evolutionary advantage of preserving limited resources for the offspring (30) or preventing competition from other males.
References and Notes
1. D. Gems, D. L. Riddle, Nature 379, 723–725 (1996).
2. T. Chapman, L. F. Liddle, J. M. Kalb, M. F. Wolfner,
L. Partridge, Nature 373, 241–244 (1995).
3. L. A. Herndon et al., Nature 419, 808–814 (2002).
4. C. F. Glenn et al., J. Gerontol. A Biol. Sci. Med. Sci. 59,
5. D. K. Chow, C. F. Glenn, J. L. Johnston, I. G. Goldberg,
C. A. Wolkow, Exp. Gerontol. 41, 252–260 (2006).
6. M. D. McGee et al., Aging Cell 10, 699–710
7. J. Hodgkin, T. M. Barnes, Proc. Biol. Sci. 246, 19–24
8. K. C. Kiontke et al., BMC Evol. Biol. 11, 339 (2011).
9. S. B. Pierce et al., Genes Dev. 15, 672–686
10. E. J. Tisdale, J. R. Bourne, R. Khosravi-Far, C. J. Der,
W. E. Balch, J. Cell Biol. 119, 749–761 (1992).
11. T. J. Maures, E. L. Greer, A. G. Hauswirth, A. Brunet,
Aging Cell 10, 980–990 (2011).
12. C. Jin et al., Cell Metab. 14, 161–172 (2011).
13. R. A. Butcher, M. Fujita, F. C. Schroeder, J. Clardy,
Nat. Chem. Biol. 3, 420–422 (2007).
14. P. Y. Jeong et al., Nature 433, 541–545 (2005).
15. J. Srinivasan et al., Nature 454, 1115–1118
16. P. T. McGrath et al., Nature 477, 321–325 (2011).
17. E. Z. Macosko et al., Nature 458, 1171–1175
18. A. H. Ludewig et al., Proc. Natl. Acad. Sci. U.S.A. 110,
19. Y. Izrayelit et al., ACS Chem. Biol. 7, 1321–1325
20. L. A. Perkins, E. M. Hedgecock, J. N. Thomson,
J. G. Culotti, Dev. Biol. 117, 456–487 (1986).
21. B. van Swinderen, L. B. Metz, L. D. Shebester,
C. M. Crowder, Genetics 161, 109–119 (2002).
22. A. D. Cutter, Mol. Biol. Evol. 25, 778–786 (2008).
23. D. Gems, D. L. Riddle, Genetics 154, 1597–1610
24. J. Apfeld, C. Kenyon, Nature 402, 804–809 (1999).
25. J. Alcedo, C. Kenyon, Neuron 41, 45–55 (2004).
26. S. Libert et al., Science 315, 1133–1137 (2007).
27. C. I. Bargmann, H. R. Horvitz, Science 251, 1243–1246
28. A. H. Ludewig, F. C. Schroeder, WormBook 2013,
29. P. Ren et al., Science 274, 1389–1391 (1996).
30. T. B. Kirkwood, Nature 270, 301–304 (1977).
Acknowledgments: We thank members of the Brunet
laboratory, S. Kim, A. Fire, and A. Villeneuve for helpful
suggestions and J. Lim and S. Zimmerman for critical reading
of the manuscript. We thank N. Kosovilka and the Protein and
Nucleic Acid Facility facility for the microarray experiments
and T. Stiernagle from the Caenorhabditis Genetics Center.
Supported by R01AG031198, DP1AG044848, the Glenn
Foundation for Medical Research (A.B.), postdoctoral fellowship
F32AG37254 (T.J.M.), T32HG000044 and the Helen Hay
Whitney Foundation (L.N.B.), Stanford Dean’s Fellowship (BAB),
R01GM088290 (F.C.S.), and T32GM008500 (Y.I.).
Materials and Methods
Figs. S1 to S3
Tables S1 and S2
Movies S1 to S6
2 August 2013; accepted 11 November 2013
Published online 28 November 2013;
Drosophila Life Span and Physiology
Are Modulated by Sexual
Perception and Reward
Christi 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 perception
of female sexual pheromones through a specific gustatory receptor expressed in a subset
of foreleg neurons in male fruit flies, Drosophila melanogaster, rapidly and reversibly
decreases fat stores, reduces resistance to starvation, and limits life span. Neurons that
express the reward-mediating neuropeptide F are also required for pheromone effects.
High-throughput whole-genome RNA sequencing experiments revealed a set of molecular
processes that were affected by the activity of the longevity circuit, thereby identifying
new candidate cell-nonautonomous aging mechanisms. Mating reversed the effects of
pheromone perception; therefore, life span may be modulated through the integrated action
of sensory and reward circuits, and healthy aging may be compromised when the expectations
defined by sensory perception are discordant with ensuing experience.
Sensory perception can modulate aging and physiology in multiple species (1–6). In Drosophila, exposure to food-based
odorants partially reverses the anti-aging effect
of dietary restriction, whereas broad reduction in
olfactory function promotes longevity and alters
fat metabolism (2, 4). Even the well-known rela-
tion between body temperature and life span may
have a sensory component (7, 8).
To identify sensory cues and neuronal circuitry that underlie the effects of sensory perception on aging, we focused on the perception of
potential mates. Social interactions are prevalent
throughout nature, and the influence of social
context on health and longevity is well known
in several species, including humans (9). Such
influences include behavioral interactions with
mates and broader physiological “costs of reproduction,” which often form the basis for evolutionary models of aging (10, 11).
In Drosophila, the presence of potential mates
is perceived largely through nonvolatile cutic-
ular hydrocarbons, which are produced by cells
called 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, we
housed “experimental” flies of the same geno-
type with “donor” animals of the same sex that
either expressed normal pheromone profiles or
were genetically engineered to express phero-
mone profiles characteristic of the opposite sex
(Fig. 1A). Donor males with feminized pheromone
profiles were generated by targeting expression
of the sex determination gene, transformer, to the
oenocytes [via OK72-GAL4 or Prom-E800-GAL4
(14) (fig. S1)], whereas masculinization of female
flies was accomplished by expressing tra-RNAi in
a similar way (15). This design allowed manipulation of the experimental animals’ perceived sexual
environment without introducing complications associated with mating itself.
In Drosophila, sensory manipulations can affect life span, fat storage [as determined by baseline measures of triacylglyceride (TAG)], and
certain aspects of stress resistance (2, 4). We
found that flies exposed to pheromones of the
opposite sex showed differences in these phenotypes. Experimental male flies exposed to male
donor pheromone had higher amounts of TAG,
were substantially more resistant to starvation,
and exhibited a significantly longer life span than
genetically identical male siblings exposed to female donor pheromone (Fig. 1, B to D). Females
exhibited similar phenotypes in response to male
donor pheromone, but the magnitude of the effects was smaller (fig. S2). Subsequent experiments
were therefore focused on males.
The characteristics of pheromone exposure
were indicative of a mechanism involving sensory perception. Effects were similar in several
genetic backgrounds, including a strain recently collected in the wild (fig. S3), and were largely unaffected by cohort composition (fig. S4).
Pheromone-induced phenotypes were detected
after as little as 2 days’ exposure to donor animals (Fig. 1, B and C), persisted with longer manipulations (Fig. 1D), and were progressively
1Department of Molecular and Integrative Physiology and
Geriatrics Center, Biomedical Sciences and Research Building, University of Michigan, Ann Arbor, MI 48109, USA. 2De-
partment of Molecular and Human Genetics, Baylor College
of Medicine, Houston, TX 77030, USA. 3Medical Scientist
Training Program, Taubman Medical Library, University of
Michigan, Ann Arbor, MI 48109, USA. 4Temasek Life Sciences
Laboratory, National University of Singapore, Singapore 117604.
5Department of Biological Sciences, National University of
Singapore, Singapore 117543.
*These authors contributed equally to this work.
†Corresponding author. E-mail: firstname.lastname@example.org