Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell. 2016 May 19;165(5):1209-1223. doi: 10.1016/j.cell.2016.04.012. Epub 2016 Apr 28.

Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.

Author information

1
Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Glenn Center for Research on Aging, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
2
Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
3
Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA.
4
Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
5
The Glenn Center for Research on Aging, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
6
Laboratory of Integrative and Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland. Electronic address: admin.auwerx@epfl.ch.
7
Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: dillin@berkeley.edu.

Abstract

Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner. A systems genetics approach in the BXD mouse reference population further indicates conserved roles of the mammalian orthologs in longevity and UPR(mt) signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations.

PMID:
27133168
PMCID:
PMC4889222
DOI:
10.1016/j.cell.2016.04.012
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center