Naturally occurring p16 Ink4a-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, Jan Van Deursen

Research output: Contribution to journalArticle

731 Citations (Scopus)

Abstract

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 K ATP 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.

Original languageEnglish (US)
Pages (from-to)184-189
Number of pages6
JournalNature
Volume530
Issue number7589
DOIs
StatePublished - Feb 11 2016

Fingerprint

Cell Aging
Transgenes
Adipocytes
Wound Healing
Embryonic Development
Carcinogenesis
Adenosine Triphosphate
Fats
Cell Proliferation
Apoptosis
Phenotype
Kidney
Injections
Therapeutics
Growth
AP20187
Genetic Background

ASJC Scopus subject areas

  • General

Cite this

Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... Van Deursen, J. (2016). Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. https://doi.org/10.1038/nature16932

Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. / Baker, Darren J; Childs, Bennett G.; Durik, Matej; Wijers, Melinde E.; Sieben, Cynthia J.; Zhong, Jian; A. Saltness, Rachel; Jeganathan, Karthik B.; Verzosa, Grace Casaclang; Pezeshki, Abdulmohammad; Khazaie, Khashayarsha; Miller, Jordan D; Van Deursen, Jan.

In: Nature, Vol. 530, No. 7589, 11.02.2016, p. 184-189.

Research output: Contribution to journalArticle

Baker, DJ, Childs, BG, Durik, M, Wijers, ME, Sieben, CJ, Zhong, J, A. Saltness, R, Jeganathan, KB, Verzosa, GC, Pezeshki, A, Khazaie, K, Miller, JD & Van Deursen, J 2016, 'Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan', Nature, vol. 530, no. 7589, pp. 184-189. https://doi.org/10.1038/nature16932
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature. 2016 Feb 11;530(7589):184-189. https://doi.org/10.1038/nature16932
Baker, Darren J ; Childs, Bennett G. ; Durik, Matej ; Wijers, Melinde E. ; Sieben, Cynthia J. ; Zhong, Jian ; A. Saltness, Rachel ; Jeganathan, Karthik B. ; Verzosa, Grace Casaclang ; Pezeshki, Abdulmohammad ; Khazaie, Khashayarsha ; Miller, Jordan D ; Van Deursen, Jan. / Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. In: Nature. 2016 ; Vol. 530, No. 7589. pp. 184-189.
@article{1b052165c39b4030b74c0c332a29e08a,
title = "Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan",
abstract = "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 K ATP 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.",
author = "Baker, {Darren J} and Childs, {Bennett G.} and Matej Durik and Wijers, {Melinde E.} and Sieben, {Cynthia J.} and Jian Zhong and {A. Saltness}, Rachel and Jeganathan, {Karthik B.} and Verzosa, {Grace Casaclang} and Abdulmohammad Pezeshki and Khashayarsha Khazaie and Miller, {Jordan D} and {Van Deursen}, Jan",
year = "2016",
month = "2",
day = "11",
doi = "10.1038/nature16932",
language = "English (US)",
volume = "530",
pages = "184--189",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7589",

}

TY - JOUR

T1 - Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan

AU - Baker, Darren J

AU - Childs, Bennett G.

AU - Durik, Matej

AU - Wijers, Melinde E.

AU - Sieben, Cynthia J.

AU - Zhong, Jian

AU - A. Saltness, Rachel

AU - Jeganathan, Karthik B.

AU - Verzosa, Grace Casaclang

AU - Pezeshki, Abdulmohammad

AU - Khazaie, Khashayarsha

AU - Miller, Jordan D

AU - Van Deursen, Jan

PY - 2016/2/11

Y1 - 2016/2/11

N2 - 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 K ATP 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.

AB - 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 K ATP 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.

UR - http://www.scopus.com/inward/record.url?scp=84958093401&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958093401&partnerID=8YFLogxK

U2 - 10.1038/nature16932

DO - 10.1038/nature16932

M3 - Article

C2 - 26840489

AN - SCOPUS:84958093401

VL - 530

SP - 184

EP - 189

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7589

ER -