When one thinks of the ageing, or ‘senescence’, of organisms, visions of aging and age-related deterioration often come to mind. But we tend to think less about how ageing affects individual cells, and this is a question that Judith Campisi and her colleagues decided to explore a few years ago when they undertook to define the characteristics of cell senescence and to assess how ageing cells might affect the health and behaviour of their neighbours.
Until Campisi and her co-workers published their PLOS Biology article in 2008 , what goes on when cells senesce had mostly been investigated at the level of genes and their transcripts. Campisi and colleagues tried something different. They set about modifying a commercially available antibody array so that they could more accurately monitor what proteins the cells actually produce as they age. And in doing so they identified a hallmark collection of proteins that are secreted by a range of different types of ageing cells into their local tissue microenvronment, a collection they named the ‘Senescence-Associated Secretory Phenotype’ (SASP).
What they found was rather interesting. Of course, the SASP of different types of cell featured distinct sets of proteins. But there was also considerable common ground. Across a variety of cells and tissues, there was a gang of “usual suspects” - inflammatory and immune-modulatory cytokines and chemokines, induced growth factors, survival factors. These showed up, time and again, under all SASP conditions tested.
But what is the effect of this plume of SASP emitted by aging cells on their neighbours? There’s evidence for the idea of senescence doing ‘good guy’ tasks, exerting a tumour suppressive influence by preventing damaged cells from dividing. But are the effects of senescence really only beneficial?
As it turns out, no, they are not; the authors found that the cocktail of proteins in SASP could have a range of other, rather undesirable, effects on nearby cells. These included the ability to induce a process called epithelial-mesenchymal transition (EMT), by which epithelial cells acquire migratory and invasive properties. These traits are associated with metastasis - the ability of cancer cells to spread to other parts of the body, with potentially disastrous consequences.
Campisi and colleagues observed that SASP could be ramped up and spurred on by two molecular features of many tumors – a hyperactive, cancer-promoting (“oncogenic”) version of the RAS gene or loss of a “tumor-suppressor” gene called p53. These genetic alterations are well-known to act within a cell, kicking it into overdrive, but here it seems that they can also make a cell cause its neighbours to behave abnormally. The take-home message of the paper is that the SASP proteins secreted by an aged or mutated cell can alter its tissue microenvironment, potentially promoting age-related malignancy.
Having had almost 31,000 views and 389 citations, this study defining the
SASP is clearly a significant one in the field. As our Advisory Board member Tom Misteli puts it, this 2008 paper by Campisi and colleagues provided “evidence for an innovative, but up to that point uncertain, idea”.
Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, & Campisi J (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology, 6 (12), 2853-68 PMID: 19053174