Methuselah life history in a variety of conditions, implications for the use of mutants in longevity research

Baldal, E.A.; Baktawar, W.; Brakefield, Paul M.; Zwaan, Bas J.

doi:10.1016/j.exger.2006.08.014

Cited by 34 publications

(35 citation statements)

References 31 publications

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“…1 Data collection on behavioral traits began within days after 1 These survival functions are in line with several previous studies of mth (Cook-Wiens and Grotewiel 2002;Mockett and Sohal 2006), shorter than those reported by Lin et al (1998), and longer than those reported by others (Cevjic et al 2004;Petrosyan et al 2007;Paaby and Schmidt 2008). These differences may be due to a variety of factors as partly described by Cook-Wiens and Grotewiel (2002), including differences in genetic backgrounds (Finch 1990), frequency of changing food media (Baldal et al 2006;Cook-Wiens and Grotewiel 2002), and number and length of times exposed to anesthesia during transfer. Significant increase in longevity by mth mutation, however, is reported in all these studies.…”

Section: Fly Stockssupporting

confidence: 78%

Improved functional abilities of the life-extended Drosophila mutant Methuselah are reversed at old age to below control levels

Petrosyan

Gonçalves

Hsieh

et al. 2013

AGE

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Methuselah (mth) is a chromosome 3 Drosophila mutant with an increased lifespan. A large number of studies have investigated the genetic, molecular, and biochemical mechanisms of the mth gene. Much less is known about the effects of mth on preservation of sensorimotor abilities throughout Drosophila's lifespan, particularly in late life. The current study investigated functional senescence in mth and its parental-control line (w1118) in two experiments that measured age-dependent changes in flight functions and locomotor activity. In experiment 1, a total of 158 flies (81 mth and 77 controls) with an age range from 10 to 70 days were individually tethered under an infrared laser-sensor system that allowed monitoring of flight duration during phototaxic flight. We found that mth has a statistically significant advantage in maintaining continuous flight over control flies at age 10 days, but not during middle and late life. At age 70 days, the trend reversed and parental control flies had a small but significant advantage, suggesting an interaction between age and genotype in the ability to sustain flight. In experiment 2, a total of 173 different flies (97 mth and 76 controls) with an age range from 50 to 76 days were individually placed in a large well-lit arena (60×45 cm) and their locomotor activity quantified as the distance walked in a 1-min period. Results showed that mth flies had lower levels of locomotor activity relative to controls at ages 50 and 60 days. These levels converged for the two genotypes at the oldest ages tested. Findings show markedly different patterns of functional decline for the mth line relative to those previously reported for other life-extended genotypes, suggesting that different life-extending genes have dissimilar effects on preservation of sensory and motor abilities throughout an organism's lifespan.

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Section: Fly Stockssupporting

confidence: 78%

Improved functional abilities of the life-extended Drosophila mutant Methuselah are reversed at old age to below control levels

Petrosyan

Gonçalves

Hsieh

et al. 2013

AGE

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“…Flies with reduced expression of the G protein-coupled receptor gene methuselah（MTH）appear to have enhanced resistance to oxidative stress [18]. Similarly, Baldal proved that MTH endogenous ligand gene knockout or overexpression of peptide antagonists of MTH receptor extends life span of fruit flies [19]. In this study, we found that flies supplementation with rosemary extract reduced mRNA level of MTH (Figure 2).…”

Section: Mrna Expression Levels Of Antioxidant Genessupporting

confidence: 49%

Rosemary Extract Mediated Lifespan Extension in Drosophila Melanogaster

Wang¹,

Zhang²,

Sun³

et al. 2016

Proceedings of the 2015 International Conference on Materials Chemistry and Environmental Protection (Meep-15)

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Abstract-Rosemary (Rosmarinus officinalis L.) has always known a versatile, aromatic herb and addition to being used as a food flavoring is also known medicinally for its powerful antioxidant activity, antibacterial and hepatoprotective properties. In this study we examined the effects of rosemary iextract on the lifespan and aging in Drosophila melanogaster against high-fat induced oxidative injury, and found that it responded to rosemary extract with an increased lifespan and reduced MDA content during aging. We found that lifespan extension by rosemary extract was attributed to its increasing the activity of SOD, CAT and decreasing the content of MDA. Moreover, Realtime-PCR analysis showed that the gene expression of SOD, and CAT was enhanced, in contrast MTH was significantly reduced. In conclusion, these results suggest that the antioxidant and antiaging effect of rosemary extract may, at least in part, be due to its interactions with endogenous antioxidant protective enzymes including SOD and CAT.

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“…However, because the role of other Mth-like receptors in longevity is unknown, and because other Mth-like extracellular domains share significant sequence similarity to the Mth ectodomain (up to 60% identity), the action of the R8-12 peptide may be through other or multiple proteins. Studying the effects of R8-12 expression on other phenotypes observed in the mth mutant may reveal the relationships between aging, synaptic transmission, and fertility 3,[17][18][19] .In vitro selection has emerged as a powerful alternative to screening approaches for the identification of modulators of G protein signaling 20,21 . Our work provides a clear strategy for designing functional ligands for class B GPCRs, a protein family associated with a number of human diseases 2 .…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor

West

Delker

et al. 2007

Nat Chem Biol

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G protein-coupled receptors (GPCRs) mediate signaling from extracellular ligands to intracellular signal transduction proteins 1 . Methuselah (Mth) is a class B (secretin-like) GPCR, a family typified by their large, ligand-binding, N-terminal extracellular domains2. Down-regulation of mth increases the lifespan of Drosophila melanogaster 3 -inhibitors of Mth signaling would thus be expected to enhance longevity. We used mRNA display selection 4,5 to identify high affinity (K D = 15 to 30 nM) peptide ligands that bind to the N-terminal ectodomain of Mth. The selected peptides are potent antagonists of Mth signaling, and structural studies suggest that they perturb the interface between the Mth ecto-and transmembrane (TM) domains. Flies constitutively expressing a Mth antagonist peptide exhibit a robust lifespan extension, suggesting that the peptides inhibit Mth signaling in vivo. Our work thus provides novel lifespan-extending ligands for a metazoan and a general approach for the design of modulators of this important class of GPCRs.Because of their participation in numerous cell processes, GPCRs are the targets of approximately half of marketed drugs, and new GPCR ligands continue to be pursued and developed 6 . Naïve approaches toward GPCR ligand identification typically involve highthroughput screening of a molecular library (10 2 to 10 5 unique members) in functional, cellbased assays [6][7][8] . A powerful, alternative approach for the rapid isolation of novel ligands is in vitro peptide selection using mRNA display, which allows access to very high library complexities (>10 13 ) in a robust format 4 . High affinity peptide ligands for RNA, small molecule, and protein targets have been identified by mRNA display selection 5 .The crystal structure of the hexahistidine-tagged Mth ectodomain was previously determined, demonstrating that the mature, N-terminal extracellular domain of Mth is a stably folded, glycosylated protein of 195 residues 9 . Since the ectodomains of other class B GPCRs maintain recognition of their cognate ligands independently of their TM cores 10,11 , we targeted the Mth ectodomain for in vitro selection to isolate putative modulators of Mth signaling. We expressed and purified a specifically biotinylated construct of the Mth ectodomain 12 to avoid using the weak hexahistidine epitope as an immobilization tag for selection 13 . Hence, the Mth ectodomain was homogeneously presented, perhaps mimicking the juxtaposition of the ectodomain and TM domain in the context of the full-length receptor.We constructed a random, 27-mer peptide mRNA display library. After eight rounds of selection, with the final four rounds including preclearing steps on matrix without target and specific elution with free, non-biotinylated Mth, we obtained a final 8 th round pool that exhibited high activity for Mth and negligible non-specific binding (Fig. 1). DNA sequencing of individual clones from the final selection round revealed a highly conserved consensus, [R/ P]xxWxxR, which we term the RWR motif ...

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Methuselah life history in a variety of conditions, implications for the use of mutants in longevity research

Cited by 34 publications

References 31 publications

Improved functional abilities of the life-extended Drosophila mutant Methuselah are reversed at old age to below control levels

Improved functional abilities of the life-extended Drosophila mutant Methuselah are reversed at old age to below control levels

Rosemary Extract Mediated Lifespan Extension in Drosophila Melanogaster

Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor

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