Research

Cellular senescence in aging and age-related diseases

Cellular senescence, a permanent state of cell cycle arrest accompanied by a complex phenotype, is an essential mechanism that limits tumorigenesis and tissue damage. In physiological conditions, senescent cells can be removed by the immune system, facilitating tumour suppression, wound healing and possibly embryonic development. However, as we age, senescent cells appear to accumulate in tissues, either because an aging immune system fails to remove them, the rate of senescent cell formation is elevated or both. If senescent cells persist and accumulate in tissues, they have the potential to paradoxically promote pathological conditions.

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Cellular senescence in premalignant lesions and cancer

Senescent cells present and secrete a variety of factors to their microenvironment. These factors impact a tissue homeostasis and can either interfere or support the normal function of the tissue. In order to understand the role of cellular senescence in tissue damage, cancer and aging our research aims to uncover the mechanisms of interaction of the senescent cells with their microenvironment.

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Cellular senescence during embryonic development

We recently demonstrated that cell-cell fusion is a previously unidentified trigger for inducing cellular senescence. This work was the first to demonstrate that fusion-induced senescent cells exist within a normally developed placenta, within an area where physiological cell-cell fusion occurs, thereby suggesting that cellular senescence plays a role in embryonic development.

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Interaction of senescent cells with the immune system

NK cells recognize and eliminate senescent cells to protect against liver fibrosis and to cause tumor regression after p53 reactivation or chemotherapy. To kill their target cells, NK cells use two mechanisms in parallel - granule exocytosis and activation of death receptors (Fig. 1). We recently discovered that inhibition of granule exocytosis or inhibition of granzyme activity prevents specific killing of the senescent cells by the NK cells in vitro (Sagiv et al., 2012). Moreover, in the mouse model of liver fibrosis, perforin knockout leads to more severe fibrosis and accumulation of senescent activated stellate cells in the liver. Therefore, perforin-mediated exocytosis is evidently necessary for NK-cell-mediated immune surveillance of senescent cells both in vitro and in vivo.

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