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Generation of mouse models for the study of cellular senescence in aging and cancer

Final Report Summary - MODELLING SENESCENCE (Generation of mouse models for the study of cellular senescence in aging and cancer)

One of the central mechanisms providing protection from cancer in mammals is a cellular programme termed cellular senescence. Senescence is activated by cells in response to various types of physiologic stress, such as deoxyribonucleic acid (DNA) damage, uncapping of telomeres (structures protecting the ends of chromosomes), oxidative stress, and aberrant activation of oncogenes - genes promoting cancer. Senescence is also thought to contribute to organismal aging, and to restrict the renewal of normal stem cells. When cells enter senescence, they cease to divide and undergo a series of dramatic metabolic and morphologic changes.

Cellular senescence has been studied for many years in cultured cells, in which the different physiological triggers for it have been characterised, as well as the genes that activate this programme. Studies in recent years have provided strong evidence that cellular senescence does occur also in vivo. It has been shown that senescent cells appear within benign tumours, and it is thought that the activation of senescence at this stage prevents these tumours from progressing to a malignant state. Furthermore, there are indications that stem cells undergo senescence during aging. However, the traits of senescent cells in vivo, their effects on tissue physiology and their subsequent fate are very poorly characterised.

To shed light on the nature of this phenomenon in vivo, we have developed mice in which the senescence programme can be activated at will in different tissues. This allows us to characterise the immediate effects of the senescence programme within a physiological tissue context, both in the normal and in the cancerous setting. We found complex and intriguing effects on tissue physiology that are caused by activating the senescence programme in vivo.