TGF-β and Insulin Signaling Regulate Reproductive Aging via Oocyte and Germline Quality Maintenance

Abstract

SUMMARY Reproductive cessation is perhaps the earliest aging phenotypes humans experience. Similarly, C. elegans’ reproduction ceases in mid-adulthood. Although somatic aging has been studied in both worms and humans, mechanisms regulating reproductive aging are not yet understood. Here we show that TGF-β Sma/Mab and Insulin/IGF-1 signaling regulate C. elegans reproductive aging by modulating multiple aspects of the reproductive process, including embryo integrity, oocyte fertilizability, chromosome segregation fidelity, DNA damage resistance, and oocyte and germline morphology. TGF-β activity regulates reproductive span and germline/oocyte quality non-cell-autonomously, and is temporally and transcriptionally separable from its regulation of growth. Chromosome segregation, cell cycle, and DNA damage response genes are upregulated in TGF-β mutant oocytes, decline in aged mammalian oocytes, and are critical for oocyte quality maintenance. Our data suggest that C. elegans and humans share many aspects of reproductive aging, including the correlation between reproductive aging and declining oocyte quality, and mechanisms determining oocyte quality.

Identification of Mutations that Delay Somatic or Reproductive Aging ofCaenorhabditis elegans

“…By day 8, some hermaphrodites began displaying detectable and even extreme degenerative changes in the gonad, as noted in previous studies (Garigan et al 2002;Herndon et al 2002;Luo et al 2010). The distal gonad displayed a decreased diameter and contained fewer germ cell nuclei ( Figure 5D).…”

“…Garigan et al (2002) showed that the distal gonad displays age-related increases in cavities and grainy material and decreases in the number of nuclei, and these changes were analyzed by assigning scores from 1 to 5 on the basis of the degree of deterioration. Luo et al (2010) reported a similar analysis of the distal gonad and an analysis of the proximal gonad that showed age-related decreases in oocyte size and increases in cavities and cluster formation. These changes were analyzed by assigning scores of normal, mild, or severe.…”

“…Similarly, body movement can be easily visualized and displays age-related degeneration (Bolanowski et al 1981;Johnson 1987;Herndon et al 2002;Huang et al 2004). To characterize aging in the reproductive system, we have focused on changes in the hermaphrodite gonad, which produces fertilized eggs (Garigan et al 2002;Hughes et al 2007;Luo et al 2009Luo et al , 2010. Reproductive aging has special significance for evolutionary biology, since reproduction is the purpose of animal life and a critical aspect of fitness.…”

DBL-1, a TGF-β, is essential for Caenorhabditis elegans aversive olfactory learning

“…Two C. elegans TGF-β ligands have been well characterized: DAF-7 and DBL-1. Whereas DAF-7 regulates multiple physiological traits, including diapause stage (dauer) entry, metabolism (8)(9)(10)(11), DBL-1 controls body morphology, innate immunity, and reproductive aging (9,12,13). Here we report that the activity of DBL-1 is critical for adult animals to learn to avoid the smell of pathogenic bacteria.…”

Identification of some unknown transcripts from SSH cDNA library of buffalo follicular oocytes

“…Continued identification of new oocyte-specific genes and their functional annotation is providing additional insight into the molecular mechanism involved in folliculogenesis, oogenesis, fertilization and early embryogenesis (Bettegowda et al, 2007;Wells et al, 2008;Luo et al, 2010). Several techniques such as differentialdisplay reverse transcription-PCR, microarray hybridization, serial analysis of gene expression and cDNA library construction have been used to reinforce the inventory of oocyte-expressed genes.…”