastname@example.org. Disclosure: Bhatia reports no relevant disclosures.