Date Published: March 01, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Bernadette Hotzi, Mónika Kosztelnik, Balázs Hargitai, Krisztina Takács‐Vellai, János Barna, Kincső Bördén, András Málnási‐Csizmadia, Mónika Lippai, Csaba Ortutay, Caroline Bacquet, Angela Pasparaki, Tamás Arányi, Nektarios Tavernarakis, Tibor Vellai.
A fascinating aspect of sexual dimorphism in various animal species is that the two sexes differ substantially in lifespan. In humans, for example, women’s life expectancy exceeds that of men by 3–7 years. Whether this trait can be attributed to dissimilar lifestyles or genetic (regulatory) factors remains to be elucidated. Herein, we demonstrate that in the nematode Caenorhabditis elegans, the significantly longer lifespan of hermaphrodites—which are essentially females capable of sperm production—over males is established by TRA‐1, the terminal effector of the sex‐determination pathway. This transcription factor directly controls the expression of daf‐16/FOXO, which functions as a major target of insulin/IGF‐1 signaling (IIS) and key modulator of aging across diverse animal phyla. TRA‐1 extends hermaphrodite lifespan through promoting daf‐16 activity. Furthermore, TRA‐1 also influences reproductive growth in a DAF‐16‐dependent manner. Thus, the sex‐determination machinery is an important regulator of IIS in this organism. These findings provide a mechanistic insight into how longevity and development are specified unequally in the two genders. As TRA‐1 is orthologous to mammalian GLI (glioma‐associated) proteins, a similar sex‐specific mechanism may also operate in humans to determine lifespan.
A remarkable phenomenon in aging biology is that the two genders display significantly different lifespans in divergent, sexually dimorphic animal species. For example, in flies, mice, and humans, females have a tendency to live longer than males (in human populations, the lifespan advantage of women over men can achieve up to 7–8 years; Blagosklonny, 2010; Eskes & Haanen, 2007; Gems, 2014; La Croix et al., 1997; Lints, Bourgois, Delalieux, Stoll & Lints, 1983; Tower, 2006; Tower & Arbeitman, 2009; Vina, Borrás, Gambini, Sastre & Pallardó, 2005). In these species, the heterogametic sex (XY) is male. In contrast, in species where the heterogametic sex (ZW) is female (e.g., in most bird species), males tend to live longer than females. Moreover, genetic and environmental factors that influence lifespan often have a larger effect in one sex than the other (Partridge, Gems & Withers, 2005). The question whether sex‐specific differences in lifespan are determined by genetic regulatory mechanisms or are merely the by‐products of different lifestyles (e.g., males are generally more predisposed than females to engage in fights) remains a great challenge for science, one with significant medical and social implications (Blagosklonny, 2010).
Caenorhabditis elegans is a tractable model system to study the molecular mechanisms underlying sex‐specific differences in various biological processes and anatomical features. In this work, we explored a novel regulatory interaction that determines lifespan and reproductive growth unequally between hermaphrodite and male animals. First, we observed that both wild‐type and IIS‐deficient daf‐2(‐) mutant hermaphrodites live significantly longer than the corresponding males (Figure 1 and Figures S1–S3). Sex differences in longevity in daf‐2(‐) mutants disappeared in daf‐16(‐) mutant genetic backgrounds (Figure 1 and Figure S3). Thus, the sex‐specific regulation of nematode lifespan depends on DAF‐16 activity. Next, we showed that the master sex‐determining factor TRA‐1 promotes the transcriptional activity of certain daf‐16 isoforms, d/f and a. TRA‐1 and these daf‐16 isoforms hence act in the same genetic pathway to modulate lifespan or development. As DAF‐16 functions as the main target of IIS in the regulation of lifespan and development, TRA‐1, and thereby the sex‐determination machinery, is an important modulator of this signaling system (Figure 5). This implies that IIS is adjusted in a sex‐specific way, leading to significant sex differences in the activity of several biological processes. Indeed, the expression of daf‐16d/f playing an important role in longevity control (Kwon et al., 2010) is elevated by TRA‐1 in hermaphrodites but not in males (Figures 2, 3, 4). Depending on population density and the ambient temperature, daf‐16a controls the decision between reproductive growth and dauer larva development (Figures 2 and 4). TRA‐1 also increases the expression of this daf‐16 isoform in hermaphrodite animals. These regulatory interactions elucidate the hermaphrodite bias toward a longer lifespan (this study) and increased dauer larval formation (Vellai, McCulloch, Gems & Kovács, 2006). Similarly, a marked sex‐specific difference was previously observed in C. elegans learning capacity, a trait that also relies on IIS (Vellai et al., 2006). It would be relevant to examine whether the TRA‐1–daf‐16 regulatory axis is involved in the control of associative learning. In case of positive results, one could provide an explanation for the tendency of hermaphrodites to perform an associative learning paradigm more effectively. In nematodes, lipid metabolism and stress resistance are also influenced by DAF‐2 and DAF‐16 (Ashrafi et al., 2003; Scott, Avidan & Crowder, 2002). Through enhancing the activity of certain daf‐16 isoforms, TRA‐1 may also strengthen these biological processes in hermaphrodite animals.
The authors declare no competing financial interest.
B.Ha. and T.V. invented the project; B.Ho. designed and performed lifespan measurements, generated transgenic strains, monitored dauer development, performed quantitative real‐time PCR and Western blot analysis, and analyzed data; M.K. performed lifespan assays, monitored dauer development, analyzed ChIP data, did quantitative real‐time PCR, and generated transgenic strains; B.Ha. identified TRA‐1‐binding sites in the daf‐16 locus, generated a TRA‐1‐specific antibody and transgenic strains, performed lifespan measurements, analyzed data, and wrote the manuscript; M.L. generated the TRA‐1‐specific antibody; K.T‐V. designed experiments, analyzed data, and wrote the manuscript; J.B. identified conserved TRA‐1‐binding sites in closely related nematode taxa, performed lifespan measurements, and analyzed data; K.B. analyzed gfp expression and performed lifespan measurements; A.M‐C. designed experiments, analyzed data, and wrote the manuscript; C.O. performed in silico analyses to identify GLI binding sites in FOXO genomic regions; C.B. performed ChIP experiments and transcript quantification; A.P. performed fluorescent microscopy analyses; T.A. designed experiments, analyzed data, and wrote the manuscript; N.T. designed experiments, analyzed data, and wrote the manuscript; and T.V. designed experiments, analyzed data, and wrote the manuscript. All authors agree with the presented findings.