Abstract: The idea that there is an impenetrable barrier that separates the germline and soma has shaped much thinking in evolutionary biology and in many other disciplines. However, recent research has revealed that the so-called ‘Weismann Barrier’ is leaky, and that information is transferred from soma to germline. Moreover, the germline itself is now known to age, and to be influenced by an age-related deterioration of the soma that houses and protects it. This could reduce the likelihood of successful reproduction by old individuals, but also lead to long-term deleterious consequences for any offspring that they do produce (including a shortened lifespan). Here, we review the evidence from a diverse and multidisciplinary literature for senescence in the germline and its consequences; we also examine the underlying mechanisms responsible, emphasizing changes in mutation rate, telomere loss, and impaired mitochondrial function in gametes. We consider the effect on life-history evolution, particularly reproductive scheduling and mate choice. Throughout, we draw attention to unresolved issues, new questions to consider, and areas where more research is needed. We also highlight the need for a more comparative approach that would reveal the diversity of processes that organisms have evolved to slow or halt age-related germline deterioration.
1. Introduction
While a mechanism whereby offspring inherit beneficial traits from their parents is central to the theory of evolution by natural selection, robust scientific information on the processes of heredity was lacking when Darwin put forward his theory in 1859 [1]. Being apparently unaware of the pioneering work of Mendel on inheritance, Darwin later suggested that inheritance might occur via ‘gemmules’, tiny particles that circulate around the body and accumulate in the gonads, a developmental process he termed ‘Pangenesis’ [2]. Attempts to test this idea, notably by Galton, provided no support and it fell by the wayside [3]. Towards the end of the nineteenth century, August Weismann put forward his ‘germ plasm’ theory, based on the idea of continuity of the germline, its high level of protection, and its isolation from the somatic cells [4,5]. In contrast to Darwin, he proposed that there was no transfer of genetic information between the soma and the germline, a separation which came to be termed the Weismann Barrier. This distinction between germline and soma became central to the neo-Darwinian evolutionary theories developed in the early twentieth century. It has also been central to key theories of the evolution of ageing in animals, such as the disposable soma theory [6], with the soma being seen as the vehicle that prioritizes, protects, and preserves the integrity of the germline, passing it on to future generations. The central argument is that, while the soma is allowed to degenerate with age, the germline is protected and damage to it should not be allowed to accumulate, either within the individual or from generation to generation.
However, we now know that Darwin's gemmule idea may not be entirely fanciful [3,7], and that the Weismann Barrier is not so impenetrable as previously thought [8]: various potential carriers of epigenetic hereditary information from the soma to the germline have been identified, particularly those involving DNA methylation, chromatin modification, small RNAs and proteins that can influence gene expression, and extracellular vesicles that potentially move from the soma to the germline [7–12]. Investigating the transfer of epigenetic information across the generations by both sexes is a fast-growing field of research. Moreover, while it appears that germline DNA is indeed afforded special protection [13], germline mutations do occur, since neither DNA replication nor repair are perfect processes and external insults can also inflict significant damage.
So to what extent is the germline imperfectly isolated from the age-related deterioration generally evident in the soma? Does the germline itself also age, and if so in what way? Is this different in male and female germ cells? How does this affect the germline DNA and other hereditary processes? Is it also the case that the material passed via the cytoplasm of the oocyte is adversely influenced by the passage of time, both by deterioration in the oocyte itself and in the somatic tissue that exists to protect it? Does all of this have implications for the shaping of animal life histories?
These questions are the focus of this review. First, we consider briefly whether there is evidence of a negative effect of parental age on offspring health and longevity, and the routes whereby such an effect of paternal and maternal age could occur. We then focus on the germline itself, examine the evidence that it can deteriorate as the soma ages, and review the mechanisms by which this occurs. We then consider what this means for relevant aspects of life-history evolution, in particular, the scheduling of reproduction and mate choice. Throughout, we highlight and discuss the most critical gaps in our current understanding.
2. Negative effects of parental age on offspring longevity
One of the first studies to demonstrate parental age effects on offspring health and longevity was undertaken by Alexander Graham Bell, inventor of the telephone. Towards the end of his life, he developed an interest in heredity (unfortunately combined with one in eugenics). Using data from the family tree of William Hyde, one of the early English settlers in Connecticut, USA, Bell showed in 1918 that children born to older mothers and fathers had reduced lifespans [14]. Jennings & Lynch followed up this idea experimentally by using parthenogenically reproducing rotifers Proales sordida [15]; their results also suggested (while not being statistically significant) that the offspring of old females do not live as long as those of young females. This was taken further by Albert Lansing, using clones of the rotifer Philodina citrina. In 1947, he showed, through selecting old animals as breeders, that the offspring of old parents had a reduced lifespan [16], an effect that has become known as the Lansing effect. Furthermore, by creating parthenogenic selection lines in which he continually used the offspring of old or young individuals as parents for the next generation, his experiments appeared to show that this adverse parental age effect became magnified over generations, leading to the relatively rapid extinction of the old breeder line. By contrast, there was no change in lifespan or viability in lines based on selecting offspring produced only by young individuals [16].
It is important to note that almost all recent studies of the Lansing effect only consider two generations (i.e. they test whether offspring of old parents have a shortened lifespan), and so cannot test whether (or how) the effect is or is not cumulative over successive generations, as suggested in Lansing's original experiments. A partial exception is a study showing a cumulative negative effect of maternal age on offspring in Drosophila: the lowest proportion of eggs that reached adulthood came from old mothers that also had old grandmothers [17]. The extent to which a parental age effect on offspring fitness persists beyond the F1 generation, and whether it is truly cumulative, is little known in other taxa. However, a substantial body of evidence does exist to show that the age of the parents at reproduction can reduce offspring longevity in the F1 generation. Early investigations of effects of parental age on offspring in sexually reproducing species (mostly Drosophila spp.) gave inconsistent results (see [18] for a critical appraisal of these early studies), but more recent studies have frequently found a negative effect on offspring longevity in a wide range of species including humans [19–23], other mammals [24,25], birds [26–29], rotifers, crustaceans, numerous insects, yeast, and nematodes [30–32]. These include studies where animals were raised in consistent and benign laboratory conditions, such that the shorter lifespan of offspring appears to be due to faster ageing independent of environmental conditions (e.g. [24]). A reduced reproductive performance in offspring of older parents has also been reported in some cases [26,27]; while this is much less frequently reported than effects on lifespan (and may not always be apparent [25]), it should be noted that studies of lifetime reproductive effects of parental age under natural conditions are very limited ([25] and references therein).
Both establishing and teasing apart the causes of effects of parental age on offspring viability is not straightforward. In sexually reproducing animals, both maternal and paternal age can potentially adversely affect the offspring; in practice however, it can be difficult to tease apart the two since the age of the two parents is often correlated under natural conditions. There are many different pre- and post-natal routes for such effects. However, it is important to mention that there can be causes of a negative relationship between parental age and offspring viability that does not involve ageing of the germline—or indeed any ageing process at all. For instance, previous reproductive effort could have effects independent of parental age [33]. Many of the studies to date, particularly in long-lived species, are non-experimental and cross-sectional (i.e. comparing young versus old members of the population at a given time) rather than longitudinal (comparing the same parents when they are young versus when they are old), and thus differential survival of parental phenotypes into old age could mask or enhance effects, as could cohort effects since in many studies the capacity to compare aged individuals born in different years is limited [34].
Germline senescence is a wide-reaching, multidisciplinary topic. We restrict our review to mechanisms related to the ageing of the germline in animals where there is a separation of the germline and the soma. We also confine ourselves to sexually reproducing animals (noting the current bias in the literature towards vertebrates), and consider effects operating via both eggs and sperm. We now briefly describe relevant aspects of the production and storage of the gametes before discussing the evidence that they deteriorate with parental age, focusing in particular on age-related changes in levels of de novo DNA mutation and aneuploidy, telomere length, and mitochondrial function since these are key factors that could give rise to both transmissible and cumulative negative effects on offspring health and longevity.
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