|
| Pletcher Lab Research |
| |
Our goal is to identify and investigate genetic mechanisms that
are likely to be important for aging and age-related disease in humans by focusing on
equivalent, conserved processes in the fruit fly, Drosophila melanogaster.
Currently we are studying genes involved in linking diet, obesity, and immune function
with aging and aging-related disease.
One particular area of research focuses on the phenomenon of dietary restriction, where lifespan
is increased by restricting nutrient intake to roughly 65% of what animals would eat when allowed
to feed ad libitum. In rodents, dietary restriction maintains most physiological processes in an
apparently youthful state, and it delays the occurrence and/or progression of age-associated disease.
In work completed during his post-doc in the Partridge lab, Dr. Pletcher described a molecular signature
of aging and used it to show that, as it does in mammals, dietary restriction delayed significant
changes in gene expression that occur in many different biological processes in the aging animal. He
was also involved in work that showed that life-long adherence to a strict dietary restriction regime
is not required for flies to experience longevity-extending benefits: as little as two days of diet
restriction will suffice. These data served as a starting point for the research that followed at Baylor.
 The traditional belief that the most
important aspect of diet is its energetic (i.e., caloric) content is currently under
challenge by hypotheses that focus on more subtle characteristics of the diet, such
as its nutritional composition. For example, although there is ancillary evidence
that certain diets, such as the protein-rich Atkins’ diet, may promote weight loss,
the underlying mechanisms for its effect are unknown, as are the medium- and long-term
consequences associated with such dietary imbalance. In D. melanogaster,
alterations in diet composition affect behavior, metabolism, and lifespan.
Providing flies with a diet rich in protein but limiting in carbohydrates
produced lean, reproductively-competent animals with a reduced appetite.
Excess dietary carbohydrates, on the other hand, promoted obesity, which was
magnified during aging. In several instances dietary protein limited or reversed
the affect of dietary carbohydrate, and flies fed a balanced diet enjoyed the
longest lifespan. These data reveal that diet composition, rather than caloric
intake, modulates aging, appetite, and fat storage in flies, and we are engaged
in studying the underlying genetic mechanisms that link diet with overall health
and longevity in this species.
 More recently we
have shown that longevity in general (and diet restriction in particular) is regulated
by olfaction and food-derived odors. Using the fruit fly, Drosophila melanogaster, we
show that exposure to nutrient-derived odorants can modulate lifespan and partially reverse
the longevity-extending effects of dietary restriction. Furthermore, mutation of odorant
receptor Or83b results in severe olfactory defects, alters adult metabolism, enhances
stress resistance, and extends lifespan. Our findings indicate that olfaction affects
adult physiology and aging in Drosophila possibly through perceived availability of
nutritional resources and that olfactory regulation of lifespan is evolutionarily
conserved.
Finally, we also use Drosophila as a model for studying the role of inflammatory
responses on aging. These processes, which originate from the innate immune system,
have been implicated as predictors/initiators of, or contributors to, chronic diseases
and conditions of human aging. Mechanisms of innate immunity are highly conserved across
species, and work from our laboratory and others has established that flies exhibit
remarkable upregulation of innate-immunity-related genes with advancing age. Expression
of these genes is dependent on NFk-Blike transcription factors, which are also critical
mediators of mammalian inflammation. We are testing the hypothesis that the observed
activation of NFk-B signaling pathways is caused by endogenous, aging-related changes
in the fly that generates a condition homologous to mammalian inflammation.
| | Selected Publications |
| |
|
(Click on the reference to view the paper) |
| |
|
Libert, S., Zwiener, J., Chu, X., Vanvoorhies, W., Roman, G., and Pletcher, S.D. (2007). Regulation of Drosophila life span by olfaction and food-derived odors. Science 315, 1133-1137. (PDF) |
| |
|
Libert, S., Chao, Y., Chu, X., and Pletcher, S.D. (2006). Trade-offs between longevity and pathogen resistance in Drosophila melanogaster are mediated by NFk-B signaling. Aging Cell 5, 533-543. (PDF) |
| |
|
Pletcher, S.D., Libert, S., and Skorupa, D. (2005). Flies and their golden apples: the effect of dietary restriction on Drosophila aging and age-dependent gene expression. Ageing Res Rev 4, 451-480. (PDF) |
| |
|
Zheng, J., Edelman, S.W., Tharmarajah, G., Walker, D.W., Pletcher, S.D., and Seroude, L. (2005). Differential patterns of apoptosis in response to aging in Drosophila. Proc Natl Acad Sci U S A 102, 12083-12088. (PDF) |
| |
|
McCarroll, S.A., Murphy, C.T., Zou, S., Pletcher, S.D., Chin, C.S., Jan, Y.N., Kenyon, C., Bargmann, C.I., and Li, H. (2004). Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet 36, 197-204. (PDF) |
| |
|
Mair, W., Goymer, P., Pletcher, S.D., and Partridge, L. (2003). Demography of dietary restriction and death in Drosophila. Science 301, 1731-1733. (PDF) |
| |
|
Pletcher, S.D., Macdonald, S.J., Marguerie, R., Certa, U., Stearns, S.C., Goldstein, D.B., and Partridge, L. (2002). Genome-Wide Transcript Profiles in Aging and Calorically Restricted Drosophila melanogaster. Curr Biol 12, 712-723. (PDF) |
| |
|
Pletcher, S.D. (1999). Model fitting and hypothesis testing for age-specific mortality data. Journal of Evolutionary Biology 12, 430-440. (PDF) |
| |
Pletcher, S.D., Houle, D., and Curtsinger, J.W. (1998). Age-specific properties of spontaneous mutations affecting mortality in Drosophila melanogaster. Genetics 148, 287-303. (PDF)
|
| |
| (See our Departmental page) | |
