Senescence is a permanent state of cell cycle arrest that—unlike quiescence—is unresponsive to growth factors. Originally described in terms of the replicative exhaustion of cultured fibroblasts (Hayflick & Moorhead, 1961), it has since been shown that senescence can occur prematurely upon oncogene induction and other cellular stresses. As it represents a permanent exit from the cell cycle, senescence has been implicated in several pathological contexts such as cancer, vascular diseases and other age-related conditions. This might sound as if the contribution of senescence is passive, but the recent discovery of the senescence-associated secretory phenotype (SASP)—also recently coined the “senescence messaging secretome”(SMS) by Daniel Peeper—suggests that senescence might have a more active and pathologically diverse role (Campisi & d’Adda di Fagagna, 2007; Kuilman & Peeper, 2009).

It has long been known within the field that the culture medium of senescent cells is enriched with secreted proteins (Krtolica & Campisi, 2002; Shelton et al, 1999). The SASP concept was first proposed by the Campisi group, when they realized that secreted factors from senescent fibroblasts promote the transformation of pre-malignant—but not of normal—mammary epithelial cells. They suggested that matrix metalloproteinase 3 (MMP3), was a candidate factor for this activity (Krtolica et al, 2001; Parrinello et al, 2005); MMP3 is a classical marker of senescence and is widely used to help confirm a senescence phenotype in vitro. This initial observation of SASP implies that senescence might not simply be a tumour suppressor mechanism, but rather a doubleedged sword within the tumour microenvironment. What remained unclear, however, were the functional effects of SASP on the senescence phenotype itself. Kortlever et al (2006) identified plasminogen activator inhibitor 1 (PAI1), another classical marker of senescence, as having a crucial role in the induction of replicative senescence downstream of p53. Together, these early studies suggest that SASP components could have diverse effects through both autocrine and paracrine mechanisms. A series of recent papers (Acosta et al, 2008; Coppé et al, 2008; Kuilman et al, 2008; Wajapeyee et al, 2008), including one in this issue of EMBO reports by the group of David Bernard (Augert et al, 2009), have added various new members involved in SASP, and collectively reinforced the idea that senescence is both regulated by and regulates the extracellular environment (Fig 1). Senescence bypass screening is a powerful tool to identify new components of the senescence machinery. Some of these factors might be potential tumour suppressors, whereas others could be ‘context-dependent’tumour suppressors or even oncogenes. Among the recent series of papers, three groups have used genome-wide