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PNAS 104 (12): 5229-5234

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / PHYSIOLOGY

Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice

Gloria I. Perez*,{dagger}, Andrea Jurisicova{ddagger}, Lisa Wise{ddagger}, Tatiana Lipina{ddagger}, Marijana Kanisek{ddagger}, Allison Bechard{ddagger}, Yasushi Takai*, Patricia Hunt§, John Roder{ddagger}, Marc Grynpas{ddagger}, and Jonathan L. Tilly*

*Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114; {ddagger}Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada M5G 1X5; and §Center for Reproductive Biology and School of Molecular Biosciences, Washingston State University, Pullman, WA 99164

Edited by John T. Potts, Massachusetts General Hospital, Charlestown, MA, and approved January 29, 2007

Received for publication September 27, 2006.

Abstract: The menopausal transition in human females, which is driven by a loss of cyclic ovarian function, occurs around age 50 and is thought to underlie the emergence of an array of health problems in aging women. Although mice do not undergo a true menopause, female mice exhibit ovarian failure long before death because of chronological age and subsequently develop many of the same age-associated health complications observed in postmenopausal women. Here we show in mice that inactivation of the proapoptotic Bax gene, which sustains ovarian lifespan into advanced age, extends fertile potential and minimizes many age-related health problems, including bone and muscle loss, excess fat deposition, alopecia, cataracts, deafness, increased anxiety, and selective attention deficit. Further, ovariectomy studies show that the health benefits gained by aged females from Bax deficiency reflect a complex interplay between ovary-dependent and -independent pathways. Importantly, and contrary to popular belief, prolongation of ovarian function into advanced age by Bax deficiency did not lead to an increase in tumor incidence. Thus, the development of methods for postponing ovarian failure at menopause may represent an attractive option for improving the quality of life in aging females.

Key Words: aging • apoptosis • menopause • ovary


Freely available online through the PNAS open access option.

Author contributions: G.I.P, A.J., L.W., and T.L. contributed equally to this work; G.I.P., A.J., J.R., M.G., and J.L.T. designed research; G.I.P., A.J., L.W., T.L., M.K., A.B., Y.T., P.H., and J.R. performed research; G.I.P., A.J., L.W., T.L., P.H., J.R., M.G., and J.L.T. analyzed data; and G.I.P., A.J., L.W., T.L., and J.L.T. wrote the paper.

{dagger}Present address: Department of Physiology, Michigan State University, East Lansing, MI 48824.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0608557104/DC1.

To whom correspondence should be addressed. E-mail: jtilly{at}partners.org

© 2007 by The National Academy of Sciences of the USA


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