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Potential long-term risks associated with maternal aging (the role of the mitochondria)

2015; Elsevier BV; Volume: 103; Issue: 6 Linguagem: Inglês

10.1016/j.fertnstert.2015.03.034

1556-5653

Martin Wilding,

Reproductive Biology and Fertility

The mean age at which women create families in Western society is increasing. This is in spite of the fact that reproduction in later life is subject to various difficulties, such as the lower probability of conception in relation to maternal age, the increase in spontaneous pregnancy loss, and higher obstetric risk. In this review of recent data, we suggest that a fourth effect, the decrease in lifespan of children in relation to the age of conception of the mother, can be added to the list. We discuss this effect in relation to the transmission of the mitochondria exclusively through the female germ line and the effect of age on this organelle. Data from our own studies and the animal literature as a whole suggest that this effect could be due to the transmission of damaged mitochondrial DNA, and further indicate that the effect is more widespread than previously considered. The mean age at which women create families in Western society is increasing. This is in spite of the fact that reproduction in later life is subject to various difficulties, such as the lower probability of conception in relation to maternal age, the increase in spontaneous pregnancy loss, and higher obstetric risk. In this review of recent data, we suggest that a fourth effect, the decrease in lifespan of children in relation to the age of conception of the mother, can be added to the list. We discuss this effect in relation to the transmission of the mitochondria exclusively through the female germ line and the effect of age on this organelle. Data from our own studies and the animal literature as a whole suggest that this effect could be due to the transmission of damaged mitochondrial DNA, and further indicate that the effect is more widespread than previously considered. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/wildingm-maternal-aging-mitochondria/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/wildingm-maternal-aging-mitochondria/ The trend in Western society is drifting toward an increase in the mean age at which females choose to conceive. This seems to be due at least in part to the fact that people have to make the difficult choice between following a career and childbirth, and these two are often fairly incompatible. The introduction of birth control methods enables women to decide when to have children, and this tends to lead to them delaying childbirth until later in life. One of the problems with delaying childbirth is that the efficiency of reproduction decreases with respect to maternal age. This is combined with an increase in the rate of spontaneous pregnancy loss and may also be associated with higher obstetric risk during pregnancy and increase in the level of early pregnancy loss after IVF (1Navot D. Bergh P.A. Williams M.A. Garrisi G.J. Guzman I. Sandler B. et al.Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility.Lancet. 1991; 337: 1375-1377Abstract PubMed Scopus (444) Google Scholar, 2Gianaroli L. Magli M.C. Ferraretti A.P. Fiorentino A. Garrisi J. Munné S. Preimplantation genetic diagnosis increases the implantation rate in human in vitro fertilization by avoiding the transfer of chromosomally abnormal embryos.Fertil Steril. 1997; 68: 1128-1131Abstract Full Text PDF PubMed Scopus (163) Google Scholar). So what can cause the loss in reproductive efficiency with respect to maternal age, and are there long-term effects associated with later-life childbearing? The relationship between age and reproductive efficiency seems to be a predominantly maternal one. The relationship could be due to an increase in errors in the oocyte and developing embryo, which would lead to a decrease in the implantation rate. Alternatively, the efficiency of the uterus in accepting the implantation embryo could decrease. In practice, clinical results with egg donation support the hypothesis that it is egg quality that determines the probability of successfully reproducing (1Navot D. Bergh P.A. Williams M.A. Garrisi G.J. Guzman I. Sandler B. et al.Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility.Lancet. 1991; 337: 1375-1377Abstract PubMed Scopus (444) Google Scholar). Egg quality seems to affect the ability of the embryo to implant and form a viable fetus through abnormalities in embryo development. The first data pointing to a high frequency of natural pregnancy wastage through abnormalities in the fertilized embryo were gathered by the embryologist Hertig, who collected 34 human embryos aged 1–17 days; 8 were considered from the preimplantation stage, and the others came from the first 2 weeks after implantation (3Hertig A.T. Rock J. Adams E.C. A description of 34 human ova within the first 17 days of development.Am J Anat. 1956; 98: 435-493Crossref PubMed Scopus (373) Google Scholar). Hertig observed that 50% of the preimplantation embryos presented such profound anomalies to force the conclusion that pregnancy could not have proceeded to term. Of the 26 remaining embryos, 6 (23%) also presented major anomalies incompatible with normal development. The study provided the first strong evidence that spontaneous loss of early human embryos by far exceeded clinically evident pregnancy losses. Since these tests, one of the major causes of embryo loss before or soon after implantation has been found to be aneuploidy in the egg (4Dailey T. Dale B. Cohen J. Munné S. Association between nondisjunction and maternal age in meiosis-II human oocytes.Am J Hum Genet. 1996; 59: 176-184PubMed Google Scholar). Clinically relevant aneuploidies during reproduction are caused by nondisjunction in the oocyte during meiosis and are related to maternal age (4Dailey T. Dale B. Cohen J. Munné S. Association between nondisjunction and maternal age in meiosis-II human oocytes.Am J Hum Genet. 1996; 59: 176-184PubMed Google Scholar, 5Hassold T. Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy.Hum Genet. 1985; 70: 11-17Crossref PubMed Scopus (371) Google Scholar, 6Antonarakis S.E. Petersen M.B. McInnis M.G. Adelsberger P.A. Schinzel A.A. Binkert F. et al.The meiotic stage of non-disjunction in trisomy 21: determination by using DNA polymorphisms.Am J Hum Genet. 1992; 50: 544-550PubMed Google Scholar, 7Hassold T. Jacobs P. Trisomy in man.Annu Rev Genet. 1984; 18: 69-97Crossref PubMed Scopus (540) Google Scholar, 8Munne S. Alikani M. Tomkin G. Grifo J. Cohen J. Embryo morphology, developmental rates and maternal age are correlated with chromosome abnormalities.Fertil Steril. 1995; 64: 382-391Abstract Full Text PDF PubMed Google Scholar). Simple mosaicisms (i.e., nondisjunction during mitosis) are probably related to this and may be a spontaneous occurrence (9Morris J.K. Trisomy 21 mosaicism and maternal age.Am J Med Genet A. 2012; 158A: 2482-2484Crossref PubMed Scopus (4) Google Scholar, 10Wilding M. De Placido G. De Matteo L. Marino M. Alviggi C. Dale B. Chaotic mosaicism in human preimplantation embryos is correlated with a low mitochondrial membrane potential.Fertil Steril. 2003; 79: 340-346Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). More serious defects in the oocyte originate from the complete disruption of the meiotic and mitotic apparatus and lead to the chaotic segregation of chromosomes between cells and the complete loss of reproductive potential in the embryo (10Wilding M. De Placido G. De Matteo L. Marino M. Alviggi C. Dale B. Chaotic mosaicism in human preimplantation embryos is correlated with a low mitochondrial membrane potential.Fertil Steril. 2003; 79: 340-346Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). The above data suggest two ways in which embryo loss occurs before or soon after implantation. First, small errors in chromosome alignment during meiosis cause missegregation of chromosomes and lead to aneuploidies that may be lethal. Evidence suggests that this has a nuclear-derived mechanism (11Liu L. Keefe D.L. Nuclear origin of ageing-associated meiotic defects in senescence-accelerated mice.Biol Reprod. 2004; 71: 1724-1729Crossref PubMed Scopus (36) Google Scholar). Second, complete disruption of the meiotic apparatus (and presumably the mitotic apparatus) leads to random segregation of chromosomes and the impossibility of the embryo to form a viable being. Many experiments point to the role of the mitochondria in the cause of chaotic mosaicism (10Wilding M. De Placido G. De Matteo L. Marino M. Alviggi C. Dale B. Chaotic mosaicism in human preimplantation embryos is correlated with a low mitochondrial membrane potential.Fertil Steril. 2003; 79: 340-346Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Mitochondria are the most abundant cell organelle. Mitochondria are also unique in that they are the only organelle outside of the nucleus that contains DNA. The number of mitochondria in a single human egg is estimated through the copies of mitochondrial DNA (mtDNA) present and is considered to be between 20,000 and 800,000 copies (12Van Blerkom J. Mitochondria in human oogenesis and preimplantation embryogenesis: engines of metabolism, ionic regulation and developmental competence.Reproduction. 2004; 128: 269-280Crossref PubMed Scopus (262) Google Scholar, 13Reynier P. May-Panloup P. Chrétien M.F. Morgan C.J. Jean M. Savagner F. et al.Mitochondrial DNA content affects the fertilizability of human oocytes.Mol Hum Reprod. 2001; 7: 425-429Crossref PubMed Scopus (374) Google Scholar, 14Brenner C. What is the role of mitochondria in embryo competence?.in: Van Blerkom J. Gregory L. Essential IVF: basic research and clinical applications. Kluwer Academic, New York2004: 273-290Crossref Google Scholar). The principle role of the mitochondrion is in the production of the cells' energy source, adenosine trisphosphate (ATP), through aerobic respiration, although many secondary functions have been ascribed to this organelle, such as calcium storage, steroid synthesis, and cell senescence (15Wallace D.C. Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease.Cold Spring Harb Perspect Med. 2013; 3: a0Google Scholar). All cells need ATP for energy, and oocytes are no exception to this rule. In fact, a positive correlation between ATP levels in blastomeres and embryo development has been shown to exist in humans (16Van Blerkom J. Davis P.W. Lee J. ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer.Hum Reprod. 1995; 10: 415-424Crossref PubMed Scopus (529) Google Scholar). Mitochondrial DNA consists of approximately 16,600 bases and codes for a total of 37 genes, including some vital proteins and transfer RNA species (15Wallace D.C. Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease.Cold Spring Harb Perspect Med. 2013; 3: a0Google Scholar). The proteins encoded by mtDNA include metabolic enzymes required for the energy production (15Wallace D.C. Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease.Cold Spring Harb Perspect Med. 2013; 3: a0Google Scholar, 17Anderson S. Bankie A.T. Barrell B.G. Sequence and organization of the mitochondrial genome.Nature. 1981; 290: 457-465Crossref PubMed Scopus (7491) Google Scholar). The genes for most mitochondrial proteins, however, exist within the nucleus, and the current theory is that all mitochondrial proteins are being slowly transferred to the nucleus, but it is also possible that the mtDNA codes for proteins that are rapidly made and destroyed and therefore the DNA is required “on site.” The fact that mtDNA is contained within the mitochondria themselves leads to a possible theory for the mechanism of the “maternal age effect.” In fact, energy production and mtDNA do not coexist in a particularly healthy relationship. Mitochondrial energy production is very efficient but highly damaging to the immediate environment of the organelle. This is because the mechanism of energy production involves the release of oxygen free radicals. These are short-lived but very powerful oxidizing agents, meaning that all material in the vicinity of these agents is a target for oxidation. Material near the site of release of oxygen free radicals includes the proteins of the oxidative phosphorylation complex (these are replaceable) but also the mtDNA. A further problem with mtDNA is that little or no mechanisms for DNA repair exist within the mitochondria. Gross levels of damage may lead to the inactivation of the DNA and the senescence of single organelles; however, minor levels could lead to mutations within the DNA sequence of mtDNA and the production of inefficient proteins. In most parts of the body, cells with defective mitochondria obviously do not survive and are replaced by new cells. The problem with reproduction is that the primordial follicles are formed within the ovary before birth and are not replaced. These data suggest that the cells within the primordial follicle are subject to aging. Because life is a continuum, mtDNA would accumulate mutations and degenerate to the point where life was impossible without a resetting mechanism. Fortunately, the “mitochondrial bottleneck” hypothesis (whereby the mtDNA pool is reduced to a few copies in the primordial oocyte) acts as this reset mechanism by naturally redistributing mtDNA species (18Hauswirth W.W. Laipis P.J. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows.Proc Natl Acad Sci U S A. 1982; 79: 4686-4690Crossref PubMed Scopus (290) Google Scholar, 19Shoubridge E.A. Wai T. Mitochondrial DNA and the mammalian oocyte.Curr Top Dev Biol. 2007; 77: 87-111Crossref PubMed Scopus (191) Google Scholar, 20Stewart J.B. Larsson N.G. Keeping mtDNA in shape between generations.PLoS Genet. 2014; 10: e1004670Crossref PubMed Scopus (77) Google Scholar). This evolutionary mechanism obviously enables the production of the best-quality eggs by detecting those with a substandard mtDNA content; however, it does not prevent the degeneration of these copies over time. In fact, the oocyte content of the female is fully determined at birth. Primordial oocytes are in a near-inactive state until adolescence; however, low levels of metabolism may occur, although data from the jellyfish Aurelia aurita suggest that no mitochondrial activity is present in the eggs themselves (21de Paula W. Lucas C. Ahmed-Noor A. Vizcay-Barrena G. Allen J. Energy, fidelity and sex: oocyte mitochondrial DNA as a protected genetic template.Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20120263Crossref PubMed Scopus (40) Google Scholar). Even if primordial oocytes have no metabolism as proposed, the mechanism of progressive damage of mtDNA still applies to the cumulus cells, suggesting that damage to these helper cells could lead to inefficient oogenesis in the egg (21de Paula W. Lucas C. Ahmed-Noor A. Vizcay-Barrena G. Allen J. Energy, fidelity and sex: oocyte mitochondrial DNA as a protected genetic template.Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20120263Crossref PubMed Scopus (40) Google Scholar). Either of these two mechanisms would probably lead to mistakes during meiosis and the increase in the number of eggs with chaotic mosaicism. This is in contrast to the sperm, which is continually produced from adolescence to death from meiosis in the testicle, and in fact is characterized by low levels of aneuploidy (22Ushijima C. Kumasako Y. Kihale P. Hirotsuru K. Utsonomiya T. Analysis of chromosomal abnormalities in human spermatozoa using multicolour fluorescence in-situ hybridization.Hum Reprod. 2000; 15: 1107-1111Crossref PubMed Google Scholar, 23Martin R.H. Lin C.C. Balkan W. Burns K. Direct chromosomal analysis of human spermatozoa: preliminary results from 18 normal men.Am J Hum Genet. 1982; 34: 459-468PubMed Google Scholar). This theory is very similar in fact to the free-radical theory of aging (24Harman D. Aging: a theory based on free radical and radiation chemistry.J Gerontol. 1956; 11: 298-300Crossref PubMed Scopus (6329) Google Scholar, 25Kirkwood T.B. Understanding the odd science of aging.Cell. 2005; 120: 437-447Abstract Full Text Full Text PDF PubMed Scopus (1238) Google Scholar), whereby free radicals progressively degenerate nonreplicating cells in the body (such as the brain and nervous system). This theory has more recently developed into a mitochondria-based theory (26Lobachev AN. Biogenesis of mitochondria during cell differentiation and aging. Deposited Doc. VINITI 19.09.85, №6756–В85, 1985, p 28. [in Russian]. Available at: http://aiexandr2010.narod.ru/Biogenesis.pdf. Last accessed April 27, 2015.Google Scholar, 27Lobachev A.N. Role of mitochondrial processes in the development and aging of organism.Aging Cancer Chem Abstracts. 1979; 91: 48Google Scholar, 28Miquel J. Economos A.C. Fleming J. Johnson Jr., J.E. Mitochondrial role in cell aging.Exp Gerontol. 1980; 15: 575-591Crossref PubMed Scopus (760) Google Scholar). Surprisingly little evidence for the relationship between mitochondrial mutations or indeed the resulting effect of these mutations on mitochondrial physiology exists. A correlation between mtDNA deletions and maternal age was found in granulosa cells (29Seifer D.B. DeJesus V. Hubbard K. Mitochondrial deletions in luteinized granulosa cells as a function of age in women undergoing in vitro fertilization.Fertil Steril. 2002; 78: 1046-1048Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), suggesting that defects in the nutrition of the oocyte during oogenesis could influence reproductive efficiency. In horses, the mtDNA copy number was found to decrease with respect to age in oocytes (30Rambags B.P. van Boxtel D.C. Tharasanit T. Lenstra J.A. Colenbrander B. Stout T.A. Advancing maternal age predisposes to mitochondrial damage and loss during maturation of equine oocytes in vitro.Theriogenology. 2014; 81: 959-965Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Mitochondrial activity has been found to decrease with respect to maternal age and influences both embryo development and IVF outcome (10Wilding M. De Placido G. De Matteo L. Marino M. Alviggi C. Dale B. Chaotic mosaicism in human preimplantation embryos is correlated with a low mitochondrial membrane potential.Fertil Steril. 2003; 79: 340-346Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 12Van Blerkom J. Mitochondria in human oogenesis and preimplantation embryogenesis: engines of metabolism, ionic regulation and developmental competence.Reproduction. 2004; 128: 269-280Crossref PubMed Scopus (262) Google Scholar, 30Rambags B.P. van Boxtel D.C. Tharasanit T. Lenstra J.A. Colenbrander B. Stout T.A. Advancing maternal age predisposes to mitochondrial damage and loss during maturation of equine oocytes in vitro.Theriogenology. 2014; 81: 959-965Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 31Wilding M. Dale B. Marino M. di Matteo L. Alviggi C. Pisaturo M.L. et al.Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos.Hum Reprod. 2001; 16: 909-917Crossref PubMed Scopus (380) Google Scholar). However, the pool of direct evidence for this relationship is not definitive. Research efforts are obviously complicated by ethical aspects of the research, the nature of mitochondria, and the fact that the egg can generate energy through a secondary line of metabolism, that of anaerobic respiration. This means that preimplantation embryos can develop normally and even implant in the total absence of mitochondrial metabolism (32Wilding M. Di Matteo L. Dale B. 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These data have led to the hypothesis of depletion of reduced nicotinamide adenine dinucleoti (NAD+) as the effect of deficiencies in mitochondrial respiration during embryogenesis (32Wilding M. Di Matteo L. Dale B. The maternal age effect: a hypothesis based on oxidative phosphorylation.Zygote. 2005; 13: 317-323Crossref PubMed Scopus (34) Google Scholar). Apart from the difficulties in measuring the output of ATP in the developing embryo, it also remains difficult to measure any increase in mitochondrial point mutations in oocyte mitochondria with respect to maternal age. This is probably due to the nature of mitochondria. Mitochondrial DNA exists in abundance in cells: it is estimated that between 100,000 and 800,000 copies are present in the human oocyte (12Van Blerkom J. Mitochondria in human oogenesis and preimplantation embryogenesis: engines of metabolism, ionic regulation and developmental competence.Reproduction. 2004; 128: 269-280Crossref PubMed Scopus (262) Google Scholar, 13Reynier P. May-Panloup P. Chrétien M.F. Morgan C.J. Jean M. Savagner F. et al.Mitochondrial DNA content affects the fertilizability of human oocytes.Mol Hum Reprod. 2001; 7: 425-429Crossref PubMed Scopus (374) Google Scholar, 14Brenner C. What is the role of mitochondria in embryo competence?.in: Van Blerkom J. Gregory L. Essential IVF: basic research and clinical applications. Kluwer Academic, New York2004: 273-290Crossref Google Scholar, 36Barritt J.A. Kokot M. Cohen J. Steuerwald N. Brenner C.A. Quantification of human ooplasmic mitochondria.Reprod Biomed Online. 2002; 4: 243-247Abstract Full Text PDF PubMed Scopus (104) Google Scholar). This is a gross difference with respect to the nuclear DNA, where two copies of each chromosome are present. The fact that so many copies are present means that the cells' mtDNA content can vary within a single cell. This phenomenon, termed heteroplasmy, suggests that it will remain difficult to observe point mutations in a subset of the mtDNA because the existence of these mutations is swamped by the number of copies of mtDNA present (15Wallace D.C. Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease.Cold Spring Harb Perspect Med. 2013; 3: a0Google Scholar). Researchers attempted to answer these questions by examining the relationship between age and mtDNA copy number or the appearance of large mtDNA deletions, such as the ΔmtDNA4977 deletion (36Barritt J.A. Kokot M. Cohen J. Steuerwald N. Brenner C.A. Quantification of human ooplasmic mitochondria.Reprod Biomed Online. 2002; 4: 243-247Abstract Full Text PDF PubMed Scopus (104) Google Scholar, 37Barritt J.A. Brenner C.A. Willadsen S. Cohen J. Spontaneous and artificial changes in human ooplasmic mitochondria.Hum Reprod. 2000; 15: 207-217Crossref PubMed Scopus (43) Google Scholar). No relationship was shown, but this is hardly surprising considering the nature of mtDNA. Recently, new techniques such as next-generation sequencing for the mitochondrial genome (38Dames S. Eilbeck K. Mao R. A high-throughput next-generation sequencing assay for the mitochondrial genome.Methods Mol Biol. 2015; 1264: 77-88Crossref PubMed Scopus (13) Google Scholar) have been developed, and it is hoped that these will elucidate the role of aging on the mutant mtDNA load in human oocytes, thereby providing a more definitive answer to this question. In fact, recent data analyzing a region of mtDNA, MT-HV2 (15Wallace D.C. Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease.Cold Spring Harb Perspect Med. 2013; 3: a0Google Scholar) did show an increase in mutations with respect to age in some patient types, and the region did seem to be transmitted through the maternal lineage (39Payne B.A. Wilson I.J. Yu-Wai-Man P. Coxhead J. Deehan D. Horvath R. et al.Universal heteroplasmy of human mitochondrial DNA.Hum Mol Genet. 2013; 22: 384-390Crossref PubMed Scopus (260) Google Scholar), suggesting that this effect occurred in the oocyte. Analysis of mother–child pairs has also revealed an increase in the transmission of heteroplasmy with respect to maternal age (40Rebolledo-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: 15474-15479Crossref PubMed Scopus (135) Google Scholar), suggesting that oocyte mtDNA does accumulate mutations with respect to female age. Lamarck proposed that organisms acquired traits from the environment and passed these to their offspring (i.e., that there was no protection of the germ-line) (21de Paula W. Lucas C. Ahmed-Noor A. Vizcay-Barrena G. Allen J. Energy, fidelity and sex: oocyte mitochondrial DNA as a protected genetic template.Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20120263Crossref PubMed Scopus (40) Google Scholar). Weismann contested this hypothesis and proposed that inheritance was protected from the environment by the production of “gametes” (21de Paula W. Lucas C. Ahmed-Noor A. Vizcay-Barrena G. Allen J. Energy, fidelity and sex: oocyte mitochondrial DNA as a protected genetic template.Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20120263Crossref PubMed Scopus (40) Google Scholar). These theories preceded Mendel, whose idea complemented Weismann, thus causing Lamarck's theory to fall out of favor (21de Paula W. Lucas C. Ahmed-Noor A. Vizcay-Barrena G. Allen J. Energy, fidelity and sex: oocyte mitochondrial DNA as a protected genetic template.Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20120263Crossref PubMed Scopus (40) Google Scholar). However, none of these theorists had any knowledge of the biology of fertilization. It is now known that the organism passes on more than the nuclear DNA content at fertilization. For example, the sperm contributes half of the DNA content of the new individual, as well as the centriole, required for formation of the mitotic aster and therefore cell division. The sperm also activates the egg and probably programs its development through the introduction of the “sperm factor” (now known to be phospholipase C zeta) (41Swann K. Larman M.G. Saunders C.M. Lai F.A. The cytosolic sperm factor that triggers Ca2+ oscillations and egg activation in mammals is a novel phospholipase C: PLCzeta.Reproduction. 2004; 127: 431-439Crossref PubMed Scopus (141) Google Scholar). The egg contributes the other half of the genome of the new individual and 100% of the mitochondrial content of the new individual (42Cummins J. The role of maternal mitochondria during oogenesis, fertilization and embryogenesis.Reprod Biomed Online. 2002; 4: 176-182Abstract Full Text PDF PubMed Scopus (84) Google Scholar). Therefore, mitochondrial inheritance is maternal. The fact that the new individual inherits the centriole from the sperm and the mitochondria from the maternal line suggests that inheritance may include components of Lamarck, Weismann, and Mendel. Although the Mendelian component does not have to be reiterated, the determination of whether oocyte mtDNA is protected from free-radical attack by complete inactivation will decide whether Lamarck's theory or that of Weismann will predominate with respect to the mitochondrial DNA. Whether mtDNA within the oocyte, or those in the cells surrounding the oocyte, are subject to free-radical attack in relation to maternal age, the question remains as to whether gestation in later life has long-term consequences with respect to the health of offspring. Apart from the obvious risks of later-life gestation, authors have suggested that a relationship exists between the lifespan of the mother, age of gestation, and lifespan of the progeny. The first to test this hypothesis was Alexander Graham Bell. He noted in a single genealogy that the lifespan of children born was in fact related to that of the mother (43Bell A.G. The duration of life and conditions associated with longevity. A study of the Hyde Genology. Genealogical Record Office, Washington, DC1918Google Scholar). In Drosophila, a relationship between the lifespan of parents and siblings was termed the “Lansing Effect” (44Lansing A.I. A transmissible, cumulative and reversible factor in aging.J Gerontol. 1947; 2: 228-239Crossref PubMed Scopus (118) Google Scholar, 45Lansing A.I. Evidence for aging as a consequence of growth cessation.Proc Natl Acad Sci U S A. 1948; 34: 304-310Crossref PubMed Scopus (35) Google Scholar). The relationship between ageing in mothers and the lifespan of their offspring has been suggested to occur in mice (46Tarín J.J. Brines J. Cano A. Long-term effects of delayed parenthood.Hum Reprod. 1998; 13: 2371-2376Crossref PubMed Scopus (117) Google Scholar, 47Tarín J.J. Gómez-Piquer V. Manzanedo C. Miñarro J. Hermenegildo C. Cano A. 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Maternal non-Mendelian inheritance of a reduced lifespan? A hypothesis.J Assist Reprod Genet. 2014; 31: 637-643PubMed Google Scholar). Interestingly, advanced paternal age (55Gavrilov L.A. Gavrilova N.S. Parental age at conception and offspring longevity.Rev Clin Gerontol. 1997; 7 (Available at: http://www.healthsters.com/Rev-Clin-Geront-1997.pdf. Last accessed April 27, 2015.): 2Crossref Scopus (41) Google Scholar, 56Gavrilov L.A. Gavrilova N.S. Semenova V.G. Evdokushkina G.N. Krut'ko V.N. Gavrilova A.L. et al.Maternal age and lifespan of offspring.Dokl Biol Sci. 1997; 354: 287-289Google Scholar) has also been suggested to affect lifespan. In 2014, I and other researchers (54Wilding M. Coppola G. De Icco F. Arenare L. Di Matteo L. Dale B. Maternal non-Mendelian inheritance of a reduced lifespan? A hypothesis.J Assist Reprod Genet. 2014; 31: 637-643PubMed Google Scholar) used a multivariate analysis to test whether there was a correlation between aging in parents and the lifespan of their progeny. We used a demographic database obtained from the University of Umea, Sweden. The advantages of this database are that it covered a 200-year period, meaning that we could obtain the full lifespan of several generations of individuals. Several factors were tested, both extrinsic (i.e., region of birth, century) and intrinsic (i.e., related to the ages of the subjects). We found that the strongest correlation with intrinsic factors was both mothers' lifespan and maternal age at gestation (54Wilding M. Coppola G. De Icco F. Arenare L. Di Matteo L. Dale B. Maternal non-Mendelian inheritance of a reduced lifespan? A hypothesis.J Assist Reprod Genet. 2014; 31: 637-643PubMed Google Scholar). If the lifespan of the progeny is related most strongly to maternal longevity and the age of the mother at gestation, a factor inherited by children uniquely from their mothers would seem to determine this relationship. Our data (54Wilding M. Coppola G. De Icco F. Arenare L. Di Matteo L. Dale B. Maternal non-Mendelian inheritance of a reduced lifespan? A hypothesis.J Assist Reprod Genet. 2014; 31: 637-643PubMed Google Scholar) suggested that this factor was inherited in a non-Mendelian fashion. An excellent candidate would then be mtDNA. Maternal transmission of low levels of mutated mtDNA has been shown to decrease both litter size and lifespan in mice (57Ross J.M. Stewart J.B. Hagström E. Brené S. Mourier A. Coppotelli G. et al.Germline mitochondrial DNA mutations aggravate ageing and can impair brain development.Nature. 2013; 501: 412-415Crossref PubMed Scopus (185) Google Scholar). We suggest that a similar effect occurs in humans (54Wilding M. Coppola G. De Icco F. Arenare L. Di Matteo L. Dale B. Maternal non-Mendelian inheritance of a reduced lifespan? A hypothesis.J Assist Reprod Genet. 2014; 31: 637-643PubMed Google Scholar, 58Wilding M. Can we define maternal age as a genetic disease?.Facts Views Vis Obgyn. 2014; 6: 105-108Google Scholar). Advanced maternal age in humans has been associated with an increase in heteroplasmy in children, suggesting transmission of mutated mtDNA species (40Rebolledo-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: 15474-15479Crossref PubMed Scopus (135) Google Scholar). The hypothesis then is that the mtDNA content of the mother's oocytes degenerates slowly throughout her lifespan, and these are inherited by the children at conception. The inheritance of damaged mtDNA suggests that mitochondrial metabolism in the offspring would start at less than optimal efficiency. The degeneration of this material by aging would then program the progeny to a shorter lifespan, probably through their diminished physiological health and susceptibility to disease. Because mtDNA is inherited in gross numbers, it is the gross efficiency of these organelles that determines the physiology of the individual. This suggests also that longer-living mothers would be expected to have higher-quality mtDNA as a starting point, therefore attenuating the effects of aging on reproductive fitness and inheritance. The inheritance of mtDNA is similar to that described by Muller for asexually reproducing organisms (59Muller H.J. Some genetic aspects of sex.Am Nat. 1932; 66: 118-138Crossref Google Scholar). This theory suggests that deleterious mutations will build up to a critical level, after which the organism will become extinct. Are we heading toward Muller's ratchet (59Muller H.J. Some genetic aspects of sex.Am Nat. 1932; 66: 118-138Crossref Google Scholar)? Probably not (60Keogh M. Chinnery P. Hereditary mtDNA heteroplasmy: a baseline for aging?.Cell Metab. 2013; 18: 463-464Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar), because the mitochondrial bottleneck probably acts as a Weismann-like protector of gametes by causing the random distribution of mtDNA species between oocytes, causing the elimination of low-quality mtDNA at the primordial follicle and therefore selectively filtering out poor-quality species (18Hauswirth W.W. Laipis P.J. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows.Proc Natl Acad Sci U S A. 1982; 79: 4686-4690Crossref PubMed Scopus (290) Google Scholar, 19Shoubridge E.A. Wai T. Mitochondrial DNA and the mammalian oocyte.Curr Top Dev Biol. 2007; 77: 87-111Crossref PubMed Scopus (191) Google Scholar, 20Stewart J.B. Larsson N.G. Keeping mtDNA in shape between generations.PLoS Genet. 2014; 10: e1004670Crossref PubMed Scopus (77) Google Scholar). Further evidence suggests that the build-up of high levels of mutated mtDNA seems to render animals infertile (57Ross J.M. Stewart J.B. Hagström E. Brené S. Mourier A. Coppotelli G. et al.Germline mitochondrial DNA mutations aggravate ageing and can impair brain development.Nature. 2013; 501: 412-415Crossref PubMed Scopus (185) Google Scholar). However, the build-up of small quantities of mtDNA does seem to be permitted, and this may lead to long-term effects on children born to aging mothers. A genetic theory of the correlation between maternal age at gestation and the lifespan of offspring is complicated by a huge range of factors. First, the definition of “natural lifespan” is subject to a great deal of confusion and therefore practically impossible to calculate. For example, if an older person dies from disease, can we be certain that they reached their natural lifespan? Second, the natural lifespan of any individual depends on a range of factors, both intrinsic (i.e., preprogrammed within the individual) and extrinsic (i.e., influenced from outside the body). Intrinsic influences on lifespan could then include the nuclear genetic makeup of the individual (i.e., their predisposition to disease), their epigenetic makeup (i.e., modifications within the program of the nuclear genome that determine predisposition to disease), and their extranuclear genetic makeup (i.e., the mtDNA content). Extrinsic influences on lifespan of an individual could include the availability of resources including medical care and nutrition, the experience of the mother, and problems during gestation that may affect the long-term well-being of the newborn. In fact, there seems to be a considerable level of cross-over between extrinsic and intrinsic influences at times, the best example being the inheritance of epigenetic imprints after starvation of the mother (61Painter R.C. Osmond C. Gluckman P. Hanson M. Phillips D.I. Roseboom T.J. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life.BJOG. 2008; 115: 1243-1249Crossref PubMed Scopus (430) Google Scholar, 62Walton A. Hammond J. The maternal effects on growth and conformation in Shire horse–Shetland pony crosses.Proc R Soc Lond B. 1938; B125: 311-335Crossref Google Scholar, 63Fish E. Shahrokh D. Bagot R. Caldji C. Bredy T. Szyf M. et al.Epigenetic programming of stress responses through variations in maternal care.Ann N Y Acad Sci. 2004; 1036: 167-180Crossref PubMed Scopus (274) Google Scholar). In conclusion, modern society has enabled women to more freely choose the age at which they can conceive and start a family. Most people would certainly agree that this was a huge sociologic advance. On the negative side, the ability to choose when to start a family often means that people delay the decision until later in life, when their peak reproductive years have passed and the probability of conceiving has diminished. Our theory is that delayed reproduction has short-term and long-term effects on society. In the short term, delayed reproduction means having fewer progeny with the consequent increase in mean age of the general population. In the long term, the inheritance of components of older eggs, particularly the mtDNA, could have longer-term consequences then previously imagined, such as the lowering of the potential lifespan of individuals conceived to older women.