Cellular senescence, a stress-induced irreversible growth arrest often characterized by p16Ink4a expression and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time and have been speculated to play a role in aging. To explore the physiological relevance and consequences of naturally occurring senescent cells, we used a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. Here we show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. Clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels, and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in multiple organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
Cellular senescence is a well-established cancer defense mechanism that has been also hypothesized to play a role in aging and age-associated diseases, presumably through depletion of stem and progenitor cells, and the adverse actions of the senescence-associated secretory phenotype (SASP), which consists of many proinflammatory cytokines and chemokines, matrix metalloproteinases and growth factors1–3. Consistent with this idea is the observation that interference with senescent cell accumulation in BubR1 progeroid mice delays several aging-associated disorders that these animals develop4, 5. However, because progeroid syndromes do not faithfully mimic the complex degenerative changes of aging, the relevance of these findings has remained unclear. Furthermore, recent studies showing that senescent cells have beneficial effects in injury repair and tissue remodelling6–10 have called into question the simplistic view of senescence as only a driver of age-dependent pathologies, raising the specter that senescent cell clearance might remove useful cells in addition to detrimental ones. Here we investigated the identity and physiological impact of naturally occurring senescent cells using INK-ATTAC (hereafter AT-TAC)4, a transgenic mouse that expresses FKBP-Casp8 and GFP under the control of a minimal p16Ink4a promoter fragment transcriptionally active in senescent cells4, 11. Earlier we have shown that, in BubR1 progeroid mice, ATTAC ablates p16Ink4a-positive senescent cells upon administration of AP20187 (AP), a dimerizer that activates FKBP-fused Casp84. Our first objective was to validate the properties of ATTAC in naturally occurring p16Ink4a-positive senescent cells.
Thus, our data best fit a model in which p16Ink4a-positive cells act to shorten healthy lifespan by promoting tumor progression and age-dependent changes that functionally impair certain tissues and organs, including vital organs such as kidney and heart. This, together with the key observation that elimination of p16Ink4a-positive cells is not associated with any overt detrimental effects raise the possibility that this approach may be useful to treat aspects of age-related functional decline, age-related diseases that involve senescent cells, or side-effects of therapies that create senescent cells36. https://www.nature.com/articles/nature16932