TGF-ß Sma/Mab Signaling Mutations Uncouple Reproductive Aging from Somatic Aging

Abstract

Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15–20 day adulthood. All of the known mutations and treatments that extend C. elegans' reproductive period also regulate longevity, suggesting that reproductive span is normally linked to life span. C. elegans has two canonical TGF-ß signaling pathways. We recently found that the TGF-ß Dauer pathway regulates longevity through the Insulin/IGF-1 Signaling (IIS) pathway; here we show that this pathway has a moderate effect on reproductive span. By contrast, TGF-ß Sma/Mab signaling mutants exhibit a substantially extended reproductive period, more than doubling reproductive span in some cases. Sma/Mab mutations extend reproductive span disproportionately to life span and act independently of known regulators of somatic aging, such as Insulin/IGF-1 Signaling and Dietary Restriction. This is the first discovery of a pathway that regulates reproductive span independently of longevity and the first identification of the TGF-ß Sma/Mab pathway as a regulator of reproductive aging. Our results suggest that longevity and reproductive span regulation can be uncoupled, although they appear to normally be linked through regulatory pathways.

Author Summary

Female reproductive cessation is the earliest aging phenotype humans experience, and its importance as a clinical issue is growing as more women opt to have children later in life. While much work has been done to understand the general aging process, little is currently known about the regulation of reproductive aging. Like longevity, the ability to produce progeny with advanced age is likely to be genetically regulated. Thus, understanding the processes that regulate reproductive aging may allow us to address the problems of maternal age-related infertility and birth defects. C. elegans and humans both have long post-reproductive life spans, leaving open the possibility that their reproductive spans might be extendable. C. elegans has been used previously to discover conserved regulators of aging, and here we use worms to identify a new regulator of reproductive aging, a highly conserved TGF-ß signaling pathway. We find that TGF-ß signaling regulates reproductive aging independently of somatic aging. This is the first identification of a pathway that breaks the coupling that normally links the two processes. Our work will provide new insights into the improvement of human fertility and prevention of age-related birth defects, and it has implications for the evolutionary relationship between reproduction and longevity regulation.