Various mechanisms that influence aging were first identified in C. elegans, in which it was discovered that lifespan is increased by reduced insulin/IGF-1 signaling (rIIS), and that this lifespan extension requires the transcription factor DAF-16/FoxO, which is inhibited by IIS. In C. elegans, DAF-16 directs development into a larval diapause (dauer) that withstands harsh conditions, and in many rIIS scenarios dauer-like traits appear in adults. Accordingly, a prominent model suggests that rIIS slows C. elegans aging by allowing DAF-16 to activate dauer-associated mechanisms during adulthood. However, rIIS can also extend C. elegans lifespan robustly without inducing dauer-like traits. Our new results explain the latter finding by suggesting that rIIS can extend lifespan not only by activating dauer associated processes, but also through an adulthood protective program that involves some different downstream mechanisms. According to this model, dauer-associated processes overcome an otherwise essential requirement for the transcription factor SKN-1/Nrf, which is also inhibited by IIS. By identifying an IIS-regulated longevity program that seems to be distinguishable from the dauer developmental pathway, this model opens up new avenues for understanding how IIS affects aging. Surprisingly, in response to rIIS SKN-1 most prominently upregulates extracellular matrix (ECM) genes, especially particular collagens. Aging leads to ECM deterioration in humans, with devastating consequences, and to a decline in adulthood collagen expression in C. elegans. We find that rIIS and various other interventions that prolong life boost collagen expression in C. elegans adults. This adulthood collagen/ECM gene expression is generally required for longevity from these interventions, except when rIIS induces dauer traits. The data suggest that ECM maintenance may be broadly important for longevity assurance, a novel model that has wide-ranging implications for the aging field, and suggests paradigms for ECM maintenance. This project will further test and develop each of these models, which were derived uniquely in our lab.
In Aim 1 it will test predictions of our hypothesis that dauer-related DAF-16 activities overcome the requirement for SKN-1 for rIIS longevity. This will involve genetic analyses, expression profiling of DAF-16 under rIIS conditions in which dauer-associated mechanisms are or are not active, and identification of downstream genes that may be important for one condition or the other (analogously to the collagens).
In Aim 2, it will investigate whether adulthood collagen expression is needed for long life because it enhances integrity of the cuticle or other structures, or affects aging more pleiotropically. It wil also employ the advantages of C. elegans for screening to identify mechanisms through which rIIS and other longevity pathways promote collagen maintenance, thereby identifying new processes that influence aging. This work is significant for human health because the effects of IIS on longevity seem to be conserved, and because it is unknown how longevity interventions might influence the ECM, deterioration of which is broadly important in aging.

Public Health Relevance

Genetics-based studies of the nematode C. elegans have identified mechanisms that profoundly influence aging, and in many cases are evolutionarily conserved. Based upon surprising recent results, we propose C. elegans experiments that will re-frame our understanding of how insulin/IGF-1 signaling (IIS) and the gene expression regulators DAF-16/FoxO and SKN-1/Nrf influence lifespan. We also will investigate for the first time in any organism how IIS and other pathways influence longevity by regulating the expression of collagens, which in humans deteriorate with age and have critical functions in many tissues.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Reddy, Michael K
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Joslin Diabetes Center
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Ewald, Collin Yvès; Castillo-Quan, Jorge Iván; Blackwell, T Keith (2018) Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling. Gerontology 64:96-104
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