The neuroendocrine regulation of Drosophila aging

The rate of aging is regulated by hormones in insects and, most likely, in mammals. Mutations of the insulin-signaling pathway extend lifespan in the fruit fly and influence the level of other hormones, specifically juvenile hormone and the sterol ecdysone, each of which may directly influence senescence. With new genetic and genomic tools in Drosophila biology we are now exploring how the neuroendocrine system responds to environmental conditions to modify insulin action, how these signals control secondary hormones, and how these messages together modulate animal aging.     

Interactions between injury, stress resistance, reproduction, and aging in Drosophila melanogaster

An important aspect of the aging process in Drosophila melanogaster is the natural loss of antennae, legs, bristles, and parts of wings with age. These injuries lead to a loss of hemolymph, which contains water and nutrients. Stress-resistant lines of D. melanogaster are sometimes longer-lived than the populations from which they are derived. One hypothesis tested here is that increased stress-resistance fosters longevity because it allows fruit flies to cope with the loss of hemolymph due to injury to the aging fly. We tested the effects of surgically induced injury on the aging and reproduction of five replicate populations. We then tested the effects of injury on populations that had been selected for different levels of stress resistance and on control populations. Injury affected aging more in males than in females, in part because of a counter-balancing reduction in female reproduction brought about by injury. More specifically, injury reduced female fecundity and male virility. Injury significantly reduced the starvation resistance in some groups of flies, but not in others. These findings undermine any simple interpretation of the interactions between injury, reproduction, and aging based on stress resistance. But they do indicate the existence of significant interactions between these biological processes, interactions that should be resolved in greater mechanistic detail than has been managed here.     

Endocrine programmed development and reproduction in Nereis

The pattern of cerebral endocrine activity in Nereis diversicolor is characterized by the maintenance of a high plateau of activity prior to, and during most of, the time occupied by gametogenesis. During the closing stages of the life cycle, the rate of secretion is progressively reduced, resulting in the production of a homogeneous population of gametocytes and subsequently in their final maturation. Secretion has been assayed in terms of the regeneration-promoting, maturation-inhibiting, and gametotrophic activities of the hormone. Assays involved transplantation of living brains, in some cases between animals at different stages of maturity, but evidence is presented that the activity of such brains reliably reflects their rate of secretion in situ. Cerebral control of growth and maturation is probably mediated by a single hormone, an ordered sequence of events occurring as different thresholds for hormone action are reached in turn.     

Endocrine markers of aging

Sophisticated methods available to quantitate hormone secretion and hormone action provide opportunities to identify potential endocrine biomarkers of aging. However, there are many challenges facing the investigator who wishes to establish an endocrine biomarker. Circulating levels of many hormones fluctuate on a circadian rhythm, and a variety of other short-term fluctuations may occur. Hormone secretion is generally tightly regulated and often affected by multiple, redundant feedback mechanisms. Interpretation of circulating hormone levels must also take into account factors affecting hormone metabolism and degradation which may be influenced by age. The rate of hormone secretion and circulating hormone levels are related to the sensitivity to hormone action by feedback control mechanisms. Thus interpretation of potential circulating endocrine markers of aging must take into account changes in sensitivity to that hormone as well.     

Endocrine and metabolic changes in human aging

Numerous alterations in hormonal secretion occur with aging. In general, these tend towards a disintegration of the normal cyclic secretory patterns resulting in lower total circulating levels. In addition, declines in receptors and postreceptor function further decreases the ability of the hormonal orchestra to maintain coordinated function throughout the organism. Clues to some of these age-related changes in humans may come from the study of simpler organisms where regulatory systems are known to modulate the aging process. In particular, the interactions among the environment, hormones, and insulin receptor genes have led to new insights into the genetic control of longevity and the development of syndrome X.     

Steroid hormone regulation of C. elegans and Drosophila aging and life history

In the last two decades it has become clear that hormones and gene mutations in endocrine signaling pathways can exert major effects on lifespan and related life history traits in worms, flies, mice, and other organisms. While most of this research has focused on insulin/insulin-like growth factor-1 signaling, a peptide hormone pathway, recent work has shown that also lipophilic hormones play an important role in modulating lifespan and other life history traits. Here we review how steroid hormones, a particular group of lipophilic hormones, affect life history traits in the nematode worm (Caenorhabditis elegans) and the fruit fly (Drosophila melanogaster), with a particular focus on longevity. Interestingly, a comparison suggests that parallel endocrine principles might be at work in worms and flies in these species and that steroid hormones interact with the gonad to affect lifespan.     

Endocrine regulation of menstruation

In women, endometrial morphology and function undergo characteristic changes every menstrual cycle. These changes are crucial for perpetuation of the species and are orchestrated to prepare the endometrium for implantation of a conceptus. In the absence of pregnancy, the human endometrium is sloughed off at menstruation over a period of a few days. Tissue repair, growth, angiogenesis, differentiation, and receptivity ensue to prepare the endometrium for implantation in the next cycle. Ovarian sex steroids through interaction with different cognate nuclear receptors regulate the expression of a cascade of local factors within the endometrium that act in an autocrine/paracrine and even intracrine manner. Such interactions initiate complex events within the endometrium that are crucial for implantation and, in the absence thereof, normal menstruation. A clearer understanding of regulation of normal endometrial function will provide an insight into causes of menstrual dysfunction such as menorrhagia (heavy menstrual bleeding) and dysmenorrhea (painful periods). The molecular pathways that precipitate these pathologies remain largely undefined. Future research efforts to provide greater insight into these pathways will lead to the development of novel drugs that would target identified aberrations in expression and/or of local uterine factors that are crucial for normal endometrial function.     

Survival costs of reproduction in Drosophila

Reproduction shortens lifespan in practically all organisms examined so far, but the underlying mechanisms remain largely unknown to date. Here I review what evolutionary and molecular biologists have learned about such "costs of reproduction" in the fruit fly (Drosophila melanogaster) since Maynard Smith's (1958) seminal discovery that sterile mutants in D. subobscura live substantially longer than fertile wildtype flies. Together with observations from the nematode worm (Caenorhabditis elegans) and other organisms, the data from Drosophila suggest that there are at least four general principles that underlie trade-offs between reproduction and lifespan: (1) trade-offs between survival and reproduction are widespread; (2) the relationship between increased lifespan and decreased fecundity can be uncoupled under certain conditions; (3) while survival costs of reproduction might not necessarily be due to competitive resource allocation, we lack robust alternative explanations for their occurrence; and (4) physiological trade-offs between reproduction and longevity do not always translate into evolutionary genetic trade-offs. I conclude that - despite much recent progress - our current understanding of the proximate basis of survival costs of reproduction remains very limited; much future work on the genetics and physiology of such trade-offs will be required to uncover their mechanistic basis.     

Endocrine treatment of aging transgender people

High quality empirical data assessing morbidity and mortality and cancer incidence among transgender people are almost non-existent. Sex hormone treatment of conditions in older non-transgender people might as yet be taken as the best available analogy to hormone administration to aging transgender persons. Testosterone administration to transgender men carries little risk with regard to cardiovascular disease and cancer. A dose adaptation may be needed in men with a high hematocrit or cardiac insufficiency. In transgender men, even after breast ablation, breast cancer may occur in residual mammary tissue. Treatment with estrogens (specifically oral ethinylestradiol) of transgender women, particularly in combination with progestins, carries a significant relative risk of developing cardiovascular disease (almost a twofold incidence compared to the general population). The dose of estrogens may have to be reduced with aging. A change from oral to probably safer transdermal estrogens must be considered. Though rare, tumors of the breasts, prostate, meninges and pituitary have been encountered. Based upon the available expertise, initiation of cross-sex hormone treatment in elderly subjects is without disproportionate risks.     

Singlet oxygen and aging in Drosophila

There was little or no improvement in the median survival times of Drosophila melanogaster fruit flies when fed high concentrations of the singlet oxygen quenchers, beta-carotene and 1,4-diazabicyclo(2.2.2)octane. Singlet oxygen was presumably generated endogenously by inactivating catalse with 3-amino-1,2,4-triazole and feeding NaOCl. This treatment caused reduction in median life span of from 14.3 to 25% depending upon the NaOCl concentration used. beta-Carotene and 1,4-diazabicyclo(2.2.2)octane gave partial protection against the singlet oxygen generated by NaOCl. These data are interpreted to mean that normally occurring singlet oxygen does not contribute to senescence in Drosophila but that artificially produced singlet oxygen accelerates the rate of aging.     

Genetics of aging in Drosophila.

The genetics of aging in Drosophila are reviewed under the separate headings of population genetics, physiological genetics, and molecular genetics. However, connections between these sub-fields are brought forward for discussion.     

Review of cell aging in Drosophila and mouse

In this review we evaluate Minot’s hypothesis that cellular aging and death of metazoan animals are the result of cell differentiation. The fine structural data suggest that aging in Drosophila is reflected in cytoplasmic organelle loss with accompanying age pigment accumulation. Apparently, a progressive disorganization of fixed postmitotic cells plays a key role in the aging process of fruit flies. In aging mice, electron microscopic studies suggest that primary senescent deterioration takes place also in fixed postmitotic cells. Intermitotic cells appear to undergo only minimal changes, while many fast dividing cells are not affected by aging. We conclude that Minot’s hypothesis is consistent with reviewed evidence on cellular aging mechanisms in Drosophila and mouse. Theoretical support for the hypothesis is derived from a systems analysis of organism-environment interaction and the consequences of cellular organization in flies and mice.     

Chromium levels and aging in mice and Drosophila

The chromium concentration in livers from C57BL/6J male mice significantly increased by 25.2% from 45 to 886 days of age. Brain chromium decreased by 19.9% but the decline was not significant. Heart and kidney showed no change with age. No significant age-related change in total chromium occurred in adult male Drosophila melanogaster fruit flies. Chromium concentrations during the developmental stages reached a maximum during the third instar stage where they were more than twice the amount as in the adult stage. Life-time feeding of chromium (0.0001 to 0.01 M) did not alter life span for Drosophila. We conclude that chromium is not a factor in senescence for either mice or fruit flies maintained under normal conditions.