Abstract
Long-lived mutants provide unique insights into the genetic factors that limit lifespan in wild-type animals. Most mutants and RNA interference targets found to extend life, typically by 1.5- to 2.5-fold, were discovered in C. elegans. Several longevity-assurance pathways are conserved across widely divergent taxa, indicating that mechanisms of lifespan regulation evolved several hundred million years ago. Strong mutations to the C. elegans gene encoding AGE-1/PI3KCS achieve unprecedented longevity by orchestrating the modulation (predominantly silencing) of multiple signaling pathways. This is evident in a profound attenuation of total kinase activity, leading to reduced phosphoprotein content. Mutations to the gene encoding the catalytic subunit of PI3K (phosphatidylinositol 3-kinase) have the potential to modulate all enzymes that depend on its product, PIP3, for membrane tethering or activation by other kinases. Remarkably, strong mutants inactivating PI3K also silence multiple signaling pathways at the transcript level, partially but not entirely mediated by the DAF-16/FOXO transcription factor. Mammals have a relatively large proportion of somatic cells, and survival depends on their replication, whereas somatic cell divisions in nematodes are limited to development and reproductive tissues. Thus, translation of longevity gains from nematodes to mammals requires disentangling the downstream consequences of signaling mutations, to avoid their deleterious consequences.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1075-1083 |
| Number of pages | 9 |
| Journal | Biochimica et Biophysica Acta - General Subjects |
| Volume | 1790 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2009 |
| Externally published | Yes |
Fingerprint
Keywords
- Caenorhabditis elegans
- IGF-1 (insulin-like growth factor 1)
- Insulin
- Lifespan
- Longevity
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Molecular Biology
Cite this
Extreme-longevity mutations orchestrate silencing of multiple signaling pathways. / Shmookler Reis, Robert J.; Bharill, Puneet; Tazearslan, Cagdas; Ayyadevara, Srinivas.
In: Biochimica et Biophysica Acta - General Subjects, Vol. 1790, No. 10, 10.2009, p. 1075-1083.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Extreme-longevity mutations orchestrate silencing of multiple signaling pathways
AU - Shmookler Reis, Robert J.
AU - Bharill, Puneet
AU - Tazearslan, Cagdas
AU - Ayyadevara, Srinivas
PY - 2009/10
Y1 - 2009/10
N2 - Long-lived mutants provide unique insights into the genetic factors that limit lifespan in wild-type animals. Most mutants and RNA interference targets found to extend life, typically by 1.5- to 2.5-fold, were discovered in C. elegans. Several longevity-assurance pathways are conserved across widely divergent taxa, indicating that mechanisms of lifespan regulation evolved several hundred million years ago. Strong mutations to the C. elegans gene encoding AGE-1/PI3KCS achieve unprecedented longevity by orchestrating the modulation (predominantly silencing) of multiple signaling pathways. This is evident in a profound attenuation of total kinase activity, leading to reduced phosphoprotein content. Mutations to the gene encoding the catalytic subunit of PI3K (phosphatidylinositol 3-kinase) have the potential to modulate all enzymes that depend on its product, PIP3, for membrane tethering or activation by other kinases. Remarkably, strong mutants inactivating PI3K also silence multiple signaling pathways at the transcript level, partially but not entirely mediated by the DAF-16/FOXO transcription factor. Mammals have a relatively large proportion of somatic cells, and survival depends on their replication, whereas somatic cell divisions in nematodes are limited to development and reproductive tissues. Thus, translation of longevity gains from nematodes to mammals requires disentangling the downstream consequences of signaling mutations, to avoid their deleterious consequences.
AB - Long-lived mutants provide unique insights into the genetic factors that limit lifespan in wild-type animals. Most mutants and RNA interference targets found to extend life, typically by 1.5- to 2.5-fold, were discovered in C. elegans. Several longevity-assurance pathways are conserved across widely divergent taxa, indicating that mechanisms of lifespan regulation evolved several hundred million years ago. Strong mutations to the C. elegans gene encoding AGE-1/PI3KCS achieve unprecedented longevity by orchestrating the modulation (predominantly silencing) of multiple signaling pathways. This is evident in a profound attenuation of total kinase activity, leading to reduced phosphoprotein content. Mutations to the gene encoding the catalytic subunit of PI3K (phosphatidylinositol 3-kinase) have the potential to modulate all enzymes that depend on its product, PIP3, for membrane tethering or activation by other kinases. Remarkably, strong mutants inactivating PI3K also silence multiple signaling pathways at the transcript level, partially but not entirely mediated by the DAF-16/FOXO transcription factor. Mammals have a relatively large proportion of somatic cells, and survival depends on their replication, whereas somatic cell divisions in nematodes are limited to development and reproductive tissues. Thus, translation of longevity gains from nematodes to mammals requires disentangling the downstream consequences of signaling mutations, to avoid their deleterious consequences.
KW - Caenorhabditis elegans
KW - IGF-1 (insulin-like growth factor 1)
KW - Insulin
KW - Lifespan
KW - Longevity
UR - http://www.scopus.com/inward/record.url?scp=69949097079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69949097079&partnerID=8YFLogxK
U2 - 10.1016/j.bbagen.2009.05.011
DO - 10.1016/j.bbagen.2009.05.011
M3 - Article
C2 - 19465083
AN - SCOPUS:69949097079
VL - 1790
SP - 1075
EP - 1083
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
SN - 0304-4165
IS - 10
ER -