Chronobiotics KL001 and KS15 Extend Lifespan and Modify Circadian Rhythms of Drosophila melanogaster
Abstract
:1. Introduction
2. Methods
3. Results and Discussion
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Bhadra, U.; Thakkar, N.; Das, P.; Pal Bhadra, M. Evolution of circadian rhythms: From bacteria to human. Sleep Med. 2017, 35, 49–61. [Google Scholar] [CrossRef] [PubMed]
- Katewa, S.D.; Akagi, K.; Bose, N.; Rakshit, K.; Camarella, T.; Zheng, X.; Hall, D.; Davis, S.; Nelson, C.S.; Brem, R.B.; et al. Peripheral Circadian Clocks Mediate Dietary Restriction-Dependent Changes in Lifespan and Fat Metabolism in Drosophila. Cell Metab. 2016, 23, 143–154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ruf, F.; Mitesser, O.; Mungwa, S.T.; Horn, M.; Rieger, D.; Hovestadt, T.; Wegener, C. Natural Zeitgebers Under Temperate Conditions Cannot Compensate for the Loss of a Functional Circadian Clock in Timing of a Vital Behavior in Drosophila. J. Biol. Rhythm. 2021, 36, 271–285. [Google Scholar] [CrossRef]
- Heyde, I.; Oster, H. Differentiating external zeitgeber impact on peripheral circadian clock resetting. Sci. Rep. 2019, 9, 20114. [Google Scholar] [CrossRef] [PubMed]
- Dubowy, C.; Sehgal, A. Circadian rhythms and sleep in Drosophila melanogaster. Genetics 2017, 205, 1373–1397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Patke, A.; Young, M.W.; Axelrod, S. Molecular mechanisms and physiological importance of circadian rhythms. Nat. Rev. Mol. Cell Biol. 2020, 21, 67–84. [Google Scholar] [CrossRef] [PubMed]
- Damulewicz, M.; Mazzotta, G.M. One actor, multiple roles: The performances of cryptochrome in Drosophila. Front. Physiol. 2020, 11, 99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fuhr, L.; Abreu, M.; Pett, P.; Relógio, A. Circadian systems biology: When time matters. Comput. Struct. Biotechnol. J. 2015, 13, 417–426. [Google Scholar] [CrossRef] [Green Version]
- Welz, P.-S.; Benitah, S.A. Molecular Connections between Circadian Clocks and Aging. J. Mol. Biol. 2020, 432, 3661–3679. [Google Scholar] [CrossRef]
- Liu, F.; Chang, H.-C. Physiological links of circadian clock and biological clock of aging. Protein Cell 2017, 8, 477–488. [Google Scholar] [CrossRef] [Green Version]
- Baba, K.; Tosini, G. Aging Alters Circadian Rhythms in the Mouse Eye. J. Biol. Rhythms 2018, 33, 441–445. [Google Scholar] [CrossRef]
- Stankiewicz, A.J.; McGowan, E.M.; Yu, L.; Zhdanova, I.V. Impaired Sleep, Circadian Rhythms and Neurogenesis in Diet-Induced Premature Aging. Int. J. Mol. Sci. 2017, 18, 2243. [Google Scholar] [CrossRef] [Green Version]
- Adler, P.; Chiang, C.-K.; Mayne, J.; Ning, Z.; Zhang, X.; Xu, B.; Cheng, H.-Y.M.; Figeys, D. Aging Disrupts the Circadian Patterns of Protein Expression in the Murine Hippocampus. Front. Aging Neurosci. 2020, 11, 368. [Google Scholar] [CrossRef] [Green Version]
- Acosta-Rodríguez, V.A.; Rijo-Ferreira, F.; Green, C.B.; Takahashi, J.S. Importance of circadian timing for aging and longevity. Nat. Commun. 2021, 12, 2862. [Google Scholar] [CrossRef]
- Yamazaki, S.; Straume, M.; Tei, H.; Sakaki, Y.; Menaker, M.; Block, G.D. Effects of aging on central and peripheral mammalian clocks. Proc. Natl. Acad. Sci. USA 2002, 99, 10801–10806. [Google Scholar] [CrossRef] [Green Version]
- Valentinuzzi, V.S.; Scarbrough, K.; Takahashi, J.S.; Turek, F.W. Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. Am. J. Physiol. 1997, 273, R1957–R1964. [Google Scholar] [CrossRef] [PubMed]
- Sellix, M.T.; Evans, J.A.; Leise, T.L.; Castanon-Cervantes, O.; Hill, D.D.; DeLisser, P.; Block, G.D.; Menaker, M.; Davidson, A.J. Aging differentially affects the re-entrainment response of central and peripheral circadian oscillators. J. Neurosci. 2012, 32, 16193–16202. [Google Scholar] [CrossRef] [Green Version]
- Lamia, K.A.; Storch, K.F.; Weitz, C.J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl. Acad. Sci. USA 2008, 105, 15172–15177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rudic, R.D.; McNamara, P.; Curtis, A.M.; Boston, R.C.; Panda, S.; Hogenesch, J.B.; Fitzgerald, G.A. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2004, 2, e377. [Google Scholar] [CrossRef] [Green Version]
- Turek, F.W.; Joshu, C.; Kohsaka, A.; Lin, E.; Ivanova, G.; McDearmon, E.; Laposky, A.; Losee-Olson, S.; Easton, A.; Jensen, D.R.; et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005, 308, 1043–1045. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dubrovsky, Y.V.; Samsa, W.E.; Kondratov, R.V. Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice. Aging 2010, 2, 936–944. [Google Scholar] [CrossRef] [Green Version]
- Hurd, M.W.; Zimmer, K.A.; Lehman, M.N.; Ralph, M.R. Circadian locomotor rhythms in aged hamsters following suprachiasmatic transplant. Am. J. Physiol. 1995, 269, R958–R968. [Google Scholar] [CrossRef] [PubMed]
- Li, H.; Satinoff, E. Fetal tissue containing the suprachiasmatic nucleus restores multiple circadian rhythms in old rats. Am. J. Physiol. 1998, 275, R1735–R1744. [Google Scholar] [CrossRef] [PubMed]
- Davidson, A.J.; Sellix, M.T.; Daniel, J.; Yamazaki, S.; Menaker, M.; Block, G.D. Chronic jet-lag increases mortality in aged mice. Curr. Biol. 2006, 16, R914–R916. [Google Scholar] [CrossRef] [Green Version]
- He, B.; Nohara, K.; Park, N.; Park, Y.S.; Guillory, B.; Zhao, Z.; Garcia, J.M.; Koike, N.; Lee, C.C.; Takahashi, J.S.; et al. The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metab. 2016, 23, 610–621. [Google Scholar] [CrossRef] [Green Version]
- Zhang, R.; Lahens, N.F.; Ballance, H.I.; Hughes, M.E.; Hogenesch, J.B. A circadian gene expression atlas in mammals: Implications for biology and medicine. Proc. Natl. Acad. Sci. USA 2014, 111, 16219–16224. [Google Scholar] [CrossRef] [Green Version]
- Asher, G.; Gatfield, D.; Stratmann, M.; Reinke, H.; Dibner, C.; Kreppel, F.; Mostoslavsky, R.; Alt, F.W.; Schibler, U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 2008, 134, 317–328. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Solovev, I.; Dobrovolskaya, E.; Shaposhnikov, M.; Sheptyakov, M.; Moskalev, A. Neuron-specific overexpression of core clock genes improves stress-resistance and extends lifespan of Drosophila melanogaster. Exp. Gerontol. 2019, 117, 61–71. [Google Scholar] [CrossRef]
- Solovev, I.A.; Shaposhnikov, M.V.; Moskalev, A.A. Genetic mechanisms of the influence of light and phototransduction on Drosophila melanogaster lifespan. Vavilov J. Genet. Breed. 2018, 22, 878–886. [Google Scholar] [CrossRef] [Green Version]
- Miller, S.; Hirota, T. Pharmacological interventions to circadian clocks and their molecular bases. J. Mol. Biol. 2020, 432, 3498–3514. [Google Scholar] [CrossRef]
- Ribeiro, R.F.; Cavadas, C.; Silva, M.M.C. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discov. Today 2021, 26, 1620–1641. [Google Scholar] [CrossRef] [PubMed]
- Jeong, Y.U.; Jin, H.E.; Lim, H.Y.; Choi, G.; Joo, H.; Kang, B.; Lee, G.H.; Liu, K.H.; Maeng, H.J.; Chung, S.; et al. Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement. Pharmaceuticals 2021, 14, 496. [Google Scholar] [CrossRef]
- Chen, Z.; Yoo, S.H.; Takahashi, J.S. Small molecule modifiers of circadian clocks. Cell. Mol. Life Sci. 2013, 70, 2985–2998. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, Z.; Yoo, S.H.; Takahashi, J.S. Development and therapeutic potential of small-molecule modulators of circadian systems. Ann. Rev. Pharmacol. Toxicol. 2018, 58, 231–252. [Google Scholar] [CrossRef]
- Chun, S.K.; Chung, S.; Kim, H.-D.; Lee, J.H.; Jang, J.; Kim, J.; Kim, D.; Son, G.H.; Oh, Y.J.; Suh, Y.-G.; et al. A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells. Biochem. Biophys. Res. Commun. 2015, 467, 441–446. [Google Scholar] [CrossRef] [PubMed]
- Cichewicz, K.; Hirsh, J. ShinyR-DAM: A program analyzing Drosophila activity, sleep and circadian rhythms. Commun. Biol. 2018, 1, 25. [Google Scholar] [CrossRef]
- Han, S.K.; Lee, D.; Lee, H.; Kim, D.; Son, H.G.; Yang, J.-S.; Lee, S.-J.V.; Kim, S. OASIS 2: Online application for survival analysis 2 with features for the analysis of maximal lifespan and healthspan in aging research. Oncotarget 2016, 7, 56147. [Google Scholar] [CrossRef] [Green Version]
- Gao, G.; Wan, W.; Zhang, S.; Redden, D.T.; Allison, D.B. Testing for differences in distribution tails to test for differences in ‘maximum’ lifespan. BMC Med. Res. Methodol. 2008, 8, 49. [Google Scholar] [CrossRef] [Green Version]
- Cox, D.R.; Oakes, D. Analysis of Survival Data; Chapman and Hall/CRC: Boca Raton, FL, USA, 2018. [Google Scholar]
- Rosato, E.; Kyriacou, C.P. Analysis of locomotor activity rhythms in Drosophila. Nat. Protoc. 2006, 1, 559–568. [Google Scholar] [CrossRef]
- Hirota, T.; Lee, J.W.; St John, P.C.; Sawa, M.; Iwaisako, K.; Noguchi, T.; Pongsawakul, P.Y.; Sonntag, T.; Welsh, D.K.; Brenner, D.A.; et al. Identification of small molecule activators of cryptochrome. Science 2012, 337, 1094–1097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Solovev, I.; Shegoleva, E.; Fedintsev, A.; Shaposhnikov, M.; Moskalev, A. Circadian clock genes’ overexpression in Drosophila alters diet impact on lifespan. Biogerontology 2019, 20, 159–170. [Google Scholar] [CrossRef]
- Nangle, S.; Xing, W.; Zheng, N. Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase. Cell Res. 2013, 23, 1417–1419. [Google Scholar] [CrossRef] [PubMed]
- Bharucha, K.N.; Tarr, P.; Zipursky, S.L. A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis. J. Exp. Biol. 2008, 211, 3103–3110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karpac, J.; Biteau, B.; Jasper, H. Misregulation of an Adaptive Metabolic Response Contributes to the Age-Related Disruption of Lipid Homeostasis in Drosophila. Cell Rep. 2013, 4, 1250–1261. [Google Scholar] [CrossRef] [Green Version]
- Bruce, K.D.; Hoxha, S.; Carvalho, G.B.; Yamada, R.; Wang, H.-D.; Karayan, P.; He, S.; Brummel, T.; Kapahi, P.; Ja, W.W. High carbohydrate–low protein consumption maximizes Drosophila lifespan. Exp. Gerontol. 2013, 48, 1129–1135. [Google Scholar] [CrossRef] [Green Version]
- Zhou, Y.; Kreek, M.J. Blockade of alcohol excessive and “relapse” drinking in male mice by pharmacological cryptochrome (CRY) activation. Psychopharmacology 2021, 238, 1099–1109. [Google Scholar] [CrossRef]
- Cvetković, V.J.; Mitrović, T.L.; Jovanović, B.; Stamenković, S.S.; Todorović, M.; Đorđević, M.; Radulović, N. Toxicity of dimethyl sulfoxide against Drosophila melanogaster. Biol. Nyssana 2015, 6, 91–95. [Google Scholar]
Treatment | N | Survival Time (h) | Percentiles of Mortality (h) | |||||
---|---|---|---|---|---|---|---|---|
Mean | ±SEM | 95% C.I. | 25% | 50% | 75% | 90% | ||
0.1% DMSO (control) | 118 | 38.44 | 0.87 | 36.74~40.15 | 32 | 32 | 48 | 48 |
0.1% DMSO, 5 µM KL001 | 125 | 41.82 * | 1 | 39.87~43.78 | 32 | 48 + | 48 | 60 |
Treatment | Sex | N | Mortality Percentiles (Days) | |||
---|---|---|---|---|---|---|
25% | 50% | 75% | 90% | |||
H2O (negative control) | ♂ | 181 | 48 | 58 | 62 | 68 |
0.1% DMSO (control) | ♂ | 152 | 54 | 58 | 58 | 60 |
0.1% DMSO, 1 µM KL001 | ♂ | 152 | 53 | 57 | 60 | 63 + |
0.1% DMSO, 5 µM KL001 | ♂ | 151 | 52 | 59 *#@ | 63 | 66 + |
0.1% DMSO, 10 µM KL001 | ♂ | 155 | 54 | 54 | 58 | 65 + |
0.1% DMSO, 50 µM KL001 | ♂ | 148 | 54 | 58 | 61 | 64 + |
H2O (negative control) | ♀ | 134 | 58 | 72 | 75 | 79 |
0.1% DMSO (control) | ♀ | 152 | 30 | 33 | 54 | 64 |
0.1% DMSO, 1 µM KL001 | ♀ | 149 | 29 | 39 + | 57 | 64 |
0.1% DMSO, 5 µM KL001 | ♀ | 151 | 28 | 45 + | 56 | 63 |
0.1% DMSO, 10 µM KL001 | ♀ | 152 | 26 | 37 | 51 | 58 |
0.1% DMSO, 50 µM KL001 | ♀ | 153 | 30 | 44 + | 52 | 61 |
Treatment | Sex | N | Mortality Percentiles (Days) | |||
---|---|---|---|---|---|---|
25% | 50% | 75% | 90% | |||
H2O (negative control) | ♂ | 181 | 48 | 58 | 62 | 68 |
0.1% DMSO (control) | ♂ | 145 | 52 | 59 | 64 | 67 |
0.1% DMSO, 1 µM KS15 | ♂ | 142 | 53 | 58 | 64 | 64 |
0.1% DMSO, 5 µM KS15 | ♂ | 153 | 50 | 57 | 64 | 64 |
0.1% DMSO, 10 µM KS15 | ♂ | 148 | 56 + | 64 * **#b | 64 | 72 |
H2O (negative control) | ♀ | 134 | 58 | 72 | 75 | 79 |
0.1% DMSO (control) | ♀ | 151 | 28 | 42 | 49 | 56 |
0.1% DMSO, 1 µM KS15 | ♀ | 148 | 28 | 42 | 53 | 60 |
0.1% DMSO, 5 µM KS15 | ♀ | 161 | 29 | 42 | 45 + | 50 |
0.1% DMSO, 10 µM KS15 | ♀ | 155 | 35 | 43 | 49 | 64 |
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Solovev, I.A.; Shaposhnikov, M.V.; Moskalev, A.A. Chronobiotics KL001 and KS15 Extend Lifespan and Modify Circadian Rhythms of Drosophila melanogaster. Clocks & Sleep 2021, 3, 429-441. https://doi.org/10.3390/clockssleep3030030
Solovev IA, Shaposhnikov MV, Moskalev AA. Chronobiotics KL001 and KS15 Extend Lifespan and Modify Circadian Rhythms of Drosophila melanogaster. Clocks & Sleep. 2021; 3(3):429-441. https://doi.org/10.3390/clockssleep3030030
Chicago/Turabian StyleSolovev, Ilya A., Mikhail V. Shaposhnikov, and Alexey A. Moskalev. 2021. "Chronobiotics KL001 and KS15 Extend Lifespan and Modify Circadian Rhythms of Drosophila melanogaster" Clocks & Sleep 3, no. 3: 429-441. https://doi.org/10.3390/clockssleep3030030