Female Reproductive Senescence Research Articles

Multiple treatments with human embryonic stem cell-derived mesenchymal progenitor cells preserved the fertility and ovarian function of perimenopausal mice undergoing natural aging

ObjectivesCurrently, no approved stem cell-based therapies for preserving ovarian function during aging. To solve this problem, we developed a long-term treatment for human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs). We investigated whether the cells retained their ability to resist ovarian aging, which leads to delayed reproductive senescence.Materials and methodsIn a middle-aged female model undergoing natural aging, we analyzed whether hESC-MPCs benefit the long-term maintenance of reproductive fecundity and ovarian reservoirs and how their transplantation regulates ovarian function.ResultsThe number of primordial follicles and mice with regular estrous cycles were increased in perimenopausal mice who underwent multiple introductions of hESC-MPCs compared to age-matched controls. The estradiol levels in the hESC-MPCs group were restored to those in the young and adult groups. Embryonic development and live birth rates were higher in the hESC-MPC group than in the control group, suggesting that hESC-MPCs delayed ovarian senescence. In addition to their direct effects on the ovary, multiple-treatments with hESC-MPCs reduced ovarian fibrosis by downregulating inflammation and fibrosis-related genes via the suppression of myeloid-derived suppressor cells (MDSCs) produced in the bone marrow.ConclusionsMultiple introductions of hESC-MPCs could be a useful approach to prevent female reproductive senescence and that these cells are promising sources for cell therapy to postpone the ovarian aging and retain fecundity in perimenopausal women.

Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility.

Mitochondrial unfolded protein stress response (mtUPR) plays a critical role in regulating cellular and metabolic stress response and helps maintain protein homeostasis. Caseinolytic peptidase P (CLPP) is one of the key regulators of mtUPR and promotes unfolded protein degradation. Previous studies demonstrated that global deletion of Clpp resulted in female infertility, whereas no impairment was found in the mouse model with targeted deletion of Clpp in cumulus/granulosa cells. These results suggest the need to delineate the function of Clpp in oocytes. In this study, we aimed to further explore the role of mtUPR in female reproductive competence and senescence using a mouse model. Oocyte-specific targeted deletion of Clpp in mice resulted in female subfertility associated with metabolic and functional abnormalities in oocytes, thus highlighting the importance of CLPP-mediated protein homeostasis in oocyte competence and reproductive function.

Di(2-ethylhexyl) phthalate induces reproductive toxicity and transgenerational reproductive aging in Caenorhabditis elegans

With the large-scale production and use of plastic products, the global plastic pollution problem is becoming more and more serious. The plasticizer di (2-ethylhexyl) phthalate (DEHP), which is widely used in the production of plastics, has caused great concern for the health of the population. Exposure of organisms to DEHP can cause a variety of health damage, of which reproductive system damage is an important part. At present, there are still few studies on DEHP in reproductive aging, and it is of great significance to explore the role of DEHP in promoting reproductive aging and its underlying mechanism. In this study, the model organism Caenorhabditis elegans (C. elegans) was used to preliminarily explore the mechanism of DEHP-induced female reproductive senescence. The results showed that DEHP reduced the number of offspring and gonad area of C. elegans, resulting in shortened reproductive and life span, abnormal phenotypes in somatic gonad structure including the Emo phenotype, the BOW phenotype, a twisted gonad arm, and atrophied oocytes. Biochemical studies showed that DEHP promoted oxidative stress and autophagy in C. elegans. Further, we found the decreased number of offspring, malformed somatic gonad structure, oxidative damage and autophagy induced by DEHP in parental worms can be inheritance to the not directly exposed offspring.

Natal environmental conditions modulate senescence of antler length in roe deer

It is now broadly admitted that female reproductive senescence – a decline in reproductive performance with increasing age – occurs in most species, at least among birds and mammals. Although information is more limited, male reproductive senescence has been regularly inferred from the decline in the size or performance of phenotypic traits that underly male reproductive success, particularly secondary sexual traits. However, the degree to which environmental conditions influence the pattern of senescence in sexual traits remains largely unknown. From the analysis of two long-term studies of populations of European roe deer (Capreolus capreolus) subjected to markedly different environmental contexts in the wild, we tested the hypothesis that harsh natal and/or current conditions should lead to earlier and/or stronger rates of senescence in the length of fully-grown antlers than good natal and/or current conditions. We found evidence of similar patterns of antler length senescence in both populations, with an onset of senescence around 7 years of age and a decrease of length by about 1–1.5 cm per additional year of life from 7 years of age onwards. We found that good early-life conditions delay senescence in antler length in roe deer. Our results also revealed that senescent males seem to be unable to allocate substantially to antler growth, confirming that antler size is, therefore, an honest signal of male individual quality. By modulating age-specific allocation to secondary sexual traits, natal and current conditions could influence female mate choice and male–male competition over mates, and as a result age-specific reproductive success, and should be accounted for when studying the dynamics of sexual selection.

Unraveling female reproductive senescence to enhance healthy longevity.

In a society where women often want successful careers and equal opportunities to men, the early nature of ovarian aging often forces women to make difficult life choices between career and family development. Fertility in women begins to decline after the age of 37 years and it is rare for pregnancies to occur after 45. This reproductive decline in women is inevitable and culminates in menopause, which is a major driver of age-related diseases. In a world where biomedical advances are leading to modifiable biological outcomes, it is time to focus on mitigating female reproductive senescence to maintain fertility and preserve age-related hormonal functions, with the goal of providing increased life choices and enhancing healthspan. To date, reproductive longevity research remains an understudied field. More needs to be done to unravel the biology of the ovarian follicles, which are the functional units of reproductive lifespan and are comprised of cell types including the oocyte (female gamete) and a group of specialized supporting somatic cells. Biological attempts to maintain the quality and quantity of follicles in animal models through manipulating pathways involved in aging can potentially prolong female reproductive lifespan and healthspan. Here, we summarize the molecular events driving ovarian aging and menopause and the interventional strategies to offset these events. Developing solutions to female reproductive senescence will open doors to discover ways to enhance true healthy longevity for both men and women.

Epigenetic modification of Kiss1 gene expression in the AVPV is essential for female reproductive aging.

Female reproductive senescence is heralded by hypothalamus region-specific changes in the transcription of genes such as Kiss1 under estradiol (E2) positive feedback, associated with luteinizing hormone (LH) surge dysfunction and reproductive decline. The current study explored whether the anteroventral periventricular nucleus (AVPV) displayed epigenetic changes mediated by age-related dysregulation of gene expression and whether an epigenetic-based intervention could alleviate an aging-related neuroendocrine disorder. Chromatin immunoprecipitation sequencing (ChIP-seq) and ChIP-qPCR were used to assess the differential acetylation of histone H3 in the AVPV and the expression of genes in hormone-primed middle-aged rats. The association between acetylated histone H3 and Kiss1 expression and the underlying mechanisms of dysregulation were determined using pharmacological inhibitors and molecular experiments in vitro and in vivo. An AVPV gene expression program failed to initiate in middle-aged females displaying typical genome-wide hypoacetylation of histone H3, and this coincided with decreased LH. Hypoacetylation of histone H3 at the 3' intergenic region of Kiss1 in particular was associated with enhanced chromatin looping between the promoter and enhancer. Restoration of physiological histone H3 acetylation by intracerebroventricular injection of trichostatin A (TSA) restored the expression of Kiss1 by modifying chromatin looping and led to the restoration of Kiss1 neuronal activation and Kiss1 synthesis as well as circulating LH. These findings have revealed novel epigenetic-associated changes in gene expression in female reproductive aging. These results also suggest that HDAC enzyme-based treatment is a potential therapeutic approach for insufficient preovulatory LH release in aging females.

MITOCHONDRIAL STRESS RESPONSE GENE CLPP IS REQUIRED FOR OOCYTE FUNCTION AND FEMALE FERTILITY

Caseinolytic Protease Proteolytic Subunit (CLPP) is a protease responsible for the degradation of misfolded mitochondrial proteins. CLPP is activated at the time of cellular metabolic stress and helps maintain homeostasis.The aim of the study was to determine the role of CLPP in female reproductive competence and senescence using a mouse model with oocyte-specific Clpp deletion.

Targeted Deletion of Mitofusin 1 and Mitofusin 2 Causes Female Infertility and Loss of Follicular Reserve.

Mitochondria are dynamic organelles that regulate their size, shape, and morphology through mechanisms called fusion and fission, to continually adapt themselves to their bioenergetic environment. These mechanisms play a critical role to maintain the mitochondrial function under metabolic and environmental stress. Mitofusin 1 (MFN1) and mitofusin 2 (MFN2) are transmembrane GTPases that regulate mitochondrial fusion mechanism and are required for the maintenance of cellular homeostasis. In this study, we aimed to determine the role of mitofusins in female reproductive competence and senescence using a mouse model with oocyte-specific double deletion of Mfn1 and Mfn2, eliminating the potential functional redundancy of these two proteins. Oocyte-specific targeted double deletion of Mfn1 and Mfn2 in mice resulted in female infertility associated with impaired follicular development and oocyte maturation. It also resulted in altered mitochondrial dynamics and mitochondrial dysfunction. Lack of Mfn1 and Mfn2 in oocytes resulted in accelerated follicular depletion and impaired oocyte quality which are consistent with phenotype of reproductive aging.

TARGETED DELETION OF MITOFUSIN 1 AND MITOSUFIN 2 CAUSES FEMALE INFERTILITY AND LOSS OF FOLLICULAR RESERVE

Mitofusin 1 (MFN1) and Mitofusin 2 (MFN2) are transmembrane GTPases that regulate mitochondrial fusion and are required for the maintenance of cellular homeostasis. The aim of the study was to determine the role of mitofusins in female reproductive competence and senescence using a mouse model with oocyte-specific deletion of Mfn1 and Mfn2. Mice with oocyte-specific double deletion of Mfn1 and Mfn2 were generated by mating Mfn1 flox/flox or Mfn2 flox/flox with Zp3-Cre Mfn1 and Mfn2 males. In all experiments, adult (8-weeks-old) Mfn1-/-/Mfn2-/- female mice were compared to wild-type (WT). To assess fertility, female mice from each group (n=5) were mated with adult WT males of proven fertility for 12 weeks. The ability to generate oocytes (germinal vesicle [GV] and metaphase II [MII]) was assessed after injection with PMSG (10IU) or PMSG and hCG (10IU). Unfertilized MII oocytes were collected 14 hours after hCG injection. Follicle development was assessed in ovaries from Mfn1-/-/Mfn2-/- and WT mice after fixation, paraffin embedding, and sectioning, followed by hematoxylin and eosin (H&E) staining. ATP levels were determined by bioluminescent assay. Mitochondrial DNA (mtDNA) copy number was measured in individual oocytes by cloning of mitochondria specific gene (Cox3) as a standard, followed by quantitative real-time PCR (qPCR). Expression levels of mitochondrial respiratory chain genes was evaluated with qRT-PCR. Student’s t-test and Chi-Square analysis were applied. Mature female Mfn1-/-/Mfn2-/- were infertile compared to WT females (0 ± 0 vs ± 5.62 ± 1.64 pups per litter; p < 0.0001). Mfn1-/-/Mfn2-/- mice showed a significant decrease in GV oocyte number (12.75 ± 1.70 vs 40.25 ± 3.5; p < 0.0001) and generated no MII oocytes (0 ± 0 vs 31.01 ± 3.5; p < 0.0001) in comparison to WT. Eight-week-old Mfn1-/-/Mfn2-/- mice ovaries had similar number of primordial, primary, and secondary follicles compared to WT. However, the number of early antral and antral follicles numbers was significantly decreased (17.2 ± 10.2 vs 55.3 ± 9.50; p < 0.03, and 2.3 ± 1.5 vs 16.3 ± 5.8; p < 0.04). At 6 months, Mfn1-/-/Mfn2-/- mice had a lower number of primordial, early antral, and antral follicles compared to WT. At 12 months, all follicle stages were found to be significantly lower in Mfn1-/-/Mfn2-/- mice. Decreased ATP production (0.62 ± 0.1 vs 1.23 ± 0.12; p = 0.002) and mtDNA copy number (446033 ± 53978 vs 706672 ± 72470; p = 0.003) were also observed in Mfn1-/-/Mfn2-/-oocytes compared to WT. Similarly, the expression of mitochondrial chain respiratory genes Cox1, Sdhb, Uqcrc2 and Atp5a1 were decreased in Mfn1-/-/Mfn2-/- oocytes compared to WT. Our findings demonstrate that lack of MFN1 and MFN2 results in infertility and accelerated loss of follicular reserve consistent with a diminished ovarian reserve (DOR) phenotype.

Is degree of sociality associated with reproductive senescence? A comparative analysis across birds and mammals.

Our understanding on how widespread reproductive senescence is in the wild and how the onset and rate of reproductive senescence vary among species in relation to life histories and lifestyles is currently limited. More specifically, whether the species-specific degree of sociality is linked to the occurrence, onset and rate of reproductive senescence remains unknown. Here, we investigate these questions using phylogenetic comparative analyses across 36 bird and 101 mammal species encompassing a wide array of life histories, lifestyles and social traits. We found that female reproductive senescence: (i) is widespread and occurs with similar frequency (about two-thirds) in birds and mammals; (ii) occurs later in life and is slower in birds than in similar-sized mammals; (iii) occurs later in life and is slower with an increasingly slower pace of life in both vertebrate classes; and (iv) is only weakly associated, if any, with the degree of sociality in both classes after accounting for the effect of body size and pace of life. However, when removing the effect of species differences in pace of life, a higher degree of sociality was associated with later and weaker reproductive senescence in females, which suggests that the degree of sociality is either indirectly related to reproductive senescence via the pace of life or simply a direct outcome of the pace of life. This article is part of the theme issue 'Ageing and sociality: why, when and how does sociality change ageing patterns?'

Female reproductive senescence across mammals: A high diversity of patterns modulated by life history and mating traits

Senescence patterns are highly variable across the animal kingdom. However, while empirical evidence of actuarial senescence in vertebrates is accumulating in the wild and life history correlates of actuarial senescence are increasingly identified, both the extent and variation of reproductive senescence across species remain poorly studied. Here, we performed the first large-scale analysis of female reproductive senescence across 101 mammalian species that encompassed a wide range of Orders. We found evidence of reproductive senescence in 68.31 % of the species, which demonstrates that reproductive senescence is pervasive in mammals. As expected from allometric rules, the onset of reproductive senescence occurs later and the rate of reproductive senescence decreases with increasing body mass and delayed age at first reproduction. Moreover, for a given pace of life, females displaying a high level of multiple mating and/or with induced ovulation senesce earlier than females displaying a low level of multiple mating and/or with spontaneous ovulation. These results suggest that both female mating behavior and reproductive physiology shape the diversity of reproductive senescence patterns across mammals. We propose future avenues of research regarding the role played by environmental conditions or reproductive features (e.g. type of placentation) on the evolution of reproductive senescence.

OVARIAN AGING AND REPRODUCTIVE SENESCENCE IN MOUSE MODEL OF MITOCHONDRIAL DYSFUNCTION

To evaluate the mechanisms of female reproductive aging and senescence induced by mitochondrial dysfunction in mice. Prospective cohort design study. 13 female mice with mitochondrial dysfunction (mtDNA-depleter) and 13 wild-type (WT) female mice were studied at three time points in their reproductive life cycle: 4-6, 8-10, and 11-12 months of age. A transgenic mouse model with an inducible gene for mitochondrial dysfunction (mtDNA-depleter) was previously created by our lab. All protocols were approved by our institutional IACUC. At each of the three time points, reproductive markers were assessed, including estrous cyclicity, plasma anti-Mullerian hormone (AMH), ovarian follicles, estrogen receptor staining, and uterine and vaginal atrophy. Breeding experiments were performed to assess fertility. Differences between the mtDNA-depleter and WT groups were evaluated by independent two-sample t-test. Twenty-six female mice were studied from 4 to 12 months of age. The estrous cycles in 4-6-month mtDNA-depleter mice were prolonged, 9.4 days (n = 7), versus 5.3 days in WT (n = 9), p-value of 0.021. By 11-12 months, both groups had prolonged estrous cycles consistent with physiologic aging. AMH levels in 4-6-month mtDNA-depleter mice were decreased, 84 (n = 4), versus 114 ng/mL in WT (n = 5), p-value of 0.013. AMH was reduced in older mice at 8-10 and 11-12 months, but there were no significant differences between groups. Looking at the data collectively for all three time points, there were fewer tertiary (early antral, antral, or pre-ovulatory) follicles in mtDNA-depleter mice than in WT, 3.5 versus 4.9 per cut section, respectively (p-value of 0.039). There were fewer corpora lutea in mtDNA-depleter mice than in WT, 0.90 versus 1.7 per cut section, respectively (p-value of 0.027). Collectively, average uterine weight in mtDNA-depleter mice was lower, 62.2, versus 92.3 mg in WT mice, p-value of 0.0028. Vaginal epithelium in 4-6-month mtDNA-depleter mice was thinner, 98 μm (n = 4), versus 200 μm in WT mice (n = 4), p-value of 0.035. In breeding experiments, mtDNA-depleter mice at age 3 and 5 months did not produce litters. Estrogen receptor levels were reduced in mtDNA-depleter mouse ovary relative to WT, evident from both immunofluorescence and semi-quantitative PCR analysis. Mitochondrial dysfunction in mice is associated with premature reproductive aging and senescence, as evidenced by early onset of prolonged estrous cycles, diminished ovarian reserve, uterine and vaginal atrophy, and sterility. Mitochondrial dysfunction is also associated with premature estrogen receptor down-regulation in the mouse ovary.

Condition-dependent mortality exacerbates male (but not female) reproductive senescence and the potential for sexual conflict.

Disentangling the relationship between age and reproduction is central to understand life-history evolution, and recent evidence shows that considering condition-dependent mortality is a crucial piece of this puzzle. For example, nonrandom mortality of 'low-condition' individuals can lead to an increase in average lifespan. However, selective disappearance of such low-condition individuals may also affect reproductive senescence at the population level due to trade-offs between physiological functions related to survival/lifespan and the maintenance of reproductive functions. Here, we address the idea that condition-dependent extrinsic mortality (i.e. simulated predation) may increase the age-related decline in male reproductive success and with it the potential for sexual conflict, by comparing reproductive ageing in Drosophila melanogaster male/female cohorts exposed (or not) to condition-dependent simulated predation across time. Although female reproductive senescence was not affected by predation, male reproductive senescence was considerably higher under predation, due mainly to an accelerated decline in offspring viability of 'surviving' males with age. This sex-specific effect suggests that condition-dependent extrinsic mortality can exacerbate survival-reproduction trade-offs in males, which are typically under stronger condition-dependent selection than females. Interestingly, condition-dependent extrinsic mortality did not affect mating success, hinting that accelerated reproductive senescence is due to a decrease in male post-copulatory fitness components. Our results support the recent proposal that male ageing can be an important source of sexual conflict, further suggesting this effect could be exacerbated under more natural conditions.

Sons accelerate maternal aging in a wild mammal

Aging, or senescence, is a progressive deterioration of physiological function with age. It leads to age-related declines in reproduction (reproductive senescence) and survival (actuarial senescence) in most organisms. However, senescence patterns can be highly variable across species, populations, and individuals, and the reasons for such variations remain poorly understood. Evolutionary theories predict that increases in reproductive effort in early life should be associated with accelerated senescence, but empirical tests have yielded mixed results. Although in sexually size-dimorphic species offspring of the larger sex (typically males) commonly require more parental resources, these sex differences are not currently incorporated into evolutionary theories of aging. Here, we show that female reproductive senescence varies with both the number and sex ratio of offspring weaned during early life, using data from a long-term study of bighorn sheep. For a given number of offspring, females that weaned more sons than daughters when aged between 2 and 7 y experienced faster senescence in offspring survival in old age. By contrast, analyses of actuarial senescence showed no cost of early-life reproduction. Our results unite two important topics in evolutionary biology: life history and sex allocation. Offspring sex ratio may help explain among-individual variation in senescence rates in other species, including humans.

The Inflammasome in Reproductive Biology: A Promising Target for Novel Therapies.

The inflammasome is a key regulator of innate immunity involved in the inflammatory response to infections as well as disease through the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. Even though the inflammasome was first described in the context of infections, most research in recent years has focused on targeting the inflammasome as a therapeutic option in sterile inflammatory events. Recent evidence indicates a clear involvement of the inflammasome in Reproductive Biology such as infertility and preeclampsia. In this mini-review, I summarize the current findings on the inflammasome that have been described in the field of Reproductive Biology and highlight the potential that the inflammasome has as a novel therapeutic option in this field. The topics covered in this review as it pertains to the inflammasome field cover the literature published on male and female infertility, endometriosis, preeclampsia, placental inflammation, and reproductive senescence.

Hormone Replacement Therapy: Risks and Benefits

The climacteric is a physiological period of the female reproductive cycle characterized by a decrease in the levels of sex hormones, mainly estrogen. It consists of several phases, with amenorrhea as the initial clinical manifestation followed by long-term changes, such as vaginal atrophy. In this context, hormone replacement therapy (HRT) aims to improve the symptoms of female reproductive senescence, seeking to provide a comfortable physical and psychological condition during this period. However, as with any drug treatment, HRT has its risks and benefits, and it is up to the medical practitioner, in agreement with the patient, looking for the best therapeutic option, minimizing the risks and consequences resulting from this clinical approach.

Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation.

Perimenopause marks initiation of female reproductive senescence. Age of onset is only 47% heritable suggesting that additional factors other than inheritance regulate this endocrine aging transition. To elucidate these factors, we characterized transcriptional and epigenomic changes across endocrine aging using a rat model that recapitulates characteristics of the human perimenopause. RNA-seq analysis revealed that hypothalamic aging precedes onset of perimenopause. In the hypothalamus, global DNA methylation declined with both age and reproductive senescence. Genome-wide epigentic analysis revealed changes in DNA methylation in genes required for hormone signaling, glutamate signaling, and melatonin and circadian pathways. Specific epignetic changes in these signaling pathways provide insight into the origin of perimenopause-associated neurological symptoms such as insomnia. Treatment with 5-aza-2'-deoxycytidine, a DNA-methyltransferase-1 inhibitor, accelerated transition to reproductive senescence/ whereas supplementation with methionine, a S-adenosylmethionine precursor, delayed onset of perimenopause and endocrine aging. Collectively, these data provide evidence for a critical period of female neuroendocrine aging in brain that precedes ovarian failure and that DNA methylation regulates the transition duration of perimenopause to menopause.

Maternal reproductive senescence shapes the fitness consequences of the parental age difference in ruffed lemurs.

In humans, pronounced age differences between parents have deleterious fitness consequences. In particular, the number of children is lower when mothers are much older than fathers. However, previous analyses failed to disentangle the influence of differential parental age per se from a direct age effect of each parent. In this study, we analyse the fitness consequences of both parental age and parental age differences on litter size and offspring survival in two closely related species of lemurs living in captivity. As captive lemurs do not choose their reproductive partner, we were able to measure litter size and offspring survival across breeding pairs showing a wide range of parental age differences. However, we demonstrated that the effect of the parental age difference on litter size was fully accounted for by female reproductive senescence because females mating with much younger males were old females. On the other hand, both parental age difference and female reproductive senescence influenced offspring survival. Our results emphasize the importance of teasing apart the effect of parental reproductive senescence when investigating the health and fitness consequences of parental age differences and also provide new insights for conservation programmes of endangered species.

Mitochondrial stress response gene clpp plays a role in female reproductive aging

CLPP (caseinolytic peptidase P) mediates degradation of unfolded mitochondrial proteins and activates mitochondrial unfolded protein response (mt-UPR) to maintain homeostasis in the presence of cellular and metabolic stress. The aim of the current study was to determine the role of mt-UPR in female reproductive competence and senescence using a mouse model with global germline ClpP deletion.

Reproductive senescence: new perspectives in the wild.

According to recent empirical studies, reproductive senescence, the decline in reproductive success with increasing age, seems to be nearly ubiquitous in the wild. However, a clear understanding of the evolutionary causes and consequences of reproductive senescence is still lacking and requires new and integrative approaches. After identifying the sequential and complex nature of female reproductive senescence, we show that the relative contributions of physiological decline and alterations in the efficiency of parental care to reproductive senescence remain unknown and need to be assessed in the light of current evolutionary theories of ageing. We demonstrate that, although reproductive senescence is generally studied only from the female viewpoint, age-specific female reproductive success strongly depends on male-female interactions. Thus, a reduction in male fertilization efficiency with increasing age has detrimental consequences for female fitness. Lastly, we call for investigations of the role of environmental conditions on reproductive senescence, which could provide salient insights into the underlying sex-specific mechanisms of reproductive success. We suggest that embracing such directions should allow building new bridges between reproductive senescence and the study of sperm competition, parental care, mate choice and environmental conditions.