Aging

Cellular senescence is a potent tumor suppressor, putting damaged cells into early retirement by halting their continued division. However, the cocktail of growth factors, cytokines, and proteases secreted by senescent cells has been shown to enhance tumor progression in neighboring cells. Baker and colleagues now show that senescent cells can also influence the apparent age of the tissues in which they reside. They constructed transgenic mice in which senescent cells can be selectively culled from tissues by adding a drug. A drug-activated, proapoptotic fusion protein is expressed under the control of a fragment of the p16 promoter, which becomes transcriptionally active as cells become senescent. To test the effect of killing off senescent cells on the aging process, the investigators turned to a mouse model in which aging is dramatically accelerated. Mice mutant for the mitotic checkpoint protein BubR1 develop age-related ailments including muscle wasting, spinal curvature, cataracts, fat loss, cardiac arrhythmia, stiffening of the arterial walls, and thinning of the skin. The mice also accumulate p16-positive cells in many of these tissues. Remarkably, selective killing of these senescent cells by treatment with the drug from 3 weeks after birth significantly reduces some of the age-related pathologies caused by BubR1 deficiency: muscle wasting, spinal curvature, and the appearance of cataracts are delayed, and fat loss is slowed. Luckily for those of us who may already be feeling the effects of our advancing years, the investigators also tested whether killing senescent cells later in life could have an impact. Mice treated with the drug from 5 months also saw significant benefits in the form of improved muscle function and fat retention. These results support the idea that senescent cells not only promote tumor progression but also impair the function of surrounding tissue, presumably via the secretion of as yet unidentified factors. However, despite these positive effects of removing senescent cells, in neither experiment did the treatment enhance life span. This may be because the likely cause of death of the BubR1 mutant mice is cardiac arrest, a phenotype that is not driven by p16-expressing senescent cells. It therefore remains to be seen whether the removal of senescent cells would enhance the health span and life span of wild-type mice. Baker, D.J., et al. (2011). Nature. Published online November 2, 2011. 10.1038/nature10600.