Sci. Aging Knowl. Environ., 5 March 2003
Vol. 2003, Issue 9, p. pe5
[DOI: 10.1126/sageke.2003.9.pe5]


Unearthing Loci That Influence Life Span

Marc Tatar

The author is in the Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA. E-mail: marc_tatar{at};2003/9/pe5

Key Words: steroid hormones • ecdysone • Drosophila • gene expression

In order to decipher how and why animals undergo senescence, we must understand the action of hormones. For example, it has been shown that in model organisms (nematodes, flies, and mice) mutations in genes that encode components of the insulin/insulin-like growth factor (IGF) hormonal signaling pathway extend longevity (1) and postpone morbidity (2) (see "One For All"). Determining the mechanisms by which hormones effect systemic changes in life span is now a central goal for current research on aging. At the heart of the problem resides the following question: To slow aging, must insulin/IGF activity be reduced in each and every cell in the adult body, or do other hormones that act downstream of some localized insulin/IGF function hold the primary role in regulating the senescence of cells and tissue? In a paper published in this week's issue of Science, Anne Simon and colleagues show for the first time that a sterol hormone--ecdysone of the fly Drosophila melanogaster--regulates aging (3).

What makes this finding so intriguing is that insulin/IGF signals control the production of ecdysone in adult insects (4, 5). Ecdysone often functions in conjunction with the hydrocarbon endocrine juvenile hormone (JH) (6). JH also has been shown to influence insect aging and to be regulated in part by insulin/IGF (7, 8). Ecdysone is a relative of the estrogen-like sterols (Fig. 1), and thus studies of the hormone can provide new and compelling insights into the parallels between aging in invertebrates and mammals.

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Fig. 1. Structures of steroid hormones.

Ecdysone (or more specifically, its activated form 20-hydroxyecdysone) has been studied extensively to determine how it regulates insect development and metamorphosis (6). In the adult insect, ecdysone takes on new roles; for instance, in yolk synthesis and behavior. Within a complex of cofactors, ecdysone binds to a nuclear hormone receptor (the ecdysone receptor, EcR), which can dimerize to a second receptor, Ultraspirical (USP). Biologists working with developmental phenotypes have used the EcR/USP complex as a premier model to explore how hormones regulate gene expression. Simon and colleagues introduced a new question into this classical mixture: Is aging slowed when ecdysone activity is reduced? Much could be learned if the answer were affirmative, because, unlike the case with JH, ecdysone receptors are well characterized and could readily point to genes that affect aging. Simon et al. set about to test this notion with an array of complementary studies. She and her colleagues were not disappointed.

Simon et al. investigated a suite of mutations in flies that block or reduce the ability of ecdysone to bind to and/or activate EcR. In every case, adult longevity was increased, often in the range of 30 to 40%. Likewise, a mutant thought to decrease ecdysone synthesis, DTS-3, increased adult longevity. These effects could be induced even when the adults had already aged for some time, and the gains could be reversed when adults were fed ecdysone. Consistent with many of the observations associated with longevity mutants of nematodes, flies, and mice, the extended life span of ecdysone mutant flies was accompanied by an increased resistance to oxidative and heat stresses. Surprisingly, although active ecdysone is crucial for reproduction, the heterozygous receptor mutants retained excellent fecundity. Thus, it is not necessary to reduce fecundity to increase longevity.

These new results can help integrate many previous findings on nematode and fly aging. In the absence of ecdysone, EcR/USP is thought to form complexes with transcriptional co-repressor proteins, including the histone deacetyase Sin3A/Rpd3 (9). When ecdysone binds to EcR/USP, it complexes with transcriptional coactivators, including heat shock proteins (10), and recruits histone acetyltranferases that facilitate binding activity and local gene transcription. Thus we see an impressive confluence of longevity-extending factors in the ecdysone nuclear complex. Overexpression of the rpd3 gene, for example, increases the life span of flies (11) (see Rogina Science article) as it does in yeast (12). And overexpression of heat shock proteins increases life span in nematodes and Drosophila (13, 14). JH, in ways that remain unclear, may be a ligand for USP (15), and reduced JH concentrations favor longevity in insects (16). Flies, like nematodes, cannot synthesize cholesterol and must obtain this sterol precursor through feeding. In nematodes, alterations in sterol metabolism have been shown to increase life span (17-19): Long-lived mutants include those carrying the daf-9 allele, which encodes an altered form of a cytochrome hydroxylase enzyme necessary for steroid hormone biosynthesis, and the daf-12 allele, which encodes an abberant sterol nuclear hormone recepter. Similarly, reduced dietary cholesterol increases longevity. Finally, the germline and somatic-derived cells of the nematode gonad interact to control endocrine signals that regulate aging (20). Whether this system also occurs in insects is unknown, but it is clear that ecdysone is produced in an insulin-dependent manner in egg follicle cells (4).

In fact, many of the existing clues converge on ecdysone. It is possible that many of the systems that delay aging in the nematode and fly could do so by altering the positive and negative transcriptional activity of ecdysone-related nuclear hormone complexes. An understanding of how EcR affects gene transcription may accelerate the discovery of loci involved in processes of aging.

Sterol hormones, of course, are key endocrine regulators of human physiology. Ecdysone shares structural similarity with estrogen, testosterone, and other mammalian sex hormones (Fig. 1). To date, none of the mammalian steroid hormones have been implicated in systems that retard aging, but it would be intriguing to consider whether the actions of these hormones are altered in mice with increased life span [for example, mice with reduced growth hormone/IGF (see Laron mice and IGF-1 deficient mice) or thyroid function (21, 22) or those undergoing calorie restriction. In addition, USP (the partner of EcR) shares similarity with the mammalian retinoid X receptor (RXR) (23). RXR complexes with other nuclear hormone receptors, including the estrogen, thyroid hormone, and peroxisome proliferator-activated receptors. It is now possible to speculate on how these various hormones and receptors might participate in the aging process: We can relate results from model organisms to mammals through the language of DNA translated by modern genomics. With the discovery of Simon et al., we are on the verge of new insights into why, how, and when we age.

March 5, 2003
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Citation: M. Tatar, Unearthing Loci That Influence Life Span. Sci. SAGE KE 2003, pe5 (5 March 2003);2003/9/pe5

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