cynthia.kenyon@ucsf.edu In the nematode Caenorhabditis elegans and the fruit fly Drosophila, loss of the germline stem cells activates lifespan-extending FOXO-family transcription facto
Trang 1A N N A L S O F T H E N E W Y O R K A C A D E M Y O F S C I E N C E S
Issue: Reproductive Aging
A pathway that links reproductive status to lifespan
Cynthia Kenyon
Department of Biochemistry and Biophysics, University of California, San Francisco, California
Address for correspondence: Cynthia Kenyon, Mission Bay Genentech Hall MC2200, 600 16th Street, Room S312A, San Francisco, California 94158-2517 cynthia.kenyon@ucsf.edu
In the nematode Caenorhabditis elegans and the fruit fly Drosophila, loss of the germline stem cells activates
lifespan-extending FOXO-family transcription factors in somatic tissues and extends lifespan, suggesting the existence of an evolutionarily conserved pathway that links reproductive state and aging Consistent with this idea, reproductive
tissues have been shown to influence the lifespans of mice and humans as well In C elegans, loss of the germ cells
activates a pathway that triggers nuclear localization of the FOXO transcription factor DAF-16 in endodermal tissue DAF-16 then acts in the endoderm to activate downstream lifespan-extending genes DAF-16 is also required for inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling to extend lifespan However, the mechanisms
by which inhibition of insulin/IGF-1 signaling and germline loss activate DAF-16/FOXO are distinct As loss of the germ cells further doubles the already-long lifespan of insulin/IGF-1 pathway mutants, a better understanding of this reproductive longevity pathway could potentially suggest powerful ways to increase healthy lifespan in humans Keywords: germ cells; DAF-12; nuclear hormone receptor; aging
The aging process touches everyone’s life, and, as a
scientific problem, it is fascinating in its own right
What determines the rate at which we age? Aging
was once thought to “just happen.” We wear out, like
old shoes Yet, the aging process is not completely
random and stochastic Different species can have
dramatically different lifespans, and, even within a
single animal species, the rate of aging can be
influ-enced by environmental factors, such as the level or
quality of nutrients, various stressors, temperature,
and sensory cues.1The mechanisms by which
en-vironmental conditions influence lifespan are now
under investigation in many labs, and in many
cases, genetic pathways employing classical
regu-latory proteins, such as kinases and transcription
factors, play important roles Moreover, some
mech-anisms that influence lifespan have been conserved
during evolution For example, reducing the level
of insulin/insulin-like growth factor 1 (IGF-1)
hor-mone signaling extends the lifespan of worms, flies,
and mammals.1,2The mechanism of this lifespan
ex-tension has been explored extensively, particularly
in worms,1,3–6where inhibition of insulin/IGF-1
sig-naling has been shown to activate specific transcrip-tion factors, including the FOXO-family member DAF-16/FOXO DAF-16/FOXO, in turn, increases lifespan by up- or downregulating a wide vari-ety of metabolic, cell-protective, chaperone, and anti-immunity genes that appear to act cumula-tively to extend lifespan Mutations that alter the
activity of this pathway can extend Caenorhabdi-tis elegans’ lifespan up to 10-fold.7 DNA variants
in a FOXO gene have now been associated with
increased longevity in seven human populations across several continents,1,8–11indicating that
hu-man longevity, too, is likely susceptible to the effects
of this transcription factor In many organisms, re-ducing insulin/IGF-1 signaling delays the onset of age-related diseases and reduces their severity, sug-gesting that this pathway couples the normal aging process to age-related disease susceptibility.6
The relationship between aging and reproduc-tion is particularly fascinating, given the signifi-cance of both processes in the life of an individual and the success of the species For example, in hu-mans, female menopause may promote longevity by
Trang 2eliminating the chance that an older woman will
die during childbirth Recently, a fascinating
rela-tionship between reproduction and aging has been
revealed in small organisms; specifically, in the
ne-matode C elegans and the fruit fly Drosophila In
both species, the germ cells; that is, the cells that
give rise to sperm and oocytes, influence the aging
of the whole animal If the germline precursor cells
are removed in either worms or flies, lifespan is
ex-tended by 40–60%.12,13These animals not only live
longer, they also remain youthful and active longer
than normal, suggesting that loss of the germline
precursor cells extends lifespan because it slows the
animals’ rate of aging Thus, in these animals, the
germ cells do not only produce the next generation,
they also influence the lifespan of the body in which
they reside This review will describe what we know
so far about how this pathway affects the aging
pro-cess in the animal in which it has been studied most
extensively, C elegans.
In C elegans, the germline can be removed by
killing the two germline precursor cells (Z2 and
Z3; Fig 1) with a laser microbeam at the time of
hatching.13Or, the germline can be removed
genet-ically;14 for example, by shifting animals carrying
the temperature-sensitive mutation glp-1(e2141) to
the nonpermissive temperature, which forces
mi-totically dividing germline stem cells to exit mitosis
and enter meiosis Lifespan can also be extended
when the germline stem cells are forced into
meio-sis during adulthood.14 At this time, the animals
contain germ cells arrested in meiosis as well as
mature sperm and oocytes, and they are
produc-ing progeny This findproduc-ing, along with others, sproduc-ingles
out the germline stem cells (as opposed to sperm,
oocytes, or meiotic cells) as being especially
im-portant in affecting aging In addition, this finding
indicates that adult tissues are susceptible to the
lifespan-extending effects of germline removal A
similar situation exists in flies.12 How this system
might have arisen during evolution is unknown,
but one hypothesis is that it might confer a selective
advantage by allowing the somatic tissues to “wait”
for the germline to mature before aging progresses
too extensively.13Such a system might help to
coor-dinate the timing of reproduction with aging
How does germline loss extend lifespan? Because
reproduction is an expensive process metabolically,
one could imagine that lifespan is extended
sim-ply because in the absence of reproduction, more
Figure 1 Removing the germline of C elegans extends
life-span (A) At the time of hatching, the animal’s entire repro-ductive system contains only four cells, so using a laser beam
to ablate either the precursors of the germline (Z2 and Z3) or the precursors of all of the reproductive tissues (Z1–Z4) with
a laser microbeam is straightforward Killing Z2 and Z3 in this way extends lifespan ∼60% (B) The diagram shows the re-productive system of the animal when it is an adult At this stage, it contains mature sperm (squares) and oocytes (large ovals), and progeny are being produced (not shown) In addi-tion, the germline contains cells arrested in meiosis (blue circles) and proliferating germline stem cells (yellow circles) When the germline stem cells are forced into meiosis during adulthood using a temperature-sensitive mutation that inhibits signaling required for germline stem cell proliferation, then lifespan is increased.
resources can be devoted to cell and tissue main-tenance This idea, that there is a “cost of repro-duction,” has been put forth by evolutionary biol-ogists, and there are many examples of reciprocal relationships between reproduction and longevity
in nature and in the laboratory.15In our case, this may be part of the answer, but there seems to be more to it When the entire reproductive system of
C elegans is removed [that is, the cells that give rise
to the somatic reproductive tissues (Z1 and Z4) as well as the cells that give rise to the germline (Z2 and Z3)], lifespan is not increased.13 Animals that lack their entire reproductive systems are also ster-ile, so these findings argue against models invoking a
Trang 3simple cost of reproduction Instead, these findings
indicate that both the germline and the somatic
re-productive tissues play an active role in influencing
lifespan Specifically, the germline and the somatic
reproductive tissues exert counterbalancing
influ-ences on lifespan, with the germline preventing, and
the somatic gonad promoting, lifespan extension
If active signaling is required for loss of the germ
cells to extend lifespan, then what are these signals
and how are they communicated to
nonreproduc-tive tissues? It seems likely that steroidal hormone
signaling plays an important role
Reduction-of-function mutations in the gene daf-12, which
en-codes a nuclear hormone receptor (NHR), or in
genes like daf-9, which encode proteins that
syn-thesize sterol ligands for DAF-12, prevent loss of
the germline from extending lifespan.13,16,17(For a
summary of genes in this pathway, see Table 1.)
DAF-12/NHR is not the only transcription fac-tor required for loss of the germ cells to extend lifespan The DAF-16/FOXO transcription factor, described above, is required as well.13Interestingly,
DAF-16/FOXO appears to act in the intestine of C elegans to extend lifespan when the germline is
re-moved.18 Under these conditions, DAF-16/FOXO accumulates primarily in intestinal nuclei This tis-sue appears to play a central role in this pathway,
as expression of DAF-16/FOXO exclusively in the intestine can completely rescue the long lifespan of
germline-defective daf-16(-) mutants.19 The
intes-tine of C elegans appears to be the animal’s en-tire endoderm C elegans does not have a distinct
adipose tissue, liver or pancreas; but the intestine stores fat (as does adipose), produces yolk (as does the liver), and produces some important insulin-like peptides, such as INS-720(as does the pancreas) It is
Table 1.Some genes required for loss of the germline to extend the lifespan of C elegans For references, see text.
daf-16 FOXO-family transcription
factor
Localizes to intestinal nuclei during adulthood Acts in the intestine to extend lifespan
Required for insulin/IGF-1-pathway mutants to live long Localizes
to nuclei in many tissues throughout life
daf-12 Nuclear hormone receptor Is partially required for DAF-16
nuclear localization, but has another, unknown, function in this pathway
Not required for lifespan extension
daf-9 Cytochrome P450 required for
DAF-12-ligand biosynthesis
Partially required for DAF-16 nuclear localization
Not required for lifespan extension
tcer-1 Ortholog of the human
transcription
elongation/splicing factor
TCERG1
Intestinal expression increases
Required for the upregulation
of some, but not all DAF-16-dependent target genes
Not required for lifespan extension
kri-1 Ortholog of the human disease
gene KRIT1 Contains protein
interaction domains (ankyrin
repeats)
Intestinal protein required for DAF-16 nuclear localization
and tcer-1 upregulation upon
germline loss
Not required for lifespan extension
K04A8.5 Fat lipase Upregulated by DAF-16 in the
intestine Could potentially produce a downstream lifespan-extending signal from the intestine to other tissues
Partially required for lifespan extension
Trang 4possible that DAF-16/FOXO has a conserved
lifespan-extending function in the intestine/adipose
tissue, as overexpression of the Drosophila
DAF-16/FOXO ortholog only in adipose tissue extends fly
lifespan.12Loss of the mouse insulin receptor
specif-ically in adipose tissue also extends lifespan.21This
intervention would be predicted to activate mouse
FOXO proteins in this tissue How DAF-16
activ-ity in the C elegans intestine extends the lifespan
of the entire animal is not known, but a fat lipase
called K04A8.5 may be involved.22The gene
encod-ing this lipase is upregulated by DAF-16/FOXO in
the intestines of germline-defective animals, and its
function is required for lifespan extension It is
pos-sible that this lipase is involved in the synthesis of
downstream signals from the intestine that
influ-ence the lifespan of the other tissues in the animal
The apparently conserved ability of adipose tissue
to produce lifespan extending signals in response
to FOXO activity makes this issue particularly
interesting
How does loss of the germ cells activate
16/FOXO? One obvious question, given
DAF-16/FOXO’s central role in the insulin/IGF-1
path-way, is whether loss of the germ cells activates
DAF-16/FOXO by inhibiting the activity of the
insulin/IGF-1 pathway Also, is the DAF-12 steroid
signaling system involved? Is the somatic gonad
required? The answers to these questions are not
known in detail; but at least part of the story has
begun to emerge (and is summarized in Figs 2
and 3)
First, the pathway that triggers DAF-16/FOXO
nuclear localization is at least partially distinct
from the pathway that localizes DAF-16 to nuclei
when insulin/IGF-1 signaling is inhibited In
long-lived daf-2 (insulin/IGF-1-receptor) mutants,
DAF-16/FOXO accumulates in most or all somatic cell
nuclei throughout life.23–25 In contrast, when the
germline is removed, DAF-16/FOXO does not
ex-hibit nuclear accumulation until adulthood, and
then it localizes primarily to nuclei in the intestine
Second, several genes that are required for
DAF-16/FOXO nuclear localization and lifespan
exten-sion in response to loss of the germ cells are not
required for lifespan extension in response to
re-duced insulin/IGF-1 signaling daf-12/NHR is one
such gene13,26 (discussed further) Another is
kri-1, the C elegans homolog of the human disease
gene KRIT1, which encodes an intestinal
ankyrin-Figure 2 Loss of the germline precursor cells at the time of hatching (circles with Xs) triggers important changes in intesti-nal cells of the adult Killing the germ cells at the time of hatch-ing triggers several important changes in the intestine of the adult The transcription factor DAF-16/FOXO accumulates in nuclei, and the level of the putative transcription-elongation fac-tor TCER-1 rises Both of these events are completely dependent
on kri-1 DAF-16 nuclear localization is partially dependent on
the DAF-12 steroid signaling pathway, but TCER-1 upregulation
is independent of DAF-12 Therefore, there must be a second gonad-to-intestine signaling pathway The site of action of
DAF-12 itself is not known (question mark) It could potentially act
in the intestine.
domain containing protein kri-1 is required for
loss of the germline to mediate DAF-16/FOXO nu-clear localization and to extend lifespan.18 In
con-trast, kri-1 is not required for daf-2 inhibition
to extend lifespan.18 Moreover, apart from DAF-16/FOXO’s nuclear accumulation, the requirements for DAF-16/FOXO-dependent gene expression are different between germline-defective animals and insulin/IGF-1-signaling mutants A putative
tran-scription elongation factor called TCER-1 (a C elegans homolog of human TCERG1) is required
for lifespan extension and for the increased ex-pression of many DAF-16-target genes in germline-deficient animals, but it is not required for lifespan
extension or daf-16-dependent gene regulation in
insulin/IGF-1 mutants.27It is not clear why
TCER-1 should be required for DAF-TCER-16 target-gene ex-pression in response to germline ablation, but (for
at least some of the same genes) not in response
to inhibition of insulin/IGF-1 signaling, and this is
an interesting question Whatever the answer, it is clear that many aspects of the reproductive longevity pathway distinguish it from the insulin/IGF-1 path-way If loss of the germline extended lifespan sim-ply by inhibiting insulin/IGF-1 signaling, then the
Trang 5Figure 3 The reproductive and insulin/IGF-1 pathways are
distinct The lifespan extension produced by loss of the germ
cells requires KRI-1, DAF-12, and TCER-1, whereas the lifespan
extension produced by daf-2(e1370) receptor mutations does
not (The question mark following “DAF-12” refers to our
un-certainty about the site of action of DAF-12.) Moreover, TCER-1
is required for the increased expression of a set of
DAF-16-regulated genes in response to germline loss, but TCER-1 is not
required for lifespan extension or for the expression of these
DAF-16-regulated genes in insulin/IGF-1 mutants (at least not
for the genes that have been examined) However, it is important
to note that mutations in the insulin/IGF-1 pathway can affect
the operation of the germline pathway (see text), so it is not yet
clear whether the two pathways act completely independently of
one another The drawings depict working models: for example,
TCER-1 and DAF-16 are hypothesized to interact on individual
promoters, but this has not been shown directly.
behavior of DAF-16/FOXO would be expected to be
more similar in the two pathways than it actually is
Finally, removing the germlines of animals
carry-ing daf-2/insulin/IGF-1-receptor mutations further
doubles the already-long lifespans of the animals.13
This effect is consistent with the idea that these two
pathways are not the same
How is intestinal DAF-16/FOXO informed about
the state of the germline? The daf-12-dependent
steroid signaling pathway appears to play a role
In germline-deficient animals lacking daf-12/NHR
or the DAF-12-ligand-synthesizing genes daf-9 or
daf-36, intestinal DAF-16/FOXO nuclear
localiza-tion is incomplete.17,18 Administering the DAF-12
ligand dafachronic acid to germline-deficient daf-9
mutants (which can not make dafachronic acid)
re-stores full DAF-16 nuclear localization and lifespan
extension.17This finding suggests that the DAF-12
signaling pathway plays a role in mediating
commu-nication between the reproductive system and the
intestine
In addition to promoting DAF-16/FOXO nu-clear localization, DAF-12 has another, unknown, function in this pathway.18 It is possible to force DAF-16 nuclear localization by mutating the AKT-phosphorylation sites on DAF-16 through which insulin/IGF-1 signaling prevents DAF-16 nuclear accumulation in normal intact animals This con-stitutively nuclear mutant DAF-16 protein can sub-stitute for wild-type DAF-16 and extend lifespan in germline-deficient animals However, this lifespan extension is still dependent on DAF-12 This find-ing indicates that DAF-12 has another function that
is essential for lifespan extension, in addition to its role in DAF-16 nuclear localization The nature of this other function is unknown
The fact that some DAF-16/FOXO nuclear local-ization takes place when the germline is removed in
daf-12(-) or daf-9(-) mutants suggests that there is a
second pathway that informs the intestine about the status of the germline This interpretation is consis-tent with another observation27: When the germline
is removed, the level of TCER-1 rises in the intestine This increase requires KRI-1, but it is completely in-dependent of DAF-12/NHR It will be very
interest-ing to learn the identity of this daf-12-independent
gonad-to-intestine signaling pathway
Many aspects of this longevity system remain mysterious Why is the somatic gonad required for loss of the germline to extend lifespan? The so-matic gonad is not required for germline loss to trigger DAF-16 nuclear localization28 or TCER-1 upregulation,27but it is required for germline loss to induce at least some DAF-16-dependent transcrip-tion.28Perhaps these DAF-16-dependent genes are essential for lifespan extension Whether the somatic gonad has other functions that do not involve
DAF-16 is unknown
Curiously, in strong daf-2(-) mutants, the somatic
reproductive tissues are no longer required for loss
of the germline to further extend lifespan.13,28Why inhibiting insulin/IGF-1 signaling removes the re-quirement for the somatic gonad is not clear One could imagine that the insulin pathway is down-stream of the somatic gonad; that is, that the so-matic gonad extends lifespan in germline-deficient animals by inhibiting insulin/IGF-1 signaling How-ever, this model does not explain the tissue-specific
localization of DAF-16, or why kri-1 and tcer-1 are
required for germline loss, but not insulin/IGF-1-pathway inhibition, to extend lifespan It is possible
Trang 6that the longevity requirement normally fulfilled
by the somatic gonad can also be fulfilled,
possi-bly in a different way, by inhibition of insulin/IGF-1
signaling
Another intriguing question is how the germline
stem cells “tell” the animal that they are present
If the presence or loss of the germline activates a
signaling pathway, what is the initiating event? How
is it linked to germline stem cell proliferation?
Finally, it is interesting to ask whether this same
reproductive signaling pathway, or a molecular
variant, might influence lifespan in higher
ani-mals There are several intriguing parallels with
Drosophila that suggest a common evolutionary
ori-gin First, as mentioned above, forcing the germline
stem cells to exit mitosis and enter meiosis
dur-ing adulthood extends the lifespan of both adult
flies and adult worms.12,14Moreover, in flies, as in
worms, this treatment activates DAF-16/FOXO
ac-tivity.12In contrast to the situation in worms, when
the germline is removed in Drosophila during
de-velopment, lifespan is not extended.29 The reason
for this is unknown, but it is tempting to speculate
that lifespan is not extended because in flies
(un-like in worms), early loss of the germline prevents
the correct development of the somatic reproductive
tissues
Less is known about mammals; however
trans-planting the ovaries of young mice into old
females extends lifespan.30,31Thus, signals from
re-productive tissues can influence mammalian
life-span Whether there are any additional similarities
between the worm pathway and the pathway
trig-gered by this transplantation in mice is not known It
is interesting to wonder whether the loss of oocytes
might extend the lifespan of human females, who
live longer than men This is of course completely
unknown, but, interestingly, if the ovaries as well as
the germ cells are absent in postmenopausal women,
then the rate of all-cause mortality (including
age-related diseases) increases.32 It will be fascinating
to watch this interesting new field grow and begin
to encompass higher organisms Whether or not
human lifespan is influenced in the same way by
reproductive tissues, if we learn how the
reproduc-tive systems of smaller animals, like worms and flies,
regulate DAF-16/FOXO activity, it may be possible
to use this information to intervene downstream of
the reproductive pathway and extend healthy
lifes-pan without affecting the germline itself
Consis-tent with this idea, in C elegans, overexpressing the putative transcription-elongation factor gene tcer-1
extends the lifespan of worms that have an intact re-productive system and are fully fertile.27This lifes-pan extension correlates with the upregulation of many germline-specific DAF-16 target genes, and
it is dependent on DAF-16 activity The evidence that FOXO proteins influence human lifespan1,8–11
makes the possibility of harnessing this informa-tion to influence human health and longevity seem increasingly possible
Acknowledgments
I thank the members of my laboratory, and the re-viewers, for helpful comments and suggestions
Conflicts of interest
The author declares no conflicts of interest
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