MODELING SENESCENCE

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

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 Obiettivo del progetto (Objective)

'Cellular senescence is a central biological mechanism for cancer prevention in mammals. Cells enter senescence when tumor-inducing genes are aberrantly activated, and in response undergo an arrest in proliferation accompanied by dramatic changes in metabolism and morphology, thus preventing their further development into tumors. Various types of physiologic stresses can also induce senescence, and this process is thought to play a central role in promoting aging, possibly by limiting the proliferative potential of stem-cell pools. While much is known about senescence in cultured cells, basic questions regarding the roles of this process in the living organism are still unanswered. In this proposal we describe the development of systems for the study of senescence in the living organism. We utilize the two central molecular activators of senescence: the p16INK4a and p19ARF genes. These genes are specifically induced during cellular senescence, and their expression is sufficient to induce this state. We will develop and characterize mice in which the expression of p16INK4a or p19ARF can be induced in multiple tissues through tetracycline administration, in order to induce cellular senescence in these tissues. This will allow us to experimentally generate senescent cells in the adult mouse and characterize their molecular and functional traits. We will study the effects of cellular senescence on tissue and organism physiology, and assess whether induction of senescence induces aging-like phenotypes. This system will provide the first genetic system to study this central biological program in its proper physiologic context, shedding light on aging processes and cancer prevention mechanisms.'

Introduzione (Teaser)

European scientists have discovered a molecular switch for cellular senescence that can make a significant contribution in the fight against cancer.

Descrizione progetto (Article)

Cellular senescence is an important mechanism for cancer prevention in mammals that involves normal cells losing their ability to divide while undergoing a series of metabolic and morphological changes. The process is activated by cells in response to physiological stress, such as DNA damage, which can cause the development of tumours. Senescence is also thought to contribute to the ageing of the entire organism and limit the renewal of normal stem cells.

Cultured cells are analysed to determine the different physiological triggers for cellular senescence, including the genes that activate the process. Recent studies have revealed that senescent cells can be found within benign tumours and may prevent these tumours from becoming malignant. There is also evidence that stem cells - the body's master cells - experience senescence during ageing. However, the action of senescent cells within the actual organism and their subsequent fate is still not well understood.

The EU-funded 'Modelling senescence' project is studying cellular senescence within the organism, rather than cultured cells. Researchers have created a technique where the senescence process can be turned on at will, enabling scientists to determine the effects of the process on both normal and cancerous tissues.

Project partners have developed mice in which expression of the two main molecular activators of the process, the p16INK4a and p19ARF genes, can be induced in multiple tissues by administering tetraclycine. This allows scientists to experimentally generate senescent cells and determine their molecular and functional traits.

Work conducted by the project consortium has provided the first genetic approach for studying this crucial biological process within tissues and organisms, rather than cultured cells. It will contribute to our growing understanding of the ageing process and cancer preventing mechanisms, as well as Europe's growing knowledge economy.