TY - JOUR
T1 - Global, cell non-autonomous gene regulation drives individual lifespan among isogenic c. Elegans
AU - Kinser, Holly E.
AU - Mosley, Matthew C.
AU - Plutzer, Isaac B.
AU - Pincus, Zachary
N1 - Funding Information:
We thank Tim Schedl, Drew Sinha, Will Pittman and Eric Kim for helpful discussions and thoughtful feedback on the manuscript. This work was supported by NIH grants T32 HG000045 and R01 AG057748, and a Beckman Young Investigator award from the Arnold and Mabel Beckman Foundation. Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrstructure Programs (P40 OD010440).
Publisher Copyright:
© Kinser et al.
PY - 2021/2
Y1 - 2021/2
N2 - Across species, lifespan is highly variable among individuals within a population. Even genetically identical Caenorhabditis elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoter:: GFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long-vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual’s lifespan.
AB - Across species, lifespan is highly variable among individuals within a population. Even genetically identical Caenorhabditis elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoter:: GFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long-vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual’s lifespan.
UR - http://www.scopus.com/inward/record.url?scp=85101980850&partnerID=8YFLogxK
U2 - 10.7554/eLife.65026
DO - 10.7554/eLife.65026
M3 - Article
C2 - 33522488
AN - SCOPUS:85101980850
SN - 2050-084X
VL - 10
SP - 1
EP - 27
JO - eLife
JF - eLife
M1 - e65026
ER -