A transplanted mouse ovary partly adjusts its gene activity to the age of the host female: an old ovary in a young female becomes younger and can still produce offspring, while a young ovary in an old female ages and also lowers the age of her brain, liver and uterus (preprint)
A transplanted mouse ovary partly adjusts its gene activity to the age of the host female: an old ovary in a young female becomes younger and can still produce offspring, while a young ovary in an old female ages and also lowers the age of her brain, liver and uterus (preprint)
On 13 October, the group of aging researcher Vadim Gladyshev posted a preprint (a paper that has not yet been peer reviewed) on bioRxiv. The authors built an aging clock for the mouse ovary that estimates its age from gene activity. They then transplanted ovaries between young and old females and joined mice through a shared blood circulation (parabiosis).
Earlier work had shown that young ovaries transplanted into 17-month-old CBA/J mice extended their lives. Females of this strain live about 644 days, females with young ovaries lived 798 days, and females with ovaries lacking germ cells lived 880 days. This means the extension came from the ovarian tissue other than the germ cells. Two questions remained open: whether the body changes the age of the ovary, and whether the ovary changes the age of other organs. Answering them required a clock built for the ovary, because universal clocks trained on many tissues predict the age of the ovary less accurately than the age of the brain or liver.
Young females received ovaries from 13-month-old donors, and old females received ovaries from young donors. In the controls, the age of the ovary matched the age of the female. Either one ovary or both were replaced.
In every type of transplant, the transplanted ovary shifted toward the age of the host and stopped short of reaching it. When only one ovary was replaced, the transplanted ovary and the female's own remaining ovary kept different molecular ages. In an old ovary placed in a young female, the activity of inflammatory genes decreased and the activity of mitochondrial genes increased. In a young ovary placed in an old female, the inflammatory genes became more active instead. The authors write:
“The state of the aging ovary thus reflects both the tissue's own history and its current systemic environment.”
The authors tested function by live birth, which requires a working ovary and uterus as well as the hypothalamus and pituitary, which control the hormonal cycle. Females were mated 4–5 months after surgery, when the old females and the old ovaries were 17–18 months old. With an old ovary, 5 of 7 young females gave birth to live pups, and none of 6 old females did. With a young ovary, 4 of 6 old females gave birth to live pups, so in some of them the hypothalamus, pituitary and uterus could still support pregnancy and delivery. In a 1985 experiment, only 9% of old mice with a young ovary were pregnant ten days after mating, and the authors of that study attributed the loss of fertility to the old hypothalamus and pituitary.
In an earlier preprint from the same group, the age of a transplanted heart, measured by marks on its DNA, shifted toward the age of the host, while the host's liver and blood barely changed. The ovary, in contrast, changed the age of the host's organs. According to the gene activity clocks, a young ovary in old females lowered the age of the brain, liver and uterus, and an old ovary in young females raised the age of the uterus only.
To separate signals carried by the blood from the effects of the transplant surgery, the authors joined pairs of mice aged 3.5 and 7.5 months through a shared circulation for three months. One month after the mice were separated, the ovary of the younger mouse was older than in pairs of mice of the same age. Shared circulation with an older partner therefore shifted the age of the ovary even without a transplant. The ovary of the older partner did not become significantly younger from exposure to young blood. The authors suggest that shared circulation alone may be insufficient for a noticeable rejuvenation, and that in a transplant the new vascular and tissue connections with a young host may contribute.
The stroma, the connective tissue of the ovary, accumulates multinucleated giant cells with age. These cells form when macrophages, a type of immune cell, fuse together. Regions containing them are older by the clock than the rest of the stroma. The genes characteristic of these regions became less active in old ovaries placed in young females and more active in young ovaries placed in old females.