In roundworms, age-related decline in egg quality is regulated by specific humoral signalling pathways. If similar mechanisms operate in mammals, these findings may suggest ways to delay reproductive ageing in women.
Female mammals are not alone in experiencing an age-related increase in birth defects and decline in fertility; the roundworm Caenorhabditis elegans faces similar reproductive challenges in mid-adulthood. Writing in Cell, Luo et al.1 report that, in C. elegans, the age-related decline in oocyte (egg) quality and increase in chromosomal abnormalities are regulated by evolutionarily conserved signal-transduction pathways. If this senescence mechanism is also conserved, age-related decline in the quality of mammalian oocytes may not be, as is commonly thought, simply due to the old age of these cells or the diminishing size of the ovarian follicle pool; it may also be influenced by molecular signalling cascades.
Previous work in C. elegans showed2 that a mutation that reduces the function of daf-2 — a gene involved in an insulin/IGF-I-like signalling pathway — delays reproductive senescence. Moreover, in an earlier study3, Luo and colleagues showed that reproductive lifespan is extended by mutations that decrease the activity of the TGF-β Sma/Mab signalling pathway, which regulates cell growth, body size and the development of male traits.
Confirming and extending these findings, Luo et al.1 now show that decreasing activity in both of these pathways increases reproductive lifespan by delaying age-specific reductions in germline cell numbers, oocyte fertilizability and embryo hatching, as well as by diminishing the age-related increase in chromosomal abnormalities. Using C. elegans stocks with pathway-specific and tissue-specific mutations in components of the insulin/IGF-I or TGF-β Sma/Mab pathways, the authors show that these signalling cascades act at distal sites to affect germline function. In fact, they propose a model to describe such neuroendocrine regulation of reproductive senescence (Fig. 1).
These ideas could be of clinical relevance owing to similarities in oocyte development between C. elegans and humans. In both species, oocyte development is temporarily halted at the prophase I stage of meiotic cell division, when chromosomal abnormalities most frequently occur. What's more, chromosomal abnormalities — including aneuploidies that result from chromosome non-disjunction — are the main defect in human embryos from ageing mothers4, and rates of chromosome non-disjunction also increase with age in C. elegans.
Luo et al.1 observe other aspects of diminished oocyte quality with reproductive ageing in C. elegans that are similar to those previously reported in older women. For instance, the authors' transcriptional analyses of worms with mutations in TGF-β signalling indicate that numerous molecular mechanisms that have a bearing on age-related diminished oocyte quality are influenced by this pathway, and that many of these mechanisms are shared between C. elegans and humans.
Two main species differences, however, temper the understandable enthusiasm that Luo and colleagues express for the possibility of translational application of their work to humans. First, the reproductive system of female mammals is more complex than that of the roundworm, with ageing involving both neuroendocrine and oocyte defects5. Second, the progressive shrinkage that occurs in the pool of ovarian follicles during mammalian ageing has no parallel in roundworms.
Indeed, mammals stop producing oocytes even before birth, whereas roundworms continue to produce them throughout their reproductive lives. Theories of mammalian reproductive ageing posit that the age-related decline in oocyte number is the primary factor driving decline in fertility, with the associated deterioration in oocyte quality and increased risk of birth defects being consequences of a suboptimal size of the oocyte pool. These theories are largely supported by studies in rats6 showing that reproductive ageing is more closely related to the size of the oocyte pool than to oocyte age.
Nevertheless, Luo and colleagues' work1 clearly illustrates that neuroendocrine cascades mediate oocyte ageing and embryo survival in C. elegans. Because such signalling has clear parallels in humans, straightforward clinical interventions that diminish the effects of insulin/IGF-I or TGF-β signalling, or both, may be feasible. However, this depends on how closely neuroendocrine-directed reproductive ageing in C. elegans models mammalian reproductive ageing.
So far, the results are inconclusive. The diminished fecundity seen in young adult C. elegans as a result of a reduction in insulin/IGF-I signalling2 may be comparable to the modest reproductive impairments of mouse models with diminished circulating levels of IGF-I7. Compared with age-matched controls, the pool of primordial oocytes in these mice is larger7, but no associated increase in reproductive lifespan has been reported. Moreover, our unpublished data indicate that, in 'little' mice (C57BL/6J-Ghrhrlit), a 90% reduction in circulating IGF-I levels has no effect on litter size or females' reproductive lifespans. In C. elegans, only one of the numerous reduction-of-function mutations in the insulin/IGF-I signalling pathway increases reproductive lifespan8.
The contrasting effects of various insulin/IGF-I signalling mutants show that subtle differences in perturbations of insulin/IGF-I signalling greatly affect reproductive outcomes in both species. The effects of diminished TGF-β signalling on reproductive lifespan in mammals has not been evaluated, and should be. In addition, it is essential to identify the secondary signals that act directly on the C. elegans germ line and oocytes to diminish their quality (Fig. 1).
Does Luo and co-workers' paper1 have a take-home message for women concerned about getting pregnant later in life and giving birth to healthy babies? No. However, this study offers specific hypotheses that can be tested in mammalian systems. It thus opens the door to the possibility of improving oocyte quality during the period of reproductive decline by reducing the effects of insulin/IGF-I or TGF-β signalling pathways, or both.
Luo, S., Kleemann, G. A., Ashraf, J. M., Shaw, W. M. & Murphy, C. T. Cell 143, 299–312 (2010).
Hughes, S. E., Evason, K., Xiong, C. & Kornfeld, K. PLoS Genet. 3, e25 (2007).
Luo, S., Shaw, W. M., Ashraf, J. & Murphy C. T. PLoS Genet. 5, e1000789 (2009).
te Velde, E. R. & Pearson, P. L. Hum. Reprod. Update 8, 141–154 (2002).
Downs, J. L. & Wise, P. M. Mol. Cell. Endocrinol. 299, 32–38 (2009).
Meredith, S., Dudenhoeffer, G., Butcher, R. L., Lerner, S. P. & Walls, T. Biol. Reprod. 47, 162–168 (1992).
Slot, K. A. et al. Reproduction 131, 525–532 (2006).
Tatar, M. Ann. NY Acad. Sci. 1204, 149–155 (2010).
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