Untangling Longevity, Dauer, and Healthspan in <b><i>Caenorhabditis elegans</i></b> 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.

The Matrisome during Aging and Longevity: A Systems-Level Approach toward Defining Matreotypes Promoting Healthy Aging

“…Comparing the gene expression or protein levels at a given chronological age between wild type and long-lived animals revealed several molecular mechanisms at work, which were then experimentally assessed for their functional importance for longevity. For instance, reduced insulin/IGF-1 signaling upregulates genes involved in antimicrobial, oxidative stress and xenobiotic responses, protein homeostasis, and metabolism, all of which are required to promote healthy aging [40]. Reanalyzing the expression profile of these long-lived mutants with reduced insulin/IGF-1 signaling [9] revealed that almost one-fifth, that is, 79 of the 426 upregulate genes are matrisome genes [31].…”

Saponin‐rich extracts fromHolothuria leucospilotamediate lifespan extension and stress resistance inCaenorhabditis elegansviadaf‐16

“…In C. elegans, events during larval development have also influence on lifespan. Overpopulation, starvation, high temperature, and other adverse conditions are capable to induce an alternative development pathway, called dauer, which is highly resistant (Ewald, Castillo‐Quan, & Blackwell, ). To determine whether H. leucospilota extracts increase lifespan through disruption of larval development, wild‐type N2 at L1 stage was treated with H. leucospilota extracts and their lifespans were determined.…”

Royalactin induces copious longevity via increased translation and proteasome activity in C. elegans

“…Due to the defensive mechanism, the proteome is stabilized and the generation of molecular damage minimized [8][9][10] . However, longevity attained as such is no clear guarantee for extended health [47][48][49][50] and may bring along certain physiological trade-offs such as a smaller body volume 51 . Looking for possible alternative mechanisms that may escape this defensive strategy and may be characterized by more appealing health parameters, we studied the mode of action of royalactin, driven by the interesting queen bee phenotype associated with it 4 .…”