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DOI: 10.1126/science.1243339, 544 (2014);343 Science
et al.Christi M. GendronPerception and Reward
Life Span and Physiology Are Modulated by SexualDrosophila
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evolutionary advantage of preserving limited re-sources for the
offspring (30) or preventing com-petition from other males.
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L. Partridge, Nature 373, 241–244 (1995).3. L. A. Herndon et
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(2011).7. J. Hodgkin, T. M. Barnes, Proc. Biol. Sci. 246,
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Acknowledgments: We thank members of the Brunetlaboratory, S.
Kim, A. Fire, and A. Villeneuve for helpfulsuggestions and J. Lim
and S. Zimmerman for critical readingof the manuscript. We thank N.
Kosovilka and the Protein andNucleic Acid Facility facility for the
microarray experimentsand T. Stiernagle from the Caenorhabditis
Genetics Center.Supported by R01AG031198, DP1AG044848, the
GlennFoundation for Medical Research (A.B.), postdoctoral
fellowshipF32AG37254 (T.J.M.), T32HG000044 and the Helen HayWhitney
Foundation (L.N.B.), Stanford Dean’s Fellowship (BAB),R01GM088290
(F.C.S.), and T32GM008500 (Y.I.).
Supplementary
Materialswww.sciencemag.org/content/343/6170/541/suppl/DC1Materials
and MethodsFigs. S1 to S3Tables S1 and S2Movies S1 to S6References
(31–37)
2 August 2013; accepted 11 November 2013Published online 28
November 2013;10.1126/science.1244160
Drosophila Life Span and PhysiologyAre Modulated by
SexualPerception and RewardChristi M. Gendron,1* Tsung-Han Kuo,2*
Zachary M. Harvanek,1,3 Brian Y. Chung,1
Joanne Y. Yew,4,5 Herman A. Dierick,2 Scott D. Pletcher1
Sensory perception can modulate aging and physiology across
taxa. We found that perceptionof female sexual pheromones through a
specific gustatory receptor expressed in a subsetof foreleg neurons
in male fruit flies, Drosophila melanogaster, rapidly and
reversiblydecreases fat stores, reduces resistance to starvation,
and limits life span. Neurons thatexpress the reward-mediating
neuropeptide F are also required for pheromone
effects.High-throughput whole-genome RNA sequencing experiments
revealed a set of molecularprocesses that were affected by the
activity of the longevity circuit, thereby identifyingnew candidate
cell-nonautonomous aging mechanisms. Mating reversed the effects
ofpheromone perception; therefore, life span may be modulated
through the integrated actionof sensory and reward circuits, and
healthy aging may be compromised when the expectationsdefined by
sensory perception are discordant with ensuing experience.
Sensory perception can modulate agingand physiology in multiple
species (1–6).In Drosophila, exposure to food-basedodorants
partially reverses the anti-aging effectof dietary restriction,
whereas broad reduction inolfactory function promotes longevity and
altersfat metabolism (2, 4). Even the well-known rela-
tion between body temperature and life span mayhave a sensory
component (7, 8).
To identify sensory cues and neuronal cir-cuitry that underlie
the effects of sensory percep-tion on aging, we focused on the
perception ofpotential mates. Social interactions are
prevalentthroughout nature, and the influence of socialcontext on
health and longevity is well knownin several species, including
humans (9). Suchinfluences include behavioral interactions
withmates and broader physiological “costs of repro-duction,” which
often form the basis for evolu-tionary models of aging (10,
11).
In Drosophila, the presence of potential matesis perceived
largely through nonvolatile cutic-ular hydrocarbons, which are
produced by cellscalled oenocytes and are secreted to the
cutic-ular surface, where they function as pheromones(12, 13). To
test whether differential pheromone
exposure influenced life span or physiology, wehoused
“experimental” flies of the same geno-type with “donor” animals of
the same sex thateither expressed normal pheromone profiles orwere
genetically engineered to express phero-mone profiles
characteristic of the opposite sex(Fig. 1A). Donor males with
feminized pheromoneprofiles were generated by targeting
expressionof the sex determination gene, transformer, to
theoenocytes [via OK72-GAL4 or Prom-E800-GAL4(14) (fig. S1)],
whereas masculinization of femaleflies was accomplished by
expressing tra-RNAi ina similar way (15). This design allowed
manipu-lation of the experimental animals’perceived
sexualenvironment without introducing complications as-sociated
with mating itself.
In Drosophila, sensory manipulations can af-fect life span, fat
storage [as determined by base-line measures of triacylglyceride
(TAG)], andcertain aspects of stress resistance (2, 4). Wefound
that flies exposed to pheromones of theopposite sex showed
differences in these pheno-types. Experimental male flies exposed
to maledonor pheromone had higher amounts of TAG,were substantially
more resistant to starvation,and exhibited a significantly longer
life span thangenetically identical male siblings exposed to
fe-male donor pheromone (Fig. 1, B to D). Femalesexhibited similar
phenotypes in response to maledonor pheromone, but the magnitude of
the ef-fects was smaller (fig. S2). Subsequent experimentswere
therefore focused on males.
The characteristics of pheromone exposurewere indicative of a
mechanism involving sen-sory perception. Effects were similar in
severalgenetic backgrounds, including a strain recent-ly collected
in the wild (fig. S3), and were large-ly unaffected by cohort
composition (fig. S4).Pheromone-induced phenotypes were
detectedafter as little as 2 days’ exposure to donor ani-mals (Fig.
1, B and C), persisted with longer ma-nipulations (Fig. 1D), and
were progressively
1Department of Molecular and Integrative Physiology
andGeriatrics Center, Biomedical Sciences and Research Build-ing,
University of Michigan, Ann Arbor, MI 48109, USA. 2De-partment of
Molecular and Human Genetics, Baylor Collegeof Medicine, Houston,
TX 77030, USA. 3Medical ScientistTraining Program, Taubman Medical
Library, University ofMichigan, Ann Arbor, MI 48109, USA. 4Temasek
Life SciencesLaboratory, National University of Singapore,
Singapore 117604.5Department of Biological Sciences, National
University ofSingapore, Singapore 117543.
*These authors contributed equally to this work.†Corresponding
author. E-mail: [email protected]
31 JANUARY 2014 VOL 343 SCIENCE www.sciencemag.org544
REPORTS
-
reversed when female donor pheromone was re-moved (Fig. 1, E and
F, and fig. S5). Pheromoneeffects appeared not to be mediated by
aberrantor aggressive interactions with donor flies, be-cause (i)
we did not observe significant differencesin such behaviors and
(ii) continuous, vigorousagitation of the vials throughout the
exposureperiod, which effectively disrupted observed be-haviors,
had no effect on the impact of donorpheromone (fig. S6).
Furthermore, exposure ofexperimental males to the purified female
pher-omone 7,11-heptacosadiene (7,11-HD) producedphysiological
changes in the absence of donoranimals (mean survival time during
starvation,51.1 T 1.7 hours and 45.4 T 1.2 hours for controland
7,11-HD exposure, respectively; P = 0.007,log-rank test).
To explore the sensorymodality throughwhichdonor pheromone
exerts its effects,we testedwhetherthe broadly expressed olfactory
co-receptorOr83b,whose loss of function renders flies largely
un-able to smell (16), was required for
pheromoneeffects.Or83bmutant flies and controls exhibitedsimilar
changes in starvation resistance (fig. S7)in response to donor
pheromone, indicating thatolfaction was not required. To test
whether taste
perception was involved, we used flies mutantfor the gene Pox
neuro (Poxn), a null mutationthat putatively transforms all
chemosensory neu-rons into mechanosensory neurons. Drosophilataste
neurons are present in the mouthparts anddistributed on different
body parts, including thewings, legs, and genitals, which allow
sensationby contact.When thePoxn nullmutation is coupledwith a
partially rescuing transgene, PoxnDM22-B5-DXB, flies are generally
healthy but gustatoryperception is eliminated in the labelum, the
legs,and the wing margins (17). PoxnDM22-B5-DXB fliesshowed no
pheromone-induced changes in star-vation resistance, TAG amounts,
or life span (Fig. 2,A to C). However, the responses of Poxn
mutantflies that carried a transgene that restores tastefunction to
the legs and wing margins [but notlabelum;PoxnDM22-B5-Full1 (17)]
were similar tothose of control flies (Fig. 2, A to C). Thus,
theeffects of pheromone exposure appear to be me-diated by taste
perception through gustatory neu-rons outside of the
mouthparts.
To identify specific gustatory receptors andneurons that might
mediate the pheromone ef-fects, we tested candidate pheromone
receptors.Of the mutants that we examined, only flies
that carried a loss-of-function mutation in thegene pickpocket
23 (ppk23) were resistant to theeffects of pheromone exposure (fig.
S8). Furtheranalysis verified that ppk23 was required for
theeffects of pheromone exposure on starvation re-sistance, TAG
amounts, and life span (Fig. 2, Dto F). Silencing ppk23-expressing
neurons onlyduring exposure to donor males by expressing
atemperature-sensitive dominant-negative allele ofthe dynamin gene
shibire (via ppk23-GAL4;UAS-shits) also eliminated the differential
response topheromones (Fig. 3A). In male Drosophila,
thetranscription factor fruitless (fru) is expressed withppk23 in
pheromone-sensing neurons located in theanimals’ forelegs (18), and
silencing fru-expressingneurons during exposure (via
fru-GAL4;UAS-shits)abrogated pheromone effects (Fig. 3B).
Consistentwith a requirement for these neurons, we foundthat
surgical amputation of the forelegs, but notinjury alone, was
sufficient to reproducibly elim-inate the effects of pheromone
exposure (Fig. 3Cand fig. S9). Moreover, acute targeted activa-tion
of ppk23-expressing neurons by means ofa temperature-sensitive
TRPA1 channel (ppk23-GAL4;UAS-TRPA1) was sufficient to mimic
theeffects of female pheromone without exposure
P
-
Control
ppk23 > shi ts
Female
FemaleMale
Male
Control
fru > shi ts
Female
FemaleMale
Male
Sur
vivo
rshi
p
Sur
vivo
rshi
p
Sur
vivo
rshi
p
Starvation Time (Hours) Starvation Time (Hours) Starvation Time
(Hours)
Sur
vivo
rshi
p
Starvation Time (Hours)
Sur
vivo
rshi
p
Age (Days)
Control
Foreleg Removed
Female
FemaleMale
Male
BA C
FD E
ppk2
3>
T
RPA1
Cont
rol
ppk23>TRPA1Control
ppk23>TRPA1Control
P=0.002P
-
(Fig. 3, D to F). Together, these data indicate
thatpheromone-sensing neurons in the foreleg of themale fly that
express the gustatory receptor ppk23and the transcription factor
fruitless influencestress resistance, physiology, and life span
inresponse to perception of female pheromones.
To examine brain circuits that may functionin transducing
pheromone perception, we selec-tively expressed UAS-shits to block
synaptic trans-mission in various neuroanatomical regions withthe
goal of disrupting the physiological effects ofdonor pheromone
exposure. The effects were ab-rogated whenUAS-shits was driven in
neurons char-acterized by expression of neuropeptide F (NPF,as
represented by npf-GAL4) (fig. S10). Furtheranalysis verified that
pheromone-induced changesin starvation resistance and TAG abundance
werelost after silencing of npf-expressing neurons(Fig. 4A).
Consistent with a possible role in trans-ducing pheromone
information, npf expressionwas significantly increased by 30% in
experimen-tal males after exposure to feminized donormales(fig.
S11), and activation of npf-expressing neu-rons was sufficient to
decrease life span in theabsence of pheromone exposure (Fig.
4B).
NPF may function as a mediator of sexualreward in Drosophila
(19), and its mammalian
counterpart, neuropeptide Y (NPY), has beenassociated with
sexual motivation and psycho-logical reward (20, 21). We tested
whether theeffects of pheromone perception might be res-cued by
allowing males to successfully mate withfemales. Neither a small
number of conjugalvisits with virgin females nor housing with
wild-type females in a 1:1 ratio was sufficient to ame-liorate the
effects of pheromone exposure (fig.S12). In this context, decreased
longevity may bea consequence of pheromone perception and notof
mating itself. MaleDrosophila are willing andable to copulate up to
five times in rapid suc-cession before requiring a refractory
period (22).We found that supplementing donor cohorts withan excess
of mating females (in a 5:1 ratio) wassufficient to significantly
reduce the effects onmortality and TAG caused by female donor
pher-omone early in life (Fig. 4C and fig. S13). Thebenefits of
mating on age-specific mortality de-creased with age, which
suggests that aging mayreduce mating efficiency or may diminish
effec-tive mating reward.
To identify how sexual perception and rewardmay alter
physiological responses in peripheraltissues, we
usedwhole-genomeRNA sequencing(RNA-seq) technology to examine
changes in gene
expression. We found 195 genes with significant-ly different
expression (using an experiment-wise error rate of 0.05) in control
male flies thatwere exposed to feminized or control donormales for
48 hours. Nearly all (188/195 = 96%)of the changes appeared to be
due to pheromoneperception, because they were not observed
inidentical experiments using ppk23 mutant flies(table S1). Males
exposed to female pheromonesdecreased the transcription of genes
encodingodorant-binding proteins and increased the tran-scription
of several genes with lipase activity(Fig. 4D). A significant
enrichment was observedin secreted molecules, which includes genes
en-coding proteins that mediate immune and stressresponses. Many of
these genes and pathwayswere highlighted in a recent meta-analysis
of geneexpression changes in response to stress andaging (23).
The activities of insulin and target of rapamycin(TOR)
signaling, which modulate aging acrosstaxa, increase sexual
attractiveness in flies (24).Our demonstration that perception of
sexual char-acteristics is sufficient to modulate life span
andphysiology suggests that aging pathways in oneindividual may
modulate health and life span inanother (fig. S14). These types of
indirect genetic
Control
npf > shi ts
Female
FemaleMale
Male
Ln(M
orta
lity
Rat
e)
Age (Days)
A B C
D
Feminized Male
Fem. Male+FemaleCont. Male+Female
Control Male
Donor Flies
P=0.02
Sur
vivo
rshi
p
Starvation Time (Hours)
−1 0 0.5 1 1.5Fold-Change
Obp
9bO
r83b
Obp
83a
Obp
28a
lush
Obp
83a
Odorant/Pheromone Binding
a5Ls
p2
Obp
99b
lush
IM4
jeb
CG
1330
9
Cht
4
Acp
76a
CH
3422
7
Ag5
r
IM1,
IM2
CG
7017
Obp
83a
Obp
83a
Acp
36D
E
PG
RP
-SB
1
TotC
upd3
Obp
28a
Lsp1
β
Est
-6*
Est
-6*
IM1,
IM2
IM23 Dpt
Npl
p3
Mur
18b
CG
1582
8Im
pL2
verm
iota
Tryu
serp
Dpt
B
Dro
Extracellular/Secreted Molecules
OR
MD
L
Pep
ckC
G10
924
Glycolysis/Gluconeogenesis
IM4
PG
RP
-SB
1
IM1,
IM2
upd3
IM23 Drofon
IM1,
IM2
TotC Dpt
Dpt
B
Immune Response
CG
8773
CG
8773
CG
3134
3
CG
5527
CG
9505
CG
3119
8C
G58
49
CG
1328
3
CG
7631
CG
1525
5
Metallopeptidase Activity
CG
1108
9
ade5
ade3
IMP Biosynthesis
Ugt
86D
e*U
gt86
De*
CG
9363
Ugt
86D
e*
Drug Metabolism
Sur
vivo
rshi
p
Age (Days)
UAS-TRPA1
npf>TRPA1npf-GAL4
CG
1035
7
CG
5966
CG
2772
CG
6296
Lipase Activity
P=0.50
P=0.001
P=0.005
Fig. 4. Aging and physiology are modulated by neuralmechanisms
of expectation and reward. (A) Inhibition ofnpf-expressing neurons
abrogates differences in starvationcaused by pheromone exposure. N
= 43 and 45 for control(npf-GAL4 only) flies exposed to male or
female donor phero-mones, respectively (P = 0.005, log-rank test).
N = 48 and 47for treatment (npf-GAL4; UAS-shits) flies exposed to
male orfemale donor pheromones, respectively (P = 0.50 by
log-ranktest). Inset is as described in Fig. 2. (B) Activation of
npf-expressing neurons causes decreased longevity in the absenceof
pheromone exposure. npf-GAL4;uas-dTRPA1 males (N = 239)exhibit
significantly shorter life span relative to UAS-dTRPA1 only(N =
235; P ≤ 0.001, log-rank test) and npf-GAL4 only (N = 179;P ≤
0.001, log-rank test) male transgene controls. (C) Mortalityrates
are reduced when males exposed to female donorpheromone (dashed
black line) are given access to excessfemales (dashed red line; P =
0.02 through 20 days of age byAalen regression). Cohorts consisted
of five experimentalmales together with (i) 30 control donor males
(solid black),(ii) 30 feminized donor males (dashed black), (iii) 5
feminizeddonor males + 25 females (dashed red), or (iv) 5 control
donor males + 25females (solid red); 20 replicate cohorts, totaling
100 experimental flies,were measured for each treatment. (D)
Significantly enriched Gene Ontology
pathways and functions whose genes are differentially regulated
after pher-omone exposure. See table S1 for a complete list of
genes with significantchanges in expression.
www.sciencemag.org SCIENCE VOL 343 31 JANUARY 2014 547
REPORTS
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effects have the potential to be influential agentsof natural
selection (25). Imbalances of expec-tation and reward may therefore
have broadeffects on health and physiology in humans andmay
represent a powerful evolutionary force innature.
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Acknowledgments: We thank the members of the Pletcherlaboratory
for Drosophila husbandry, N. Linford for commentson the revision,
P. J. Lee for figure illustration, and membersof the Dierick and
Pletcher laboratories for suggestions onexperiments and comments on
the manuscript. Supportedby NIH grants R01AG030593, TR01AG043972,
andR01AG023166, the Glenn Foundation, the AmericanFederation for
Aging Research, and the Ellison MedicalFoundation (S.D.P.); Ruth L.
Kirschstein National Research
Service Award F32AG042253 from the National Institute onAging
(B.Y.C.); NIH grant T32AG000114 (B.Y.C.); NIH grantsT32GM007863 and
T32GM008322 (Z.M.H.), a Glenn/AFARScholarship for Research in the
Biology of Aging (Z.M.H.); NSFgrant IOS-1119473 (H.A.D.); and the
Alexander von HumboldtFoundation and Singapore National Research
Foundation grantRF001-363 (J.Y.Y.). This work made use of the
DrosophilaAging Core of the Nathan Shock Center of Excellence in
theBiology of Aging, funded by National Institute on Aging
grantP30-AG-013283. RNA-seq expression data are provided intable
S1. The funders had no role in study design, datacollection and
analysis, decision to publish, or preparationof the manuscript. The
authors declare that they have nocompeting interests. C.M.G.,
T.-H.K., Z.M.H., and S.D.P.conceived and designed the experiments;
C.M.G., T.-H.K.,Z.M.H., B.Y.C., J.Y.Y., H.A.D., and S.D.P.
performed theexperiments; C.M.G., T.-H.K., Z.M.H., B.Y.C., J.Y.Y.,
andS.D.P. analyzed the data; and C.M.G., T.-H.K., J.Y.Y.,
H.A.D.,and S.D.P. wrote the paper.
Supplementary
Materialswww.sciencemag.org/content/343/6170/544/suppl/DC1Materials
and MethodsFigs. S1 to S14Table S1References (26–28)
16 July 2013; accepted 31 October 2013Published online 28
November 2013;10.1126/science.1243339
Savanna Vegetation-Fire-ClimateRelationships Differ Among
ContinentsCaroline E. R. Lehmann,1,2* T. Michael Anderson,3 Mahesh
Sankaran,4,5
Steven I. Higgins,6,7 Sally Archibald,8,9 William A. Hoffmann,10
Niall P. Hanan,11
Richard J. Williams,12 Roderick J. Fensham,13 Jeanine Felfili,14
Lindsay B. Hutley,15
Jayashree Ratnam,4 Jose San Jose,16 Ruben Montes,17 Don
Franklin,15
Jeremy Russell-Smith,15 Casey M. Ryan,2 Giselda Durigan,18
Pierre Hiernaux,19
Ricardo Haidar,14 David M. J. S. Bowman,20 William J. Bond21
Ecologists have long sought to understand the factors
controlling the structure of savannavegetation. Using data from
2154 sites in savannas across Africa, Australia, and South
America,we found that increasing moisture availability drives
increases in fire and tree basal area, whereasfire reduces tree
basal area. However, among continents, the magnitude of these
effects variedsubstantially, so that a single model cannot
adequately represent savanna woody biomassacross these regions.
Historical and environmental differences drive the regional
variation inthe functional relationships between woody vegetation,
fire, and climate. These same differenceswill determine the
regional responses of vegetation to future climates, with
implications forglobal carbon stocks.
Savannas cover 20% of the global land sur-face and account for
30% of terrestrial netprimary production (NPP) and the vast
ma-jority of annual global burned area (1–3). Savannaecosystem
services sustain an estimated one-fifthof humans, and savannas are
also home to mostof the remaining megafauna (1). Tropical savannais
characterized by the codominance of C3 treesand C4 grasses that
have distinct life forms andphotosynthetic mechanisms that respond
differ-ently to environmental controls (4). Examplesinclude the
differing responses of these func-tional types to temperature and
atmospheric CO2concentrations, predisposing savannas to altera-
tions in structure and extent in the coming cen-tury (4–6).
Tropical savannas are defined by a contin-uous C4 herbaceous
layer, with a discontinuousstratum of disturbance-tolerant woody
species(7). Although savanna tree cover varies greatly inspace and
time (8, 9), the similarities in structureamong the major savanna
regions of Africa,Australia, and South America have led to
anassumption that the processes regulating veg-etation structure
within the biome are equiva-lent (10, 11). Current vegetation
models treatsavannas as a homogenous entity (12, 13).
Recentstudies, however, have highlighted differences
in savanna extent across continents (14, 15), andit remains
unknown how environmental driversinteract to determine the
vegetation dynamicsand limits of the biome (10, 14, 15).
We sought universal relationships betweensavanna tree basal area
(TBA, m2 ha−1), a keymetric of woody biomass within an
ecosystem,and the constraints imposed by resource availa-bility
(moisture and nutrients), growing condi-tions (temperature), and
disturbances (fire).Ecologists have devoted considerable effort
tothe identification of universal relationships to de-scribe the
structure and function of biomes (16).However, it has not been
clear whether such re-lationships exist. Any such relationships
maybe confounded by the unique evolutionary andenvironmental
histories of each ecological set-ting (11).
Across Africa and Australia, TBA scales sim-ilarly with
rainfall, but the intercepts and the 95thquantile differ
substantially (Fig. 1, A to C). Onaverage, at a given level of
moisture availability,TBA is higher in Africa and lower in
Australia.However, in South America there is almost norelationship
between rainfall and TBA, which isprobably in part attributable to
the narrow rangeof rainfall that savanna occupies on this
continent(Fig. 2). Further, across the observed range ofrainfall,
the upper limits of TBA increase linearlywith effective rainfall
for Australian savannas(Fig. 1B) but show a saturating response
inAfrican and South American savannas (Fig. 1, Aand C). When TBA is
used to estimate above-ground woody biomass (AWB) (17), the
largedifferences in intercepts between Africa andAustralia are
reduced but substantial differencesin the limits remain (fig. S1, A
to C). By con-
31 JANUARY 2014 VOL 343 SCIENCE www.sciencemag.org548
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