Advertisement

Extended fertility and longevity: the genetic and epigenetic link

      Many women now choose to develop their careers before having children. Thus, it is becoming increasingly important to assess a woman's potential for extended fertility and to understand the health consequences of having children at a late age. In particular, there is a striking positive correlation between extended fertility and longevity in women, which poses important implications for medicine, biology, and evolution. In this article we review the diverse epidemiologic evidence for the link between fertility potential, age of menopause, and women's lifespan. Then we discuss the recent advances using genomic technology to better understand biological mechanisms driving this association. At the genetic level, there are polymorphisms that may be driving both extended fertility and longevity. At the cellular and molecular levels, changes in the genome (both nuclear and mitochondrial), epigenome, and transcriptome during oocyte aging have important implications for fertility. By synthesizing results from diverse domains, we hope to provide a genomic-era conceptual framework in which this important connection can be investigated and understood.

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/wainerkatsirk-fertility-longevity-genetics-epigenetics/
      Diverse epidemiologic evidence shows that women who have children at late age are more likely to live longer. However, the genetic connection remains obscure. In this article we summarize and discuss the current understanding of the biological mechanisms underlying this link, many of which were recently uncovered using genomic technologies. This raises a set of questions that are relevant for both basic research and clinical practice: [1] Do women with extended fertility really live longer? [2] To what extent is this phenomenon explainable in genetics terms? Are there mutations/genomic variations that increase fertility? [3] What are the molecular mechanisms behind the convergence of fertility and longevity? [4] How can the resulting insights on genomic, epigenetic, and gene expression data impact medical practice?
      We present information to address these questions under two contexts: [1] the genetic context in which stable and heritable polymorphisms in the DNA affect extended fertility and longevity; and [2] a complementary cellular view that describes the age-dependent, functional profiles of the cell. The conceptual framework of the study is presented in Figure 1. The bulk of the relevant literature comes from genetic analysis of cohorts of women and high-throughput studies of epigenetics (Table 1) and gene expression of oocytes and related cells.
      Figure thumbnail gr1
      Figure 1Schematic showing the molecular components connecting extended fertility in women with longevity.
      Table 1Genomics and genetics definitions.
      TermDefinition
      AneuploidyAn abnormal number of chromosomes in the cells. In embryo, it describes the excess or missing of chromosomes.
      Copy number variant (CNV)A stretch of nucleotides in the DNA that varies between individuals.
      DNA methylationThe process of adding a methyl group to the base of cytosine. Methylated regions often overlap with regions of transcription repression.
      DNA arrayA platform for detecting the expression of thousands of sequences in parallel (often called microarray). Routine platforms are for coding exons, messenger RNA, or microRNAs. The hybridization intensity is a reflection of the amount of RNA that is in tested samples.
      EpigeneticsAn additional layer of genetic information that passes to daughter cells. The heritable information is not defined by the DNA sequence per se.
      Genome-wide association study (GWAS)This study type seeks risk factors and genomic loci that are associated with a particular phenotype. The method relies on genotyping of a population.
      InversionA segment of a chromosome that appears in the reverse orientation.
      MicroRNA (miRNA)Short, noncoding RNAs that bind the target messenger RNA and attenuate the level of its expression and protein product.
      Mitochondrial genomeA nonnuclear genome with 37 encoded genes in the mitochondria.
      Single-nucleotide polymorphism (SNP)A single-nucleotide change in the DNA of individuals. An SNP determines the identity of the allele that characterizes an individual genotype.
      TelomereA stretch of repetitive DNA that caps and protects the end of the chromosome.

      Evolutionary theories for the role of the postfertility lifespan

      Females of most animal species reproduce throughout life until they die (
      • Lahdenpera M.
      • Lummaa V.
      • Helle S.
      • Tremblay M.
      • Russell A.F.
      Fitness benefits of prolonged post-reproductive lifespan in women.
      ). This is consistent with one of the basic tenets of evolution, which equates the fitness of a species with the number of successful offspring. Humans are different from most animals and primates in this regard; women live approximately half of their lives in the postproductive phase.
      Researchers propose that the extended postfertility lifespan in humans confers evolutionary advantage because substantially more resources are channeled for the success of the offspring (
      • Hawkes K.
      • O’Connell J.F.
      • Jones N.G.
      • Alvarez H.
      • Charnov E.L.
      Grandmothering, menopause, and the evolution of human life histories.
      ). This is formulated as the “grandmother hypothesis.” A study across several geographically diverse populations shows that women with longer postreproduction span improve the reproductive success of their children and have more grandchildren, thus increasing the fitness of their own genes. Furthermore, the mortality rates of the mothers accelerate from the time when their own offspring begin to terminate reproduction (
      • Lahdenpera M.
      • Lummaa V.
      • Helle S.
      • Tremblay M.
      • Russell A.F.
      Fitness benefits of prolonged post-reproductive lifespan in women.
      ).

      Epidemiologic link between women fertility and longevity

      Genealogic records are the best resource for the phenomenologic trends on extended fertility and longevity. A key factor in many of the large population analyses is the need to remove the socioeconomic covariates from the genetic component (
      • Chen C.T.
      • Liu C.T.
      • Chen G.K.
      • Andrews J.S.
      • Arnold A.M.
      • Dreyfus J.
      • et al.
      Meta-analysis of loci associated with age at natural menopause in African-American women.
      ). Moreover, it is important to note that there are multiple definitions for fertility potential and aging. Menopause age, the number of children, and the ability to have children in the fifth decade are all indirect manifestations of fertility. Similarly, loss of cognitive and physical capabilities, onset of neurodegenerative diseases, and mortality serve as sign posts to the processes of aging.
      The rapid drop in female fertility at age 40 years has been documented and extensively studied. It is largely explained by an age-related increase in chromosomal aneuploidy (Table 1) that results in early pregnancy loss (
      • te Velde E.R.
      • Pearson P.L.
      The variability of female reproductive ageing.
      ). Nevertheless, fertility at a late age has been shown to positively correlate with longevity (
      • Kuningas M.
      • Altmae S.
      • Uitterlinden A.G.
      • Hofman A.
      • van Duijn C.M.
      • Tiemeier H.
      The relationship between fertility and lifespan in humans.
      ,
      • Perls T.T.
      • Alpert L.
      • Fretts R.C.
      Middle-aged mothers live longer.
      ,
      • Perls T.T.
      • Fretts R.C.
      The evolution of menopause and human life span.
      ). For example, on the basis of approximately 2,600 women, it was shown that women with two to three children had significantly lower mortality (a hazard ratio of 0.82 at 95% confidence) compared with women with no children (
      • Kuningas M.
      • Altmae S.
      • Uitterlinden A.G.
      • Hofman A.
      • van Duijn C.M.
      • Tiemeier H.
      The relationship between fertility and lifespan in humans.
      ). Another study (of approximately 5,300 white women, aged 55–100 years) showed that women with natural menopause before age 40 years had an odds ratio of death of 1.95 (95% confidence interval) compared with natural menopause at ages 50 to 54 years (
      • McArdle P.F.
      • Pollin T.I.
      • O’Connell J.R.
      • Sorkin J.D.
      • Agarwala R.
      • Schaffer A.A.
      • et al.
      Does having children extend life span? A genealogical study of parity and longevity in the Amish.
      ,
      • Muller H.G.
      • Chiou J.M.
      • Carey J.R.
      • Wang J.L.
      Fertility and life span: late children enhance female longevity.
      ). Extensive genealogic records for approximately 2,000 women and thousands of birth records from the Amish community for 150 years (
      • McArdle P.F.
      • Pollin T.I.
      • O’Connell J.R.
      • Sorkin J.D.
      • Agarwala R.
      • Schaffer A.A.
      • et al.
      Does having children extend life span? A genealogical study of parity and longevity in the Amish.
      ) also revealed that a later age at last birth was associated with longer lifespan. A similar trend was confirmed for cohorts from different geographic locations and ethnic groups (e.g., the Netherlands, United States, Canada, and Finland) (
      • Lahdenpera M.
      • Lummaa V.
      • Helle S.
      • Tremblay M.
      • Russell A.F.
      Fitness benefits of prolonged post-reproductive lifespan in women.
      ,
      • Kuningas M.
      • Altmae S.
      • Uitterlinden A.G.
      • Hofman A.
      • van Duijn C.M.
      • Tiemeier H.
      The relationship between fertility and lifespan in humans.
      ,
      • Muller H.G.
      • Chiou J.M.
      • Carey J.R.
      • Wang J.L.
      Fertility and life span: late children enhance female longevity.
      ,
      • Murabito J.M.
      • Yang Q.
      • Fox C.
      • Wilson P.W.
      • Cupples L.A.
      Heritability of age at natural menopause in the Framingham Heart Study.
      ).
      The correlation between extended fertility and longevity is not limited to modern cohorts. Historical support comes from analysis of a cohort of women born in the year 1896. Only 5% gave birth after age 40 years. However, among the centenarian women in this cohort, this fraction reaches 20% (
      • Perls T.T.
      • Alpert L.
      • Fretts R.C.
      Middle-aged mothers live longer.
      ). Additional historical records include more than 1,600 French-Canadian women from the 17th and 18th century who lived at least 50 years. Quantitatively, 50-year-old mothers experience a mortality decrease of 38%, and an increase of remaining lifetime of approximately 4 years for every 10-fold decrease in the age of their youngest child (
      • Smith K.R.
      • Gagnon A.
      • Cawthon R.M.
      • Mineau G.P.
      • Mazan R.
      • Desjardins B.
      Familial aggregation of survival and late female reproduction.
      ). Thus, the primary and the most dominant feature that links longevity with fertility is the time of birth of the youngest child. The number of children, the spacing between births, and the first reproduction age were unrelated to longevity (
      • Snowdon D.A.
      • Kane R.L.
      • Beeson W.L.
      • Burke G.L.
      • Sprafka J.M.
      • Potter J.
      • et al.
      Is early natural menopause a biologic marker of health and aging?.
      ). Interestingly, male brothers whose sisters gave birth at late age tend to have significantly longer lifespan (
      • Smith K.R.
      • Gagnon A.
      • Cawthon R.M.
      • Mineau G.P.
      • Mazan R.
      • Desjardins B.
      Familial aggregation of survival and late female reproduction.
      ). This suggests that the link between extended fertility and longevity have a genetic component that is independent of physiologic changes from having the offspring. Nevertheless, the causality of the two phenotypes—extended fertility and longevity—is not evident. It could be a simple reflection of the likelihood of women with a long lifespan to conceive at a more advanced age. Whether this link has a genetic or a social basis remains to be determined.
      Economic and sociologic constraints, family planning programs, and abortion policy obscure the subset of women that would have otherwise identified with natural extended fertility. To overcome this limitation, the menopause age was proposed as a physiologic index for fertility capacity (
      • Snowdon D.A.
      • Kane R.L.
      • Beeson W.L.
      • Burke G.L.
      • Sprafka J.M.
      • Potter J.
      • et al.
      Is early natural menopause a biologic marker of health and aging?.
      ,
      • Torgerson D.J.
      • Thomas R.E.
      • Reid D.M.
      Mothers and daughters menopausal ages: is there a link?.
      ). The menopause age occurs approximately 10 years after the fast drop in oocyte number and quality. Using this measure, greater odds was associated with extended menopause age and surviving to unusually old age (
      • Sun F.
      • Sebastiani P.
      • Schupf N.
      • Bae H.
      • Andersen S.L.
      • McIntosh A.
      • et al.
      Extended maternal age at birth of last child and women’s longevity in the Long Life Family Study.
      ). The heritability for menopause age between mothers and daughters is approximately 50% (
      • Torgerson D.J.
      • Thomas R.E.
      • Reid D.M.
      Mothers and daughters menopausal ages: is there a link?.
      ,
      • van Asselt K.M.
      • Kok H.S.
      • Pearson P.L.
      • Dubas J.S.
      • Peeters P.H.
      • Te Velde E.R.
      • et al.
      Heritability of menopausal age in mothers and daughters.
      ). Thus, at least 50% of the interindividual variability in menopausal age seems to be attributable to genetic effects (
      • Murabito J.M.
      • Yang Q.
      • Fox C.
      • Wilson P.W.
      • Cupples L.A.
      Heritability of age at natural menopause in the Framingham Heart Study.
      ,
      • de Bruin J.P.
      • Bovenhuis H.
      • van Noord P.A.
      • Pearson P.L.
      • van Arendonk J.A.
      • te Velde E.R.
      • et al.
      The role of genetic factors in age at natural menopause.
      ). Early menopause age has also been shown to be a risk factor for cardiovascular mortality in women (
      • van der Schouw Y.T.
      • van der Graaf Y.
      • Steyerberg E.W.
      • Eijkemans J.C.
      • Banga J.D.
      Age at menopause as a risk factor for cardiovascular mortality.
      ).

      Genetic basis of fertility and longevity

      Advances in genomic technologies make it possible to investigate population cohorts from the genetic–statistic perspective (
      • Westendorp R.G.
      • van Heemst D.
      • Rozing M.P.
      • Frolich M.
      • Mooijaart S.P.
      • Blauw G.J.
      • et al.
      Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: The Leiden Longevity Study.
      ). Earlier studies from the 2000s focused on finding links between estrogen-related or vascular functions and the age of natural menopause (
      • Stolk L.
      • Perry J.R.
      • Chasman D.I.
      • He C.
      • Mangino M.
      • Sulem P.
      • et al.
      Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
      ). In an attempt to identify genetic markers for menopause age, preselected genes that are involved in primordial follicle recruitment were searched, to identify informative single-nucleotide polymorphisms (SNPs) (Table 1). On the basis of more than 3,600 Dutch women, the effect of several SNPs on delayed menopause was quantified. For example, one of the SNPs within the AMHR2 gene was associated with a 1-year delay in the natural menopause age. Other SNPs were associated with a modest delay of a few months in menopause age (
      • Voorhuis M.
      • Broekmans F.J.
      • Fauser B.C.
      • Onland-Moret N.C.
      • van der Schouw Y.T.
      Genes involved in initial follicle recruitment may be associated with age at menopause.
      ). Significant drawbacks of these early studies were that they focused on biased selection of genes and relatively small cohorts (approximately 3,000 women). This led to a poor reproducibility in follow-up studies (
      • Voorhuis M.
      • Onland-Moret N.C.
      • van der Schouw Y.T.
      • Fauser B.C.
      • Broekmans F.J.
      Human studies on genetics of the age at natural menopause: a systematic review.
      ).
      Genome-wide association study (GWAS) (Table 1) is an unbiased method to discover genetic loci associated with particular phenotypes (
      • He C.
      • Murabito J.M.
      Genome-wide association studies of age at menarche and age at natural menopause.
      ). In a typical GWAS, a homogeneous population is genotyped on a DNA array (Table 1). Then each SNP is correlated against the phenotype. Only SNPs with correlation above a statistical threshold are candidate drivers of the subjected phenotype. A large-scale study on menopause timing has been conducted on a large population (approximately 40,000) of European descent women. Each woman was genotyped, and the age of natural menopause was recorded (
      • Stolk L.
      • Perry J.R.
      • Chasman D.I.
      • He C.
      • Mangino M.
      • Sulem P.
      • et al.
      Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
      ). Analysis confirmed four previously reported SNPs and discovered 13 new loci with statistically significant SNPs. Carrying one minor allele of these SNPs affected menopause timing on average by 9–50 weeks. All together they explain 2.5%–4.1% of the population variation in menopause date (
      • Perry J.R.
      • Corre T.
      • Esko T.
      • Chasman D.I.
      • Fischer K.
      • Franceschini N.
      • et al.
      A genome-wide association study of early menopause and the combined impact of identified variants.
      ). A more recent study investigated the genetic basis of early menopause, defined as menopause before age 45 years, by comparing approximately 3,500 women with age at menopause <45 years and 13,600 women with age at menopause between 50 and 60 years. It showed that 17 SNPs account for approximately 30% of the variance in early menopause (
      • Perry J.R.
      • Corre T.
      • Esko T.
      • Chasman D.I.
      • Fischer K.
      • Franceschini N.
      • et al.
      A genome-wide association study of early menopause and the combined impact of identified variants.
      ). Genome-wide association study analysis for menopause timing in the European population from the 1,000 Genome Project revealed a single significant SNP in the regulatory region of the mismatch repair gene MSH6 (
      • Perry J.R.
      • Hsu Y.H.
      • Chasman D.I.
      • Johnson A.D.
      • Elks C.
      • Albrecht E.
      • et al.
      DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.
      ). This discovery suggests that the DNA repair process plays a role in fertility and ovarian aging (
      • Stolk L.
      • Perry J.R.
      • Chasman D.I.
      • He C.
      • Mangino M.
      • Sulem P.
      • et al.
      Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
      ).
      Genome-wide association study has also identified genetic loci associated with human longevity. More than 400 unrelated nonagenarians (human at age 90–99 years) were compared with younger population controls. One locus had a strong association to longevity. This locus is related to the apolipoprotein E (APOE) gene (
      • Deelen J.
      • Beekman M.
      • Uh H.W.
      • Helmer Q.
      • Kuningas M.
      • Christiansen L.
      • et al.
      Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited.
      ). A strong association between this locus and serum levels of insulin-like growth factor 1 (IGF-1) in women is an attractive link between a major regulator of metabolism and longevity in women (
      • van Heemst D.
      Insulin, IGF-1 and longevity.
      ). In another meta-analysis for tracing loci for healthy aging, a number of neuronal-related genes that are implicated in neurodegeneration were identified (
      • Walter S.
      • Atzmon G.
      • Demerath E.W.
      • Garcia M.E.
      • Kaplan R.C.
      • Kumari M.
      • et al.
      A genome-wide association study of aging.
      ).
      Human genomes differ from each other not only in their SNP profiles but also in the numbers and properties of copy number variant (Table 1) regions. On the basis of very large cohorts it was shown that common copy number variant regions (frequency >1%) are associated with mortality (
      • Kuningas M.
      • Estrada K.
      • Hsu Y.H.
      • Nandakumar K.
      • Uitterlinden A.G.
      • Lunetta K.L.
      • et al.
      Large common deletions associate with mortality at old age.
      ). A more direct evidence for a genomic signature that is associated with fertility concerns a population study that linked fertility to a large chromosomal rearrangement. Specifically, an inversion (Table 1) in chromosome 17 (17q21.31, 0.9 × 106 bases) was associated with a statistically increased number of children and consequently an extended fertility in the Icelandic population (
      • Stefansson H.
      • Helgason A.
      • Thorleifsson G.
      • Steinthorsdottir V.
      • Masson G.
      • Barnard J.
      • et al.
      A common inversion under selection in Europeans.
      ).
      The evidence we present suggests that a common genetic basis could explain some of the correlation between fertility and longevity. In other settings, it is possible that the physiologic effects of menopause change risk factors for mortality. The reality is likely a confluence of many of these factors.

      Oocyte aging and fertility

      The association of extended fertility with longevity suggests an overlap in the underlying biological processes (Table 2). Although aging is a property at the organism level, our knowledge is often limited to individual cells (e.g., oocyte, granulosa cells). The hallmarks of cell aging include [1] integrity of the nuclear genome, [2] integrity of the mitochondrial genome (Table 1), and [3] the shortening of the telomeres (Table 1).
      Table 2Genes and pathways relevant for both fertility and longevity.
      Selected genesPathwaysOrganism (cell type)MethodologyReference
      Fertility
       [1] NCKAP1, PSIP2, HOOK1; [2] HSP70, UBC, UBE1C; [3] SMAD1, BMPR1; [4] BMI1, DNMT1O, SUV3; [5] MT-ND3, NFKBIA, SOD1[1] Apoptotic response; [2] Chaperones and ubiquitination; [3] TGF-β signaling; [4] DNA dynamics and chromatin; [5] Mitochondrial function and oxidative stressMus (o)Transcrip. (G)
      • Hamatani T.
      • Falco G.
      • Carter M.G.
      • Akutsu H.
      • Stagg C.A.
      • Sharov A.A.
      • et al.
      Age-associated alteration of gene expression patterns in mouse oocytes.
       [1] ACAT2, MVK; [2] MT-ATP6, ATP5I; [3] MT-ATP6, ATP5I[1] Metabolic signaling; [2] Mitochondrial function; [3] Posttranscription regulationHum (GC)Proteomics (G)
      • McReynolds S.
      • Dzieciatkowska M.
      • McCallie B.R.
      • Mitchell S.D.
      • Stevens J.
      • Hansen K.
      • et al.
      Impact of maternal aging on the molecular signature of human cumulus cells.
       [1] ATR, NBS1, RAD17; [2] SMC3, STK6; [3] TERT; [4] STK3, HMGN1; [5] KIF5B, RANBP2, SUV3[1] DNA damage and repair; [2] Chr segregation; [3] Telomerase; [4] Chromatin structure; [5] Mitochondrial functionHum (o)Transcrip. (G)
      • Steuerwald N.M.
      • Bermudez M.G.
      • Wells D.
      • Munne S.
      • Cohen J.
      Maternal age-related differential global expression profiles observed in human oocytes.
       [1] CD40; [2] TNFRSF10A, BCL2, CFLAR[1] Immune function; [2] Apoptotic responseHum (o)Transcrip. (C)
      • Santonocito M.
      • Guglielmino M.R.
      • Vento M.
      • Ragusa M.
      • Barbagallo D.
      • Borzi P.
      • et al.
      The apoptotic transcriptome of the human MII oocyte: characterization and age-related changes.
       [1] EXO1, HELQ; [2] IL11, NLRP11; [3] FSHB, STAR[1] DNA damage and repair; [2] Immune function; [3] Mitochondrial functionHumGenomics (G)
      • Stolk L.
      • Perry J.R.
      • Chasman D.I.
      • He C.
      • Mangino M.
      • Sulem P.
      • et al.
      Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
       [1] GDF9, BMP15; [2] FOXL2; [3] APOE[1] TGF-β signaling and differentiation; [2] Tfac; [3] Lipoprotein metabolismHumGenomics (C)
      • Broekmans F.J.
      • Knauff E.A.
      • te Velde E.R.
      • Macklon N.S.
      • Fauser B.C.
      Female reproductive ageing: current knowledge and future trends.
       [1] NRAS, IL-15; [2] CAST, FLNA; [3] ACVR1, IGF1R[1] Apoptotic response; [2] Ubiquitination; [3] Metabolic signalingHum (PBMC)Transcrip. (G)
      • Gielchinsky Y.
      • Bogoch Y.
      • Rechavi G.
      • Jacob-Hirsch J.
      • Amariglio N.
      • Shveiky D.
      • et al.
      Gene expression in women conceiving spontaneously over the age of 45 years.
       [1] PFKP, HADH; [2] PGR; [3] P53[1] Metabolic signaling; [2] Differentiation; [3] Apoptotic responseHum (gc, cc)Transcrip. (C)
      • Pacella L.
      • Zander-Fox D.L.
      • Armstrong D.T.
      • Lane M.
      Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment.
       [1] SMAD2, CDKN1C, NASP; [2] MTFR1; [3] CASP9; [4] ESPL1, CSPP; [5] UBE2D, UBE1[1] Cell cycle and oxidative stress; [2] Mitochondrial function; [2] Apoptosis; [4] SAC and Chr. segregation; [5] UbiquitinationHum (o)Transcrip. (G)
      • Grondahl M.L.
      • Yding Andersen C.
      • Bogstad J.
      • Nielsen F.C.
      • Meinertz H.
      • Borup R.
      Gene expression profiles of single human mature oocytes in relation to age.
       [1] TGFBR3, FGF2, AMH, TGFB1; [2] IGFBP3, PIK3R1; [3] miRNAs[1] Cell differentiation and signaling; [2] Metabolic signaling; [3] Posttranscription regulationHum (cc)Transcrip. (G)
      • Al-Edani T.
      • Assou S.
      • Ferrieres A.
      • Bringer Deutsch S.
      • Gala A.
      • Lecellier C.H.
      • et al.
      Female aging alters expression of human cumulus cells genes that are essential for oocyte quality.
      AMHR2TGF-β signalingHumGenomics (C)
      • Voorhuis M.
      • Broekmans F.J.
      • Fauser B.C.
      • Onland-Moret N.C.
      • van der Schouw Y.T.
      Genes involved in initial follicle recruitment may be associated with age at menopause.
      BRCA1, MRE11, RAD51, ATMDNA damage and repairMus, Hum (o)Transcrip. (C)
      • Titus S.
      • Li F.
      • Stobezki R.
      • Akula K.
      • Unsal E.
      • Jeong K.
      • et al.
      Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans.
      FOXO3TFac and metabolic signalingMus (o)Transcrip. (C)
      • Pelosi E.
      • Omari S.
      • Michel M.
      • Ding J.
      • Amano T.
      • Forabosco A.
      • et al.
      Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice.
      IL-1, IL-6Immune functionHum (gc)Transcrip. (G)
      • Hurwitz J.M.
      • Jindal S.
      • Greenseid K.
      • Berger D.
      • Brooks A.
      • Santoro N.
      • et al.
      Reproductive aging is associated with altered gene expression in human luteinized granulosa cells.
      MAD2, BUB1SACHum (o)Transcrip. (C)
      • Steuerwald N.
      • Cohen J.
      • Herrera R.J.
      • Sandalinas M.
      • Brenner C.A.
      Association between spindle assembly checkpoint expression and maternal age in human oocytes.
      MCAK, AURKBSACMus (o)Proteomics (C)
      • Eichenlaub-Ritter U.
      • Staubach N.
      • Trapphoff T.
      Chromosomal and cytoplasmic context determines predisposition to maternal age-related aneuploidy: brief overview and update on MCAK in mammalian oocytes.
      MSH6DNA damage and repairHumGenomics (G)
      • Perry J.R.
      • Hsu Y.H.
      • Chasman D.I.
      • Johnson A.D.
      • Elks C.
      • Albrecht E.
      • et al.
      DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.
      TP73Apoptotic response and DNA damageHum (o)Transcrip. (C)
      • Guglielmino M.R.
      • Santonocito M.
      • Vento M.
      • Ragusa M.
      • Barbagallo D.
      • Borzi P.
      • et al.
      TAp73 is downregulated in oocytes from women of advanced reproductive age.
      Longevity
      HECW2, KCNQ4, HIP1, BIN2, GRIA1Membrane functionHumGenomics (G)
      • Walter S.
      • Atzmon G.
      • Demerath E.W.
      • Garcia M.E.
      • Kaplan R.C.
      • Kumari M.
      • et al.
      A genome-wide association study of aging.
       [1] ASF1A; [2] IL7R[1] Chromatin structure; [2] Immune systemHumTranscrip. (G)
      • Passtoors W.M.
      • Boer J.M.
      • Goeman J.J.
      • Akker E.B.
      • Deelen J.
      • Zwaan B.J.
      • et al.
      Transcriptional profiling of human familial longevity indicates a role for ASF1A and IL7R.
      APOELipoprotein metabolismHumGenomics (G)
      • Deelen J.
      • Beekman M.
      • Uh H.W.
      • Helmer Q.
      • Kuningas M.
      • Christiansen L.
      • et al.
      Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited.
      IGF-1Metabolic signalingHumGenomics (G)
      • van Heemst D.
      Insulin, IGF-1 and longevity.
      IGF-1, FOXO3A, FOXO1TFac and metabolic signalingHumGenomics (C)
      • Kenyon C.J.
      The genetics of ageing.
       Loci-11p15.5 (41 genes)Cancer and metabolic genesHumGenomics (G)
      • Kuningas M.
      • Estrada K.
      • Hsu Y.H.
      • Nandakumar K.
      • Uitterlinden A.G.
      • Lunetta K.L.
      • et al.
      Large common deletions associate with mortality at old age.
       miRNAs (miR-17, miR-20a)Apoptotic response and DNA damageHumTranscrip. (G)
      • ElSharawy A.
      • Keller A.
      • Flachsbart F.
      • Wendschlag A.
      • Jacobs G.
      • Kefer N.
      • et al.
      Genome-wide miRNA signatures of human longevity.
      SIRT1Metabolic signaling, agingMusProteomics (C)
      • Herranz D.
      • Munoz-Martin M.
      • Canamero M.
      • Mulero F.
      • Martinez-Pastor B.
      • Fernandez-Capetillo O.
      • et al.
      Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer.
      SIRT1, HCFC1R1Metabolic signaling, agingMusProteomics (C)
      • Rizki G.
      • Iwata T.N.
      • Li J.
      • Riedel C.G.
      • Picard C.L.
      • Jan M.
      • et al.
      The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
      Note: C = candidate genes analysis; cc = cumulus cells; Chr = chromosome; G = global analysis; gc = granulosa cells; Hum = Homo sapiens; Mus = Mus musculus; o = oocytes; PBMC = peripheral blood mononuclear cell; SAC = spindle association complex; Tfac = transcription factor; Transcrip. = transcriptomics.

       Integrity of the Nuclear Genome

      The presence of DNA double-strand breaks is a reliable detector of aging in mouse and human oocytes. Knockout of major genes involved in double-strand break repair (BRCA1, MRE11, Rad51, and ATM) reduces oocyte survival in human and mouse (
      • Titus S.
      • Li F.
      • Stobezki R.
      • Akula K.
      • Unsal E.
      • Jeong K.
      • et al.
      Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans.
      ). Additionally, fertility potential was associated with the checkpoint pathway that regulates the metaphase-to-anaphase transition. A reduced expression in the components of this pathway (e.g., MAD2 and BUB1) was postulated to increase the incidence of aneuploidy in oocytes of older women (
      • Steuerwald N.
      • Cohen J.
      • Herrera R.J.
      • Sandalinas M.
      • Brenner C.A.
      Association between spindle assembly checkpoint expression and maternal age in human oocytes.
      ). The MCAK (mitotic-centromere-associated protein) and aurora kinase B (AURKB) are components of the chromosomal passenger complex that are needed for chromosome accurate positioning. Testing oocytes showed that the reduced expression and mis-localization of MCAK and AURKB lead to an increase in aneuploidy rate (
      • Eichenlaub-Ritter U.
      • Staubach N.
      • Trapphoff T.
      Chromosomal and cytoplasmic context determines predisposition to maternal age-related aneuploidy: brief overview and update on MCAK in mammalian oocytes.
      ). The importance of genome integrity is further illustrated by monitoring the differential expression of p53/p73. p73 is a genome stability regulator. In both mice and humans, the expression level of p73 was attenuated in oocytes from the older group (
      • Guglielmino M.R.
      • Santonocito M.
      • Vento M.
      • Ragusa M.
      • Barbagallo D.
      • Borzi P.
      • et al.
      TAp73 is downregulated in oocytes from women of advanced reproductive age.
      ).

       Integrity of the Mitochondrial Genome

      It is known that oocytes contain a high amount of mitochondria. During the long phase of quiescence between oocyte formation and maturation, mutations in the mitochondria genome might accumulate (
      • Bentov Y.
      • Yavorska T.
      • Esfandiari N.
      • Jurisicova A.
      • Casper R.F.
      The contribution of mitochondrial function to reproductive aging.
      ). In addition, reactive oxygen species accumulate as a byproduct of the energy production by mitochondria during the lifetime. Cells that are exposed to reactive oxygen species become prone to DNA damage, whereas the most sensitive genome is the mitochondrial genome itself (
      • Wei Y.H.
      • Lee H.C.
      Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging.
      ). Comparison of oocytes and granulosa cells of older vs. younger subjects finds that older women's cells have fewer mitochondria and possess more damaged ones (
      • Murakoshi Y.
      • Sueoka K.
      • Takahashi K.
      • Sato S.
      • Sakurai T.
      • Tajima H.
      • et al.
      Embryo developmental capability and pregnancy outcome are related to the mitochondrial DNA copy number and ooplasmic volume.
      ). The impact of the mitochondrial genome integrity on extended fertility is evidenced by the fact that mitochondrial quality predicts the success of IVF (
      • May-Panloup P.
      • Chretien M.F.
      • Jacques C.
      • Vasseur C.
      • Malthiery Y.
      • Reynier P.
      Low oocyte mitochondrial DNA content in ovarian insufficiency.
      ,
      • Thouas G.A.
      • Trounson A.O.
      • Wolvetang E.J.
      • Jones G.M.
      Mitochondrial dysfunction in mouse oocytes results in preimplantation embryo arrest in vitro.
      ,
      • Schatten H.
      • Sun Q.Y.
      • Prather R.
      The impact of mitochondrial function/dysfunction on IVF and new treatment possibilities for infertility.
      ). The mutation rate in the mitochondria genome is 10-fold higher with respect to the nuclear DNA. Furthermore, the children of mothers in advanced ages possess higher heterogeneity in their mitochondria genome compared with children of younger mothers (
      • Rebolledo-Jaramillo B.
      • Su M.S.
      • Stoler N.
      • McElhoe J.A.
      • Dickins B.
      • Blankenberg D.
      • et al.
      Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA.
      ).

       Shortening of the Telomeres

      Telomere shortening is a hallmark of cell aging in mammals (
      • Schatten H.
      • Sun Q.Y.
      • Prather R.
      The impact of mitochondrial function/dysfunction on IVF and new treatment possibilities for infertility.
      ). The shortened telomeres can be recovered by telomerase that acts mainly in the early phase of development and in pluripotent cells (
      • Cong Y.S.
      • Wright W.E.
      • Shay J.W.
      Human telomerase and its regulation.
      ). Oocytes usually start with long telomeres that are shortened during their maturation. Reduction in telomerase activity is an indication for early infertility (
      • Wright D.L.
      • Jones E.L.
      • Mayer J.F.
      • Oehninger S.
      • Gibbons W.E.
      • Lanzendorf S.E.
      Characterization of telomerase activity in the human oocyte and preimplantation embryo.
      ), whereas a high level of telomerase is predictive for the success of IVF (
      • Liu L.
      • Blasco M.
      • Trimarchi J.
      • Keefe D.
      An essential role for functional telomeres in mouse germ cells during fertilization and early development.
      ). The granulosa cells that support the oocyte also possess active telomerase. There are indications that telomerase activity in the granulosa cells correlates with success in IVF (
      • Wang W.
      • Chen H.
      • Li R.
      • Ouyang N.
      • Chen J.
      • Huang L.
      • et al.
      Telomerase activity is more significant for predicting the outcome of IVF treatment than telomere length in granulosa cells.
      ) and decreases with age (
      • Butts S.
      • Riethman H.
      • Ratcliffe S.
      • Shaunik A.
      • Coutifaris C.
      • Barnhart K.
      Correlation of telomere length and telomerase activity with occult ovarian insufficiency.
      ).
      A decline in oocyte quality during aging is also reflected in changes in the oocyte's epigenetics. Because of the sensitive nature of the cell type involved, many of the epigenetic studies have been performed on mice oocytes, and little is known about the epigenetics of aging in human oocyte (
      • Bird A.
      DNA methylation patterns and epigenetic memory.
      ). Deoxyribonucleic acid methylation is the most characterized epigenetic modification and is involved in repression of transcription and genomic imprinting (
      • Bird A.
      DNA methylation patterns and epigenetic memory.
      ). In mice oocytes, DNA methylation (Table 2) decreases significantly with maternal aging (
      • Yue M.X.
      • Fu X.W.
      • Zhou G.B.
      • Hou Y.P.
      • Du M.
      • Wang L.
      • et al.
      Abnormal DNA methylation in oocytes could be associated with a decrease in reproductive potential in old mice.
      ). Consistent with this, both regulators of methylation, DNA methyltransferase (Dnmt1) and associated factors (Dmap1), are down-regulated in older oocytes (
      • Ratnam S.
      • Mertineit C.
      • Ding F.
      • Howell C.Y.
      • Clarke H.J.
      • Bestor T.H.
      • et al.
      Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development.
      ).

      Differential expression in extended fertility and longevity

      Several studies profiled the expression difference of messenger RNA between old and young oocytes in human and mouse cells. These studies sought to find differential expression genes either from a set of candidate genes or from the entire genome. Table 2 shows that among many independent fertility-based studies only a limited number of pathways dominate. Notably, some of these pathways also prevail in the longevity-related studies (e.g., metabolic signaling, chromatin, immune system).
      Starting with research focused on preselected genes: in mice, overexpression of Foxo3 increased the ovary reservoir and therefore increased fertility (
      • Pelosi E.
      • Omari S.
      • Michel M.
      • Ding J.
      • Amano T.
      • Forabosco A.
      • et al.
      Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice.
      ). Foxo3 transgenic mouse showed an increase in follicle numbers compared with wild-type littermates and a 30%–50% increase in their fertility. A gain of function was observed in transgenic Foxo3 on a background of the Foxo3 knockout. The aged Foxo3 transgenic ovaries were characterized by a distinctive young appearance in view of the entire transcriptomes (
      • Pelosi E.
      • Omari S.
      • Michel M.
      • Ding J.
      • Amano T.
      • Forabosco A.
      • et al.
      Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice.
      ). Thus, a role of Foxo3 as a guardian of the ovarian follicle pool in mammals is strongly supported.
      Additional candidate genes were investigated because of their involvement in oocyte failure. For instance, GDF-9, BMP-15, and Foxl2 encode extracellular factors that participate in the transition from primordial follicles into growing follicles. Using fertility malfunction (e.g., early age of menopause) as a filter, genes such as apolipoprotein E, clotting factor VII, and the estrogen-inactivating CYP1B1 were exposed. All of these were linked to early age of menopause (
      • Broekmans F.J.
      • Knauff E.A.
      • te Velde E.R.
      • Macklon N.S.
      • Fauser B.C.
      Female reproductive ageing: current knowledge and future trends.
      ). Similarly, genes that are associated with apoptosis were studied. Analysis was performed on single mature metaphase II oocytes from younger (<35 years) and older (>38 years) women (
      • Santonocito M.
      • Guglielmino M.R.
      • Vento M.
      • Ragusa M.
      • Barbagallo D.
      • Borzi P.
      • et al.
      The apoptotic transcriptome of the human MII oocyte: characterization and age-related changes.
      ). Approximately 10 candidate genes were identified that separate the two age groups. Significant up-regulation of proapoptotic genes was associated with the older group (e.g., CD40, TNFRSF10A, TNFRSF21), as well as a parallel effect of down-regulation the antiapoptotic genes (e.g., BCL2 and CFLAR) (
      • Santonocito M.
      • Guglielmino M.R.
      • Vento M.
      • Ragusa M.
      • Barbagallo D.
      • Borzi P.
      • et al.
      The apoptotic transcriptome of the human MII oocyte: characterization and age-related changes.
      ).
      Most studies apply a global, unbiased approach. Comparison of the gene expression in oocytes from women aged >40 or <32 years reveals approximately 5% differences. The processes that were associated with the age-dependent expression include regulation of cell cycle, DNA damage, energy production, and regulation of transcription (
      • Steuerwald N.M.
      • Bermudez M.G.
      • Wells D.
      • Munne S.
      • Cohen J.
      Maternal age-related differential global expression profiles observed in human oocytes.
      ).
      In an additional comparative study, mature oocytes of women (
      • Grondahl M.L.
      • Yding Andersen C.
      • Bogstad J.
      • Nielsen F.C.
      • Meinertz H.
      • Borup R.
      Gene expression profiles of single human mature oocytes in relation to age.
      ) and mice (
      • Hamatani T.
      • Falco G.
      • Carter M.G.
      • Akutsu H.
      • Stagg C.A.
      • Sharov A.A.
      • et al.
      Age-associated alteration of gene expression patterns in mouse oocytes.
      ) were partitioned according to age, and comparative gene expression studies were performed. Cellular processes related to cell cycle, chromosome alignment and sister chromatid separation, oxidative stress, and ubiquitination were enriched for the differentially expressed sets. Note that the overlap in the pathways for the fertility and the longevity-based research is exceptional high (Table 2). In mice, an additional process such as spindle assembly checkpoint was also detected (
      • Hamatani T.
      • Falco G.
      • Carter M.G.
      • Akutsu H.
      • Stagg C.A.
      • Sharov A.A.
      • et al.
      Age-associated alteration of gene expression patterns in mouse oocytes.
      ). A recent study examined cumulus cells removed from oocytes in IVF from three different age groups: <30, 31–34, and 35–36 years. The expression of the older groups includes a reduction in expression in genes that associate with the TGF-β signaling pathway (
      • Al-Edani T.
      • Assou S.
      • Ferrieres A.
      • Bringer Deutsch S.
      • Gala A.
      • Lecellier C.H.
      • et al.
      Female aging alters expression of human cumulus cells genes that are essential for oocyte quality.
      ). In addition, differential profiles of microRNAs in cumulus cells suggest that an additional layer of regulation may be involved in characterization of aging and fertility capacity. Testing granulosa cells from two groups of women, aged >30 years and >40 years, identified the expression of interleukins to be different. This finding is in accord with the role of interleukins in follicles maturation (
      • Hurwitz J.M.
      • Jindal S.
      • Greenseid K.
      • Berger D.
      • Brooks A.
      • Santoro N.
      • et al.
      Reproductive aging is associated with altered gene expression in human luteinized granulosa cells.
      ).
      Focusing on the cumulus cells, the expression of all proteins was monitored from nonfertile women (aged 40–45) and fertile young women. The study observed a 7.7% difference in the expression of the tested proteomes. The most sensitive processes to the change in the fertility profile were related to respiration and metabolism (
      • McReynolds S.
      • Dzieciatkowska M.
      • McCallie B.R.
      • Mitchell S.D.
      • Stevens J.
      • Hansen K.
      • et al.
      Impact of maternal aging on the molecular signature of human cumulus cells.
      ). In fact, the dominant processes related to metabolism were shared for cumulus and granulosa cells (
      • Pacella L.
      • Zander-Fox D.L.
      • Armstrong D.T.
      • Lane M.
      Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment.
      ).
      Studies using global transcriptomics approaches, DNA array and RNA-seq, to investigate extended fertility and longevity revealed clear overlap in the pathways and some specific genes. Studies exploring differences in expression between older and younger individuals have also been conducted. These studies convincingly position insulin-like growth factor 1 signaling as a hub for longevity, together with SIRT and Foxo genes. These genes are functionally connected, and their regulatory network is conserved from worm to human (
      • Kenyon C.J.
      The genetics of ageing.
      ). The Foxo3 is a tumor suppressor and a transcription factor that plays a key role in longevity. Specifically, the Foxo3 is a direct target of p53, which transactivates its expression (
      • Renault V.M.
      • Thekkat P.U.
      • Hoang K.L.
      • White J.L.
      • Brady C.A.
      • Kenzelmann Broz D.
      • et al.
      The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor.
      ). The outcome is an alteration in longevity, as well as in p53-dependent apoptosis. Additionally, it is suggested that the manifestation of longevity is linked to chromatin structure and the immune system (
      • Passtoors W.M.
      • Boer J.M.
      • Goeman J.J.
      • Akker E.B.
      • Deelen J.
      • Zwaan B.J.
      • et al.
      Transcriptional profiling of human familial longevity indicates a role for ASF1A and IL7R.
      ).
      An overlooked layer of regulation that differentiates between young and old cells and organisms was attributed to microRNA (miRNA) (Table 1) expression (
      • ElSharawy A.
      • Keller A.
      • Flachsbart F.
      • Wendschlag A.
      • Jacobs G.
      • Kefer N.
      • et al.
      Genome-wide miRNA signatures of human longevity.
      ). In a study that compared blood samples of individuals aged >90 years with individuals of aged <50 years, approximately 70 miRNAs were identified according to their differential expression. Several miRNAs targeting the p53 tumor suppressor network have been implicated to differentiate between the two groups. However, the role of miRNAs in cell homeostasis during aging and extended fertility needs to be substantiated.
      In conclusion, we have reviewed numerous studies showing that women with extended fertility are more likely to live longer. The observation that males whose sisters have extended fertility also have a longer lifespan strongly suggests that there is a genetic link between extended fertility and longevity. Recent GWAS on large population cohorts have discovered numerous genetic loci contributing to fertility and a separate set of loci contributing to longevity. This is an important first step toward untangling the genetic basis of extended fertility and longevity. A promising direction of future research would be to investigate whether there are common genetic loci and pathways that show enriched association with both phenotypes.
      Complementary to the genetic studies, functional studies have uncovered many molecular factors that mechanistically shape fertility timing and longevity. Although the information regarding the key genes and loci that link longevity and extended fertility has not yet crystalized, important overlapping in the pathways that affect both phenotypes is noted (Table 2). The main conclusions for the genetic link are as follows. [1] Genomic stability mediated by telomerase impacts both oocyte aging and longevity. [2] Apoptosis mediated through p53/p73 is a shared junction for these traits. [3] The Foxo transcription factors (e.g., Foxo3) dominate oocytes reservoir and longevity. [4] The expression of APOE, a known risk factor in Alzheimer's disease, is associated with both extended fertility and longevity. [5] Oxidative stress, mitochondrial function, and to some extent the immune system play roles in both processes. At the genome levels the importance and impact of the chromatin structure, epigenetic modifications, and posttranslational regulations by miRNAs are not fully appreciated. Additional large-scale studies are needed in assessing the genomic features for extended fertility. Recent developments in single-cell technologies and powerful genomics and cellular methodologies (e.g., RNA-seq, live imaging, bisulfite sequencing for DNA methylation) will likely play an important role in further illuminating this link. We also expect high-resolution genome-editing techniques (i.e., clustered regularly interspaced short palindromic repeat [CRISPER], transcription activator-like effector nucleases [TALEN]) to provide exciting new insights into the precise genetic and functional changes that affect both fertility and longevity.

      References

        • Lahdenpera M.
        • Lummaa V.
        • Helle S.
        • Tremblay M.
        • Russell A.F.
        Fitness benefits of prolonged post-reproductive lifespan in women.
        Nature. 2004; 428: 178-181
        • Hawkes K.
        • O’Connell J.F.
        • Jones N.G.
        • Alvarez H.
        • Charnov E.L.
        Grandmothering, menopause, and the evolution of human life histories.
        Proc Natl Acad Sci U S A. 1998; 95: 1336-1339
        • Chen C.T.
        • Liu C.T.
        • Chen G.K.
        • Andrews J.S.
        • Arnold A.M.
        • Dreyfus J.
        • et al.
        Meta-analysis of loci associated with age at natural menopause in African-American women.
        Hum Mol Genet. 2014; 23: 3327-3342
        • te Velde E.R.
        • Pearson P.L.
        The variability of female reproductive ageing.
        Hum Reprod Update. 2002; 8: 141-154
        • Kuningas M.
        • Altmae S.
        • Uitterlinden A.G.
        • Hofman A.
        • van Duijn C.M.
        • Tiemeier H.
        The relationship between fertility and lifespan in humans.
        Age (Dordr). 2011; 33: 615-622
        • Perls T.T.
        • Alpert L.
        • Fretts R.C.
        Middle-aged mothers live longer.
        Nature. 1997; 389: 133
        • Perls T.T.
        • Fretts R.C.
        The evolution of menopause and human life span.
        Ann Hum Biol. 2001; 28: 237-245
        • McArdle P.F.
        • Pollin T.I.
        • O’Connell J.R.
        • Sorkin J.D.
        • Agarwala R.
        • Schaffer A.A.
        • et al.
        Does having children extend life span? A genealogical study of parity and longevity in the Amish.
        J Gerontol A Biol Sci Med Sci. 2006; 61: 190-195
        • Muller H.G.
        • Chiou J.M.
        • Carey J.R.
        • Wang J.L.
        Fertility and life span: late children enhance female longevity.
        J Gerontol A Biol Sci Med Sci. 2002; 57: B202-B206
        • Murabito J.M.
        • Yang Q.
        • Fox C.
        • Wilson P.W.
        • Cupples L.A.
        Heritability of age at natural menopause in the Framingham Heart Study.
        J Clin Endocrinol Metab. 2005; 90: 3427-3430
        • Smith K.R.
        • Gagnon A.
        • Cawthon R.M.
        • Mineau G.P.
        • Mazan R.
        • Desjardins B.
        Familial aggregation of survival and late female reproduction.
        J Gerontol A Biol Sci Med Sci. 2009; 64: 740-744
        • Snowdon D.A.
        • Kane R.L.
        • Beeson W.L.
        • Burke G.L.
        • Sprafka J.M.
        • Potter J.
        • et al.
        Is early natural menopause a biologic marker of health and aging?.
        Am J Public Health. 1989; 79: 709-714
        • Torgerson D.J.
        • Thomas R.E.
        • Reid D.M.
        Mothers and daughters menopausal ages: is there a link?.
        Eur J Obstet Gynecol Reprod Biol. 1997; 74: 63-66
        • Sun F.
        • Sebastiani P.
        • Schupf N.
        • Bae H.
        • Andersen S.L.
        • McIntosh A.
        • et al.
        Extended maternal age at birth of last child and women’s longevity in the Long Life Family Study.
        Menopause. 2015; 22: 26-31
        • van Asselt K.M.
        • Kok H.S.
        • Pearson P.L.
        • Dubas J.S.
        • Peeters P.H.
        • Te Velde E.R.
        • et al.
        Heritability of menopausal age in mothers and daughters.
        Fertil Steril. 2004; 82: 1348-1351
        • de Bruin J.P.
        • Bovenhuis H.
        • van Noord P.A.
        • Pearson P.L.
        • van Arendonk J.A.
        • te Velde E.R.
        • et al.
        The role of genetic factors in age at natural menopause.
        Hum Reprod. 2001; 16: 2014-2018
        • van der Schouw Y.T.
        • van der Graaf Y.
        • Steyerberg E.W.
        • Eijkemans J.C.
        • Banga J.D.
        Age at menopause as a risk factor for cardiovascular mortality.
        Lancet. 1996; 347: 714-718
        • Westendorp R.G.
        • van Heemst D.
        • Rozing M.P.
        • Frolich M.
        • Mooijaart S.P.
        • Blauw G.J.
        • et al.
        Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: The Leiden Longevity Study.
        J Am Geriatr Soc. 2009; 57: 1634-1637
        • Stolk L.
        • Perry J.R.
        • Chasman D.I.
        • He C.
        • Mangino M.
        • Sulem P.
        • et al.
        Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
        Nat Genet. 2012; 44: 260-268
        • Voorhuis M.
        • Broekmans F.J.
        • Fauser B.C.
        • Onland-Moret N.C.
        • van der Schouw Y.T.
        Genes involved in initial follicle recruitment may be associated with age at menopause.
        J Clin Endocrinol Metab. 2011; 96: E473-E479
        • Voorhuis M.
        • Onland-Moret N.C.
        • van der Schouw Y.T.
        • Fauser B.C.
        • Broekmans F.J.
        Human studies on genetics of the age at natural menopause: a systematic review.
        Hum Reprod Update. 2010; 16: 364-377
        • He C.
        • Murabito J.M.
        Genome-wide association studies of age at menarche and age at natural menopause.
        Mol Cell Endocrinol. 2014; 382: 767-779
        • Perry J.R.
        • Corre T.
        • Esko T.
        • Chasman D.I.
        • Fischer K.
        • Franceschini N.
        • et al.
        A genome-wide association study of early menopause and the combined impact of identified variants.
        Hum Mol Genet. 2013; 22: 1465-1472
        • Perry J.R.
        • Hsu Y.H.
        • Chasman D.I.
        • Johnson A.D.
        • Elks C.
        • Albrecht E.
        • et al.
        DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.
        Hum Mol Genet. 2014; 23: 2490-2497
        • Deelen J.
        • Beekman M.
        • Uh H.W.
        • Helmer Q.
        • Kuningas M.
        • Christiansen L.
        • et al.
        Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited.
        Aging Cell. 2011; 10: 686-698
        • van Heemst D.
        Insulin, IGF-1 and longevity.
        Aging Dis. 2010; 1: 147-157
        • Walter S.
        • Atzmon G.
        • Demerath E.W.
        • Garcia M.E.
        • Kaplan R.C.
        • Kumari M.
        • et al.
        A genome-wide association study of aging.
        Neurobiol Aging. 2011; 32: 2109.e15-2109.e28
        • Kuningas M.
        • Estrada K.
        • Hsu Y.H.
        • Nandakumar K.
        • Uitterlinden A.G.
        • Lunetta K.L.
        • et al.
        Large common deletions associate with mortality at old age.
        Hum Mol Genet. 2011; 20: 4290-4296
        • Stefansson H.
        • Helgason A.
        • Thorleifsson G.
        • Steinthorsdottir V.
        • Masson G.
        • Barnard J.
        • et al.
        A common inversion under selection in Europeans.
        Nat Genet. 2005; 37: 129-137
        • Titus S.
        • Li F.
        • Stobezki R.
        • Akula K.
        • Unsal E.
        • Jeong K.
        • et al.
        Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans.
        Sci Transl Med. 2013; 5: 172ra21
        • Steuerwald N.
        • Cohen J.
        • Herrera R.J.
        • Sandalinas M.
        • Brenner C.A.
        Association between spindle assembly checkpoint expression and maternal age in human oocytes.
        Mol Hum Reprod. 2001; 7: 49-55
        • Eichenlaub-Ritter U.
        • Staubach N.
        • Trapphoff T.
        Chromosomal and cytoplasmic context determines predisposition to maternal age-related aneuploidy: brief overview and update on MCAK in mammalian oocytes.
        Biochem Soc Trans. 2010; 38: 1681-1686
        • Guglielmino M.R.
        • Santonocito M.
        • Vento M.
        • Ragusa M.
        • Barbagallo D.
        • Borzi P.
        • et al.
        TAp73 is downregulated in oocytes from women of advanced reproductive age.
        Cell Cycle. 2011; 10: 3253-3256
        • Bentov Y.
        • Yavorska T.
        • Esfandiari N.
        • Jurisicova A.
        • Casper R.F.
        The contribution of mitochondrial function to reproductive aging.
        J Assist Reprod Genet. 2011; 28: 773-783
        • Wei Y.H.
        • Lee H.C.
        Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging.
        Exp Biol Med (maywood). 2002; 227: 671-682
        • Murakoshi Y.
        • Sueoka K.
        • Takahashi K.
        • Sato S.
        • Sakurai T.
        • Tajima H.
        • et al.
        Embryo developmental capability and pregnancy outcome are related to the mitochondrial DNA copy number and ooplasmic volume.
        J Assist Reprod Genet. 2013; 30: 1367-1375
        • May-Panloup P.
        • Chretien M.F.
        • Jacques C.
        • Vasseur C.
        • Malthiery Y.
        • Reynier P.
        Low oocyte mitochondrial DNA content in ovarian insufficiency.
        Hum Reprod. 2005; 20: 593-597
        • Thouas G.A.
        • Trounson A.O.
        • Wolvetang E.J.
        • Jones G.M.
        Mitochondrial dysfunction in mouse oocytes results in preimplantation embryo arrest in vitro.
        Biol Reprod. 2004; 71: 1936-1942
        • Schatten H.
        • Sun Q.Y.
        • Prather R.
        The impact of mitochondrial function/dysfunction on IVF and new treatment possibilities for infertility.
        Reprod Biol Endocrinol. 2014; 12: 111
        • Rebolledo-Jaramillo B.
        • Su M.S.
        • Stoler N.
        • McElhoe J.A.
        • Dickins B.
        • Blankenberg D.
        • et al.
        Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA.
        Proc Natl Acad Sci U S A. 2014; 111: 15474-15479
        • Cong Y.S.
        • Wright W.E.
        • Shay J.W.
        Human telomerase and its regulation.
        Microbiol Mol Biol Rev. 2002; 66: 407-425
        • Wright D.L.
        • Jones E.L.
        • Mayer J.F.
        • Oehninger S.
        • Gibbons W.E.
        • Lanzendorf S.E.
        Characterization of telomerase activity in the human oocyte and preimplantation embryo.
        Mol Hum Reprod. 2001; 7: 947-955
        • Liu L.
        • Blasco M.
        • Trimarchi J.
        • Keefe D.
        An essential role for functional telomeres in mouse germ cells during fertilization and early development.
        Dev Biol. 2002; 249: 74-84
        • Wang W.
        • Chen H.
        • Li R.
        • Ouyang N.
        • Chen J.
        • Huang L.
        • et al.
        Telomerase activity is more significant for predicting the outcome of IVF treatment than telomere length in granulosa cells.
        Reproduction. 2014; 147: 649-657
        • Butts S.
        • Riethman H.
        • Ratcliffe S.
        • Shaunik A.
        • Coutifaris C.
        • Barnhart K.
        Correlation of telomere length and telomerase activity with occult ovarian insufficiency.
        J Clin Endocrinol Metab. 2009; 94: 4835-4843
        • Bird A.
        DNA methylation patterns and epigenetic memory.
        Genes Dev. 2002; 16: 6-21
        • Yue M.X.
        • Fu X.W.
        • Zhou G.B.
        • Hou Y.P.
        • Du M.
        • Wang L.
        • et al.
        Abnormal DNA methylation in oocytes could be associated with a decrease in reproductive potential in old mice.
        J Assist Reprod Genet. 2012; 29: 643-650
        • Ratnam S.
        • Mertineit C.
        • Ding F.
        • Howell C.Y.
        • Clarke H.J.
        • Bestor T.H.
        • et al.
        Dynamics of Dnmt1 methyltransferase expression and intracellular localization during oogenesis and preimplantation development.
        Dev Biol. 2002; 245: 304-314
        • Pelosi E.
        • Omari S.
        • Michel M.
        • Ding J.
        • Amano T.
        • Forabosco A.
        • et al.
        Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice.
        Nat Commun. 2013; 4: 1843
        • Broekmans F.J.
        • Knauff E.A.
        • te Velde E.R.
        • Macklon N.S.
        • Fauser B.C.
        Female reproductive ageing: current knowledge and future trends.
        Trends Endocrinol Metab. 2007; 18: 58-65
        • Santonocito M.
        • Guglielmino M.R.
        • Vento M.
        • Ragusa M.
        • Barbagallo D.
        • Borzi P.
        • et al.
        The apoptotic transcriptome of the human MII oocyte: characterization and age-related changes.
        Apoptosis. 2013; 18: 201-211
        • Steuerwald N.M.
        • Bermudez M.G.
        • Wells D.
        • Munne S.
        • Cohen J.
        Maternal age-related differential global expression profiles observed in human oocytes.
        Reprod Biomed Online. 2007; 14: 700-708
        • Grondahl M.L.
        • Yding Andersen C.
        • Bogstad J.
        • Nielsen F.C.
        • Meinertz H.
        • Borup R.
        Gene expression profiles of single human mature oocytes in relation to age.
        Hum Reprod. 2010; 25: 957-968
        • Hamatani T.
        • Falco G.
        • Carter M.G.
        • Akutsu H.
        • Stagg C.A.
        • Sharov A.A.
        • et al.
        Age-associated alteration of gene expression patterns in mouse oocytes.
        Hum Mol Genet. 2004; 13: 2263-2278
        • Al-Edani T.
        • Assou S.
        • Ferrieres A.
        • Bringer Deutsch S.
        • Gala A.
        • Lecellier C.H.
        • et al.
        Female aging alters expression of human cumulus cells genes that are essential for oocyte quality.
        Biomed Res Int. 2014; 2014: 964614
        • Hurwitz J.M.
        • Jindal S.
        • Greenseid K.
        • Berger D.
        • Brooks A.
        • Santoro N.
        • et al.
        Reproductive aging is associated with altered gene expression in human luteinized granulosa cells.
        Reprod Sci. 2010; 17: 56-67
        • McReynolds S.
        • Dzieciatkowska M.
        • McCallie B.R.
        • Mitchell S.D.
        • Stevens J.
        • Hansen K.
        • et al.
        Impact of maternal aging on the molecular signature of human cumulus cells.
        Fertil Steril. 2012; 98: 1574-1580.e5
        • Pacella L.
        • Zander-Fox D.L.
        • Armstrong D.T.
        • Lane M.
        Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment.
        Fertil Steril. 2012; 98: 986-994.e1–2
        • Kenyon C.J.
        The genetics of ageing.
        Nature. 2010; 464: 504-512
        • Renault V.M.
        • Thekkat P.U.
        • Hoang K.L.
        • White J.L.
        • Brady C.A.
        • Kenzelmann Broz D.
        • et al.
        The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor.
        Oncogene. 2011; 30: 3207-3221
        • Passtoors W.M.
        • Boer J.M.
        • Goeman J.J.
        • Akker E.B.
        • Deelen J.
        • Zwaan B.J.
        • et al.
        Transcriptional profiling of human familial longevity indicates a role for ASF1A and IL7R.
        PLoS One. 2012; 7: e27759
        • ElSharawy A.
        • Keller A.
        • Flachsbart F.
        • Wendschlag A.
        • Jacobs G.
        • Kefer N.
        • et al.
        Genome-wide miRNA signatures of human longevity.
        Aging Cell. 2012; 11: 607-616
        • Gielchinsky Y.
        • Bogoch Y.
        • Rechavi G.
        • Jacob-Hirsch J.
        • Amariglio N.
        • Shveiky D.
        • et al.
        Gene expression in women conceiving spontaneously over the age of 45 years.
        Fertil Steril. 2008; 89: 1641-1650
        • Herranz D.
        • Munoz-Martin M.
        • Canamero M.
        • Mulero F.
        • Martinez-Pastor B.
        • Fernandez-Capetillo O.
        • et al.
        Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer.
        Nat Commun. 2010; 1: 3
        • Rizki G.
        • Iwata T.N.
        • Li J.
        • Riedel C.G.
        • Picard C.L.
        • Jan M.
        • et al.
        The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
        Plos Genet. 2011; 7: e1002235