Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Feb;41(1):25-38.
doi: 10.1007/s11357-018-0049-4. Epub 2018 Dec 13.

Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice

Tracy L Habermehl  1 , Kate C Parkinson  1 , Gene B Hubbard  2   3 , Yuji Ikeno  2   3   4 , Jennifer I Engelmeyer  5 , Björn Schumacher  5 , Jeffrey B Mason  6
Affiliations

Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice

Tracy L Habermehl et al. Geroscience. 2019 Feb.

Abstract

Cardiovascular disease, rare in premenopausal women, increases sharply at menopause and is typically accompanied by chronic inflammation. Previous work in our laboratory demonstrated that replacing senescent ovaries in post-reproductive mice with young, actively cycling ovaries restored many health benefits, including decreased cardiomyopathy and restoration of immune function. Our objective here was to determine if depletion of germ cells from young transplanted ovaries would alter the ovarian-dependent extension of life and health span. Sixty-day-old germ cell-depleted and germ cell-containing ovaries were transplanted to post-reproductive, 17-month-old mice. Mean life span for female CBA/J mice is approximately 644 days. Mice that received germ cell-containing ovaries lived 798 days (maximum = 815 days). Mice that received germ cell-depleted ovaries lived 880 days (maximum = 1046 days), 29% further past the time of surgery than mice that received germ cell-containing ovaries. The severity of inflammation was reduced in all mice that received young ovaries, whether germ cell-containing or germ cell-depleted. Aging-associated inflammatory cytokine changes were reversed in post-reproductive mice by 4 months of new-ovary exposure. In summary, germ cell depletion enhanced the longevity-extending effects of the young, transplanted ovaries and, as with germ cell-containing ovaries, decreased the severity of inflammation, but did so independent of germ cells. Based on these observations, we propose that gonadal somatic cells are programed to preserve the somatic health of the organism with the intent of facilitating future germline transmission. As reproductive potential decreases or is lost, the incentive to preserve the somatic health of the organism is lost as well.

Keywords: Aging; Germ cell; Inflammation; Life span; Menopause; Ovarian.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Experimental design. One-month-old mice were treated for 15 days with VCD or oil-only. Ovaries were collected from 2-month-old oil-only mice for transplantation to 13-month-old, acyclic recipients. Ovaries were also collected from 2-month-old VCD and oil-only mice for transplantation to 17-month-old, acyclic recipients. Thirteen-month-old controls and transplant recipients were collected at 17 months of age. Seventeen-month-old VCD and oil-only transplant recipients were collected at death
Fig. 2
Fig. 2
VCD depletion of small follicles in CBA/J mice. H&E-stained sections showing (a) abundant small follicles in oil-treated (n = 6) mice, (b) reduced numbers of small follicles in VCD-treated (n = 4) mice, and (c) and already displayed significant differences in both primordial and primary follicle numbers by 45 days of age. Arrows indicate primordial and primary follicles
Fig. 3
Fig. 3
Influence of young ovaries on life span in post-reproductive recipients. Young ovaries transplanted (Tx) to 11 month-old mice (GC-Tx@11mo, n = 30) extended life span by 13% past the time of surgery, compared with sham operated mice (Sham, n = 34). Young ovaries Tx at 17mo (GC-Tx@17, n = 5) or 18mo (GC-Tx@18, n = 6) were no different from 11mo Tx. Depleting the germ cells from young ovaries prior to Tx (GD-Tx@17mo, n = 5) more than doubled (29%) the life span extension of GC ovaries. AAD, age at death. Patterned bars represent the current longevity experiments. * P < 0.05, ** P < 0.1. Error bars are SE. (Mason et al. 2009)
Fig. 4
Fig. 4
Influence of young ovaries on survival. At 750 days of age, 50% of sham mice had died. At this same age, 81% of mice transplanted with young ovaries at 11 months of age were still alive and 100% of mice transplanted at 17 and 18 months of age were still alive. Maximum life span, but not mean life span was influenced by the number of mice per group. a Mice that underwent sham surgery (mean LS = 728 days) and mice that received 60-day ovaries at 11 months of age (mean LS = 793 days). b Mice that received intact 60-day ovaries at 17 and 18 months of age (mean LS = 798 days and 802 days, respectively) and mice that received germ cell-depleted 60-day ovaries at 17 months of age (mean LS = 880 days)
Fig. 5
Fig. 5
Influence of young ovaries on glomerulonephritis and inflammation in post-reproductive recipients. Young ovaries transplanted (Tx) to 13 month-old mice (GC-Tx@13mo) decreased the severity of glomerulonephritis and inflammation at 4 months post-transplantation (17 months of age), compared with mice that did not receive new ovaries (No-Tx@13mo). Error bars are SE
Fig. 6
Fig. 6
Influence of germ cell depletion of young ovaries on glomerulonephritis and inflammation in post-reproductive recipients. Germ cell depletion of young ovaries prior to transplantation to 17 month-old mice (GD-Tx@17mo) had little to no influence of the severity of inflammation or glomerulonephritis at death, compared with mice that received germ cell-containing new ovaries at 17 months of age (GC-Tx@17mo). Error bars are SE
Fig. 7
Fig. 7
Inflammatory cytokines. Both pro- and anti-inflammatory cytokines decreased from the time of reproductive senescence at 13 months to 17 months of age. These decreases were reversed by exposure to new ovaries in mice that received new ovaries at 13 months of age (GC-Tx@17mo). Values are 1/1000 of actual values. * P < 0.05. Error bars are SE
Fig. 8
Fig. 8
Theory of longevity extension in post-reproductive recipients. a In wild-type mice, reproductive cycling continuously recruits both ovarian germ and somatic cells. At reproductive senescence, both germ and somatic cells are lost, along with the female health advantage. We hypothesize that Foxo signaling from ovarian somatic cells contributes to the female health advantage. In mammals, Foxo suppresses the de novo methyltransferase Dnmt3b and reduces the age-associated erosion of methylation patterns and epigenetic reprogramming. Foxo signaling is also linked to gender-specific longevity in centenarians. Ovarian Foxo signaling is significantly reduced at menopause due to the loss of Foxo-producing ovarian tissue. b Young, germ cell-containing ovaries (GC) transplanted to 13 month-old mice extended life span by supplying new ovarian somatic cells and resetting the Foxo clock. c Deleting the germ cells from young ovaries (GD) prior to transplantation prevented reproductive cycling and the continuous recruitment of ovarian somatic cells. This extended the influence of the transplanted somatic cells and further extended the Foxo clock
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Arantes-Oliveira N, Apfeld J, Dillin A, Kenyon C. Regulation of life-span by germ-line stem cells in Caenorhabditis elegans. Science. 2002;295(5554):502–505. - PubMed
    1. Ashpole NM, Logan S, Yabluchanskiy A, Mitschelen MC, Yan H, Farley JA, Hodges E, LUngvari Z, Csiszar A, Chen S, Georgescu C, Hubbard GB, Ikeno Y, Sonntag WE. IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. GeroScience. 2017;39(2):129–145. - PMC - PubMed
    1. Barnett KR, Schilling C, Greenfeld CR, Tomic D, Flaw JA. Ovarian follicle development and transgenic mouse models. Hum Reprod Update. 2006;12(5):537–555. - PubMed
    1. Bronson RT, Lipman RD. Reduction in rate of occurrence of age-related lesions in dietary restricted laboratory mice. Growth Dev Aging. 1991;55(3):169–184. - PubMed
    1. Cargill SL, Medrano JF, Anderson GB. Infertility in a line of mice with the high growth mutation is due to luteal insufficiency resulting from disruption at the hypothalamic-pituitary axis. Biol Reprod. 1999;61(1):283–287. - PubMed

Publication types