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An Insulin-like Signaling Pathway Affects Both Longevity and Reproduction in Caenorhabditis elegans
Heidi A. Tissenbauma and Gary Ruvkunaa Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114
Corresponding author: Gary Ruvkun, Department of Molecular Biology, Massachusetts General Hospital, Wellman Building--8th floor, 50 Blossom St., Boston, MA 02114, ruvkun{at}molbio.mgh.harvard.edu (E-mail).
Communicating editor: I. GREENWALD
| ABSTRACT |
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Mutations in daf-2 and age-1 cause a dramatic increase in longevity as well as developmental arrest at the dauer diapause stage in Caenorhabditis elegans. daf-2 and age-1 encode components of an insulin-like signaling pathway. Both daf-2 and age-1 act at a similar point in the genetic epistasis pathway for dauer arrest and longevity and regulate the activity of the daf-16 gene. Mutations in daf-16 cause a dauer-defective phenotype and are epistatic to the diapause arrest and life span extension phenotypes of daf-2 and age-1 mutants. Here we show that mutations in this pathway also affect fertility and embryonic development. Weak daf-2 alleles, and maternally rescued age-1 alleles that cause life span extension but do not arrest at the dauer stage, also reduce fertility and viability. We find that age-1(hx546) has reduced both maternal and zygotic age-1 activity. daf-16 mutations suppress all of the daf-2 and age-1 phenotypes, including dauer arrest, life span extension, reduced fertility, and viability defects. These data show that insulin signaling, mediated by DAF-2 through the AGE-1 phosphatidylinositol-3-OH kinase, regulates reproduction and embryonic development, as well as dauer diapause and life span, and that DAF-16 transduces these signals. The regulation of fertility, life span, and metabolism by an insulin-like signaling pathway is similar to the endocrine regulation of metabolism and fertility by mammalian insulin signaling.
GENETIC screens for mutants with increased life spans have identified genes that may regulate the aging process (![]()
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The C. elegans dauer larva is a specialized third larval stage adapted for survival in nonoptimal environmental conditions. In response to high levels of a continuously secreted pheromone and low amounts of food, that is, unfavorable growth conditions, animals form a dauer larva (![]()
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Genes that affect dauer formation (daf) fall into two classes: genes that mutate to a dauer-constitutive phenotype, where animals enter dauer inappropriately, and dauer-defective mutants, where, even under unfavorable growth conditions, animals will not arrest as a dauer. Based on genetic epistasis analysis, these genes have been ordered into a pathway (![]()
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Unlike all other daf genes, weak or conditional alleles of daf-2 and age-1 exhibit an increase in the post-dauer life span (![]()
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Molecular characterization of daf-2 and age-1 indicates that an insulin-like signaling pathway regulates diapause and longevity in C. elegans: daf-2 encodes a member of the insulin receptor family and age-1 encodes the catalytic subunit of phosphatidylinositol-3-kinase (PI-3-kinase), a molecule that has been shown to act downstream of the mammalian insulin receptor (reviewed in ![]()
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In a genetic screen for long-lived mutants, age-1 (hx546) was recovered (![]()
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We show that at the nonpermissive temperature, daf-2 mutants show markedly reduced fertility as well as partially penetrant embryonic lethal phenotypes. Similarly, we show that maternally rescued age-1 null mutants cause the same spectrum of phenotypes. The increased life span and dauer constitutive phenotypes (![]()
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| MATERIALS AND METHODS |
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Methods and strains:
All strains used were maintained and handled as described in ![]()
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Mapping between unc-4 and sqt-1:
age-1(hx546) was three-factor mapped in the 1.4 map unit (Acedb) unc-4 sqt-1 interval. age-1(hx546) males were obtained by heat shock and mated into unc-4(e120) sqt-1(sc13) hermaphrodites at 20°. Non-Sqt-non-Unc progeny were picked to separate plates. From these plates, recombinants (Sqt-non-Unc and Unc-non-Sqt animals) were picked to individual plates and allowed to self-fertilize to isolate a homozygous strain.
Mapping between sqt-1 and lin-29 :
age-1(hx546) was three-factor mapped in the 1.2 map unit (![]()
Complementation test:
age-1(hx546) males were mated with sqt-1(sc13) age-1(mg44) hermaphrodites at 20°. F1 Non-Sqt Non-Daf cross progeny were picked to separate plates. Individual heterozygotes were singled to plates at 25°, 20°, or 15° and transferred daily (20° and 25°) or every 23 days (20° and 15°). Progeny of the age-1(hx546)/sqt-1(sc13) age-1(mg44) strain were counted and scored for dauer and non-dauer after either 3 days (25°), 4 days (20°) or 7 days (15°). For sqt-1(sc13) age-1(mg44)/sqt-1(sc13)age-1(mg44) progeny from sqt-1(sc13) age-1(mg44)/sqt-1(sc13)age-1(mg44) mothers, hermaphrodites were allowed to lay eggs for 6-14 hours and then removed from the plate, because these animals tend to be egg-laying defective such that their eggs hatched within them. Plates were scored for dauer and nondauer after either 3 days (25°), 4 days (20°) or 7 days (15°).
Testing recombinants for maternal age-1 activity:
unc-4(e120) age-1(m333)/mnC1 males were mated with all of the recombinant hermaphrodites with the exception outlined below. Wild-type hermaphrodite cross-progeny were singled to 25° and their progeny scored for whether unc-4(e120) age-1 (m333) homozygous progeny arrest as dauer larvae. For the Unc-non-Sqt recombinants, sqt-1(sc13) age-1(mg44)/mnC1 males were obtained by heat shock and were mated with the recombinants. For the Lin-non-Sqt recombinants, sqt-1(sc13) age-1 (mg44)/mnC1; him-8(e1489) males were mated with the homozygous Lin recombinants. Prior to mating, Lin recombinants were opened at the vulva with an injection needle.
Isolation of new daf-16 alleles:
daf-2(e1370); daf-12(m20) animals were grown at 15° and then placed in a bleach solution to isolate eggs. Animals were then grown until the L4 and mutagenized with ethylmethanesulfonate, then placed at 15° and allowed to grow for one full generation. Gravid F1s were grouped together and then placed in a bleach solution to isolate F2 eggs. The eggs were placed in S medium overnight at 25° on a rocking platform. Each 15 ml tube contained a different set of animals and remained separate. The synchronous preparations of F2 larvae were placed on large plates seeded with bacteria at 25° and 23 days later examined for any animals that failed to arrest at the dauer stage. Each individual plate from independent mutagenized parents on which a nondauer suppressor mutant was isolated was named mg51, mg52, mg53, mg54. Only one suppressor mutant was studied from each egg pool; thus the suppressor mutants are independent.
Mapping and complementation tests of mg51, mg52, mg53, mg54:
Because daf-16 had been previously identified as a suppressor of daf-2 (![]()
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The newly isolated mutants were also genetically mapped. At 15°, daf-2(e1370) males were mated with mg51, daf-2(e1370), daf-12(m20) hermaphrodites and male cross-progeny were picked. These mg51/+; daf-2(e1370); daf-12(m20) males were mated with each of the following hermaphrodite strains; Chromosome I dpy-5(e61); daf-2(e1370); Chromosome II sqt-1 (sc13); daf-2(e1370); Chromosome III daf-2(e1370) unc-32 (e189); Chromosome IV daf-2(e1370); unc-5(e53); Chromosome V daf-2(e1370); dpy-11(e229); Chromosome X daf-2 (e1370); lon-2(e678). The cross progeny were either daf-2 (e1370); mg51/+; marker/+; daf-12(m20)/+ or daf-2(e1370); marker/mg51; daf-12(m20)/+. From these plates, nonmarked individual progeny were singled at 15° and allowed to self-fertilize. From this brood, a total of 50 L4s or young adults homozygous marker progeny were singled to 25° from 23 individual plates and their broods examined for dauers and nondauers. If the marker was unlinked to the suppressor, then the progeny were either marked dauers, marked arrested larvae (daf-2; daf-12), or marked dauers and nondauers. If the marker was linked to the suppressor then all of the animals would be dauers, unless there was recombination between the marker and the suppressor.
Life span assays:
Life span assays were done at 25°. Adult hermaphrodites were picked (56 per plate) from each strain and allowed to undergo one full generation at 15° or 20° to ensure the animals being tested had not starved or gone through dauer. From these plates, individual L4 or young adult animals were picked to plates at 25°. Occasionally, individual L4 or young adult animals were picked from a well-seeded nonstarved plate as well. Day 1 of the life span was the day that the animal was picked to 25°. Therefore, life spans are either post-L4 or post-young adult. Animals were transferred to new plates every 12 days while producing progeny. After egg production ceased, animals were transferred to new plates every 47 days. Animals were tapped with a pick every 24 days and were scored as dead when they did not move after repeated taps with the pick. Animals that did not have any progeny, were egg-laying defective such that their eggs hatched within them, or had crawled off the plate, were not included in the study. For each analysis, N2 and age-1 (hx546) were also tested for life span as controls, to account for any changes in the incubator environment.
Fertility measures:
Adult hermaphrodites were picked (56 per plate) from each strain and allowed to undergo one full generation at 15° or 20° to ensure the parental strain had not starved or gone through dauer. From these plates, individual L4 or young adult animals were singled to individual plates at 25°. The parental animals were transferred daily to fresh plates and the number of eggs laid overnight was counted. Plates at 25° were scored for dauers, nondauers, dead eggs and arrested larvae two days later. Dauers that had crawled off the side of the plate were counted as well. Plates at 15° were scored for dauers, nondauers, dead eggs, and arrested larvae 56 days later.
Strain constructions:
daf-16(m27); daf-2(e1391): daf-16(m27) males were mated into daf-2(e1391) hermaphrodites at 15°. Cross-progeny were singled to individual plates at 25° and allowed to self-fertilize. The F2 brood plates segregated dauers and nondauers. From one plate, sixteen dauers were singled to 15° and allowed to recover. When the F2 animals developed into fertile adults, they were shifted again to 25° and allowed to self-fertilize. The progeny were then scored for dauers and nondauers. Many nondauers were singled onto separate plates from a plate segregating both dauers and nondauers [daf-16(m27)/+; daf-2(e1391) parent]. A non-dauer that produced all nondauers at 25° and established the strain was tested to confirm the presence of daf-2 in the strain by crossing to daf-2(e1370) males and looking for dauer cross-progeny in the F1 at 25°.
daf-16(m27); daf-2(e1370); osm-5(p802):
daf-16(m27); daf-2(e1370) males were mated with daf-2(e1370); osm-5(p805) hermaphrodites at 15°. Cross-progeny were singled to individual plates at 25° and allowed to self-fertilize. The F2 brood plates segregated dauers and nondauers. However, since the daf-2(e1370); osm-5(p805) strain had been previously reported to result in 5075% arrested L1s at 25° (![]()
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| RESULTS |
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Fine mapping of age-1(hx546):
Animals carrying the age-1(hx546) allele live 23 times as long as wild-type animals, and arrest at the dauer stage at temperatures above which animals are standardly cultivated (![]()
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age-1(mg44), a putative null allele of age-1, substitutes a stop codon at amino acid position 405 (Trp405Amber) that is predicted to truncate AGE-1 upstream of the kinase domain (![]()
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age-1(hx546) was originally reported to map to the left of sqt-1, close to unc-4 (![]()
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Recombinants were also tested for life span (Table 1; all of the life span values are mean ± SE). 3/3 Sqt-non-Unc non-Age recombinants that maternally complemented age-1(m333) mutants had life spans similar to wild-type (8.9 ± 0.2 days, n = 170). The mean life spans of the recombinants were 9.7 ± 0.7 (n = 25), 9.7 ± 0.4 (n = 31), and 8.1 ± 0.4 days (n = 29). An Unc-non-Sqt Age recombinant that failed to complement age-1(mg44) maternally was long-lived relative to wild type with a mean life span of 18.5 ± 1.8 days (n = 21). Animals that carry the marker mutations sqt-1(sc13) or unc-4(e120) had mean life spans similar to wild type, of 11.4 ± 0.4 (n = 34) and 10.8 ± 1.3 days (n = 13), respectively.
In summary, we found a total of 17 recombinants in the unc-4 sqt-1 interval. All of the Unc-non-Sqt recombinants fail to maternally complement age-1(mg44) and a recombinant tested for life span was long-lived. The Sqt-non-Unc recombinants maternally complemented age-1(m333) and the three recombinants tested for life span were short-lived (Table 1).
We also collected recombinants between a sqt-1 lin-29 chromosome in trans to age-1(hx546). For the 17 Sqt-non-Lin recombinants, 3/17 were Sqt-Age and 14/17 were Sqt-non-Age (![]()
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age-1(hx546) affects maternal age-1 gene activity at all temperatures:
age-1(hx546) fails to contribute maternal age-1 activity at 25°: 100% of the age-1(mg44) homozygous progeny of age-1(hx546)/age-1(mg44) heterozygotes arrest at the dauer stage (![]()
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age-1(hx546) supplies sufficient zygotic activity to allow reproductive development: age-1(hx546)/age-1 (mg44) progeny of age-1(hx546)/age-1(mg44) mothers form fertile adults, like +/age-1(mg44) progeny (![]()
age-1(hx546) supplies some age-1 maternal gene activity at lower temperatures (Figure 1). At 20°, 100% of age-1(mg44) progeny from age-1(mg44) hermaphrodites arrest as dauers. However, fewer of the age-1(mg44) progeny of age-1(hx546)/age-1(mg44) arrest development as dauer larvae at 20°; most continue development as dauer-like animals that are dark, developing into sterile adults, and 4% of age-1(mg44) progeny of age-1(hx546)/age-1(mg44) parents are fertile (Figure 1). Therefore, age-1(hx546) maternal activity is temperature sensitive.
At 15°, age-1(hx546) shows considerable maternal age-1 activity, although less than wild-type levels. Fifty-five percent of age-1(mg44) progeny of age-1(hx546)/age-1(mg44) parents are fertile (Figure 1). Because the age-1(mg44)/age-1(mg44) progeny of age-1(hx546)/age-1(mg44) hetero-zygous parent do not all arrest as dauers at lower temperatures, the age-1(hx546) mutant has sufficient maternal age-1 gene activity at lower temperatures to develop as a reproductive adult. There is still, however, a decrease in maternal age-1(hx546) activity: 45% of age-1(mg44) progeny of age-1(hx546)/age-1(mg44) parents arrest development without reproduction. However, most of the arrested animals develop to sterile adults rather than dauers. This suggests that decreases in maternal age-1 activity cause developmental arrest as a sterile adult, whereas complete lack of both zygotic and maternal age-1 activity results in arrest as a dauer larva.
The data suggest that age-1(hx546) is a temperature-sensitive allele. Alternatively, it is possible that the reduced level of maternal age-1(hx546) activity is sufficient at lower temperatures. This difference is not due to the intrinsic temperature sensitivity of the dauer pathway because, at all these temperatures, 100% of the progeny of parents carrying null age-1 alleles arrest as dauers (![]()
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Decreased zygotic age-1(hx546) activity confers long life:
Animals lacking both zygotic and maternal age-1 activity will arrest development as dauers [age-1(mg44)/age-1(mg44) progeny from age-1(mg44)/age-1(mg44) mothers]. Lack of only maternal age-1 activity does not affect life span or development; age-1(mg44)/+ animals derived from age-1(mg44)/age-1(mg44) mothers develop as nondauers with normal senescence (Table 2 and Table 3; Figure 2A). Thus, age-1 is completely zygotically rescued (![]()
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age-1(hx546) animals show an increase in life span but do not arrest at the dauer stage under normal growth conditions (![]()
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These results suggest that age-1(hx546) is a maternal enhancer of age-1(mg44). In addition, age-1(mg44) is a zygotic enhancer of age-1(hx546). These data along with the genetic mapping results presented in Table 1 and Figure 1 further endorse that age-1(hx546) is a mutation in the PI-3-kinase.
daf-2 and age-1 have pleiotropic effects on reproduction and viability:
daf-2(e1370) and daf-2(e1391) are temperature-sensitive dauer-constitutive alleles that substitute conserved amino acids in the kinase domain of the DAF-2 insulin-like receptor protein (![]()
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At the permissive temperature, daf-2(e1370) and daf-2(e1391) animals produce nearly wild-type brood size (Table 5). As well, less than 1% of the progeny of these daf-2 mutants arrest at embryonic and larval stages. Thus, only at the nonpermissive temperature do the daf-2 mutant alleles significantly reduce fertility and viability of progeny.
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We further examined whether or not the decreased fertility was due to a mutation unrelated to daf-2. We constructed a daf-2(e1370) dpy-17(e164) double mutant to eliminate any closely linked as well as unlinked mutations. This strain was then crossed to wild-type and a Daf-non-Dpy recombinant was collected in order to isolate a twice backcrossed homozygous daf-2 strain. This resulted in a slight increase in brood size and a slight decrease in the associated larval arrest/dead eggs (Table 4 and Table 5). However, the resulting backcrossed daf-2 (e1370) strain still exhibited a reduction in the brood size with associated larval arrest/dead eggs when shifted either as young adult (88 ± 8 total progeny with 6.9% arrest/dead eggs) or as L4 animals (71 ± 7 total progeny with 9.3% arrest/dead eggs). Because the reduction in fertility, the arrested larvae and dead eggs are seen in two daf-2 alleles as well as in a backcrossed strain; these data suggest that daf-2 controls function in other than dauer formation and that the reduction in brood size is indeed a phenotype of the daf-2 mutation itself.
Because age-1 and daf-2 show many similar defects, we examined the fertility of age-1 at 25°. age-1(mg44) homozygous animals also have severely reduced fertility at 25° with a mean of 76 total progeny (Table 4). Moreover, 5.8% of the total brood result in either dead eggs or larval arrest similar to daf-2 mutants. This reduction in fertility is not specific to this allele. age-1(hx546) also shows a 26% reduction in fertility compared to wild-type N2 at 25° (![]()
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The amount of time that daf-2 mutants are allowed to develop at the permissive temperature affects fertility. As shown in Table 4, daf-2(e1370) mutants shifted to 25° at L4 have a mean brood size of 44 with 15.4% of the total brood either arrested as L1/L2 larvae or dying as eggs. Whereas, if daf-2(e1370) animals are shifted as young adults, the brood size increases to a mean of 67 with 8.9% arrest/lethality. A similar trend is shown for both daf-2(e1391) and the daf-2(e1370) backcrossed strain (Table 4). This indicates that daf-2 acts late in development to affect reproduction and progeny viability and, therefore, has activity well past the temperature-sensitive period for dauer formation.
In the life span assays, we noted the days that the animals laid progeny. In general, wild-type N2 animals produced progeny for the first four days of its 8-day life span. Therefore, approximately half of the wild-type animal's adult life span is postreproduction. However, in daf-2 mutants, progeny are produced very late into the life span. This suggests that daf-2 animals do not live very long postreproduction; instead they show extended reproductive life spans albeit with lower fertility. They produce progeny up to the day they die. It is interesting to note that daf-2(e1391) animals exhibit a fourfold increase in life span, which is higher than reported for other daf-2 alleles (![]()
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Longevity defects in daf-2 and age-1 are not due to reduced fertility:
We examined whether the increase in longevity in daf-2 mutants was associated with the reduced brood size of these mutants. Previously it had been reported that daf-2(e1370) had a wild-type brood size but a twofold increase in life span at 15° (![]()
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Because we observed differences in brood size when animals were shifted to the nonpermissive temperature at different stages of development, we examined whether life span was also affected in a similar manner. In Figure 3, we plot the life spans of wild-type N2, daf-2 (e1370), daf-2(e1391), and daf-2(e1370) backcrossed when shifted as L4 and young adult. For all strains there was no significant difference in life span between the L4 and adult temperature-shifted animals, suggesting again that there is no correlation between the number of progeny produced and life span.
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daf-2 reduced brood size and lethality/arrest is suppressed by daf-16:
Because daf-16 suppresses all known daf-2 and age-1 phenotypes (![]()
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The daf-2 larval arrest and embryonic lethal phenotype is completely suppressed by a mutation in daf-16. Even though daf-16(m27) is a partial suppressor of the dauer arrest and brood size defects of daf-2(e1391), it potently suppresses the arrest/lethality associated with daf-2(e1391) mutants at 25°, because none of the progeny laid arrested as L1/L2 or died as eggs in the double mutant (Table 6).
We further examined the ability of daf-16 to suppress the aging defects in both daf-2(e1370) and age-1(mg44) at 25°. L4 animals were shifted from 15° to 25° and life span was determined. The mean life span of both daf-16(m27); daf-2(e1370) and daf-16(m27); sqt-1 (sc13) age-1(mg44) were similar to wild type (data not shown). Therefore, daf-16 completely suppresses the life span defects in both age-1 and daf-2 mutants.
Both daf-2 and age-1 show a synthetic lethality with the mutations affecting the amphid processes (che/osm class of mutations; ![]()
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daf-16 is the major downstream target of daf-2:
In mam- malian cells, insulin receptor couples to many downstream targets that mediate several different signaling cascades, including PI-3-kinase, Grb-2, pp60 c-src, Shc and PLC gamma (reviewed in ![]()
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Double mutants of both daf-2 and daf-12 at the nonpermissive temperature and age-1 and daf-12 result in an arrest at the L1 and L2 stage (![]()
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| DISCUSSION |
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An insulin-like signaling pathway controls C. elegans longevity, metabolism, and fertility:
Mutations in daf-2 or age-1 affect life span (![]()
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Animals that arrest at the dauer diapause stage, such as daf-2 and age-1 mutants, show a decrease in the rate of metabolism, suspend development of both somatic and germline tissues, and age more slowly, allowing the animals to survive long periods under suboptimal conditions (reviewed in ![]()
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Mutations in daf-2 affect embryogenesis, reproduction, longevity, and dauer arrest. We have shown that several daf-2 alleles cause a small percentage of the animals to arrest as larvae or die as eggs. None of the daf-2 alleles generated so far are null alleles (![]()
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All of the phenotypes caused by mutations in either age-1 or daf-2, including the embryonic lethality and fertility defects, are suppressed by mutations in daf-16 (![]()
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Our results do not support a model that fertility decline is the cause of longevity increase. We find that life span in these mutants can be decoupled from their effects on brood size, similar to previous reports of daf-2 (e1370) by ![]()
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In C. elegans, two studies that examine the relationship between mating and life span find that mating can reduce male life span (![]()
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In wild-type animals, half of the life span is postreproductive, which is significantly different from daf-2 mutants where progeny can be produced up until the day of death. Brood size is limited by the number of sperm in a wild-type hermaphrodite (![]()
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age-1(hx546) affects maternal and zygotic age-1 activity:
age-1(hx546) animals are long-lived compared to wild type (![]()
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The age-1 alleles (mg109, mg44, m333), including those that are predicted to truncate the AGE-1 protein, show a dauer-constitutive phenotype that can be rescued by wild-type maternal gene activity (![]()
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age-1(hx546) is modulated by temperature:
We have examined the maternal contribution of age-1(hx546) at several temperatures to establish that this allele is temperature sensitive for maternal activity. Dauer formation is modulated by temperature (![]()
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Temperature input to dauer formation has been previously reported for daf-2. Analysis of a daf-2 allelic series suggests that the level of daf-2 signaling is modulated by temperature (![]()
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Temperature input to the parallel DAF-7 (TGF-ß) and daf-11 signaling pathways have also been detected, though unlike daf-2 and age-1, even null alleles of daf-7 are temperature sensitive (![]()
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Dauer formation itself is modulated by temperature and this occurs during L1 and part of L2 for daf-2 mutants (![]()
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daf-2 and age-1 affect senescence:
In animals carrying weak daf-2 or age-1 alleles, conditions that induce a longevity increase and a reduction in fertility and also cause a metabolic shift to fat storage (![]()
It is still unclear, however, why animals bearing mutations in daf-2 and age-1 live longer. One of the main theories of aging is the oxidative stress/free radical hypothesis whereby the progressive and irreversible accumulation of oxidative damage leads to declines in viability (reviewed in ![]()
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Identifying new genes that regulate longevity may help to uncover how life span is itself regulated. We suggest that longevity is intrinsically linked to metabolism in C. elegans similar to mammalian studies linking caloric restriction and longevity. Molecular identification of other genes in the pathway may help to uncover the link between metabolism and longevity.
| ACKNOWLEDGMENTS |
|---|
We thank JIM THOMAS, SHOSHANNA GOTTLIEB, SUZANNE PARADIS, and ANN ROUGVIE for providing many of the strains used in this study. Some of the strains were obtained from the Caenorhabditis Genetics Center, which is supported by the National Institutes of Health National Center for Research Resources. We thank members of the RUVKUN and KAPLAN labs for helpful discussions and suggestions and critical reading of the manuscript. We thank JUAN ABRAHANTE LLORENS for helpful suggestions on mating with lin-29. Special thanks to GARTH PATTERSON, SUZANNE PARADIS, JASON MORRIS, SHOSHANNA GOTTLIEB, and ALLAN DINES for advice, assistance, and suggestions. This work was funded by a grant from Hoescht (AG) and a National Institutes of Health grant AG-14161 to G.R.
Manuscript received July 28, 1997; Accepted for publication October 31, 1997.
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