alg-1 knockdown somente durante a fase adulta, previne a longevidade do glp-1(e2144), e há miRNAs diferencialmente expressos concomitantemente nesses animais e na superexpressão de alg-1 que podem estar relacionados com mecanismos de proteção contra o estresse. Entretanto, apesar do knockdown de alg-1 ser suficiente para diminuir o tempo de vida de C. elegans selvagens, sua superexpressão não o modula. ALG-1 O/E, porém, aumenta a resistência dos animais aos estressores oxidativos NaAsO2, e metil viologênio, e a desta é bloqueada pela ausência de cel-miR- 71, o qual ainda previne as regulações negativas dos 5 reguladores transcricionais de alg-1 identificados. Esses resultados constituem indícios de que ALG-1 pode participar na regulação da healthspan ao atuar na defesa a estressores oxidativos em situações fisiopatológicas (Figura 17).
Figura 17. Modelo para a regulação do envelhecimento saudável mediada por ALG-1. ALG-1 está em um
mecanismo de retroalimentação com cel-miR-71. Essa interação diminui a expressão de alg-1, e influencia a ação de repressores transcricionais. A superexpressão de alg-1 parece, por sua vez, influenciar tanto a expressão de miRNAs, como a resistência a estressores oxidativos.
Referências Bibliográficas
AALTO, A. P. et al. Opposing roles of microRNA Argonautes during Caenorhabditis elegans aging. PLoS Genetics, v. 14, n. 6, p. e1007379, 2018.
ALEMAYEHU, B.; WARNER, K. E. The lifetime distribution of health care costs. Health
Services Research, v. 39, n. 3, p. 627–642, 2004.
AMRIT, F. R. G. et al. The C. elegans lifespan assay toolkit. Methods, v. 68, n. 3, p. 465–475, 2014.
ARANTES-OLIVIERA, N. et al. Regulation of Life-Span by germ -line stem cells in Caenorhabditis elegans. Science, v. 295, n. 2002, p. 502–505, 2002.
ARAYA, C. L. et al. Regulatory analysis of the C. elegans genome with spatiotemporal resolution. Nature, v. 512, n. 7515, p. 400–405, 2014.
BARTEL, D. P. MicroRNA Target Recognition and Regulatory Functions. Cell, v. 136, n. 2, p. 215–233, 2009.
BERNSTEIN, E.; DENLI, A. M.; HANNON, G. J. The Rest is Silence. RNA, v. 7, n. 11, p. 1509–1521, 2001.
BLUM, J.; FRIDOVICH, I. Superoxide, hydrogen peroxide, and oxygen toxicity in two free-living nematode species. Archives of Biochemistry and Biophysics, v. 222, n. 1, p. 35–43, 1983.
BOEHM, M.; SLACK, F. A developmental timing microRNA and its target regulate life span in C. elegans. Science, v. 310, n. 5756, p. 1954–1957, 2005.
BROUGHTON, J. P. et al. Pairing beyond the Seed Supports MicroRNA Targeting Specificity. Molecular Cell, v. 64, n. 2, p. 320–333, 2016.
BROWN, K. C. et al. ALG-5 is a miRNA-associated Argonaute required for proper developmental timing in the Caenorhabditis elegans germline. Nucleic Acids
Research, v. 45, n. 15, p. 9093–9107, 2017.
BYERLY, L.; CASSADA, R. C.; RUSSELL, R. L. The life cycle of the nematode Caenorhabditis elegans. Developmental Biology, v. 51, n. 1, p. 23–33, 1976. CARAVIA, X. M. et al. Functional relevance of miRNAs in premature ageing.
Mechanisms of Ageing and Development, n. October 2016, p. 1–10, 2017.
CHENDRIMADA, T. P. et al. MicroRNA silencing through RISC recruitment of eIF6.
Nature, v. 447, n. 7146, p. 823–828, 2007.
CHITI, F. et al. Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature, v. 424, n. 6950, p. 805–808, 2003.
ELGAR, G.; VAVOURI, T. Tuning in to the signals: noncoding sequence conservation in vertebrate genomes. Trends in Genetics, v. 24, n. 7, p. 344–352, 2008.
EWALD, C. Y. et al. Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature, v. 519, n. 7541, p. 97–101, 2015.
FAY, D. Genetic mapping and manipulation: Chapter 1-Introduction and basics (T. C. elegans R. Community, Ed.)WormBookWormBook, , 2015. Disponível em:
<http://www.wormbook.org>
FONTANA, L.; PARTRIDGE, L.; LONGO, V. D. D. Extending healthy lifespan - from yeast to humans. Science, v. 328, n. 5976, p. 321–326, 2010.
GALLAGHER, M.; STOCKER, A.; KOH, M. T. Mindspan: Lessons from Rat Models of Neurocognitive Aging. ILAR J, v. 52, n. 1, p. 32–40, 2011.
GEMS, D.; DOONAN, R. Antioxidant defense and aging in C. elegans: Is the oxidative damage theory of aging wrong? Cell Cycle, v. 8, n. 11, p. 1681–1687, 2009.
GRISHOK, A. et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing.
Cell, v. 106, n. 1, p. 23–34, 2001.
HERSKIND, A. M. et al. The heritability of human longevity : a population-based study of 2872 Danish twin pairs born 1870-1900. Human Genetics, v. 97, n. 3, p. 319–323, 1996.
HÖCK, J.; MEISTER, G. The Argonaute protein family. Genome biology, v. 9, n. 2, p. 210, 2008.
HOFFMAN, J. M. et al. The companion dog as a model for human aging and mortality.
Aging Cell, 2018.
HOLZENBERGER, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature, v. 421, n. 6919, p. 182–187, 2003.
HOOGSTRATE, S. W. et al. Nematode endogenous small RNA pathways. Worm, v. 3, n. March, p. e28234, 2014.
HSIN, H.; KENYON, C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature, v. 399, n. 6734, p. 362–366, 1999.
IBÁÑEZ-VENTOSO, C. et al. Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell, v. 5, n. 3, p. 235–246, 2006.
IBÁÑEZ-VENTOSO, C.; VORA, M.; DRISCOLL, M. Sequence relationships among C. elegans, D. melanogaster and human microRNAs highlight the extensive conservation of microRNAs in biology. PLoS ONE, v. 3, n. 7, 2008.
INSTITUTO BRASILEIRO DE GEOGRAFIA E ESTATÍSTICA - IBGE. Tábuas
Abreviadas de mortalidade por sexo e idade. Rio de Janeiro: Diretoria de Pesquisas,
2010.
INSTITUTO BRASILEIRO DE GEOGRAFIA E ESTATÍSTICA - IBGE. Tábua completa de mortalidade para o Brasil - 2016 Breve análise da evolução da mortalidade no Brasil. 2016.
INUKAI, S. et al. A microRNA feedback loop regulates global microRNA abundance during aging. RNA, v. 24, n. 2, p. 159–172, 2017.
JACKSON LABORATORY. Mouse Strain Datasheet. Disponível em: <https://www.jax.org/strain/000664>. Acesso em: 20 maio. 2016.
JONES, O. R. et al. Diversity of ageing across the tree of life. Nature, v. 505, n. 7482, p. 169–173, 2013.
KAMATH, R. S. et al. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome biology, v. 2, n. 1, p. 0002.1-0002.10, 2001.
KAPPUS, H. Overview of enzyme systems involved in bioreduction of drugs and in redox cycling. Biochemical Pharmacology, v. 35, n. 1, p. 1–6, 1986.
KENYON, C. J. The genetics of ageing. Nature, v. 464, n. 7288, p. 504–512, 2010. KIM, J. et al. Identification of many microRNAs that copurify with polyribosomes in
mammalian neurons. Proceedings of the National Academy of Sciences, v. 101, n. 1, p. 360–365, 2004.
KIM, J. et al. A miRNA-101-3p / Bim axis as a determinant of serum deprivation-induced endothelial cell apoptosis. Cell Death and Disease, v. 18, n. 8, p. 5, 2017.
KIRKWOOD, T. B. L.; AUSTAD, S. N. Why do we age? Nature, v. 408, n. 6809, p. 233– 238, 2000.
KOMATSU, R. Como cuidar dos idosos. In: RODRIGUES, R. A. P.; DIOGO, M. J. D. (Eds.). . Como cuidar dos idosos. Coleção Vi ed. Campinas: Papirus, 1996.
LABBADIA, J.; MORIMOTO, R. I. Proteostasis and longevity: when does aging really begin? F1000Prime Reports, v. 6, n. February, 2014.
LAI, C. H. et al. Identification of novel human genes evolutionarily conserved in
Caenorhabditis elegans by comparative proteomics. Genome Research, v. 10, n. 5, p. 703–13, 2000.
LAKOWSKI, B.; HEKIMI, S. The genetics of caloric restriction in Caenorhabditis
elegans. Proceedings of the National Academy of Sciences of the United States of
America, v. 95, p. 13091–13096, 1998.
LANDER, E. S. et al. Initial sequencing and analysis of the human genome. Nature, v. 409, n. 6822, p. 860–921, 2001.
LEE, R. C.; FEINBAUM, R.; AMBROS, V. The C . elegans Heterochronic Gene lin-4 Encodes Small RNAs with Antisense Complementarity to lin-14. Cell, v. 75, n. 5, p. 843– 854, 1993.
LENCASTRE, A. DE et al. Article MicroRNAs Both Promote and Antagonize Longevity in C . elegans. Current Biology, v. 20, n. 24, p. 2159–2168, 2010.
LIVAK, K. J.; SCHMITTGEN, T. D. Analysis of relative gene expression data using real- time quantitative PCR and the 2-ΔΔCT method. Methods, v. 25, n. 4, p. 402–408, 2001. LÓPEZ-OTÍN, C. et al. The Hallmarks of Aging. Cell, v. 153, n. 6, p. 1194–217, 2013. LÓPEZ-OTÍN, C. et al. Metabolic Control of Longevity. Cell, v. 166, n. 4, p. 802–821, 2016.
MATTISON, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nature Communications, v. 8, n. May 2016, p. 1–12, 2017.
MCCAY, C. M.; CROWELL, M. F.; MAYNARD, L. A. THE EFFECT OF RETARDED GROWTH UPON THE LENGTH OF LIFE SPAN AND UPON THE ULTIMATE BODY SIZE. The Journal of Nutrition, 1935.
MCDONALD, R. B.; RUHE, R. C. Aging and Longevity: Why Knowing the Difference Is Important to Nutrition Research. Nutrients, v. 3, p. 274–282, 2011.
MISKA, E. A. et al. Most Caenorhabditis elegans microRNAs are individually not
essential for development or viability. PLoS Genetics, v. 3, n. 12, p. 2395–2403, 2007. MITCHELL, S. J. et al. Animal Models of Aging Research: Implications for Human Aging
and Age-Related Diseases. Annual Review of Animal Biosciences, v. 3, p. 283–303, 2015.
MORI, M. et al. Role of microRNA Processing in Adipose Tissue in Stress defense and longevity. Cell Metabolism, v. 16, n. 3, p. 336–347, 2012.
MORI, M. A. Editorial: Non-Coding RNAs: Entwining Metabolism and Aging. Frontiers
in Endocrinology, v. 9, n. 111, p. 1–2, 2018.
MOUSTAFA, H. Intracellular Production of Superoxide Peroxide by Redox Active Radical and of Hydrogen Compounds ’. v. 196, n. 2, p. 385–395, 1979.
NOSTRAND, E. L. VAN; KIM, S. K. Integrative analysis of C . elegans modENCODE ChIP-seq data sets to infer gene regulatory interactions. p. 941–953, 2013.
OLSEN, A.; VANTIPALLI, M. C.; LITHGOW, G. J. Using Caenorhabditis elegans as a model for aging and age-related diseases. Annals of the New York Academy of
Sciences, v. 1067, n. 1, p. 120–128, 2006.
PANOWSKI, S. H.; DILLIN, A. Signals of youth: endocrine regulation of aging in Caenorhabditis elegans. Trends in Endocrinology and Metabolism, v. 20, n. 6, p. 259–264, 2009.
PERLS, T. T. et al. Siblings of centenarians live longer. The Lancet, v. 351, p. 2215, 1998.
RATNAPPAN, R. et al. Germline Signals Deploy NHR-49 to Modulate Fatty-Acid ??- Oxidation and Desaturation in Somatic Tissues of C. elegans. PLoS Genetics, v. 10, n. 12, 2014.
REINHART, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, v. 403, n. 6772, p. 901–906, 2000.
REYNOLDS, B. S.; LEFEBVRE, H. P. Feline CKD: Pathophysiology and risk factors - what do we know? Journal of Feline Medicine and Surgery, v. 15, n. 1 SUPPL., p. 3– 14, 2013.
ROTH, G. S. et al. Biomarkers of caloric restriction may predict longevity in humans.
Science, v. 297, n. 5582, p. 811, 2002.
SAHU, S. N. et al. Genomic Analysis of Stress Response against Arsenic in Caenorhabditis elegans. PLoS ONE, v. 8, n. 7, 2013.
SAMUELSON, A. V.; CARR, C. E.; RUVKUN, G. Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes and Development, v. 21, n. 22, p. 2976–2994, 2007.
SENCHUK, M.; DUES, D.; VAN RAAMSDONK, J. Measuring Oxidative Stress in Caenorhabditis elegans: Paraquat and Juglone Sensitivity Assays. Bio-Protocol, v. 7, n. 1, p. 1–16, 2017.
SHEN, Y. et al. A Steroid Receptor-MicroRNA Switch Regulates Life Span in Response to Signals from the Gonad. Science, v. 338, n. 6113, p. 1472–1476, 2012.
SMITH-VIKOS, T. et al. MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Current Biology, v. 24, n. 19, p. 2238–2246, 2014.
SMITH-VIKOS, T.; SLACK, F. J. MicroRNAs and their roles in aging. Journal of cell
science, v. 125, n. Pt 1, p. 7–17, 2012.
SOHAL, R. S.; ORR, W. C. Relationship between Antioxidants, Prooxidants, and the Aging Process. Annals of the New York Academy of Sciences, v. 663, n. 1, p. 74–84, 1992.
SONG, J.-J. et al. The crystal structure of the Argonaute2 PAZ domain reveals an RNA binding motif in RNAi effector complexes. Nature structural biology, v. 10, n. 12, p. 1026–1032, 2003.
STEFANI, M.; DOBSON, C. M. Protein aggregation and aggregate toxicity: New insights into protein folding, misfolding diseases and biological evolution. Journal of Molecular
Medicine, v. 81, n. 11, p. 678–699, 2003.
STIERNAGLE, T. Maintenance of C. elegans. Disponível em: <http://www.wormbook.org>. Acesso em: 30 abr. 2016.
TANG, L.; CHOE, K. P. Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans; pleiotrophy, aging, glutathione, and interactions with other longevity pathways.
Mechanisms of Ageing and Development, v. 149, p. 88–98, 2015.
The miRBase Sequence Database. Disponível em: <http://www.mirbase.org/>. Acesso
em: 1 ago. 2018.
The Nobel Prize in Physiology or Medicine 2006. Disponível em:
<http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/>. Acesso em: 10 ago. 2018.
UHLÉN, M. et al. Tissue-based map of the human proteome. Science, v. 347, n. 6220, p. 12604191–9, 2015.
UN/DESA. Ageing in the Twenty-First Century: A Celebration and A Challenge. New York e London: UNFPA and HelpAge International, 2012. Disponível em: <http://www.unfpa.org/publications/ageing-twenty-first-century>.
UN/DESA. World Population Ageing 2017 - Highlights. [s.l: s.n.].
UNITED NATIONS, DEPARTMENT OF ECONOMIC AND SOCIAL AFFAIRS, P. D. World Population Prospects: The 2017 Revision, Key Findings and Advance Tables.
Working Paper No, v. ESA/P/WP/2, 2017.
VAHIDNIA, A.; VAN DER VOET, G. B.; DE WOLFF, F. A. Arsenic neurotoxicity - A review. Human and Experimental Toxicology, v. 26, n. 10, p. 823–832, 2007. VANHOOREN, V.; LIBERT, C. The mouse as a model organism in aging research: Usefulness, pitfalls and possibilities. Ageing Research Reviews, v. 12, n. 1, p. 8–21, 2013.
VASQUEZ-RIFO, A. et al. Developmental characterization of the microRNA-specific C. elegans argonautes alg-1 and alg-2. PLoS ONE, v. 7, n. 3, p. 1–11, 2012.
VENTER, J. C. et al. The Sequence of the Human Genome. Science, v. 291, n. 5507, p. 1304–1351, 2001.
WALTER, L. et al. The homeobox protein CEH-23 mediates prolonged longevity in response to impaired Mitochondrial Electron Transport Chain in C. elegans. PLoS
Biology, v. 9, n. 6, 2011.
WHO. World Health Statistics 2016: monitoring health for the SDGs, sustainable development goals. 2016.
WIGHTMAN, B.; HA, I.; RUVKUN, G. Posttranscriptional regulation of the heterochronic gene lin- 14 by lin-4 mediates temporal pattern formation in C. elegans. Cell, v. 75, p. 855–862, 1993.
WILLCOX, B. J. et al. FOXO3A genotype is strongly associated with human longevity.
Proceedings of the National Academy of Sciences of the United States of America,
v. 105, n. 37, p. 13987–13992, 2008.
WOLFF, S. et al. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell, v. 124, n. 5, p. 1039–1053, 2006.
YAN, K. S. et al. Structure and conserved RNA binding of the PAZ domain. Nature, v. 426, n. 6965, p. 468–74, 2003.
ZHANG, Y. et al. Selection of reliable reference genes in caenorhabditis elegans for analysis of nanotoxicity. PLoS ONE, v. 7, n. 3, 2012.
ZINOVYEVA, A. Y. et al. Mutations in Conserved Residues of the C. elegans microRNA Argonaute ALG-1 Identify Separable Functions in ALG-1 miRISC Loading and Target Repression. PLoS Genetics, v. 10, n. 4, 2014.