The evolutionary biology of telomeres

在美国和其他许多国家，人们越来越多地将生儿育女的时间推迟到晚年。相应地，人们越来越担心母亲和父亲的年龄对其后代生物学的影响。这项研究考察了一种重要的衰老遗传标记--端粒长度，人们认为端粒长度受父亲年龄的影响。端粒是覆盖在染色体末端的DNA，随着细胞复制、氧化应激和年龄的增长而缩短。与其他发现相反，父亲年龄较大可能会对端粒长度产生积极影响，从而促进后代寿命。这项建议将收集家族史并测量端粒长度，以便更好地辨别父亲的年龄是否确实影响端粒长度，以及这种影响是否会在几代人之间持续(例如，祖父的年龄或曾祖父的生殖年龄是否影响后代的端粒长度)。此外，这项建议还将研究端粒长度除了影响衰老之外，是否还会影响早期的免疫功能。因此，这些研究将有助于更广泛地了解人类生命历史的演变。更广泛的影响包括产生与人类生物学家和公共卫生研究人员相关的有价值的共享数据集，以及将项目分析和数据纳入学生培训、指导和课程。衰老进化的模型假设，当个体在高龄繁殖时，选择将有利于增加维持努力和相应的延缓衰老。模式生物的种间比较和选择实验表明，较低的死亡率/较晚的生殖年龄与寿命延长有关，这广泛支持了这些理论预期。虽然基因频率上的自然选择被认为是这种变异的大部分基础，但最近在端粒生物学方面的研究为代际可塑性机制提供了证据，这种机制可能导致维持努力的快速变化，以响应生殖调度的变化。端粒缩短限制了细胞分裂，并被认为有助于损害细胞增殖依赖的特征，如免疫和组织修复，从而加速衰老。与大多数组织中端粒长度(TL)随年龄增长而发生的磨损不同，精子是唯一一种端粒长度随年龄增加的细胞类型。由于端粒是DNA，任何由于生殖延迟而导致的精子TL的延长都应该高保真地传递给后代，这导致了多代长期趋势向受孕时父亲年龄的高龄(PAC)将导致遗传TL的累积和快速延长。尽管任何一代的PAC会因出生顺序和其他因素而有所不同，但PAC效应的累积多代特征可能会导致更稳定、因此更可靠的近代人生殖年龄指标--从而提供一个有用的信号，用于校准影响老龄化速度的资源分配模式。最近的试点数据显示，在菲律宾宿务生活的两代人中，这种累积的政治行动委员会效应。然而，尚不清楚PAC对目标语的影响持续了多少代，从而也不清楚通过目标语传达的历史人口信号有多深和多完整。因此，该项目将1)检查PAC对后代TL的影响在四代之间的代际稳定性；2)表征TL的特定性别遗传力模式；以及3)评估遗传TL可能对健康的影响，反映在早期生命、传染病相关的发病率和死亡率上。

In the U.S. and many other countries people are increasingly putting off starting families until later in life. Correspondingly there is growing concern about the effects of mothers' and fathers' ages on the biology of their offspring. This research examines an important genetic marker of aging, telomere length, that is thought to be influenced by paternal age. Telomeres are DNA that cap the ends of chromosomes, and that shorten with cell replication, oxidative stress, and age. Contrary to other findings, older paternal age might have positive influences on telomere length that promote offspring longevity. This proposal will collect family tree histories and measure telomere lengths in order to better discern whether paternal age actually influences telomere length, and whether this effect persists across generations (e.g. whether grandfather's age or great-grandfather's age at reproduction influences descendants' telomere lengths). Additionally this proposal will examine whether telomere length influences early life immune function in addition to aging. These investigations will therefore contribute to the larger understanding of the evolution of human life history. Broader impacts include the production of a valuable shared dataset that will be relevant to human biologists and public health researchers, and integration of the project analysis and data into student training, mentoring and curricula. Models for the evolution of senescence assume that when individuals reproduce at advanced ages, selection will favor increased maintenance effort and a corresponding slowing of senescence. Inter-specific comparisons and selection experiments in model organisms have demonstrated that lower mortality/later ages of reproduction are associated with lifespan extension, broadly supporting these theoretical expectations. While natural selection operating on gene frequencies is assumed to form the basis of much of this variation, recent work in telomere biology provides evidence for a mechanism of intergenerational plasticity that could lead to rapid changes in maintenance effort in response to shifts in reproductive scheduling. Telomere shortening places limits on cell division, and is thought to contribute to impairment of cell proliferation-dependent traits such as immunity and tissue repair, and thereby to accelerate senescence. Unlike the telomere length (TL) attrition that occurs with age in most tissues, sperm are the only cell type in which TL increases with age. Because telomeres are DNA, any lengthening of sperm TL due to delayed reproduction should be passed on to offspring with high fidelity, leading to the hypothesis that multi-generational secular trends towards older paternal age at conception (PAC) will result in cumulative and rapid lengthening of inherited TL. Although PAC in any one generation will vary due to birth order and other factors, the cumulative multi-generational character of the PAC effect could lead to a more stable, and thus reliable, indicator of age at reproduction in recent ancestors--thus providing a useful signal from which to calibrate patterns of resource allocation that influence the pace of aging. Recent pilot data demonstrated this cumulative PAC effect across two generations living in Cebu, the Philippines. However, it remains unclear how many generations the PAC effect on TL persists, and thus, how deep and integrative the historical demographic signal conveyed via TL is. This project will therefore 1) examine the intergenerational stability of the PAC effect on descendants' TL across four generations; 2) characterize the sex-specific heritability patterns of TL; and 3) assess possible fitness impacts of inherited TL as reflected in early life infectious disease related morbidity and mortality.