Endocrine regulation of aging and reproduction in Drosophila

Abstract

Hormonal signals can modulate lifespan and reproductive capacity across the animal kingdom. The use of model organisms such as worms, flies and mice has been fundamentally important for aging research in the discovery of genetic alterations that can extend healthy lifespan. The effects of mutations in the insulin and insulin-like growth factor-like signaling (IIS) pathways are evolutionarily conserved in that they can increase lifespan in all three animal models. Additionally, steroids and other lipophilic signaling molecules modulate lifespan in diverse organisms. Here we shall review how major hormonal pathways in the fruit fly Drosophila melanogaster interact to influence reproductive capacity and aging.

Introduction

In many multicellular organisms, coordination of the activities of spatially separated organs is achieved by diffusible messengers, hormones, produced within endocrine tissues or specialized cells of the body. Hormones are secreted and circulated in the body, and trigger intracellular events in the target tissues, through the ligand binding domain of the cognate hormone receptors. Upon hormonal exposure, cellular function is modified by activation of cytoplasmic signaling cascades (e.g. receptor tyrosine kinases, such as the insulin receptor) or by direct alteration of transcriptional activity of the receptor (e.g. nuclear receptors). The outcome of hormone binding can be modified by other intracellular signaling pathways that interact with downstream components of the primary signal, by co-regulators that activate or repress the receptor, and by feedback signals from secondary hormones. Such integrated systems between organs allow orchestration of growth and development and maintenance of metabolic homeostasis in response to environmental changes, such as in nutrient availability. Furthermore, hormonal signals modulate lifespan and reproduction (Tatar et al., 2003, Taguchi and White, 2008, Russell and Kahn, 2007, Piper et al., 2008).

Insect endocrinology is one of the oldest branches of insect physiology (Nijhout, 1994, Nation, 2002). Drosophila has brought to this topic the power of molecular genetics and genomics. Much of our understanding of genetic transmission is based on early experiments with the fruit fly Drosophila melanogaster (Kohler, 1994, Sturtevant, 2001). Because of its small size, it is not an ideal organism for endocrinological studies using approaches such as microsurgery or tissue transplantation, for which larger species such as some moths, locusts or cockroaches are more convenient. However, the plethora of genetic techniques available (Dow, 2007) allows other kinds of precise manipulation of endocrinological systems. For example, genetic ablation of specific neurosecretory glands or neuroendocrine cell populations has provided valuable insights into endocrinology of metabolism and longevity (Rulifson et al., 2002, Lee and Park, 2004, Broughton et al., 2005, Grönke et al., 2007, McBrayer et al., 2007). Drosophila also has tissues that more strongly resemble those of mammals that do those of the nematode Caenorhabditis elegans, the other major multicellular invertebrate model organism (Partridge and Tower, 2008). Functional genetic analysis in flies is facilitated by a vast and constantly growing collection of mutations and mis-expression lines, such as RNAi lines, available from public stock centers (e.g. Bloomington Drosophila Stock Center, Indiana, U.S.A. (http://flystocks.bio.indiana.edu/), Vienna Drosophila RNAi Center, Austria (Dietzl et al., 2007, http://stockcenter.vdrc.at/control/main), National Institute of Genetics, Japan (http://www.shigen.nig.ac.jp/fly/nigfly/index.jsp)) and by sequenced genomes for several related species (Crosby et al., 2007, Clark et al., 2007). A large fraction of human genes, including those implicated in aging and aging-related disease, have orthologues in flies (Bernards and Hariharan, 2001) and, importantly, complications in the analysis of gene function can often be avoided because the fly genome (Adams et al., 2000) carries a smaller number of gene paralogues than do those of mammals or worms, and is hence less redundant. Additionally, most of the basic metabolic functions are conserved between Drosophila and mammals (Baker and Thummel, 2007) making flies ideal organism for genetic probing of metabolic homeostasis, endocrinology and aging (Partridge and Tower, 2008). However, the life history of Drosophila involves a radical metamorphosis, in which larval tissues are replaced or remodeled to give a morphologically quite different adult fly. Most work on Drosophila endocrinology, and indeed most other aspects of Drosophila biology, has been done in embryos and larvae, mainly through work on control of growth and development. It is clear from systematic studies of RNA expression (Chintapalli et al., 2007) that genes involved in endocrinological regulation of pre-adult events are also expressed in the adult fly. However, their functions in the adult, and hence any role in regulation of aging and reproduction, largely await elucidation.

Like mammals, Drosophila has discrete endocrine organs and cells (Fig. 1). Glandular tissues, such as the prothoracic gland (PG), corpus allatum (CA) and corpus cardiacum (CC), produce hormones that regulate developmental timing, metamorphosis, metabolism and reproduction (Leopold and Perrimon, 2007, Nijhout, 1994, Tatar et al., 2003, Flatt et al., 2005, Grönke et al., 2007, Mirth and Riddiford, 2007, Colombani et al., 2005, Belgacem and Martin, 2007). In larvae, these three endocrine tissues constitute the ring gland, a master endocrine organ located dorsally between the two hemispheres of the brain. The ring gland undergoes a dramatic change during metamorphosis (Dai and Gilbert, 1991). The PG degenerates and the CA/CC complex migrates to its distinctive location above the junction between the crop (food storage organ) and the midgut (stomach). Larval ecdysteroids (steroids with molt-promoting activity) are produced in the PG. After PG-degeneration, in adult females the ovarian follicle cells are thought to take over this function (Riddiford, 1993). Little is known about ecdysteroid synthesis in other tissues in Drosophila. Ecdysteroids are present in adult males, where they play role in control of fertility and reproductive behaviour (Wismar et al., 2000, Ganter et al., 2007). In both larvae and adults, the CA are the source of the sequiterpenoid juvenile hormone (JH), while the lipid-mobilizing adipokinetic hormone (AKH) is produced in the CC. Some of the Drosophila insulin-like peptides (DILPs) are produced in large, specialized neurons of the central nervous system, the DILP-producing median neurosecretory cells (hereafter called MNCs) (Cao and Brown, 2001, Ikeya et al., 2002). Products of other distinct populations of neurosecretory cells (not shown in Fig. 1, for clarity) include biogenic amines such as dopamine and serotonin, which also work as neurotransmitters and neuromodulators (Monastirioti, 1999).

This review focuses on endocrinological systems that that have been demonstrated or proposed to influence adult lifespan in Drosophila, and hormones with relevant functions have been listed in Table 1. Developmental phenotypes controlled by endocrine signaling have been well reviewed elsewhere (Truman and Riddiford, 2002, Mirth and Riddiford, 2007). In Drosophila, representatives of peptide hormones, lipophilic hormones and bioactive amines have been shown to modulate lifespan and reproduction, by manipulations that directly decrease hormone production (Broughton et al., 2005), through inactivating mutations in hormone receptors or their downstream targets (Tatar et al., 2001, Clancy et al., 2001, Simon et al., 2003) or by polymorphic alterations in the genes required for hormone biosynthesis (De Luca et al., 2003, Carbone et al., 2006). Many of these systems also affect reproduction, and we shall discuss this connection. We shall also discuss other phenotypes that commonly associate with longevity, such as changes in lipid and carbohydrate homeostasis, and resistance to starvation or oxidative stress. Of special interest here will be how these major hormonal pathways interact with each other to influence both reproductive capacity and aging. Although recent work has made important strides, undoubtedly much information about the endocrinology of adult Drosophila remains to be discovered.