We are witnessing the progressive increase of paternal age at conception. The birth rate among 35 to 49 year old American men in 2015 was 69.1 per thousand compared with 42.8 per thousand in 1980 (1). Other countries have reported a similar trend (2) that appears to be consistent across all races, ethnicities, regions and level of education (3). While controversies exist, a preponderance of evidence from recent scientific literature affirms a negative impact of advanced paternal aging on reproductive health. In this review we will begin by discussing the role of animal models as a valuable research tools to study the effects of paternal aging. After presenting how advanced paternal age impacts the fertility status of men, reproductive outcomes and offspring health, we will provide an opinionated analysis on the challenges faced by healthcare providers and health authorities in the development and implementation of practical strategies designed to reduce or mitigate the negative impact of advanced paternal age from a public health point of view.

A wide range of animal models ranging from insects to worms, birds, fish and mammals have been used to investigate the effects of paternal aging on male reproduction function. However, rodent models have become the predominant species for determining the cellular and molecular changes with aging that occur in the testis and epididymis (4–6). Outbred rodents are often used in drug testing or environmental exposure studies so to increase the genetic variability in the population. However, inbred rodents are preferred for aging studies that focus specifically on the mechanistic pathways in question. A potential limitation is that several pathologies associated with aging including pituitary, adrenal or testis tumors may complicate result interpretation. An ideal animal model should be long-lived and free from the systemic aging-related diseases, while maintaining other reproductive changes that emulate those in aging men.

Studies in animal models suggest that the constitution of the male germline is relatively robust with far fewer spontaneous mutations compared to somatic tissues (102, 103). This high level of genetic fidelity in part explains why even after exposure to chemotoxic agents or radiation in men, no increase in the incidence of birth defects, sperm DNA chromatin abnormalities or de novo germline mutations are noted in their offspring (104, 105). In contrast, paternal aging has been shown to be unique for the creation of de novo mutations in male germline (106). Several mechanisms of age-induced de novo germline mutations have been proposed. Cumulative replication error from repeated cell divisions represents a significant source of germline mutation (107, 108). Based on whole-genome sequencing studies of parent-offspring trios, approximately one to three de novo mutations are introduced to the germline mutational load of the offspring for each additional year in the father’s age at conception (109, 110). Selfish spermatogonial selection from preferentially amplified mitotic clonal expansion of mutated spermatogonial stem cells (111–113) is another proposed mechanism to explain why several genetic diseases associated with advanced paternal age follow the autosomal dominant pattern. Age-related epigenomic modifications in men, as reported by our group (114) and others (115) are speculated to increase the risk of some rare epigenetic disorders in offspring conceived with ARTs (116). Other proposed mechanisms involve post meiotic damage of sperm DNA secondary to the combined effects of increased oxidative stress (117) and nuclease activities and aberrant or inadequate repair of such damage by oocytes (118).

Few professional organizations have provided a clear definition of advanced paternal age. The American College of Medical Genetics has defined advanced paternal age as >40yrs at conception (76) for the purpose of risk counselling. While the American Society of Reproductive Medicine states that the sperm donor should be “young enough” (119), the Canadian Fertility and Andrology Society have set an upper age limit for sperm donation at 40yrs (120). However, no organizations have made any clear statements as to whether access to reproductive technologies after this age should be restricted.

The lack of clear, authoritative clinical guidelines not only poses challenges to health providers to decline services, but it also inadvertently allows patients to downplay or ignore the negative impact of paternal aging. Additional factors further aggravate the situation: increased access to contraceptives (121), delayed marriage, high divorce and remarriage rates, increased life-expectancy (122), increased access to erectile dysfunction treatment (123) leading to extension of active sex-life expectancy, continuous spermatogenic activities with aging, social acceptance in delaying fatherhood as modeled by a number of male celebrities having children at advanced age, and widespread usage of social media and dating apps to increase the odds of courtship (124). These factors have provided elements for a perfect storm resulting in a rising number of aging men entering or re-entering fatherhood.

Though experts recognize the importance of disseminating current knowledge on the negative impacts of advanced paternal age to clinicians and prospective parents, in practice, this task is far from simple to execute. For example, when counselling a couple with an aging male partner seeking fertility care, merely informing the couple of the potential adverse outcomes serves little more than risk disclosure. Obviously, the couple could do nothing to change the age factor. Alternative options such as using donor gametes or adoption are unlikely to be accepted when the male partner still has functional sperm. From their perspectives, risk is not a certainty. Infertile couples who are determined enough to pursue fertility treatment may feel entirely rational to accept such risks (125). Additionally, there is ample evidence suggesting that children born to parents of more advanced age may enjoy further benefits in life chances such as financial security, parental psychological maturity and a wider network of support for upbringing, education and future career development (125, 126). Taken together, the impact of counselling solely for risk disclosure may not be effective in modifying behavior or improving treatment outcomes.

To add yet another layer of complexity, denying this couple further fertility evaluation is not correct since there could be significant medical conditions including varicoceles, obstruction of the excurrent ductal system, genetic and endocrinological disorders that can contribute to impaired semen parameters. Some causes of male infertility may be correctable to improve the fertility status of the male partner and allow for a better chance of conception. Further, detection of impaired semen parameters may lead to early detection of potential chronic diseases such as cardiovascular diseases and diabetes mellitus, and even cancers (127–129). It may be unethical not to diagnose and treat their infertility. Even for these couples with no correctable male infertility factors who choose to use ARTs, denying such care based solely on age may be viewed as age-discrimination. Additionally, there is a substantial number of children born to aging fathers from natural pregnancies, yet healthcare providers generally take no action in prohibiting aging men in the society at large to have children. Is it rational for them not to intervene with all men at advanced age who are attempting to have children?

One may propose that a more sensible strategy is perhaps through general public education for a “preventative” approach. Unfortunately, this will also encounter obstacles at a different level. The message that “delayed parenthood could lead to adverse outcomes” may be misinterpreted as “education and career commitment are less important” (130, 131). which would not echo well with the ambitious-minded youngsters Further, as the negative impact of female aging on reproduction risks is arguably stronger than that in male aging (44), if the message is therefore more strongly emphasized to young females than to young males, one could only imagine the severity of backlash it would spark from the public.

With regards to reproductive technologies, though planned or elective egg freezing for non-medical reasons is an established strategy to reduce the reproductive risks associated with female aging, planned or elective sperm freezing has not been shown to be effective in mitigating reproductive and offspring health risks associated with paternal aging. This is in part related to the fact that the well-documented chromatin cryodamage from sperm cryopreservation (132–136) can potentially offset any potential benefits from sperm banking. Though sperm cryopreservation is non-invasive and widely accessible, the fees associated with semen storage for years can be significant. Of note, ARTs are required when using cryopreserved sperm. Intra-uterine insemination (IUI) can be used but given its lower success rate compared to in vitro fertilization (IVF) and intracytoplasic sperm injection (ICSI), multiple semen samples may have to be cryopreserved to allow for repeated trials of IUI to have a reasonable success rate. In practice, advanced assisted reproduction such as ICSI are often required when using cryopreserved sperm. Aging men who previously banked sperm at a younger age may opt to attempt conception through intercourse when they realize the cost, invasiveness and potential risks on the female partners and offspring associated with using ICSI (137–139). Ultimately, large scale studies to unbiasedly compare the reproductive outcomes and long-term offspring health of with natural conception versus long-term cryopreserved sperm with ICSI are required to establish the benefits and cost-effectiveness of planned or elective sperm freezing against male aging.

Accumulating evidence from the past two decades links impaired sperm chromatin integrity and DNA fragmentation to increased risk of pregnancy loss and reduced success rate with assisted reproductive technologies. Growing interest in recent years on various sperm selection strategies has led to studies that provided preliminary evidence of improving reproductive outcomes in selected infertile couples (140, 141). However, the question of whether these sperm selection strategies are effective in cases of advanced paternal age, particularly in lowering the risks of health conditions linked to aberrant chromatin, remains to be answered.

In dealing with the risks association with advanced paternal age, too often wrong questions were asked: “how old is too old?”, “What is the paternal age cut-off at which we can justify imposing restriction of access to reproductive care?” Although most experts agree that the negative impacts of advanced paternal age can be detected in some men after the age of 40 years, currently there is no consensus on the optimal definition of advanced paternal age as studies have used different age inclusion and different outcomes with different definitions. The progressive nature of the physiological changes associated with male aging is a main reason why it is challenging for investigators to reach agreement on a clear definition for aging.

To begin the mission to reduce risks associated with paternal aging, paradoxically, the focus of discussion must first be shifted away from chronological age to gamete-mediated risk on reproductive outcomes and offspring health. In other words, advanced paternal age should be treated as other male factor infertility causes with a focus on identifying elements that can be ameliorated, assessment of gamete functional status, and selection of the gametes with the best chance for a successful procreation. Health policy makers and healthcare providers may have to accept the fact that the growing number of aging men having children is an inevitable phenomenon in the current direction of societal evolution. It is equally important to recognize that strategies aiming to prohibit or dissuade this behavior through establishing a clear paternal age limit for provision of fertility care or through education and counselling can readily be challenged and therefore deemed ineffective.

An alternative approach is to have policy makers, clinicians and investigators work closely together to synthesize information on the risks that can be disseminated to prospective parents to allow them to engage in a shared decision-making model with their healthcare providers. Risks on adverse reproductive outcomes and offspring health that are gamete mediated should be comprehensively assessed and defined, using established diagnostic tools at the molecular levels. It is important to emphasize that, in addition to aging, gamete mediated risks may well be attributed to other health conditions such as intrinsic genetic disorders, gonadotoxin exposure, history of cytotoxic therapies, metabolic derangements, obesity, smoking, and varicoceles. Thus, communication of gamete mediated reproductive risks should be conducted across the board as a standard of practice to all male partners seeking fertility care and not just to those at an advanced age. Shifting the focus of counselling from chronological age to gamete mediated risks allows clinicians to formulate a treatment plan or decline treatment without being accused of age discrimination. Finally, additional psychosocial concerns beyond gamete quality in the context of advanced paternal age such as life-expectancy of parents, should also be an important consideration in this shared decision-making model.

To minimize or mitigate the negative impact of advanced paternal age, comprehension of the collective body of scientific evidence is only the first step. Continued dialogues must be maintained among stakeholders at all levels, including investigators, healthcare providers, health policy makers and patients, on emerging data and their implications at the personal as well as societal levels. Most importantly, it is imperative for all parties to collaborate rigorously, with the goal of catalyzing a new agenda to reconceptualize the management strategy of advanced paternal age in the context of reproductive care of prospective parents.

PC and BR contributed to the writing and the editing of this manuscript. All authors contributed to the article and approved the submitted version.

This research has been funded by the CIHR Institute for Gender and Health Team Grant TE1-138298. BR is a James McGill Professor.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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