Abstract
Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues.
Highlights
Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes
Some oncogenes, such as the BRAF oncogene, may trigger senescence acting via mitochondrial pyruvate kinase metabolism to regulate cell cycle progression
It is hoped that the AFFIRM LITE study will demonstrate the safety of higher dose Fisetin, to permit clinical trials to assess the potential impact of Fisetin on resilience, age-related dysfunction, and chronic diseases, and as an adjunctive treatment for cancer
Summary
Life-expectancy has doubled in the past 200 years and, whilst most of the early gains were in childhood longevity, in the past 70 years the majority of gains have been in older people [1,2]. The oldest old group of over 85 year olds is predicted to double over the same period, from 2 to 4% [3]. This increase in lifespan has been accompanied by an increase in rates of chronic disease. Life-span has outpaced health-span [4], as the burden of chronic health conditions has increased in this older population. Cancer is more common in older age groups with predictions of substantial increases in the 15 years of approximately 50% in developed countries,. One of the key processes of aging—senescence—links aging and cancer together, and this is the focus of this article
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