Targeting Cellular Senescence in Cancer and Ageing - Dr. Daniel Muñoz-Espín

Targeting Cellular Senescence in Cancer and Ageing

Global populations continue to age, increasing the prevalence of chronic age-related pathologies, and producing an associated public health pandemic. Since we are born, and even before, we all are constantly exposed to multiple sources of damage and stress in our tissues that, eventually, cannot be repaired and, ultimately, this is the origin of many age-related disorders. Severe or unrepairable damage often triggers a stereotypic and conserved cellular response during evolution, known as senescence. Senescent cells are unrepairable – damaged – cells that implement a stable cell cycle arrest and recruit the immune system in order to mediate their own clearance. The main purpose of cellular senescence is hence to prevent the proliferation of damaged cells and, at the same time, to trigger tissue repair through the secretion of a complex mixture of extracellular – remodelling – factors. This is exemplified by "The Light Side of Senescence", which results in an efficient role in promoting wound healing, tissue homeostasis and tissue regeneration. Remarkably, senescence also plays programmed physiological functions and contributes to tissue remodelling during embryonic development.
However, all of these beneficial aspects demand an efficient subsequent clearance of senescent cells by the immune system, the so-called "immunosurveillance". When the damage is permanent the clearance process deregulates at some point and senescent cells accumulate in our tissues, this is what we call "Zombie Cells". These cells are characterised by an intense secretion of (SASP) factors affecting surrounding tissue and causing chronic inflammation. During ageing, our percentage of "Zombie Cells" relentlessly increases causing tissue dysfunction, and these cells associate with a wide variety of age-related disorders, including cancer, fibrosis, cardiovascular disorders, diabetes, obesity, sarcopenia, osteoarthritis and osteoporosis, and neurological disorders. This is "The Dark Side of Senescence". Besides multiple human chronic age-related disorders, senescence is also a defining feature of precancerous lesions and it is an important response to cancer therapy-induced stress. When senescent or "zombie" cells accumulate in damaged tissues can drive a variety of tumour-promoting activities, either by non-cell autonomous events (by releasing complex proinflammatory/protumorigenic cocktails of factors) or by cell autonomous events (by re-entering the cell cycle and the acquisition of aggressive clonogenic growth potentials).
Preclinical studies have convincingly concluded that the elimination of senescent cells by pharmacologically-active compounds (Senotherapies) can ameliorate and even revert the pathological manifestations of multiple disorders in animal models and, importantly, significantly increase their lifespan. The field of Senotherapies has now ballooned and the first drugs with senolytic activity are already in early phase clinical trials to treat several chronic age-related disorders and for a more efficient management of cancer. This is currently a hot topic in translational research and involves countless laboratories and new and consolidated Pharmas developing and validating new generation senotherapies. We are entering an exciting era, where we will be able to move anti- senescent therapies towards medical applications, a strategy that may have important impacts on precision medicine, healing, tissue repair, regeneration, cancer and, ultimately, on human healthspan and longevity, although this remains a formidable challenge in medicine.

Dr. Daniel Muñoz-Espín
CRUK Early Detection Programme Group Leader
Department of Oncology, University of Cambridge