Abstract
Lifespan in Caenorhabditis elegans, Drosophila, and mice is regulated by conserved signaling networks, including the insulin/insulinlike growth factor 1 (IGF-1) signaling cascade and pathways depending on sirtuins, a family of NAD+-dependent deacetylases. Small molecules such as resveratrol are of great interest because they increase lifespan in many species in a sirtuin-dependent manner. However, no endogenous small molecules that regulate lifespan via sirtuins have been identified, and the mechanisms underlying sirtuin-dependent longevity are not well understood. Here, we show that in C. elegans, two endogenously produced small molecules, the dauer-inducing ascarosides ascr#2 and ascr#3, regulate lifespan and stress resistance through chemosensory pathways and the sirtuin SIR-2.1. Ascarosides extend adult lifespan and stress resistance without reducing fecundity or feeding rate, and these effects are reduced or abolished when nutrients are restricted. We found that ascaroside-mediated longevity is fully abolished by loss of SIR-2.1 and that the effect of ascr#2 requires expression of the G protein-coupled receptor DAF-37 in specific chemosensory neurons. In contrast to many other lifespan-modulating factors, ascarosidemediated lifespan increases do not require insulin signaling via the FOXOhomologDAF-16 or the insulin/IGF-1-receptor homologDAF-2. Our study demonstrates that C. elegans produces specific small molecules to control adult lifespan in a sirtuin-dependent manner, supporting the hypothesis that endogenous regulation ofmetazoan lifespan functions, in part, via sirtuins. These findings strengthen the link between chemosensory inputs and conserved mechanisms of lifespan regulation in metazoans and suggest a model for communal lifespan regulation in C. elegans.
| Original language | English |
|---|---|
| Pages (from-to) | 5522-5527 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 110 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - 2013 Apr 2 |
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Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1. / Ludewig, Andreas H.; Izrayelit, Yevgeniy; Park, Donha; Malik, Rabia U.; Zimmermann, Anna; Mahanti, Parag; Fox, Bennett W.; Bethke, Axel; Doering, Frank; Riddle, Donald L.; Schroeder, Frank C.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 14, 02.04.2013, p. 5522-5527.Research output: Contribution to journal › Article
TY - JOUR
T1 - Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1
AU - Ludewig, Andreas H.
AU - Izrayelit, Yevgeniy
AU - Park, Donha
AU - Malik, Rabia U.
AU - Zimmermann, Anna
AU - Mahanti, Parag
AU - Fox, Bennett W.
AU - Bethke, Axel
AU - Doering, Frank
AU - Riddle, Donald L.
AU - Schroeder, Frank C.
PY - 2013/4/2
Y1 - 2013/4/2
N2 - Lifespan in Caenorhabditis elegans, Drosophila, and mice is regulated by conserved signaling networks, including the insulin/insulinlike growth factor 1 (IGF-1) signaling cascade and pathways depending on sirtuins, a family of NAD+-dependent deacetylases. Small molecules such as resveratrol are of great interest because they increase lifespan in many species in a sirtuin-dependent manner. However, no endogenous small molecules that regulate lifespan via sirtuins have been identified, and the mechanisms underlying sirtuin-dependent longevity are not well understood. Here, we show that in C. elegans, two endogenously produced small molecules, the dauer-inducing ascarosides ascr#2 and ascr#3, regulate lifespan and stress resistance through chemosensory pathways and the sirtuin SIR-2.1. Ascarosides extend adult lifespan and stress resistance without reducing fecundity or feeding rate, and these effects are reduced or abolished when nutrients are restricted. We found that ascaroside-mediated longevity is fully abolished by loss of SIR-2.1 and that the effect of ascr#2 requires expression of the G protein-coupled receptor DAF-37 in specific chemosensory neurons. In contrast to many other lifespan-modulating factors, ascarosidemediated lifespan increases do not require insulin signaling via the FOXOhomologDAF-16 or the insulin/IGF-1-receptor homologDAF-2. Our study demonstrates that C. elegans produces specific small molecules to control adult lifespan in a sirtuin-dependent manner, supporting the hypothesis that endogenous regulation ofmetazoan lifespan functions, in part, via sirtuins. These findings strengthen the link between chemosensory inputs and conserved mechanisms of lifespan regulation in metazoans and suggest a model for communal lifespan regulation in C. elegans.
AB - Lifespan in Caenorhabditis elegans, Drosophila, and mice is regulated by conserved signaling networks, including the insulin/insulinlike growth factor 1 (IGF-1) signaling cascade and pathways depending on sirtuins, a family of NAD+-dependent deacetylases. Small molecules such as resveratrol are of great interest because they increase lifespan in many species in a sirtuin-dependent manner. However, no endogenous small molecules that regulate lifespan via sirtuins have been identified, and the mechanisms underlying sirtuin-dependent longevity are not well understood. Here, we show that in C. elegans, two endogenously produced small molecules, the dauer-inducing ascarosides ascr#2 and ascr#3, regulate lifespan and stress resistance through chemosensory pathways and the sirtuin SIR-2.1. Ascarosides extend adult lifespan and stress resistance without reducing fecundity or feeding rate, and these effects are reduced or abolished when nutrients are restricted. We found that ascaroside-mediated longevity is fully abolished by loss of SIR-2.1 and that the effect of ascr#2 requires expression of the G protein-coupled receptor DAF-37 in specific chemosensory neurons. In contrast to many other lifespan-modulating factors, ascarosidemediated lifespan increases do not require insulin signaling via the FOXOhomologDAF-16 or the insulin/IGF-1-receptor homologDAF-2. Our study demonstrates that C. elegans produces specific small molecules to control adult lifespan in a sirtuin-dependent manner, supporting the hypothesis that endogenous regulation ofmetazoan lifespan functions, in part, via sirtuins. These findings strengthen the link between chemosensory inputs and conserved mechanisms of lifespan regulation in metazoans and suggest a model for communal lifespan regulation in C. elegans.
UR - http://www.scopus.com/inward/record.url?scp=84875874024&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875874024&partnerID=8YFLogxK
U2 - 10.1073/pnas.1214467110
DO - 10.1073/pnas.1214467110
M3 - Article
C2 - 23509272
AN - SCOPUS:84875874024
VL - 110
SP - 5522
EP - 5527
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 14
ER -