Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice

Abstract

The aim of the current work was to evaluate the ovarian follicle reserve and the ovarian transcriptome in Ames dwarf (df/df) mice. The results suggest a delayed ovarian aging in df/df mice compared to normal (N) mice. Although a high number of genes were differentially expressed during aging of N mice, only a small fraction of these changed with aging in df/df mice. These alterations involved more than 500 categorized biological processes. The majority of these biological processes, including inflammatory/immune responses, were up-regulated with aging in N mice, while old df/df mice were characterized by down-regulation of these same processes in comparison to age matched N mice. However, biological processes related to DNA damage and repairing were commonly down-regulated with aging in both genotypes. In conclusion, delayed ovarian aging in long-living df/df mice was associated with reduced expression of genes related to the inflammatory and immune responses.

Changes of Ovarian microRNA Profile in Long-Living Ames Dwarf Mice during Aging

“…The PI3K/Akt, FoxO and mTOR signaling pathways are essential for the maintenance of the quiescent stage and initiation of primordial follicle growth [17, 18, 29] and can be regarded as regulators of the rate of ovarian aging. In agreement with that, we have previously observed using the same ovarian RNA samples as the ones employed in the current study for RNASeq transcriptome evaluation and observed that ovarian expression of the Pi3k/Akt pathway is one of the main regulated pathways in df/df mice compared to N mice [20]. In addition, FoxO3a phosphorylation was reduced in primordial follicles of GH-deficient df/df mice [19, 42], suggesting that inhibition of this pathway (insulin/PI3k/Akt/FoxO) is essential for maintenance of primordial follicle quiescence.…”

“…Of these, only three miRNAs were commonly regulated with age between N and df/df mice, indicating a very divergent profile of ovarian miRNAs as both mice genotypes age. It was previously demonstrated that the size of the primordial follicle reserve decreases by approximately 90% from the ages of 0.5 to 1.5 years in N female mice [12], and we demonstrated before that the ovarian reserve of primordial follicles in df/df mice is three times larger than in N mice [19, 20]. Therefore, our finding indicates that changes in the ovarian reserve with aging are reflected in changes in the ovarian miRNA profile of N and df/df mice.…”

“…Although female df/df mice have normal ovarian cyclicity and can maintain pregnancy under hormonal stimulation, they have delayed puberty [16]. We previously reported that Forkhead Box O3a (Foxo3a) phosphorylation, one of the main pathways implicated in irreversible primordial follicle activation [17, 18], is reduced in oocytes enclosed in primordial follicles from df/df mice, preventing primordial follicle activation [19, 20]. As a result df/df mice have a delayed ovarian aging and an increased number of primordial follicles compared to old Normal (N) mice [19, 20].…”

“…We previously reported that Forkhead Box O3a (Foxo3a) phosphorylation, one of the main pathways implicated in irreversible primordial follicle activation [17, 18], is reduced in oocytes enclosed in primordial follicles from df/df mice, preventing primordial follicle activation [19, 20]. As a result df/df mice have a delayed ovarian aging and an increased number of primordial follicles compared to old Normal (N) mice [19, 20]. Activation of primordial follicle growth is also impaired in GH receptor disrupted mice [21] and mice subjected to caloric restriction [22], also culminating in delayed ovarian aging and a greater number of primordial follicles in the quiescent stage.…”

“…However, very little is known about the miRNA profile associated with ovarian aging, since most mouse models for ovarian aging (knockouts for PTEN and FoxO3 for example) have complete ovarian failure early after puberty [17, 29]. df/df mice can maintain the ovarian reserve for a longer period than N mice [19, 20], which allows for comparison of expression profiles at different stages of life, making it a very valuable model of ovarian aging. Therefore, the aim of the current work is to evaluate the ovarian miRNA profile in young and aged df/df and N mice in order to establish miRNAs potentially involved in ovarian aging.…”