Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

Darren J. Baker (), Bennett G. Childs, Matej Durik, Melinde E. Wijers, Cynthia J. Sieben, Jian Zhong, Rachel A. Saltness, Karthik B. Jeganathan, Grace Casaclang Verzosa, Abdulmohammad Pezeshki, Khashayarsha Khazaie, Jordan D. Miller and Jan M. van Deursen ()
Additional contact information
Darren J. Baker: Mayo Clinic College of Medicine
Bennett G. Childs: Mayo Clinic College of Medicine
Matej Durik: Mayo Clinic College of Medicine
Melinde E. Wijers: Mayo Clinic College of Medicine
Cynthia J. Sieben: Mayo Clinic College of Medicine
Jian Zhong: Mayo Clinic College of Medicine
Rachel A. Saltness: Mayo Clinic College of Medicine
Karthik B. Jeganathan: Mayo Clinic College of Medicine
Grace Casaclang Verzosa: Mayo Clinic College of Medicine
Abdulmohammad Pezeshki: Mayo Clinic College of Medicine
Khashayarsha Khazaie: Mayo Clinic College of Medicine
Jordan D. Miller: Mayo Clinic College of Medicine
Jan M. van Deursen: Mayo Clinic College of Medicine

Nature, 2016, vol. 530, issue 7589, 184-189

Abstract: Abstract Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16Ink4a (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 p16Ink4a-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 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 several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

Date: 2016
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DOI: 10.1038/nature16932

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