Leukocyte Telomere Length and the Father's Age Enigma
Leukocyte Telomere Length and the Father's Age Enigma
What are the implications for population health of the demographic trend toward increasing paternal age at conception (PAC) in modern societies? We propose that the effects of older PAC are likely to be broad and harmful in some domains of health but beneficial in others. Harmful effects of older PAC have received the most attention. Thus, for example, older PAC is associated with an increased risk of offspring having rare conditions such as achondroplasia and Marfan syndrome, as well as with neurodevelopmental disorders such as autism. However, newly emerging evidence in the telomere field suggests potentially beneficial effects, since older PAC is associated with a longer leukocyte telomere length (LTL) in offspring, and a longer LTL is associated with a reduced risk of atherosclerosis and with increased survival in the elderly. Thus, older PAC may cumulatively increase resistance to atherosclerosis and lengthen lifespan in successive generations of modern humans. In this paper we: (i) introduce these novel findings; (ii) discuss potential explanations for the effect of older PAC on offspring LTL; (iii) draw implications for population health and for life course; (iv) put forth an evolutionary perspective as a context for the multigenerational effects of PAC; and (v) call for broad and intensive research to understand the mechanisms underlying the effects of PAC. We draw together work across a range of disciplines to offer an integrated perspective of this issue.
In high-income countries, growing numbers of men as well as women are choosing to postpone parenthood. On average, both parents conceive their first child at an older age. If sustained, this demographic shift may have manifold implications for the health of successive generations. We discuss here the evidence for a beneficial effect of increasing paternal age at conception (PAC) on the health of descendants.
Basic genetics offers a strong foundation for hypothesizing that increased PAC creates an increased risk for a host of disorders in offspring. In utero, the female germ cells undergo an estimated 22 cell divisions before meiosis and two divisions during meiosis. However, as only one chromosome replication takes place during meiosis, the female germ cells undergo a total of 23 chromosome replications. Postnatally, the meiotic process is arrested at the first meiosis and this persists until puberty. Thus, between the mother's birth and the conception of her offspring, her germ cells undergo no chromosome replication and only one cell division (regardless of her age at conception). In contrast, spermatogenesis goes on throughout most of the male's life course. For instance, the estimated cumulative numbers of germ-line stem cell (GSC) replications in men by the ages of 20 and 40 years are 150 and 610, respectively. This provides a greater chance for spontaneous, male-biased mutations.
It has long been recognised that rare conditions such as achondroplasia (the prevalence of which is ~ one per twenty thousand) and Marfan syndrome (which has a prevalence of ~ one per five thousand) may arise from mutations in the male GSCs. However, in the past decade, a large number of studies have linked increased PAC to severe conditions that are not so rare in offspring, including autism, schizophrenia, and other neurodevelopmental disorders. It is often assumed, but not proven, that this is also due to mutations in the male germ line. Perhaps because of the gravity of these diseases, their associations with PAC have generated substantial media attention and even entered public discourse.
Studies now suggest, however, that older PAC may also confer benefits on the health of offspring. This poses a dilemma for public health. If increased PAC may have both adverse and beneficial effects, understanding the balance of its risks and benefits will require the consideration of a broad scope of relationships between increased PAC and offspring health. Yet we have only just begun to explore the potential benefits of older PAC, and the evidence for them is still not widely understood.
We therefore integrated work done across disciplines to articulate the case for a potentially major benefit of older PAC on the basis of an intriguing finding in recent studies that leukocyte telomere length (LTL) is on average longer in the offspring of older fathers. This association of PAC with offspring LTL has no threshold, as it has been observed for increasing PAC from the age of ~20 up to 60 years. As a longer LTL predicts reduced atherosclerotic risk and longer survival in the elderly, it is possible that older fathers, by endowing their offspring with a longer LTL, may also confer on them resistance to atherosclerosis and an advantage for increased longevity.
That older PAC is related to longer offspring LTL is an enigma. To some, it might even seem counter-intuitive, given the widespread awareness of genetic abnormalities related to both increased maternal age at conception (e.g., chromosomal aneuploidy) and PAC (e.g., de novo mutations). The PAC effect on offspring LTL is also perplexing on a deeper level, however, because of what it implies about age-related changes in the male germ line and how they are transmitted to offspring. Yet the outcome of these age-related changes, namely, longer telomere length (TL), is probably transmitted in Mendelian fashion. We discuss below how this enigma could be resolved.
For understanding of the following discussion, it is important to recognize four major aspects of TL in general and LTL in particular. First, telomeres are the TTAGGG tandem repeats at both ends of each of the mammalian chromosomes, and together with telomere-binding proteins they cap the chromosomes. This capping stabilizes the telomere and prevents the chromosomal ends from being recognized by the DNA repair processes in cells as DNA break points and potential sites of chromosomal fusions. Second, as somatic cells replicate, their telomeres undergo progressive attrition because DNA polymerase cannot completely replicate the 3' end of linear duplex DNA. This is referred to as the end-replication problem. Once telomeres become very short, they often cause cells to exit from the replicative cycle and become senescent. Third, LTL is a complex human genetic trait in that it is determined by many genes, and its dynamics (birth LTL and age-dependent telomere attrition thereafter) reflect telomere dynamics in hematopoietic stem cells. Fourth, because the hematopoietic system is probably the most proliferative system among somatic tissues, LTL, and by inference TL in hematopoietic stem cells, can become critically short during the long human life course, thereby imposing a limit on the longevity of some individuals.
Abstract and Introduction
Abstract
What are the implications for population health of the demographic trend toward increasing paternal age at conception (PAC) in modern societies? We propose that the effects of older PAC are likely to be broad and harmful in some domains of health but beneficial in others. Harmful effects of older PAC have received the most attention. Thus, for example, older PAC is associated with an increased risk of offspring having rare conditions such as achondroplasia and Marfan syndrome, as well as with neurodevelopmental disorders such as autism. However, newly emerging evidence in the telomere field suggests potentially beneficial effects, since older PAC is associated with a longer leukocyte telomere length (LTL) in offspring, and a longer LTL is associated with a reduced risk of atherosclerosis and with increased survival in the elderly. Thus, older PAC may cumulatively increase resistance to atherosclerosis and lengthen lifespan in successive generations of modern humans. In this paper we: (i) introduce these novel findings; (ii) discuss potential explanations for the effect of older PAC on offspring LTL; (iii) draw implications for population health and for life course; (iv) put forth an evolutionary perspective as a context for the multigenerational effects of PAC; and (v) call for broad and intensive research to understand the mechanisms underlying the effects of PAC. We draw together work across a range of disciplines to offer an integrated perspective of this issue.
Introduction
In high-income countries, growing numbers of men as well as women are choosing to postpone parenthood. On average, both parents conceive their first child at an older age. If sustained, this demographic shift may have manifold implications for the health of successive generations. We discuss here the evidence for a beneficial effect of increasing paternal age at conception (PAC) on the health of descendants.
Basic genetics offers a strong foundation for hypothesizing that increased PAC creates an increased risk for a host of disorders in offspring. In utero, the female germ cells undergo an estimated 22 cell divisions before meiosis and two divisions during meiosis. However, as only one chromosome replication takes place during meiosis, the female germ cells undergo a total of 23 chromosome replications. Postnatally, the meiotic process is arrested at the first meiosis and this persists until puberty. Thus, between the mother's birth and the conception of her offspring, her germ cells undergo no chromosome replication and only one cell division (regardless of her age at conception). In contrast, spermatogenesis goes on throughout most of the male's life course. For instance, the estimated cumulative numbers of germ-line stem cell (GSC) replications in men by the ages of 20 and 40 years are 150 and 610, respectively. This provides a greater chance for spontaneous, male-biased mutations.
It has long been recognised that rare conditions such as achondroplasia (the prevalence of which is ~ one per twenty thousand) and Marfan syndrome (which has a prevalence of ~ one per five thousand) may arise from mutations in the male GSCs. However, in the past decade, a large number of studies have linked increased PAC to severe conditions that are not so rare in offspring, including autism, schizophrenia, and other neurodevelopmental disorders. It is often assumed, but not proven, that this is also due to mutations in the male germ line. Perhaps because of the gravity of these diseases, their associations with PAC have generated substantial media attention and even entered public discourse.
Studies now suggest, however, that older PAC may also confer benefits on the health of offspring. This poses a dilemma for public health. If increased PAC may have both adverse and beneficial effects, understanding the balance of its risks and benefits will require the consideration of a broad scope of relationships between increased PAC and offspring health. Yet we have only just begun to explore the potential benefits of older PAC, and the evidence for them is still not widely understood.
We therefore integrated work done across disciplines to articulate the case for a potentially major benefit of older PAC on the basis of an intriguing finding in recent studies that leukocyte telomere length (LTL) is on average longer in the offspring of older fathers. This association of PAC with offspring LTL has no threshold, as it has been observed for increasing PAC from the age of ~20 up to 60 years. As a longer LTL predicts reduced atherosclerotic risk and longer survival in the elderly, it is possible that older fathers, by endowing their offspring with a longer LTL, may also confer on them resistance to atherosclerosis and an advantage for increased longevity.
That older PAC is related to longer offspring LTL is an enigma. To some, it might even seem counter-intuitive, given the widespread awareness of genetic abnormalities related to both increased maternal age at conception (e.g., chromosomal aneuploidy) and PAC (e.g., de novo mutations). The PAC effect on offspring LTL is also perplexing on a deeper level, however, because of what it implies about age-related changes in the male germ line and how they are transmitted to offspring. Yet the outcome of these age-related changes, namely, longer telomere length (TL), is probably transmitted in Mendelian fashion. We discuss below how this enigma could be resolved.
For understanding of the following discussion, it is important to recognize four major aspects of TL in general and LTL in particular. First, telomeres are the TTAGGG tandem repeats at both ends of each of the mammalian chromosomes, and together with telomere-binding proteins they cap the chromosomes. This capping stabilizes the telomere and prevents the chromosomal ends from being recognized by the DNA repair processes in cells as DNA break points and potential sites of chromosomal fusions. Second, as somatic cells replicate, their telomeres undergo progressive attrition because DNA polymerase cannot completely replicate the 3' end of linear duplex DNA. This is referred to as the end-replication problem. Once telomeres become very short, they often cause cells to exit from the replicative cycle and become senescent. Third, LTL is a complex human genetic trait in that it is determined by many genes, and its dynamics (birth LTL and age-dependent telomere attrition thereafter) reflect telomere dynamics in hematopoietic stem cells. Fourth, because the hematopoietic system is probably the most proliferative system among somatic tissues, LTL, and by inference TL in hematopoietic stem cells, can become critically short during the long human life course, thereby imposing a limit on the longevity of some individuals.