The evolutionary biology of telomeres

University Of Washington, Seattle WA

Investigators

Abstract

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.