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1 Role of increased male age in IVF and egg donation: is sperm DNA fragmentation responsible? Kathryn C. Humm, M.D., a,b and Denny Sakkas, Ph.D. a a Boston IVF, Waltham; and b Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts The well documented increase in age that women conceive their first child has detracted from a similar change observed in males. As both males and females decide to conceive later, the question of whether this may impact their fertility individually and as a couple becomes even more crucial. A paternal age of over 40 years at the time of conception is a frequently quoted male age threshold, however, currently there is no clearly accepted definition of advanced paternal age or even a consensus on the implications of advancing male age. In this paper, we review some of the potential risks to the offspring of advancing male age and examine. The data available regarding pregnancy outcomes based on paternal age in both the fertile and infertile populations. Within the infertile population specifically, we examine the association between male age and outcomes based on treatment modality, including intrauterine insemination (IUI), in vitro fertilization (IVF), and donor oocyte IVF. Finally, we discuss the various mechanisms by which male age may impact sperm and fertility potential, including sperm DNA damage. (Fertil Steril Ò 2013;99:30 6. Ó2013 by American Society for Reproductive Medicine.) Key Words: Male age, paternal effect, male infertility, paternal genome Discuss: You can discuss this article with its authors and with other ASRM members at fertstertforum.com/hummkc-male-age-ivf-paternal-effect/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for QR scanner in your smartphone s app store or app marketplace. It has been well established that increasing maternal age leads to a higher risk of infertility, miscarriage, and chromosomal defects in offspring. The well documented increase in age at which women conceive their first child, has detracted from a similar change observed in males. In fact since 1980, U.S. birth rates have increased 40% for men years and have decreased 20% for men less than 30 years (1). As both males and females decide to delay conception, the question of whether this may impact their fertility individually and as a couple becomes even more crucial. While paternal age of over 40 years at the time of conception is a frequently quoted male age threshold, currently there is no clearly accepted definition of advanced paternal age or even a consensus on the implications of advancing male age (2). In this paper, we will briefly review some of the potential risks to the offspring of advancing male age. We will also review the data available regarding pregnancy outcomes based on paternal age in both the fertile and infertile populations. Within the infertile population specifically, we will examine the association between male age and outcomes based on treatment modality, including intrauterine insemination (IUI), in vitro fertilization (IVF) and donor oocyte IVF. Finally, we will discuss the various mechanisms by which male age may impact sperm and fertility potential. Received October 2, 2012; revised and accepted November 14, K.C.H. has nothing to disclose. D.S. has nothing to disclose. Reprint requests: Denny Sakkas, Ph.D., Boston IVF, 130 Second Ave., Waltham, MA ( dsakkas@bostonivf.com). Fertility and Sterility Vol. 99, No. 1, January /$36.00 Copyright 2013 American Society for Reproductive Medicine, Published by Elsevier Inc. OVERVIEW OF RISKS TO OFFSPRING OF ADVANCING MALE AGE Advancing male age has been associated with an increased risk of rare autosomal dominant genetic disorders including Pfeiffer syndrome, Crouzon syndrome, achondroplasia, Apert syndrome, and MEN2A and MEN2B. Risch et al. (3) reported that the offspring of males >50 yearswere7.8timesmorelikelytobediagnosed with achondroplasia and 9.5 times more likely to be diagnosed with Apert syndrome as compared to the offspring of males years. These authors did not include the 95% confidence intervals (CI), so it is difficult to assess the statistical significance of these findings, however these possible associations with advancing paternal age remain intriguing. There is also growing interest in the association between paternal age and an increased risk for schizophrenia, autism spectrum disorders, and some forms of cancer. Malaspina et al. (4) 30 VOL. 99 NO. 1 / JANUARY 2013

2 Fertility and Sterility found a significant association between advancing paternal age and the risk of schizophrenia in a cohort of 87,907 individuals after controlling for maternal age and other confounding factors. These authors reported that the offspring of men R50 years were 2.96 times (95% CI ) more likely to be diagnosed with schizophrenia as compared to the offspring of men years. Reichenberg et al. (5) found a significant association between advancing paternal age and the risk of autism spectrum disorders in a population based cohort study including 132,271 individuals. These authors reported that the offspring of men R40 years were 5.75 times (95% CI ) more likely to have an autism spectrum disorder compared to offspring of men <30 years. More recently, Kong et al. (6) reported an increased risk of schizophrenia and autism spectrum disorders with increasing paternal age in an Icelandic population. These authors used genome wide sequencing to conclude that the paternal de novo mutation rate increases with paternal age. Other studies evaluating the association between advancing paternal age and the increased risk for autism spectrum disorders and schizophrenia have reported mixed results, thus it is likely that many factors play a role in these complex diagnoses (7). There is minimal compelling evidence that chromosomal abnormalities are significantly increased in offspring as paternal age advances. Wyrobek et al. (8) reported male age was not associated with sperm diploidies or sperm aneuploides involving chromosomes X, Y, or 21 in a cohort of 97 men ranging in age from years. Yang et al. (9) found a weak association between advancing paternal age and trisomy 21 as well as other chromosomal abnormalities in a cohort of 5,213,248 subjects. These authors reported a RR of 1.28 (95% CI ) and a relative risk (RR) of 1.39 (95% CI ) for trisomy 21 in the offspring of males years and >49 years respectively as compared to males years. The authors concluded paternal age appears to play a small role in the etiology of chromosomal abnormalities (9). A recent study by Green et al. (10) found that paternal age may be a risk factor for some multifactorial birth defects using data from the National Birth Defects Prevention Study. An elevated odds ratio (OR) for each yearly increase in paternal age was reported for cleft palate (OR 1.02, 95% CI ), diaphragmatic hernia (OR 1.04, 95% CI ), and right ventricular outflow tract obstruction (OR 1.03, 95% CI ). Despite a growing body of evidence that advancing paternal age is associated with rare autosomal dominant disorders as well as other complex disorders such as autism and schizophrenia, there are no screening or diagnostic tests which specifically target those conditions that may increase with paternal age (2). Regardless, as the population of patients seeking infertility care continues to age, we should be prepared to discuss the potential risks of advancing paternal age in addition to those of advanced maternal age. PATERNAL AGE AND PREGNANCY RATES Numerous studies have demonstrated that natural fertility appears to decline with advancing paternal age. A large population based study by Ford et al. (11) investigated the effect of paternal age on the time to natural conception in 8,515 couples living in the Avon Health district in the UK. These authors reported that after adjusting for maternal age and other potential confounders, that the likelihood of conception within 12 months was significantly lower in men R40 years as compared to men <25 years (OR 0.51, 95% CI ). Hassan et al. (12) also found that increasing male age was associated with an increased time to pregnancy in a cohort study of 2,112 consecutive pregnancies. Males >45 years were 4.6 times and 12.5 times more likely to have had a time to pregnancy of >1 year or >2 years respectively relative to men %25 years. Dunson et al. (13) reported similar findings in a study of 782 healthy couples in whom natural fertility was significantly reduced for men over age 35 years. These authors controlled for both maternal age as well as sexual behavior (Table 1). Increasing paternal age has also been reported to be associated with an increased risk of spontaneous pregnancy loss. In a prospective study of 5,121 women who conceived naturally, Slama et al. (14) reported that the risk of spontaneous abortion associated with paternal age of R35 years was 1.26 times (95% CI ) higher relative to paternal age <35 years. In a large French study, Belloc et al. (15) analyzed 17,000 intrauterine insemination cycles and reported a miscarriage rate of 13.7% per pregnancy in men <30 years versus 32.4% in men R45 years (P<.001). Other studies evaluating the association between advancing paternal age and the risk of spontaneous abortion have reported mixed results, thus this relationship remains unclear (16 19). While there are a few studies suggesting that male age may play some role in the success of intrauterine insemination cycles, most studies focus on the importance of maternal age, semen characteristics, and the number of mature follicles (20). Mathieu et al. (21) published an analysis of 901 cycles of intrauterine insemination in 274 couples. Multivariate analysis revealed that male age R35 years was associated with decreased rates of conception. Demir et al. (22) reported similar findings in a small study including 253 intrauterine insemination cycles in which increasing male age was also found to be associated with decreasing success, even in the setting of normal semen parameters. In a French study of more than 17,000 intrauterine insemination cycles, the authors suggest that the clinical pregnancy rate decreased significantly with increasing paternal age. The authors reported a pregnancy rate of 12.3% per cycle for men <30 years versus 9.3% per cycle for men R45 years (P<.001) (15). Contrary to the studies just discussed, Bellver et al. (23) analyzed 2,204 intrauterine insemination cycles in 971 patients and reported no association between paternal age and outcomes, however only eight men in this study were >50 years of age (Table 1). Numerous studies have examined the role of paternal age on outcomes in couples undergoing conventional IVF. In a prospective study of 221 couples undergoing conventional IVF, Klonoff-Cohen et al. (18) reported that pregnancy rates declined with advancing male age. These authors reported a 38% live birth rate for men %35 years, 17% for men years, and only 7% for men >40 years. Each additional VOL. 99 NO. 1 / JANUARY

3 VIEWS AND REVIEWS TABLE 1 Brief overview of selected studies examining the effect of paternal age on outcomes in both natural conception and assisted reproductive technologies as well as the reported paternal age threshold of interest. Observed paternal Study Number Maternal age age effect Age threshold (y) Natural conception Ford 2000 (11) 8,515 couples Adjusted for maternal age Time to conception greater in men R40 y R40 Dunson 2002 (13) 782 couples Adjusted for maternal age Fertility lower in men >35 y >35 Hassan 2003 (12) 2,112 pregnant Men >45 y with longer time to >45 women conception Adjusted for maternal age and subgroup analysis of women <25 y Intrauterine insemination Mathieu 1995 (21) 901 cycles Adjusted for maternal age Pregnancy rate lower in men R35 y Belloc 2008 (15) 17,000 cycles Paternal age independent of Pregnancy rate lower in R45 maternal age men R45 y Bellver 2008 (23) 2,204 cycles Adjusted for maternal age IVF and/or ICSI with autologous oocytes Spandorfer 1998 (25) 398 couples Subgroup analysis of women <35 y Klonoff-Cohen 2004 (18) 221 cycles Adjusted for maternal age Live birth rate lower in men >40 y De La Rochebrochard 1,938 couples Adjusted for maternal age Likelihood of conception lower in 2006 (24) men R40 y Aboulghar 2007 (53) 545 couples Subgroup analysis of Fertilization rate lower in women <40 y men >50 y; no effect on pregnancy rate Ferreira 2010 (17) 1,024 couples Adjusted for maternal age Pregnancy rate lower with each year of advancing paternal age in oligozoospermic men only IVF and/or ICSI with donor oocytes Gallardo 1996 (28) 345 cycles Donor population; not adjusted Paulson 2001 (27) 558 cycles Donor population, not adjusted Frattarelli 2008 (19) 1,023 cycles Donor population; not adjusted Bellver 2008 (23) 1,412 cycles Donor population; not adjusted Luna 2009 (16) 672 cycles Donor population; not adjusted Whitcomb 2012 (26) 1,083 couples Donor population; adjusted for recipient age Humm. Impact of advanced male age on ART. Fertil Steril R35 >40 R40 >50 Live birth rate lower in men >50 y >50 Implantation rate lower in men >60 y >60 year of paternal age was associated with a 12% increased odds of not having a successful live birth (P¼.01; 95% CI ). These authors did not find a statistically significant association between paternal age and spontaneous pregnancy loss. A French study including 1,938 infertile couples undergoing conventional IVF due to bilateral tubal obstruction reported that paternal age over 40 years was an important risk factor for failure to conceive. These authors reported the odds ratio of failure to conceive with IVF for paternal age R40 years was 1.70 (95% CI ) compared with males <30 years. When taking into account an interaction between male and female ages, the odds ratio of failure to conceive for paternal age R40 years was 2.00 (95% CI ) when female age was years, 2.03 (95% CI ) for female age years, and 5.74 (95% CI ) for females R41 years. Clearly the effect of male age is greater as the female age increases leading to the intriguing suggestion that an older oocyte is less able to rescue an older sperm (24) (Table 1). Of course the advent of intracytoplasmic sperm injection (ICSI) has led to a male patient population being treated that in addition to age may also possess a sperm population that is much less likely to lead to conception naturally or with routine IUI and IVF. Numerous studies have also evaluated the role of paternal age on outcomes in couples undergoing IVF with ICSI. Spandorfer et al. (25) analyzed 398 couples undergoing IVF with ICSI in which the female partner was %35 years. These authors reported that pregnancy outcomes were not influenced by the age of the male partner, although this cohort only included nine men R40 years. A case-control study including 1,024 couples undergoing IVF with ICSI found that for couples in which the men were oligozoospermic (sperm concentration < /ml), the chance of pregnancy decreased by 5% for each year of advancing paternal age. There was no influence of paternal age observed in normozoospermic patients. The authors used multiple binary logistic regression analysis to adjust for maternal age and other potential confounding variables. Interestingly, these authors 32 VOL. 99 NO. 1 / JANUARY 2013

4 Fertility and Sterility noted that paternal age did not influence the rate of spontaneous pregnancy loss in either oligozoospermic or normozoospermic patients (17) (Table 1). Perhaps the best group in which to study the effects of advancing paternal age on pregnancy outcomes in the human is the donor oocyte population. Since donor oocytes are generally obtained from young healthy women, maternal age is mostly eliminated as a confounding variable. Numerous groups have examined this particular question. Frattarelli et al. (19) evaluated 1,023 infertile couples undergoing an anonymous oocyte donation cycle. After controlling for female age with use of the donor oocyte model, these authors reported that male age >50 years significantly affected pregnancy outcomes as well as blastocyst formation rates. The live birth rate in men %50 years was 56.0% versus 41.3% in men >50 years (P<.01). The pregnancy loss rate in men %50 years was 24.4% versus 41.5% in men >50 years (P<.01). Implantation rate, pregnancy rate, and initial embryo development were not affected by paternal age. The authors noted that they did not adjust for the age of the female recipient based on previous studies demonstrating no effect of recipient age on outcomes in the setting of oocyte donation. These findings are further supported by a study including 672 donor oocyte cycles in which the authors report a significantly decreased fertilization rate as well as implantation rate seen with males >60 years of age (16). Most recently, a large study published by Whitcomb et al. (26) evaluated 1,083 infertile couples also undergoing their first anonymous oocyte donation cycle. Unlike previous studies, these authors adjusted for female recipient age and found that male age had no significant association with pregnancy outcomes. The adjusted odds ratio of having a live birth among men <50 years was 1.08 (95% CI ) as compared to men R50 years. In a retrospective study by Bellver et al. (23), the authors also found no paternal age effect on pregnancy rates or miscarriage rates in 1,412 donor oocyte cycles. These findings are further supported by multiple smaller studies reporting no association between male age and outcomes including pregnancy rate and live birth rate in couples undergoing oocyte donation (27, 28) (Table 1). The numerous studies discussed above come to conflicting conclusions regarding the association between advancing paternal age and infertility. Major limitations include both the retrospective nature of the majority of these studies, as well as the low numbers of older males (i.e., those >50 years) included in many of these studies. Most of these studies make an effort to adjust for maternal age which is clearly an important confounding variable when evaluating the effects of paternal age, however some evidence would suggest that the complex relationship of these two variables may not simply be resolved by adjusting for maternal age or solely studying the donor oocyte population. Studies indicate that maternal DNA repair mechanisms in the oocyte are capable of repairing endogenous and exogenous DNA damage of paternal origin, therefore rescuing the aging sperm (29, 30). An oocyte from an older woman may be less capable of rescuing an aging sperm, resulting in infertility or pregnancy failure. Donor oocytes, generally obtained from young healthy women, may be better able to repair DNA damage in aging sperm, therefore studies including only donor oocyte cycles or subgroups of women <35 years may underestimate the potential impact of aging sperm. MALE AGE AND SEMEN PARAMETERS The impact of male age on semen parameters is inconclusive with a variety of different findings reported in the literature. The only consistent finding appears to be a decrease in semen volume with advancing paternal age. A review by Kidd et al. (31) reported that increased male age was associated with a decline in semen volume, sperm motility, and sperm morphology, but not with sperm concentration. A review of five studies by Dain et al. (32) reported a linear decline in semen volume with paternal age. There was no relationship between sperm concentration, motility, morphology and male age, however a decline in total sperm count and total motile sperm count was noted due to the reduced semen volume. On the other hand, Whitcomb et al. (26) reported that increasing paternal age was associated with a significant decrease in sperm motility and volume, however there was no association between paternal age and sperm concentration. Large well designed studies are clearly needed to have a better understanding of the true impact of advancing paternal age on semen parameters. MECHANISMS FOR THE EFFECTS OF AGING SPERM While there is no clear consensus regarding the implications of advancing paternal age as illustrated by the conflicting conclusions of the studies discussed above, the mechanisms accounting for any potential effect of advancing paternal age also remain unclear. Unlike the dramatic rise in aneuploidy rates seen in the aging oocyte, sperm likely undergo more subtle changes as the male ages. One parameter that has attracted a significant amount of interest is nuclear sperm DNA damage. Sperm DNA damage has been implicated in both male aging and infertility. Multiple studies have demonstrated that sperm DNA damage increases with advancing male age. Wyrobek et al. (8) reported that male aging was significantly associated with increases in sperm DNA fragmentation. These authors reported a 5 fold increase in percent DNA fragmentation (DFI) between 20 and 80 years of age. Moskovtsev et al. (33) found that sperm DNA damage was significantly increased in men R45 years compared to all other age groups in a cohort of 1,125 men presenting for fertility evaluation. These authors reported a 15.2% DFI in men <30 years versus a 32.0% DFI in men R45 years (P<.01). Schmid et al. (34) showed that the sperm of older men had significantly higher frequencies of DNA damage when measured under alkaline conditions, however age was not associated with sperm DNA damage under neutral conditions. How the DNA damage arises may be linked to environmental, hormonal or degenerative events that take place as males age. A study by El-Domyati et al. (35) has shown statistically significant differences in DNA damage repair associated proteins and apoptosis markers in testicular samples from older men. These differences were most marked in spermatocytes. This study showed that the VOL. 99 NO. 1 / JANUARY

5 VIEWS AND REVIEWS testes may be more taxed to perform DNA repair as the male ages. This implies that failure to control DNA repair could amount to more ejaculated spermatozoa being produced possessing abnormal paternal DNA. It appears clear that DNA damage increases with advancing male age, however how this impacts fertility potential as well as pregnancy outcomes is less obvious. Clinical studies have demonstrated that sperm DNA integrity is impaired among infertile men as compared to fertile men (36, 37). Some studies have suggested that increased DNA fragmentation is associated with lower pregnancy rates through natural conception as well as intrauterine insemination (38). Interestingly, studies evaluating an association between sperm DNA fragmentation and outcomes using assisted reproductive technologies have been less consistent (39). A meta-analysis by Collins et al. (40) reported a clinically limited association between sperm DNA integrity and IVF or ICSI outcomes. A prospective study by Esbert et al. (41) of 77 couples using autologous oocytes and 101 couples using donor oocytes found that sperm DNA damage was not related to outcomes in either group. Interestingly, these authors report that miscarriage rates were higher in the high DNA fragmentation population for both autologous and donor oocyte couples, however numbers were small. This study highlights the fact that to come to a stronger conclusion about the impact of sperm DNA fragmentation and male age on outcome, a much larger study population needs to be assessed. The use of DNA fragmentation tests in infertile couples has been questioned (42), therefore it may make it difficult to extrapolate its importance in assessing the more subtle sperm anomalies that could impact advancing male age. In reality, the way we examine sperm DNA is only providing a gross analysis. The subtle changes inherited through the paternal genome leading to miscarriage or other abnormalities are probably beyond the scope of current diagnostic methods. With respect to this, the subtle changes occurring in DNA related to epigenetic modifications may offer some additional insight into possible mechanisms for the effect of advancing paternal age. Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Several studies have suggested that there is a relationship between sperm DNA methylation levels and IVF outcomes (43, 44). Houshdaran et al. (45) reported that DNA methylation may be elevated in DNA from poor quality sperm. These authors suggested that abnormal epigenetic reprogramming of the germline may lead to compromised spermatogenesis and subsequent infertility. Other studies have suggested that sperm DNA methylation is lower in asthenozoospermia and teratozoospermia as compared to normal ejaculates (44). Epigenetic alterations have also been implicated in the aging process; however Benchaib et al. (44) reported no correlation between sperm DNA methylation level and paternal age. A significant limitation of each of these studies is the use of immunohistochemistry as the only method for evaluation of sperm DNA methylation status rather than a genome wide approach. Despite the inadequate quantification of sperm DNA methylation discussed in these studies, epigenetic alterations such as DNA methylation and histone modification may offer some insight into the effect of male aging on sperm. Oxidative stress, characterized by an excess of reactive oxygen species, has also been implicated in the setting of male aging and decreased fertility. Excessive oxidative stress may be responsible for an increase in DNA damage seen with age, as well as negatively affect sperm quality and function. Cocuzza et al. (46) prospectively evaluated semen samples collected from 98 fertile men presenting for vasectomy. These authors found that men R40 years had significantly higher levels of reactive oxygen species compared with younger men ( /cpm vs /cpm; P¼.0009). Pasqualotto et al. (47) reported that higher levels of reactive oxygen species were seen in sperm collected from 167 infertile males versus 17 controls, suggesting that oxidative stress may also play a role in male infertility. Interestingly, our own data examining semen samples of 2281 men has shown a significant relationship between sperm DNA damage and age, however when examining oxidative stress levels in sperm, no association was found with male age (48). The question of paternal age becomes more complicated as it was recently reported that children of older fathers have longer telomeres than those of younger fathers. The increase in telomere length per year of fathers' age is just about the same amount as telomere length lost per year in normal aging, so the longer telomeres in sperm roughly offset normal aging, potentially giving children of older fathers an advantage (49). Finally, morphological changes in the testis may also be a mechanism by which advancing paternal age impacts fertility and pregnancy outcomes. Plas et al. (50) demonstrated that aging men have decreased numbers of Leydig cells, arteriosclerotic lesions, thickening of the basal membrane of the seminiferous tubules, and fibrotic thickening of the tunica albuginea. These alterations in the male reproductive tract could induce a decrease in quality and quantity of spermatozoa production (50). CONCLUSIONS It has been well established that advancing maternal age leads to an increased risk of infertility and miscarriage; however there is no consensus on the implications of advancing paternal age. The question of the role of paternal age on reproductive outcome is made complex because of the multifactorial nature of reproduction. Across species, there is a tendency for females to mate with older males and this pattern has been found to persist among humans cross-culturally (51, 52). Whether this has evolved due to social or biological reasons is still unclear. Despite the variety of different findings reported in the literature, it is clear that fertility is more complicated than just maternal and paternal age. The prevailing impact of the female only serves to further complicate matters. As we develop stronger molecular tools to examine paternal DNA our understanding of the relationship between paternal age and reproductive outcomes should become clearer. Finally, regardless of the conflicting data, we should be prepared to 34 VOL. 99 NO. 1 / JANUARY 2013

6 Fertility and Sterility discuss the potential risks of advancing paternal age in addition to those of advanced maternal age with our patients. REFERENCES 1. Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Kirmeyer S, Mathews TJ, et al. Births: final data for Natl Vital Stat Rep 2011;60: Toriello HV, Meck JM. Statement on guidance for genetic counseling in advanced paternal age. Genet Med 2008;10: Risch N, Reich EW, Wishnick MM, McCarthy JG. Spontaneous mutation and parental age in humans. Am J Hum Genet 1987;41: Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, et al. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001;58: Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, et al. Advancing paternal age and autism. Arch Gen Psychiatry 2006;63: Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father's age to disease risk. 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7 VIEWS AND REVIEWS 45. Houshdaran S, Cortessis VK, Siegmund K, Yang A, Laird PW, Sokol RZ. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS One 2007;2: e Cocuzza M, Athayde KS, Agarwal A, Sharma R, Pagani R, Lucon AM, et al. Age-related increase of reactive oxygen species in neat semen in healthy fertile men. Urology 2008;71: Pasqualotto FF, Sharma RK, Potts JM, Nelson DR, Thomas AJ, Agarwal A. Seminal oxidative stress in patients with chronic prostatitis. Urology 2000; 55: Tirado E. Concurrent sperm DNA fragmentation and oxidative stress assessment on 2,281 male semen samples. Fertil Steril 2012; 98(Suppl):S Eisenberg DT. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Am J Hum Biol 2011;23: Plas E, Berger P, Hermann M, Pfluger H. Effects of aging on male fertility? Exp Gerontol 2000;35: Brooks R, Kemp DJ. Can older males deliver the good genes? Trends Ecol Evol 2001;16: Fenner JN. Cross-cultural estimation of the human generation interval for use in genetics-based population divergence studies. Am J Phys Anthropol 2005;128: Aboulghar M, Mansour R, Al-Inany H, Abou-Setta AM, Mourad L, Serour G. Paternal age and outcome of intracytoplasmic sperm injection. Reprod Biomed Online 2007;14: VOL. 99 NO. 1 / JANUARY 2013

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