Aging and Longevity: Short and sweet
A truncated version of the only insulin receptor in C. elegans has been discovered.
- Department of Molecular Biology, Princeton University, United States
- LSI Genomics, Princeton University, United States
It would be hard to overstate the importance of a receptor called DAF-2 to our understanding of aging and longevity. Almost 30 years ago it was discovered that loss of the daf-2 gene doubles lifespan in the worm C. elegans (Kenyon et al., 1993), and a few years later it was reported that DAF-2 is the only insulin/IGF-1-like receptor in C. elegans (Kimura et al., 1997). These findings led to an explosion of research into aging and longevity, revealing an intricate insulin signaling pathway that coordinates the sensing of nutrient levels with the regulation of age-related decline. In particular, it was found that reduced insulin signaling extends lifespan and increases stress resistance in flies and mice (Clancy et al., 2001; Holzenberger et al., 2003). Moreover, mutations in some of the genes associated with this pathway were found in centenarians (Suh et al., 2008). And in worms it became clear that, in addition to longevity and age-related declines, DAF-2 is involved in the regulation of a wide range of biological processes, including development, reproduction, memory, and stress responses.
DAF-2 was originally discovered for its role in controlling the dauer stage – an alternative stage of development in which a larva goes into a type of stasis to help it survive harsh conditions (Riddle et al., 1981). A lack of DAF-2 causes C. elegans to enter dauer, as does a lack of a number of other kinases (Paradis and Ruvkun, 1998). An ongoing mystery is why C. elegans has just a single gene for an insulin receptor despite having 40 different insulin-like peptides (Pierce et al., 2001). Some of these peptides are agonists (that is, they activate the receptor) and others are antagonists (they inhibit the receptor).
Given three decades of extensive research into the insulin signaling pathway in C. elegans, it would be shocking to find new functions for DAF-2 at this point. However, in a new paper in eLife, Matthew Gill of the Scripps Research Institute and colleagues – including Bryan Martinez and Pedro Reis Rodrigues as joint first authors – report evidence for such a shock: the gene for DAF-2 can also express another, truncated isoform of this protein as a result of alternative splicing (Martinez et al., 2020). The truncated version, which is called DAF-2B, can still form dimers but, unlike the full-length version, it is not expected to be able to span the membrane: this suggests that the truncated form could be secreted.
Truncated insulin receptors that have extracellular ligand-binding domains, but lack intracellular signaling domains, have been reported in both Drosophila and mammals, and are known to sequester insulin peptides. However, in these cases the full-length receptors and the truncated receptors are expressed from separate genes. Martinez et al. found that although DAF-2B was expressed in neuronal cells, it accumulated in cells called coelomocytes (macrophage-like cells that attack invading organisms such as bacteria and viruses). These results suggest that DAF-2B can indeed be secreted, rather than being retained in the neurons in which it is expressed and spliced.
But what does this shortened form of DAF-2 do? The best-characterized functions of the insulin signaling pathway are dauer formation and lifespan regulation, so Martinez et al. used these phenotypes to study DAF-2B. They found that overexpressing DAF-2B increased dauer formation, slowed dauer exit, and increased lifespan, whereas a lack of DAF-2B had the opposite effect. Basically, the data suggest that the function of DAF-2B is essentially the opposite of the function of DAF-2.
Martinez et al. also explored the interactions between DAF-2B and insulin-like peptides that were either agonists or antagonists. Overexpression of two peptides that are agonists (DAF-28 and INS-6) reduced the dauer-promoting effects of DAF-2B. Conversely, the overexpression of a peptide that is an antagonist (INS-18) would be expected to promote dauer, but this effect was blunted when DAF-2B was also overexpressed. Additionally, the researchers found that a point mutation in the proposed insulin-binding domain resulted in a form of DAF-2B that exhibited reduced dauer formation. Together, these results suggest that DAF-2B binds and may sequester insulin-like peptides, and/or form dimers with DAF-2.
Of course, mysteries remain. Given that worms have dozens of insulin-like peptides (Pierce et al., 2001), which of these bind to DAF-2B, and under what circumstances? And if DAF-2B is secreted, why does it matter where it is expressed, unless there are highly localized interactions? Finally, the mechanism by which DAF-2B acts and its dimerization state is not entirely understood.
The discovery of the truncated version of DAF-2, and the fact that it essentially works in opposition to the full-length version, raises new questions and will change how we think about DAF-2's role in insulin signaling regulation of aging and longevity.
References
Article and author information
Author details
Publication history
Copyright
© 2020, Murphy
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,194
- views
-
- 177
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Aging and Longevity: Short and sweet
eLife 9:e55220.
https://doi.org/10.7554/eLife.55220
Further reading
-
- Developmental Biology
Proteins that allow water to move in and out of cells help shape the development of new blood vessels.
-
- Developmental Biology
During the first lineage segregation, mammalian embryos generate the inner cell mass (ICM) and trophectoderm (TE). ICM gives rise to the epiblast (EPI) that forms all cell types of the body, an ability referred to as pluripotency. The molecular mechanisms that induce pluripotency in embryos remain incompletely elucidated. Using knockout (KO) mouse models in conjunction with low-input ATAC-seq and RNA-seq, we found that Oct4 and Sox2 gradually come into play in the early ICM, coinciding with the initiation of Sox2 expression. Oct4 and Sox2 activate the pluripotency-related genes through the putative OCT-SOX enhancers in the early ICM. Furthermore, we observed a substantial reorganization of chromatin landscape and transcriptome from the morula to the early ICM stages, which was partially driven by Oct4 and Sox2, highlighting their pivotal role in promoting the developmental trajectory toward the ICM. Our study provides new insights into the establishment of the pluripotency network in mouse preimplantation embryos.
