Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling

Abstract

The groundbreaking discovery that lower levels of insulin/IGF-1 signaling (IIS) can induce lifespan extension was reported 24 years ago in the nematode Caenorhabditis elegans. In this organism, mutations in the insulin/IGF-1 receptor gene daf-2 or other genes in this pathway can double lifespan. Subsequent work has revealed that reduced IIS (rIIS) extends lifespan across diverse species, possibly including humans. In C. elegans, IIS also regulates development into the diapause state known as dauer, a quiescent larval form that enables C. elegans to endure harsh environments through morphological adaptation, improved cellular repair, and slowed metabolism. Considerable progress has been made uncovering mechanisms that are affected by C. elegans rIIS. However, from the beginning it has remained unclear to what extent rIIS extends C. elegans lifespan by mobilizing dauer-associated mechanisms in adults. As we discuss, recent work has shed light on this question by determining that rIIS can extend C. elegans lifespan comparably through downstream processes that are either dauer-related or -independent. Importantly, these two lifespan extension programs can be distinguished genetically. It will now be critical to tease apart these programs, because each may involve different longevity-promoting mechanisms that may be relevant to higher organisms. A recent analysis of organismal "healthspan" has questioned the value of C. elegans rIIS as a paradigm for understanding healthy aging, as opposed to simply extending life. We discuss other work that argues strongly that C. elegans rIIS is indeed an invaluable model and consider the likely possibility that dauer-related processes affect parameters associated with health under rIIS conditions. Together, these studies indicate that C. elegans and analyses of rIIS in this organism will continue to provide unexpected and exciting results, and new paradigms that will be valuable for understanding healthy aging in humans.

Keywords: Aging; Caenorhabditis elegans; Dauer; Insulin/IGF-1 signaling; Longevity.

Figure 1. C. elegans hermaphrodite life cycle

The reproductive life cycle includes four larval stages, each separated by a molt. Unfavorable conditions (high temperature, crowding, low food availability) favor development into dauer, a diapause state that is characterized by relative immobility, decreased body and organ size, and a distinct cuticle [9,10]. Dauer represents an alternative L3 stage, but the decision to enter dauer is made late during L1. Dauer larvae survive without food for many weeks (2–3 months[10,12]), and are highly resistant to environmental stress. When conditions improve, dauers reenter the reproductive life cycle by developing into L4 larvae. Mutations that reduce IIS predispose to dauer entry even under favorable conditions [9,10].

Figure 2. Simplified model of the IIS pathway that indicates some processes regulated by rIIS in C. elegans

Under well-fed conditions, Insulin/IGF-1 like peptides bind to the Insulin/IGF-1 receptor (DAF-2), initiating a downstream kinase cascade via AGE-1 (phosphoinositide 3-kinase) in which Phosphatidylinositol 2-phosphate phosphorylation (PIP2 to PIP3) activates PDK-1 (3-phosphoinositide-dependent kinase 1). This in turn activates AKT-1/2, which phosphorylates DAF-16 (FOXO transcription factor) and SKN-1 (Nrf1,2,3 transcription factor), thereby inhibiting their nuclear translocation and target gene transcription initiation. DAF-18 is the ortholog of the human PTEN phosphatase. SKN-1 is discussed later in this manuscript. Processes that are regulated by both DAF-16 and SKN-1 are shown in purple. For details, see references [1,7,8,12].

Figure 3. Phenotypes resulting from by daf-2 mutation and RNAi

Knockdown of daf-2 by RNAi results in stress-resistant and long-lived animals over a wide range of temperatures (15°C–25°C), but does not induce dauer development. The daf-2 class 1 mutants will additionally form dauers when placed as larvae at higher temperatures (>20°C), but do not show dauer-associated phenotypes during adulthood. Only daf-2 class 2 mutants will display adulthood dauer-associated phenotypes at higher temperatures (>20°C), in addition to being stress-resistant and long-lived at high or low temperatures.