The MRC Clinical Science Centre’s (CSC) Jesus Gil and Dominic Withers appear in Nature this week with a comment piece on the journal’s latest paper on ageing and senescence. Read an extract and link through to the article below.

The research was also reported in Science and New Scientist, with Dominic Withers quoted in Nature, the Daily Mail and Scientific American.

The selective elimination of cells that have adopted an irreversible, senescent state has now been shown to extend the lifespan of mice and to ameliorate some age-related disease processes.

Jesus Gil and Dominic J. Withers

The ability to fight the ageing process has been a long-held human desire. Although this quest often seems to be driven by vanity, ageing is the major risk factor for many of the diseases that plague modern society. More than 50 years ago, it was suggested that ageing is linked to a state of arrested cell growth known as senescence¹, but this link has remained unproven, and the molecular basis for  organismal ageing has been elusive. In a paper online in Nature, Baker et al.² demonstrate that the removal of senescent cells does indeed delay ageing and increase healthy lifespan (healthspan).

Senescence is a cellular state in which cells permanently stop dividing. It is mediated by two signalling pathways — the p53 pathway and the p16^Ink4a–Rb pathway. Senescent cells secrete a complex cocktail of factors called the senescence-associated secretory phenotype (SASP), which includes matrix metallo proteinases (enzymes that break down the extra cellular matrix) and pro-inflammatory signalling molecules. Such cells have been shown to accumulate during ageing, and their presence has been associated with a broad range of diseases, including diabetes, kidney disease and many cancers³.

The group that performed the current study previously showed that removing senescent cells from a mouse model of accelerated ageing delays the onset of several disease-related processes⁴. However, the relevance of these observations to the normal ageing process was unclear. Baker et al. have now directly tackled this uncertainty using a genetically engineered mouse model that they had developed previously⁴, called INK–ATTAC. These mice produce a caspase enzyme specifically in cells that express the p16^Ink4a gene. The caspase can be activated by the injection of a drug; the activated caspase then triggers cell death, eliminating senescent cells in which it is expressed.

Baker and colleagues found that the elimination of p16^Ink4a-expressing cells increased lifespan, regardless of the sex or strain of mouse examined, and ameliorated a range of age-dependent, disease-related abnormalities, including kidney dysfunction and abnormalities in heart and fat tissue (Fig. 1). The authors observed increased activity and exploratory behaviour and a decrease in the incidence of cataracts (although this improvement was strain-dependent). Senescent-cell removal also delayed the onset of cancer, without affecting the range of observed tumour types. Together, these findings suggest that the accumulation of p16^Ink4a-expressing cells during normal ageing shortens healthspan.

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