Sandra Yin

September 27, 2011

September 27, 2011 (Washington, DC) — Mouse studies suggest that the ticking of a biological clock is not inevitable, Jonathan Tilly, PhD, professor of the Department of Obstetrics, Gynecology, and Reproductive Biology at Harvard Medical School, Boston, Massachusetts, told attendees here at the North American Menopause Society (NAMS) 22nd Annual Meeting.

In a keynote address, entitled Ovarian Aging: Can Science Turn Back the Clock?, he challenged a decades-old view of the biological clock in which the ovarian reserve, or egg supply, becomes depleted over time.

Unlike the "hour glass" view of the biological clock, in which the upper reservoir represents the ovarian reserve and the bottom reservoir represents oocytes that have been lost, he argued that the ovarian pool can be replenished.

He said that in mouse studies, the stem cell population can generate oocytes. When human oogonial stem cells are transplanted into mice, the stem cell divides and creates itself over again. One of the 2 daughter cells goes on to differentiate through meiosis, and an oocyte is formed. The ovarian reserve can rebuild itself, Dr. Tilly explained.

His theory challenges the view that ovaries fail as a consequence of advancing age. Dr. Tilly's research, which involved taking half the ovary tissue from menopausal or "mouseopausal" female mice and then grafting it into the ovaries of young wild female mice, showed that dormant premeiotic germline stem cells from the older mouse's ovaries can be reactivated and will resume production of oocytes when transplanted into the ovary of a young nonmenopausal mouse.

"The cells do persist," he said. "They're dormant." They aren't disappearing with age, they are just undergoing a period of quiescence due to failure of the support system in the ovary.

Exposure to younger mouse ovaries awakened the old stem cells, which started to produce oocytes again. If what works in mice could work in humans, it would be possible to effectively turn back a woman's biological clock.

Advancing age might shut the germ cells down, making them unable to complete the differentiation process for oocytes. However, if you take those aged premeiotic germ cells and put them in a young ovary, more than half resume their function. "So they're not shut down permanently," Dr. Tilly said. "They're sort of in a temporary state of [suspended] animation. Once you reactivate these cells, by whatever is the magical elixir in young adult ovaries, they reactivate the process of oogenesis."

To examine human possibilities, researchers noted that human oogonial stem cells will spontaneously generate what appear to be immature oocytes in vitro. To test whether that was an in vitro artifact, researchers tried to get in vivo proof. Because they couldn't repeat the mouse study on humans, they took human oogonial stem cells from a menopausal woman and xenografted them into immunodeficient mice. There was clear evidence of positive oocytes in the grafted tissue.

To determine whether females age better if you turn back the biological clock, Dr. Tilly and his team compared a mouseopausal mouse they created with her nonmouseopausal sisters born at the same time. They found that the nonmouseopausal mice did not suffer from the ravages of time, such as hair loss, wrinkly skin, or cancer, whereas their mouseopausal sister looked "ratty," he said.

Ovarian replacement therapy is something that could improve the life course of women, Dr. Tilly said, because it could improve quality of life without necessarily putting the focus on making babies.

As Dr. Tilly spoke, Diane Pace, PhD, FNP, FAANP, NCMP, NAMS trustee and director of university health services at the University of Tennessee Health Science Center College of Nursing in Memphis, noticed attendees leaning forward, their eyes wide. She later told Medscape Medical News that she wants to know how the findings would apply outside the realm of research, in true clinical practice. She also wonders whether ethical issues would be a concern. "Just because something can be done," she said, "should we do it?"

Carol Caico, PhD, OGNP, NCMP, assistant professor of nursing at the New York Institute of Technology, told Medscape Medical News that she was leery of the implications of the research. "I don't see this happening," she said. "It sounds like science fiction."

If a postmenopausal woman were to have a younger ovary spliced in, she said she would worry about chromosomal abnormalities and the implications of somebody 50 or 60 having a child. "There may always be somebody who will pay enough for somebody's ovary to do this," she said, "but I think it's a terrible idea."

Dr. Tilly, Dr. Pace, and Dr. Caico have disclosed no relevant financial relationships.

North American Menopause Society (NAMS) 22nd Annual Meeting. Presented September 22, 2011.

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