The Metabolic Profile of Long-Lived Drosophila melanogaster (original) (raw)
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Longevity is determined by ETS transcription factors in multiple tissues and diverse species
PLOS Genetics, 2019
Ageing populations pose one of the main public health crises of our time. Reprogramming gene expression by altering the activities of sequence-specific transcription factors (TFs) can ameliorate deleterious effects of age. Here we explore how a circuit of TFs coordinates pro-longevity transcriptional outcomes, which reveals a multi-tissue and multi-species role for an entire protein family: the E-twenty-six (ETS) TFs. In Drosophila, reduced insulin/IGF signalling (IIS) extends lifespan by coordinating activation of Aop, an ETS transcriptional repressor, and Foxo, a Forkhead transcriptional activator. Aop and Foxo bind the same genomic loci, and we show that, individually, they effect similar transcriptional programmes in vivo. In combination, Aop can both moderate or synergise with Foxo, dependent on promoter context. Moreover, Foxo and Aop oppose the gene-regulatory activity of Pnt, an ETS transcriptional activator. Directly knocking down Pnt recapitulates aspects of the Aop/Foxo transcriptional programme and is sufficient to extend lifespan. The lifespan-limiting role of Pnt appears to be balanced by a requirement for metabolic regulation in young flies, in which the Aop-Pnt-Foxo circuit determines expression of metabolic genes, and Pnt regulates lipolysis and responses to nutrient stress. Molecular functions are often conserved amongst ETS TFs, prompting us to examine whether other Drosophila ETS-coding genes may also affect ageing. We show that five out of eight Drosophila ETS TFs play a role in fly ageing, acting from a range of organs and cells including the intestine, adipose and neurons. We expand the repertoire of lifespan-limiting ETS TFs in C. elegans, confirming their conserved function in ageing and revealing that the roles of ETS TFs in physiology and lifespan are conserved throughout the family, both within and between species.
A Conserved Regulatory System for Aging
Cell, 2001
that move normally, are fully fertile, and have a normal San Francisco, California 94143 metabolic rate. In addition, it has also been possible to obtain long-lived genetic mosaics that do not produce fat. The fact that these long-lived mutants can appear While many processes in biology, such as cell differentiso normal makes one optimistic that if this system exists ation and development, increase complexity, the aging in humans, then by perturbing it in the right way, it may process increases entropy and culminates in the death be possible to extend normal youthfulness and lifespan. of the animal. Thus, the discovery that single gene muta-So far, the only dauer-like trait that has not been untions in many organisms can extend lifespan dramaticoupled from longevity in C. elegans is stress resistance. cally was surprising. These mutations indicated that the Thus, it is possible that the ability to detoxify reactive aging process is subject to regulation; it is not as random oxygen species is what extends lifespan. This is plausiand haphazard as it seems. Even more surprising are ble, because catalytic antioxidants are known to extend some recent findings suggesting that a conserved systhe lifespan of C. elegans (Melov et al., 2000) and betem regulating lifespan may have arisen early in evolucause overexpression of superoxide dismutase (SOD) tion. This regulatory system also controls diapause-like has been shown to extend the lifespan of Drosophila states, which are relatively quiescent states that allow an (Sun and Tower, 1999). animal to postpone reproduction in response to adverse The C. elegans DAF-2 pathway acts non cell autonoenvironmental conditions. This connection is particumously to regulate dauer formation and adult lifespan. larly intriguing because, in at least some cases, lifespan The gene acts in neuroectoderm and, to a lesser extent, extension can be uncoupled from other aspects of diain internal organs, to produce one or more downstream pause, allowing active and fertile animals to remain signals or hormones which, in turn, regulate lifespan youthful much longer than normal. and dauer formation. DAF-2 also acts non cell autono-Insulin/IGF-1 Signaling in C. elegans mously to regulate adult fertility and intestinal fat metab-A pathway that regulates both lifespan and diapause olism. One downstream hormone may be a steroid liwas first discovered in C. elegans (reviewed in Guarente gand for DAF-12, a nuclear hormone receptor homolog and Kenyon, 2000). In response to food limitation and that promotes dauer formation. crowding, juvenile worms enter a state of diapause, It is not known whether adult longevity, like dauer called dauer. Dauers are developmentally arrested, reformation, can be regulated by environmental stimuli. productively immature, resistant to oxidative stress, and This may be the case, since mutations and cell ablations long-lived. As they enter the dauer state, the animals affecting sensory neurons increase longevity, at least synthesize food-storage substances such as fat, which in part by modulating components of the insulin/IGF-1 they metabolize as dauers. When conditions improve, pathway. they become fertile adults with normal lifespans (Fig-Insulin/IGF-1 Signaling in Drosophila ure 1). Replete environments stimulate growth to adult-In Drosophila, an insulin/IGF-1 pathway regulates body hood by activating an insulin/IGF-1 signaling pathway. size; animals carrying mutations in this pathway are Loss-of-function mutations in the insulin/IGF-1 recepsmall (reviewed in Weinkove and Leevers, 2000). This tor homolog daf-2, or in downstream components of pathway also regulates lifespan. In Drosophila, as in a conserved PI3-kinase/PDK/Akt pathway cause dauer vertebrates, an insulin-receptor substrate (IRS) protein formation even when food is present. This pathway apcouples receptor activation to PI3-kinase signaling. Null mutations in the Drosophila IRS homolog, chico, extend pears to act by downregulating a forkhead/winged-helix lifespan by %54ف (Clancy et al., 2001). In addition, anitranscription factor called DAF-16 (Figure 2). In the abmals heterozygous for two different mutations in the sence of DAF-16, neither food limitation nor insulin/IGF-1 insulin/IGF-1 receptor live 85% longer than normal (Tapathway mutations induce dauer formation. tar et al., 2001). Weak mutations in the insulin/IGF-1 pathway allow In addition to increased lifespan, the fly insulin/IGF-1 the animals to grow to adulthood, where they remain pathway mutants have another similarity to the C. eleyouthful much longer than normal, and live more than gans story. The animals appear to be in a state of reprotwice as long. Animals carrying different insulin/IGF-1 ductive diapause (Tatar et al., 2001). During the winter, pathway mutations differ in the extent to which they flies do not reproduce, and egg development is arrested express other dauer-like traits (see Guarente and Kenat previtellogenic stages. The Drosophila insulin/IGF-1 yon, 2000). Certain mutations cause adults to reproduce receptor mutants are sterile and their ovaries resemble late in life (or not at all), to lie still, adopting a curved, the ovaries of wild-type flies in diapause. dauer-like posture, and/or to synthesize high levels of Reproductive diapause is known to be regulated by fat. Like dauers, some mutant adults have a low metajuvenile hormone (JH), which is produced by a group of bolic rate, and all mutants tested exhibit resistance to neurosecretory cells called the corpus allatum. Insulin/ IGF-1 pathway mutants have low levels of JH. Treating these animals with methoprene, an analog of JH, can
Healthy Aging – Insights from Drosophila
Frontiers in Physiology, 2012
Human life expectancy has nearly doubled in the past century due, in part, to social and economic development, and a wide range of new medical technologies and treatments. As the number of elderly increase it becomes of vital importance to understand what factors contribute to healthy aging. Human longevity is a complex process that is affected by both environmental and genetic factors and interactions between them. Unfortunately, it is currently difficult to identify the role of genetic components in human longevity. In contrast, model organisms such as C. elegans, Drosophila, and rodents have facilitated the search for specific genes that affect lifespan. Experimental evidence obtained from studies in model organisms suggests that mutations in a single gene may increase longevity and delay the onset of age-related symptoms including motor impairments, sexual and reproductive and immune dysfunction, cardiovascular disease, and cognitive decline. Furthermore, the high degree of conservation between diverse species in the genes and pathways that regulate longevity suggests that work in model organisms can both expand our theoretical knowledge of aging and perhaps provide new therapeutic targets for the treatment of age-related disorders.
Genome-Wide Transcript Profiles in Aging and Calorically Restricted Drosophila melanogaster
Current Biology, 2002
Aging is characterized by an age-dependent increase The Darwin Building in the probability of death and concomitant decline in Gower Street reproductive output. A powerful experimental approach London, WC1E 6BT for investigating mechanisms of aging is provided by United Kingdom interventions that slow down or accelerate the normal 2 Department of Ecology and Evolutionary Biology process. Manipulations that increase life span, such as Box 208106 mutants in single genes [1], are strong candidates for such Yale University interventions. More problematic are progerias, in which New Haven, Connecticut 06520-8106 aspects of normal aging appear to be accelerated. Diffi-3 F. Hoffmann La Roche & Company culties in interpretation arise because interventions that Roche Genet shorten life span could do so, at least in part, by intro-CH 4070 Basel ducing novel pathologies. The lack of reliable, quantita-Switzerland tive descriptions of the normal aging process [2] has frustrated efforts to develop a direct test of the effect of interventions that alter life span by changing the rate Summary of normal aging. A case in point is caloric restriction (CR), in which nutrient intake is restricted to about 65% Background: We characterized RNA transcript levels of voluntary levels. CR has been shown to increase life for the whole Drosophila genome during normal aging. span in taxonomically diverse organisms including yeast We compared age-dependent profiles from animals [3], nematode worms [4], fruit flies [5], and rodents [6]
Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity
Aging cell, 2018
Lifespan varies dramatically among species, but the biological basis is not well understood. Previous studies in model organisms revealed the importance of nutrient sensing, mTOR, NAD/sirtuins, and insulin/IGF1 signaling in lifespan control. By studying life-history traits and transcriptomes of 14 Drosophila species differing more than sixfold in lifespan, we explored expression divergence and identified genes and processes that correlate with longevity. These longevity signatures suggested that longer-lived flies upregulate fatty acid metabolism, downregulate neuronal system development and activin signaling, and alter dynamics of RNA splicing. Interestingly, these gene expression patterns resembled those of flies under dietary restriction and several other lifespan-extending interventions, although on the individual gene level, there was no significant overlap with genes previously reported to have lifespan-extension effects. We experimentally tested the lifespan regulation potent...
Biochemical Genetic Pathways that Modulate Aging in Multiple Species: Figure 1
Cold Spring Harbor Perspectives in Medicine, 2015
The mechanisms underlying biological aging have been extensively studied in the past 20 years with the avail of mainly four model organisms: the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the domestic mouse Mus musculus. Extensive research in these four model organisms has identified a few conserved genetic pathways that affect longevity as well as metabolism and development. Here, we review how the mechanistic target of rapamycin (mTOR), sirtuins, adenosine monophosphate-activated protein kinase (AMPK), growth hormone/insulin-like growth factor 1 (IGF-1), and mitochondrial stress-signaling pathways influence aging and life span in the aforementioned models and their possible implications for delaying aging in humans. We also draw some connections between these biochemical pathways and comment on what new developments aging research will likely bring in the near future.
Transcriptome Analysis of Long- lived Drosophila melanogaster E(z) Mutants sheds Light on the Molecular Mechanisms of Longevity , 2019
The E(z) histone methyltransferase heterozygous mutation in Drosophila is known to increase lifespan and stress resistance. However, the longevity mechanisms of E(z) mutants have not been revealed. Using genome-wide transcriptome analysis, we demonstrated that lifespan extension, increase of resistance to hyperthermia, oxidative stress and endoplasmic reticulum stress, and fecundity enhancement in E(z) heterozygous mutants are accompanied by changes in the expression level of 239 genes (p < 0.05). Our results demonstrated sex-specific effects of E(z) mutation on gene expression, which, however, did not lead to differences in lifespan extension in both sexes. We observed that a mutation in an E(z) gene leads to perturbations in gene expression, most of which participates in metabolism, such as Carbohydrate metabolism, Lipid metabolism, Drug metabolism, Nucleotide metabolism. Age-dependent changes in the expression of genes involved in pathways related to immune response, cell cycle, and ribosome biogenesis were found. Gene expression fluctuates in different tissues and the chromatin landscape changes during aging 1. Site-specific repression of the genome is known to be observed in aged individuals, as well as multifocal (or global) derepres-sion, the latter process dominates 2,3. Gene expression is usually influenced by the chromatin state, but the tran-scriptional profile also may influence epigenome, especially when sequences regulating chromatin-remodeling complexes are affected 4,5. The lowering of age-related gene expression profiles is known to be associated with heterochromatin formation and histone methylation. This statement is true for histone H3 lysine 9 (H3K9) and histone H3 lysine 27 (H3K27) loci in Drosophila and is connected to the pool of histone methyltransferases 3. The H3K9 age-related loss results in the Heterochromatin Protein 1 (HP1) concentration lowering, this phenomenon is strongly associated with heterochromatin decompactization and genomic instability 6. In addition, the epigenome-wide loss of H3K9 methylation has been observed in cell culture modeling Hutchinson-Gilford progeria syndrome and also in aged Drosophila melanogaster, as an exception, several chromatin islands are hypermethylated in both cases 3,6,7. Histone H3 lysine 9 methylation is carried out by dSETDB1, Su(var)3-9, G9a, and E(z) 8,9. The H3K27 meth-ylation levels are associated mainly with E(z) and ESC subunits of polycomb repressive complex 2 (PRC2). Wild type E(z) (Enhancer of zeste) is a gene coding protein that belongs to the class V-like SAM-binding methyltrans-ferase superfamily, histone-lysine methyltransferase family, and EZ subfamily. E(z) is also known to have transcription factor activity 5,10. The loss-of-function mutations in PRC2 components extend the lifespan 11 and take part in transgenera-tional inheritance mechanism detected for this effect, as well as the antagonistic enzyme UTX-1 demethylat-ing H3K27me3 12. PRC2, and especially its subunit E(z), are known as suppressors of stress-response genes (e.g. Odc1). This complex is working in an ensemble with trithorax (TRX), which has the opposite function 11. In the present work, we aim to unravel specific mechanisms which cause life extension, fecundity augmentation, and 1 engelhardt institute