Wnt10b and Dkk-1 gene therapy differentially influenced trabecular bone architecture, soft tissue integrity, and osteophytosis in a skeletally mature rat model of osteoarthritis.

AIMS: Our goals in the current experiments were to determine if (a) upregulation of Wnt signaling would induce osteoarthritis changes in stable stifle joints and (b) if downregulation of Wnt signaling in destabilized joints would influence the progression of OA. METHODS: At 37 weeks of age, rats were injected in the stifle joint with a recombinant adeno-associated viral vector containing the Wnt-inhibitor Dkk-1 or a Wnt10b transgene. At 40 weeks of age, rats underwent surgical destabilization of the joint. At 50 weeks of age, stifle joints were submitted for micro-computed tomography and histopathological analysis. RESULTS: Injection of either Wnt10b or Dkk-1 transgenes in stable joints improved bone architectural parameters, but worsened soft tissue integrity. Osteophytosis was decreased by Dkk-1, but unchanged by Wnt10b. Destabilization negatively influenced bone architecture, increased osteophytosis, and decreased soft tissue integrity. Dkk-1 exacerbated the negative effects of destabilization, whereas Wnt10b had little effect on these parameters. Osteophytosis was improved, whereas soft tissue integrity was worsened by both transgenes in destabilized joints. CONCLUSIONS: The Wnt-inhibitor Dkk-1 does not appear to completely inhibit the effects of Wnt signaling on bone remodeling. In vivo upregulation of Wnt10b and its inhibitor, Dkk-1, can produce both parallel or contrasting phenotypic responses depending on the specific parameter measured and the fidelity of the examined joint. These observations elucidate different roles for Wnt signaling in stable versus destabilized joints and may help to explain the conflicting results previously reported for the role of Dkk-1 in joint disease.

Restoration of immune and renal function in aged females by re-establishment of active ovarian function.

Proper immune functioning is necessary to maximize reproductive success. In addition, age-associated uremia in women is often associated with hypothalamic--pituitary-gonadal dysfunction. In the present experiments, we tested immune and renal function to determine if exposure of postreproductive mice to young, reproductively cycling ovaries would influence non-reproductive physiological functions. Control female CBA/J mice were evaluated at 6, 13 and 16 months of age. Additional mice received new (60-day-old) ovaries at 12 months of age and were evaluated at 16 months of age. Consequently, 6-month-old control mice and 16-month-old recipient mice both possessed 6-month-old ovaries and were reproductively cycling. A significant age-related decline in immune function (T-cell subset analysis) was found in 16-month-old mice, but was improved 64% by ovarian transplantation. Renal function (blood urea nitrogen:creatinine ratio) was also decreased with aging, but ovarian transplantation restored function to levels found in 6-month-old mice. In summary, we have shown that immune and renal function, which are negatively influenced by aging, can be positively influenced or restored by re-establishment of active ovarian function in aged female mice. These findings provide a strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females.

Chronological and reproductive aging-associated changes in resistance to oxidative stress in post-reproductive female mice.

Effort toward reproduction is often thought to negatively influence health and survival. Reproduction has been shown to influence metabolism, but the pathways and mechanisms have yet to be thoroughly elucidated. In the current experiments, our aim was to dissect the role of young and old ovarian tissues in the response to oxidative stress, through changes in liver oxidative stress response proteins. Liver proteins were analyzed in control mice at 4, 13, and 27 months of age and compared to 23-month-old mice which received young ovarian tissue transplants (intact or follicle-depleted) at 13 months of age. In control mice, of the 29 oxidative stress response proteins measured, 31% of the proteins decreased, 52% increased, and 17% were unchanged from 13 to 27 months. The greatest changes were seen during the period of reproductive failure, from 4 to 13 months of age. In transplanted mice, far more proteins were decreased from 13 to 23 months (93% in follicle-containing young ovary recipients; 62% in follicle-depleted young ovary recipients). Neither transplant group reflected changes seen in control mice between 13 and 27 months. Estradiol levels in transplant recipient mice were not increased compared with age-matched control mice. The current results suggest the presence of a germ cell- and estradiol-independent ovarian influence on aging-associated changes in the response to oxidative stress, which is manifest differently in reproductive-aged adults and post-reproductive-aged mice. The results presented here separate chronological and ovarian aging and the influence of estradiol in the response to aging-associated oxidative stress and support a novel, estradiol-independent role for the ovary in female health and survival.

Effect of calorie restriction on redox status during chemically induced estropause in female mice.

In females, there is a continuous decline of the ovarian reserve with age, which results in menopause in women or estropause in mice. Loss of ovarian function results in metabolic alterations in mice and women. Based on this, we aimed to evaluate the effect of caloric restriction (CR) on redox status and metabolic changes in chemically induced estropause in mice. For this, mice were divided into four groups (n = 10): cyclic ad libitum (AL), cyclic 30% CR, AL estropause, and estropause 30% CR. Estropause was induced using 4-vinylcyclohexene diepoxide (VCD) for 20 consecutive days in 2-month-old females. The CR protocol started at 5 months of age and the treatments lasted for 4 months. The CR females gained less body weight than AL females (p < 0.001) and had lower glycemic curves in response to glucose tolerance test (GTT). The AL estropause females had the highest body weight and body fat, despite having lower food intake. However, the estropause females on 30% CR lost the most body weight and had the lowest amount of body fat compared to all groups. The effect of 30% CR on redox status in fat and liver tissue was similar for cyclic and estropause females. Interestingly, estropause decreased ROS in adipose tissue, while increasing it in the liver. No significant effects of CR on redox status were observed. Chemically induced estropause did not influence the response to 30% CR on glucose tolerance and redox status; however, weight loss was exarcebated compared to cyclic females.

Senolytic treatment fails to improve ovarian reserve or fertility in female mice.

Senescent cell number increases with age in different tissues, leading to greater senescent cell load, proinflammatory stress, and tissue dysfunction. In the current study, we tested the efficacy of senolytic drugs to reduce ovarian senescence and improve fertility in reproductive age female mice. In the first experiment, 1-month-old C57BL/6 female mice were treated every other week with D + Q (n = 24) or placebo (n = 24). At 3 and 6 months of age, female mice were mated with untreated males to evaluate pregnancy rate and litter size. In the second experiment, 6-month-old C57BL/6 female mice were treated monthly with D + Q (n = 30), fisetin (n = 30), or placebo (n = 30). Females were treated once a month until 11 months of age, then they were mated with untreated males for 30 days to evaluate pregnancy rate and litter size. In the first experiment, D + Q treatment did not affect pregnancy rate (P = 0.68), litter size (P = 0.58), or ovarian reserve (P > 0.05). Lipofuscin staining was lower in females treated with D + Q (P = 0.04), but expression of senescence genes in ovaries was similar. In the second experiment, D + Q or fisetin treatment also did not affect pregnancy rate (P = 0.37), litter size (P = 0.20), or ovarian reserve (P > 0.05). Lipofuscin staining (P = 0.008) and macrophage infiltration (P = 0.002) was lower in fisetin treated females. Overall, treatment with D + Q or fisetin did not affect ovarian reserve or fertility but did decrease some senescence markers in the ovary.

Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice.

The decline in the ovarian reserve leads to menopause and reduced serum estrogens. MicroRNAs are small non-coding RNAs, which can regulate gene expression and be secreted by cells and trafficked in serum via exosomes. Serum miRNAs regulate tissue function and disease development. Therefore, the aim of this study was to identify miRNA profiles in serum exosomes of mice induced to estropause and treated with 17ß-estradiol (E2). Female mice were divided into three groups including control (CTL), injected with 4-Vinylcyclohexene diepoxide (VCD), and injected with VCD plus E2 (VCD + E2). Estropause was confirmed by acyclicity and a significant reduction in the number of ovarian follicles (p < 0.05). Body mass gain during estropause was higher in VCD and VCD + E2 compared to CTL females (p = 0.02). Sequencing of miRNAs was performed from exosomes extracted from serum, and 402 miRNAs were detected. Eight miRNAs were differentially regulated between CTL and VCD groups, seven miRNAs regulated between CTL and VCD + E2 groups, and ten miRNAs regulated between VCD and VCD + E2 groups. Only miR-200a-3p and miR-200b-3p were up-regulated in both serum exosomes and ovarian tissue in both VCD groups, suggesting that these exosomal miRNAs could be associated with ovarian activity. In the hepatic tissue, only miR-370-3p (p = 0.02) was up-regulated in the VCD + E2 group, as observed in serum. Our results suggest that VCD-induced estropause and E2 replacement have an impact on the profile of serum exosomal miRNAs. The miR-200 family was increased in serum exosomes and ovarian tissue and may be a candidate biomarker of ovarian function.

Effect of senolytic drugs in young female mice chemically induced to estropause.

AIMS: This study aimed to assess metabolic responses and senescent cell burden in young female mice induced to estropause and treated with senolytic drugs. MAIN METHODS: Estropause was induced by 4-vinylcyclohexene diepoxide (VCD) injection in two-month-old mice. The senolytics dasatinib and quercetin (D + Q) or fisetin were given by oral gavage once a month from five to 11 months of age. KEY FINDINGS: VCD-induced estropause led to increased body mass and reduced albumin concentrations compared to untreated cyclic mice, without affecting insulin sensitivity, lipid profile, liver enzymes, or total proteins. Estropause decreased catalase activity in adipose tissue but had no significant effect on other redox parameters in adipose and hepatic tissues. Fisetin treatment reduced ROS levels in the hepatic tissue of estropause mice. Estropause did not influence senescence-associated beta-galactosidase activity in adipose and hepatic tissues but increased senescent cell markers and fibrosis in ovaries. Senolytic treatment did not decrease ovarian cellular senescence induced by estropause. SIGNIFICANCE: Overall, the findings suggest that estropause leads to minor metabolic changes in young females, and the senolytics D + Q and fisetin had no protective effects despite increased ovarian senescence.

MASLD does not affect fertility and senolytics fail to prevent MASLD progression in male mice.

Senescent cells have been linked to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effectiveness of senolytic drugs in reducing liver damage in mice with MASLD is not clear. Additionally, MASLD has been reported to adversely affect male reproductive function. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in male mice with MASLD. Three-month-old male mice were fed a standard diet (SD) or a choline-deficient western diet (WD) until 9 months of age. At 6 months of age mice were randomized within dietary treatment groups into senolytic (dasatinib + quercetin [D + Q]; fisetin [FIS]) or vehicle control treatment groups. We found that mice fed choline-deficient WD had liver damage characteristic of MASLD, with increased liver size, triglycerides accumulation, fibrosis, along increased liver cellular senescence and liver and systemic inflammation. Senolytics were not able to reduce liver damage, senescence and systemic inflammation, suggesting limited efficacy in controlling WD-induced liver damage. Sperm quality and fertility remained unchanged in mice developing MASLD or receiving senolytics. Our data suggest that liver damage and senescence in mice developing MASLD is not reversible by the use of senolytics. Additionally, neither MASLD nor senolytics affected fertility in male mice.

Estradiol-independent restoration of T-cell function in post-reproductive females.

Aging leads to a general decline in protective immunity. The most common age-associated effects are in seen T-cell mediated immune function. Adult mice whose immune systems show only moderate changes in T-cell subsets tend to live longer than age-matched siblings that display extensive T-cell subset aging. Importantly, at the time of reproductive decline, the increase in disease risks in women significantly outpace those of men. In female mice, there is a significant decline in central and peripheral naïve T-cell subsets at the time of reproductive failure. Available evidence indicates that this naïve T-cell decline is sensitive to ovarian function and can be reversed in post-reproductive females by transplantation of young ovaries. The restoration of naïve T-cell subsets due to ovarian transplantation was impressive compared with post-reproductive control mice, but represented only a partial recovery of what was lost from 6 months of age. Apparently, the influence of ovarian function on immune function may be an indirect effect, likely moderated by other physiological functions. Estradiol is significantly reduced in post-reproductive females, but was not increased in post-reproductive females that received new ovaries, suggesting an estradiol-independent, but ovarian-dependent influence on immune function. Further evidence for an estradiol-independent influence includes the restoration of immune function through the transplantation of young ovaries depleted of follicles and through the injection of isolated ovarian somatic cells into the senescent ovaries of old mice. While the restoration of naïve T-cell populations represents only a small part of the immune system, the ability to reverse this important functional parameter independent of estradiol may hold promise for the improvement of post-reproductive female immune health. Further studies of the non-reproductive influence of the ovary will be needed to elucidate the mechanisms of the relationship between the ovary and health.

Dasatinib and quercetin increase testosterone and sperm concentration in mice.

Cellular senescence is a defense mechanism to arrest proliferation of damaged cells. The number of senescent cells increases with age in different tissues and contributes to the development of age-related diseases. Old mice treated with senolytics drugs, dasatinib and quercetin (D+Q), have reduced senescent cells burden. The aim of this study was to evaluate the effects of D+Q on testicular function and fertility of male mice. Mice (n = 9/group) received D (5 mg kg-1) and Q (50 mg kg-1) via gavage every moth for three consecutive days from 3 to 8 months of age. At 8 months mice were breed with young non-treated females and euthanized. The treatment of male mice with D+Q increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology. Sperm motility, seminiferous tubule morphometry, testicular gene expression and fertility were not affected by treatment. There was no effect of D+Q treatment in ß-galactosidase activity and in lipofuscin staining in testes. D+Q treatment also did not affect body mass gain and testes mass. In conclusion, D+Q treatment increased serum testosterone levels and sperm concentration and decreased abnormal sperm morphology, however did not affect fertility. Further studies with older mice and different senolytics are necessary to elucidate the effects in the decline of sperm output (quality and quantity) associated with aging.

The Interrelationship Between Female Reproductive Aging and Survival.

The link between survival and reproductive function is demonstrated across many species and is under both long-term evolutionary pressures and short-term environmental pressures. Loss of reproductive function is common in mammals and is strongly correlated with increased rates of disease in both males and females. However, the reproduction-associated change in disease rates is more abrupt and more severe in women, who benefit from a significant health advantage over men until the age of menopause. Young women with early ovarian failure also suffer from increased disease risks, further supporting the role of ovarian function in female health. Contemporary experiments where the influence of young ovarian tissue has been restored in postreproductive-aged females with surgical manipulation were found to increase survival significantly. In these experiments, young, intact ovaries were used to replace the aged ovaries of females that had already reached reproductive cessation. As has been seen previously in primitive species, when the young mammalian ovaries were depleted of germ cells prior to transplantation to the postreproductive female, survival was increased even further than with germ cell-containing young ovaries. Thus, extending reproductive potential significantly increases survival and appears to be germ cell and ovarian hormone-independent. The current review will discuss historical and contemporary observations and theories that support the link between reproduction and survival and provide hope for future clinical applications to decrease menopause-associated increases in disease risks.

Aging-associated changes in motor function are ovarian somatic tissue-dependent, but germ cell and estradiol independent in post-reproductive female mice exposed to young ovarian tissue.

A critical mediator of evolution is natural selection, which operates by the divergent reproductive success of individuals and results in conformity of an organism with its environment. Reproductive function has evolved to support germline transmission. In mammalian ovaries, this requires healthy, active gonad function, and follicle development. However, healthy follicles do not contribute to germline transmission in a dead animal. Therefore, support of the health and survival of the organism, in addition to fertility, must be considered as an integral part of reproductive function. Reproductive and chronological aging both impose a burden on health and increase disease rates. Tremors are a common movement disorder and are often correlated with increasing age. Muscle quality is diminished with age and these declines are gender-specific and are influenced by menopause. In the current experiments, we evaluated aging-associated and reproduction-influenced changes in motor function, utilizing changes in tremor amplitude and grip strength. Tremor amplitude was increased with aging in normal female mice. This increase in tremor amplitude was prevented in aged female mice that received ovarian tissue transplants, both in mice that received germ cell-containing or germ cell-depleted ovarian tissue. Grip strength was decreased with aging in normal female mice. This decrease in grip strength was prevented in aged female mice that received either germ cell-containing or germ cell-depleted tissue transplants. As expected, estradiol levels decreased with aging in normal female mice. Estradiol levels did not change with exposure to young ovarian tissues/cells. Surprisingly, estradiol levels were not increased in aged females that received ovaries from actively cycling, young donors. Overall, tremor amplitude and grip strength were negatively influenced by aging and positively influenced by exposure to young ovarian tissues/cells in aged female mice, and this positive influence was independent of ovarian germ cells and estradiol levels. These findings provide a strong incentive for further investigation of the influence of ovarian somatic tissue on health. In addition, changes in tremor amplitude may serve as an additional marker of biological age.

GH deficiency confers protective advantages against Alzheimer's disease through rescued miRNA expression profile in APP/PS1 mice.

Alzheimer's disease (AD) is the most common form of dementia, affecting approximately 6.5 million Americans age 65 or older. AD is characterized by increased cognitive impairment and treatment options available provide minimal disease attenuation. Additionally, diagnostic methods for AD are not conclusive with definitive diagnoses requiring postmortem brain evaluations. Therefore, miRNAs, a class of small, non-coding RNAs, have garnered attention for their ability to regulate a variety of mRNAs and their potential to serve as both therapeutic targets and biomarkers of AD. Several miRNAs have already been implicated with AD and have been found to directly target genes associated with AD pathology. The APP/PS1 mice is an AD model that expresses the human mutated form of the amyloid precursor protein (APP) and presenilin-1 (PS1) genes. In a previous study, it was identified that crossing long-living growth hormone (GH)-deficient Ames dwarf (df/df) mice with APP/PS1 mice provided protection from AD through a reduction in IGF-1, amyloid-ß (Aß) deposition, and gliosis. Hence, we hypothesized that changes in the expression of miRNAs associated with AD mediated such benefits. To test this hypothesis, we sequenced miRNAs in hippocampi of df/df, wild type (+ / +), df/ + /APP/PS1 (phenotypically normal APP/PS1), and df/df/APP/PS1 mice. Results of this study demonstrated significantly upregulated and downregulated miRNAs between df/df/APP/PS1 and df/ + /APP/PS1 mice that suggest the df/df mutation provides protection from AD progression. Additionally, changes in miRNA expression with age were identified in both df/df and wild-type mice as well as df/df/APP/PS1 and APP/PS1 mice, with predictive functional roles in the Pi3k-AKT/mTOR/FOXO pathways potentially contributing to disease pathogenesis.

Growth hormone increases DNA damage in ovarian follicles and macrophage infiltration in the ovaries.

Evidence points to an important role of the growth hormone (GH) in the aging process and longevity. GH-deficient mice are smaller, live longer than normal littermates, and females have an increased ovarian reserve. The aim of the study was to evaluate the role of GH in the ovarian reserve by evaluating DNA damage, macrophage infiltration, and granulosa cell number in primordial and primary follicles. Experiment 1 used GH-deficient Ames dwarf mice (df/df, n = 12) and their normal littermates (N/df, n = 12), receiving GH or saline injections. Experiment 2 included transgenic mice overexpressing bovine GH (bGH) (n = 6) and normal mice (N, n = 6). DNA damage (anti-γH2AX) and macrophage counting (anti-CD68) were evaluated by immunofluorescence. Female df/df mice had lower γH2AX foci intensity in both oocytes and granulosa cells of primordial and primary follicles (p < 0.05), indicating fewer DNA double-strand breaks (DSBs). GH treatment increased DSBs in both df/df and N/df mice. Inversely, bGH mice had a higher quantity of DSBs in both oocytes and granulosa cells of primordial and primary follicles (p < 0.05). Df/df mice showed ovarian tissue with less macrophage infiltration than N/df mice (p < 0.05) and GH treatment increased macrophage infiltration (p < 0.05). In contrast, bGH mice had ovarian tissue with more macrophage infiltration compared to normal mice (p < 0.05). The current study shows that GH increases DNA DSBs in oocytes and granulosa cells and raises macrophage infiltration in the ovaries, pointing to the role of the GH/IGF-I axis in maintenance of oocyte DNA integrity and ovarian macrophage infiltration in mice.

Senolytic treatment reverses obesity-mediated senescent cell accumulation in the ovary.

Senescent cells are in a cell cycle arrest state and accumulate with aging and obesity, contributing to a chronic inflammatory state. Treatment with senolytic drugs dasatinib and quercetin (D + Q) can reduce senescent cell burden in several tissues, increasing lifespan. Despite this, there are few reports about senescent cells accumulating in female reproductive tissues. Therefore, the aim of the study was to characterize the ovarian reserve and its relationship with cellular senescence in genetically obese mice (ob/ob). In experiment 1, ob/ob (n = 5) and wild-type (WT) mice (n = 5) at 12 months of age were evaluated. In experiment 2, 2-month-old female ob/ob mice were treated with senolytics (D + Q, n = 6) or placebo (n = 6) during the 4 months. Obese mice had more senescent cells in ovaries, indicated by increased p21 and p16 and lipofuscin staining and macrophage infiltration. Treatment with D + Q significantly reduced senescent cell burden in ovaries of obese mice. Neither obesity nor treatment with D + Q affected the number of ovarian follicles. In conclusion, our data indicate that obesity due to leptin deficiency increases the load of senescent cells in the ovary, which is reduced by treatment by senolytics. However, neither obesity nor D + Q treatment affected the ovarian reserve.

Cranial Cruciate Ligament Desmotomies in Sheep Resulting in Peroneus Tertius Injury.

Surgical destabilization of the stifle joint via cranial cruciate ligament desmotomy (CCLD) is a routine procedure for the study of osteoarthritis (OA). Traditionally performed in rats, rabbits, cats, and dogs, CCLD in sheep provides an opportunity to study the pathology and treatment of joint instability in a species whose stifle better represents the equivalent human femorotibial joint. The surgical approaches for CCLD in sheep are variable and can result in inconsistent outcomes. Eight sheep underwent CCLD for use in a gene therapy study. We report this case in which six of the eight sheep were clinically diagnosed by pathognomonic signs and later confirmed by postmortem dissection, with injury of the peroneus tertius (PT) muscle. The PT plays a crucial role in the normal gait of large animals, including sheep. Injury to the PT results in failure of the reciprocal apparatus of the hind limb in which the hock can be extended during stifle flexion creating a varied gait and an indiscriminate increase in instability of the stifle and hock joints. Restricted movement postoperatively may provide decreased variability in surgical outcomes. Alternatively, increased stifle instability via CCLD coupled with PT transection or PT transection alone could potentially provide a superior model of stifle instability and OA development in sheep.

Specific PIWI-Interacting RNAs and Related Small Noncoding RNAs Are Associated With Ovarian Aging in Ames Dwarf (df/df) Mice.

The Ames dwarf (df/df) mouse is a well-established model for delayed aging. MicroRNAs (miRNAs), the most studied small noncoding RNAs (sncRNAs), may regulate ovarian aging to maintain a younger ovarian phenotype in df/df mice. In this study, we profile other types of ovarian sncRNAs, PIWI-interacting RNAs (piRNAs) and piRNA-like RNAs (piLRNAs), in young and aged df/df and normal mice. Half of the piRNAs derive from transfer RNA fragments (tRF-piRNAs). Aging and dwarfism alter the ovarian expression of these novel sncRNAs. Specific tRF-piRNAs that increased with age might target and decrease the expression of the breast cancer antiestrogen resistance protein 3 (BCAR3) gene in the ovaries of old df/df mice. A set of piLRNAs that decreased with age and map to D10Wsu102e mRNA may have trans-regulatory functions. Other piLRNAs that decreased with age potentially target and may de-repress transposable elements, leading to a beneficial impact on ovarian aging in df/df mice. These results identify unique responses in ovarian tissues with regard to aging and dwarfism. Overall, our findings highlight the complexity of the aging effects on gene expression and suggest that, in addition to miRNAs, piRNAs, piLRNAs, tRF-piRNAs, and their potential targets can be central players in the maintenance of a younger ovarian phenotype in df/df mice.

The Interconnections Between Somatic and Ovarian Aging in Murine Models.

The mammalian female is born with a limited ovarian reserve of primordial follicles. These primordial follicles are slowly activated throughout the reproductive lifecycle, thereby determining lifecycle length. Once primordial follicles are exhausted, women undergo menopause, which is associated with several metabolic perturbations and a higher mortality risk. Long before exhaustion of the reserve, females experience severe declines in fertility and health. As such, significant efforts have been made to unravel the mechanisms that promote ovarian aging and insufficiency. In this review, we explain how long-living murine models can provide insights in the regulation of ovarian aging. There is now overwhelming evidence that most life-span-extending strategies, and long-living mutant models simultaneously delay ovarian aging. Therefore, it appears that the same mechanisms that regulate somatic aging may also be modulating ovarian aging and germ cell exhaustion. We explore several potential contributing mechanisms including insulin resistance, inflammation, and DNA damage-all of which are hallmarks of cellular aging throughout the body including the ovary. These findings are in alignment with the disposable soma theory of aging, which dictates a trade-off between growth, reproduction, and DNA repair. Therefore, delaying ovarian aging will not only increase the fertility window of middle age females, but may also actively prevent menopausal-related decline in systemic health parameters, compressing the period of morbidity in mid-to-late life in females.

Decreased Sarcopenia in Aged Females with Young Ovary Transplants was Preserved in Mice that Received Germ Cell-Depleted Young Ovaries.

Previously, transplantation of young, cycling, ovaries increased life and health span in post-reproductive female mice. The current study addressed the influence of ovarian germ cells in the improvement in health by performing transplantations of young, germ cell-depleted ovaries. The purpose of this study is to further the understanding of reproductive influences on aging health. Control mice were grouped by age. Treatment mice were age-matched and received either germ cell depleted ovaries or germ cell containing ovaries at 400 days of age. All groups underwent health span assays until sacrifice (treatment and age-matched control groups were between 680 and 700 days). Body composition results displayed an improvement of body composition in both treatment groups, compared to the controls, but no significant difference between the germ cell-depleted or germ cell-containing groups. Grip test results showed no improvement in musculoskeletal endurance and no change to mild loss of grip strength with both transplant groups compared to control groups. The research presented here suggests that reproductive status has a positive influence in post-reproductive health. A portion of this influence may be germ cell independent.

Manipulation of ovarian function influenced glucose metabolism in CBA/J mice.

Menopause is associated with a decline in overall health in women. One health aspect impacted is glucose metabolism. As women experience menopause, their metabolism declines dramatically. The current study addressed the influence of ovarian somatic cells on the improvement of metabolic health through transplantations of young, germ cell-depleted ovaries. The purpose of this study is to expand the understanding of female reproductive health on metabolism. Control mice were grouped by age and treatment mice were age-matched. Treatment mice were placed into one of three groups: 1) mice received germ cell-depleted ovaries, 2) mice received germ cell-containing ovaries, and 3) mice received ovarian somatic cells via injection directly to their original ovary. All mice were subject to a glucose tolerance test, during which a bolus of dextrose was administered, and blood glucose levels were collected and recorded. Mice were euthanized between 680 and 700 days. Metabolic results showed an improvement of glucose metabolism in both germ cell-depleted and germ cell-containing groups compared to controls. No significance difference was noted between the germ cell-containing and germ cell-depleted groups. Somatic cell injection groups also showed improved glucose metabolism compared to controls. This experiment has shown that post-reproductive health is positively influenced by reproductive status. Additionally, somatic cells play an important role in the restoration of health to post-reproductive mice.