Aging in C. elegans
Much progress has been made in recent years in identifying a number of
genes that influence the longevity of C. elegans. (See Kenyon
1996 and Johnson
1997 for recent reviews of this work.) Thus far, several genes that
increase lifespan when mutated have been genetically defined. However,
much work remains to characterize these genes on a molecular level, as
the literature contains reports of only three of these genes that have
been cloned and sequenced. The genetic and molecular characterizations
of these genes conducted to date have yielded some intriguing glimpses
into the processes involved in aging and longevity, in C. elegans and perhaps
in other organisms.
It appears that most life-extending mutations confer greater resistance
to a variety of stresses, including reactive oxygen species (ROS), UV exposure,
and elevated temperature (Johnson,
1997 | Martin,
1996). Mutations in the clock (clk) genes affect cell cycle timing
and the length of life history events, including development and adult
life span, possibly through altered regulation of metabolism (Ewbank,
1997). Molecular analysis of the daf-23/age-1 longevity gene indicates
that phosphatidylinositol signalling pathways may be involved in controlling
longevity and stress responses
(Morris, 1996). Thus, it appears that regulation of physiological stress
responses, metabolic control and signalling processes play significant
roles in the aging process of C. elegans. Further genetic and molecular
analyses will entend these observations and will undoubtedly uncover additional
mechanisms and pathways of aging and lifespan control.
Below is a detailed listing of the known genes that affect the life
span of C. elegans.
Genes involved in dauer larva function and lifespan
Dauer larva are an alternate developmental stage that C. elegans enters
under adverse conditions (such as lack of adequate food). Although the
normal lifespan of C. elegans is two to three weeks, dauer larvae can survive
for much longer and are considered "non-aging" since adult lifespan is
not affected by the amount of time spent in the dauer stage. A brief summary
of the link between aging and dauer larva is provided by Don
Riddle's lab Research Summary. Following is a list of genes that have
been shown to be involved in both dauer functions and adult life span.
Many of these genes have been ordered into a pathway
of genetic interaction.
age-1/daf-23
-
Mutations increase life expectancy by 65% (Friedman
1988)
-
age-1 mutants have greater metabolic rate potential than wild-type, and
activities of enzymes that regulate metabolic activity are altered in age-1
mutants, suggesting a central role for genes regulating metabolic control
in longevity (Vanfleteren,
1995 | Vanfleteren
1996)
-
age-1 mutants exhibit a greater resistance to oxidative stress (Larsen,1993
| Vanfleteren,
1993), thermal stress (Lithgow
1994 | Lithgow
1995) and UV irradiation (Murakami
1996)
-
age-1 and daf-23 may be the same gene according to mapping and complementation
data (Malone
1996)
-
age-1/daf-23 has been cloned, sequenced ( GenBank
entry | mouse
homolog) and shown to be homologous to mammalian phosphatidylinositol-3-OH
kinase catalytic subunits, thus implicating phosphatidylinositol signalling
in the control of lifespan (Morris
1996)
daf-2
-
Mutations in daf-2 increase life span by > 200% ( Kenyon
1993); daf-2/daf-12 double mutants exhibit a 400% increase in life
span (Larsen
1995)
-
Life span extension in daf-2 mutants depends on the functions of at least
two downstream genes, daf-16 and daf-18 (Kenyon
1993 | Dorman
1995 | Larsen
1995).
-
daf-2 mutants also have a greater metabolic rate potential (Vanfleteren,
1995)
-
daf-2 mutants exhibit greater resistance to thermal stress (Lithgow
1995) and UV irradiation (Murakami
1996)
-
Cloning of daf-2 gene has not yet been reported
daf-12
-
Mutations in daf-12 do not extend lifespan; however, certain combinations
of daf-2 and daf-12 mutant alleles can interact to extend lifespan by fourfold
(Larsen
1995).
-
Cloning of the daf-12 gene has not been reported in the literature.
daf-16
-
daf-16 function required for the lifespan extension of daf-2 and age-1/daf-23
mutations, i.e., mutations in daf-16 do not extend lifespan, rather they
can suppress the lifespan extension of daf-2 and daf-23 mutations (Kenyon
1993 | Larsen
1995 | Dorman
1995)
-
Cloning of the daf-16 gene not yet reported.
daf-18
-
daf-18 function also seems to be required for lifespan extension of the
daf-2 and age-1/daf-23 mutations, and likewise, they do not extend lifespan
but rather suppress the extension of lifespan of the daf-2 and age-1 mutations
(Larsen
1995 | Dorman
1995)
-
Cloning of the daf-18 gene not yet reported.
daf-28
-
Mutations in daf-28 result in modest increases in life span and show genetic
interactions that are similar to those of daf-2 and daf-23 (Malone
1996)
-
Cloning of the daf-28 gene has not been reported
Clock genes
clk-1
-
Mutations in clk-1 increase lifespan modestly, particularly at lower temperatures,
and affect the length of various developmental and behavioral events (Lakowski
1996)
-
clk-1/clk-2 and clk-1/clk-3 double mutants exhibit much longer lifespans
that clk-1 alone; clk-1/daf-2 double mutants have an extroardinarily long
lifespan of five- to six-fold greater than wild type (Lakowski, 1996)
-
clk-1 has been cloned and sequenced (Ewbank,
1997) and the putative protein was found to be structurally similar
to the yeast metabolic regulator Cat5p/Coq7p.
-
Gene sequence: GenBank
entry (whole cosmid sequence only) | mouse
homolog | rat
homolog | human
homolog | yeast
homolog
-
Both clk-1 and the rat homolog of clk-1 can complement a yeast strain deleted
for Cat5p/Coq7p for growth on glycerol (Ewbank,
1997 | Jonassen
T ), demonstrating a strong conservation across eukaryotes.
clk-2
clk-3
gro-1
Other genes
spe-26
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