Naturally occurring p16[Ink4a]-positive cells shorten healthy lifespan. Nature. doi:10.1038/nature16932
Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16[Ink4a] (encoded by the Ink4a/Arf locus, also known as Cdkn2a) 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 have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16[Ink4a]-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16[Ink4a]-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, p16[Ink4a]-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
老化に伴って増加する senescent cells を取り除いたら健康寿命が延びますよと。senescent cellで特異的に発現が高くなるp16[Ink4a]のプロモーター制御下にアポトーシスを誘導できるFKBP–Casp8を組み込まれたマウス（INK-ATTAC）では、老化とともに出現するsenescent cellがアポトーシスを起こして除去されていくという仕掛け。このマウスでは様々な臓器における老化現象が抑制され、平均寿命も３割ぐらい伸びている。なんか見た目もコントロールに比べてだいぶ若いな。ふーむ、cellular senescenceってなんなんやろかと考えさせられる。