調降氧化還原的平衡常與加速老化過程做連結。核糖-5-磷酸異構酶(RPIA)作為人體中調控磷酸戊糖途徑(pentose phosphate pathway, PPP)的重要速率調控酵素，能將PPP由氧化階段轉換為非氧化階段，且過去也已被證實參與壽命調控機制。實驗室先前發表的文章中證實在果蠅中降低Rpi的表現量可以藉由提升葡萄糖-6-磷酸脫氫酶(G6PD)活性並促進煙酰胺腺嘌呤二核苷酸磷酸(NADPH)表現量以促進長壽。然而，此壽命調控機制是否在其他物種中具有演化保留性仍未可知。故，在此計畫中，我探討降低線蟲RPIA同源基因，rpia-1，是否也具相同壽命調控現象。從實驗結果我證實在線蟲中，於特定時間點或組織降低rpia-1表現具有與果蠅中相同的壽命調控現象，能夠延長線蟲壽命及改善線蟲的老化現象。全身性或是於神經元中抑制線蟲的rpia-1表現量能延長線蟲的壽命並且提升其氧化壓力耐受性。此外，在線蟲的麩胺酸神經元及膽鹼性神經元中抑制rpia-1表現量就足以延長其壽命。除此之外，抑制線蟲的rpia-1表現量能有效延緩PolyQ堆積以及改善因PolyQ堆積而造成的運動能力率退現象。另一方面，過表現rpia-1基因的線蟲會縮短壽命，而此壽命縮短現象能因抑制rpia-1表現量而部分改善。為深入探討是否有其他已知壽命調控相關的分子機制參與在此壽命調控機制中，我利用分子生物實驗驗證是否有典型的分子機制路徑，如細胞自噬、AMPK或是TOR訊息傳遞路徑，受抑制線蟲的rpia-1表現量影響。西方墨點法及壽命測試結果皆顯示抑制線蟲的rpia-1表現量能促進細胞自噬及AMPK，並同時抑制TOR訊息傳遞路徑。更重要的是，抑制線蟲的rpia-1表現量可藉由促進細胞自噬及AMPK，並同時抑制TOR訊息傳遞路徑延長壽命。此外，透過RNA-seq的分析結果除得以驗證先前的實驗結果外，更提佐證降低rpia-1可能調控此壽命延長現象的分子交互作用機制。綜上研究結果，我提出詳細的於特定時間及空間中，降低線蟲rpia-1表現量影響壽命及其影響之分子調控機制。

Deregulation of redox homeostasis often associates with accelerated aging process. Ribose-5-phosphate isomerase A (RPIA), an important rate-limiting enzyme, which modulates pentose phosphate pathway (PPP) from oxidative phase to non-oxidative phase, has been reported to participate in lifespan regulation in our previous study. Our previous study demonstrated that knockdown of Rpi , the gene encodes RPIA in Drosophila, promotes longevity through inducing G6PD activity and increasing NADPH level. However, whether RPIA-mediated longevity is evolutionarily conserved in other species, such as C. elegans, remains unclear. In my thesis, I reported that knockdown of rpia-1 in the specific spatial and temporal points prolongs lifespan and improves healthspan in C. elegans, sharing the evolutionarily conserved phenotypes in Drosophila. Knockdown of rpia-1 ubiquitously in adult N2 and pan-neuronally in TU3401 both enhance lifespan and tolerance to oxidative stress in C. elegans. In addition, rpia-1 knockdown in glutamatergic and cholinergic neurons both are sufficient to increase lifespan. Furthermore, rpia-1 knockdown reduces polyQ aggregation and improves the deteriorated body bending rate caused by polyQ aggregation. On the other hand, transgenic overexpression of rpia-1 exhibits reduced lifespan, which it can be partially rescued by rpia-1 knockdown, suggesting rpia-1 regulates lifespan in C. elegans. To further investigate the underlying molecular mechanisms which are responsible for these longevity-related phenotypical changes, I conducted several experiments to validate the candidate canonical pathways, such as autophagy, AMPK and TOR pathway, in rpia-1 knockdown worms. Both western blotting and lifespan assay results revealed that rpia-1 reduction accompanies with induction of autophagic flux, activation of AMPK and inhibition of TOR signaling. Importantly, the experimental results suggested that knockdown of rpia-1 activated autophagy, AMPK, and reduced TOR signaling to extend lifespan. In addition, the RNA-seq analysis not only supported the experimental findings but also pointed out the potential molecular intervention in this lifespan-regulated mediation by rpia-1 knockdown. Together, my data disclose the specific spatial and temporal effects and the underlying molecular mechanism on rpia-1 knockdown-mediated longevity in C. elegans.

Ahmad, T., and Suzuki, Y.J. (2019). Juglone in Oxidative Stress and Cell Signaling. Antioxidants (Basel) 8.
Ajayi, A., Yu, X., Lindberg, S., Langel, Ü., and Ström, A.-L. (2012). Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model. BMC Neuroscience 13, 86.
Alers, S., Löffler, A.S., Wesselborg, S., and Stork, B. (2012). Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32, 2-11.
Allen, E.A. (2020). Identification of a myotubularin-related phosphatase that regulates autophagic flux and lysosome homeostasis.
An, J.H., and Blackwell, T.K. (2003). SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17, 1882-1893.
Andriotis, V.M.E., and Smith, A.M. (2019). The plastidial pentose phosphate pathway is essential for postglobular embryo development in Arabidopsis. Proceedings of the National Academy of Sciences 116, 15297-15306.
Apel, K., and Hirt, H. (2004). Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annu Rev Plant Biol 55, 373-399.
Asby, D.J., Cuda, F., Beyaert, M., Houghton, F.D., Cagampang, F.R., and Tavassoli, A. (2015). AMPK Activation via Modulation of De Novo Purine Biosynthesis with an Inhibitor of ATIC Homodimerization. Chem Biol 22, 838-848.
Barbosa, M.C., Grosso, R.A., and Fader, C.M. (2019). Hallmarks of Aging: An Autophagic Perspective. Frontiers in Endocrinology 9.
Bermúdez-Muñoz, J.M., Celaya, A.M., Hijazo-Pechero, S., Wang, J., Serrano, M., and Varela-Nieto, I. (2020). G6PD overexpression protects from oxidative stress and age-related hearing loss. Aging Cell 19, e13275.
Bertoni, A., Giuliano, P., Galgani, M., Rotoli, D., Ulianich, L., Adornetto, A., Santillo, M.R., Porcellini, A., and Avvedimento, V.E. (2011). Early and late events induced by polyQ-expanded proteins: identification of a common pathogenic property of polYQ-expanded proteins. J Biol Chem 286, 4727-4741.
Bhatla, N., and Horvitz, H.R. (2015). Light and hydrogen peroxide inhibit C. elegans Feeding through gustatory receptor orthologs and pharyngeal neurons. Neuron 85, 804-818.
Blackwell, T.K., Steinbaugh, M.J., Hourihan, J.M., Ewald, C.Y., and Isik, M. (2015). SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic Biol Med 88, 290-301.
Blanco Ayala, T., Andérica-Romero, A., and Pedraza-Chaverri, J. (2014). New insights into antioxidant strategies against paraquat toxicity. Free radical research 48.
Bradshaw, P.C. (2019). Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging. Nutrients 11, 504.
Brignull, H.R., Moore, F.E., Tang, S.J., and Morimoto, R.I. (2006). Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model. J Neurosci 26, 7597-7606.
Butler, R.N. (1980). Meeting the challenges of health care for the elderly. J Allied Health 9, 161-168.
Cai, H. (2016). Genetic and transcriptomic analysis of axenic longevity in Caenorhabditis elegans.
Cantón-Habas, V., Rich-Ruiz, M., Romero-Saldaña, M., and Carrera-González, M.D.P. (2020). Depression as a Risk Factor for Dementia and Alzheimer's Disease. Biomedicines 8.
Chen, H.D., Kao, C.Y., Liu, B.Y., Huang, S.W., Kuo, C.J., Ruan, J.W., Lin, Y.H., Huang, C.R., Chen, Y.H., Wang, H.D., et al. (2017). HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. Autophagy 13, 371-385.
Chou, Y.T., Chen, L.Y., Tsai, S.L., Tu, H.C., Lu, J.W., Ciou, S.C., Wang, H.D., and Yuh, C.H. (2019). Ribose-5-phosphate isomerase A overexpression promotes liver cancer development in transgenic zebrafish via activation of ERK and β-catenin pathways. Carcinogenesis 40, 461-473.
Chou, Y.T., Jiang, J.K., Yang, M.H., Lu, J.W., Lin, H.K., Wang, H.D., and Yuh, C.H. (2018). Identification of a noncanonical function for ribose-5-phosphate isomerase A promotes colorectal cancer formation by stabilizing and activating β-catenin via a novel C-terminal domain. PLoS Biol 16, e2003714.
Ciou, S.C., Chou, Y.T., Liu, Y.L., Nieh, Y.C., Lu, J.W., Huang, S.F., Chou, Y.T., Cheng, L.H., Lo, J.F., Chen, M.J., et al. (2015). Ribose-5-phosphate isomerase A regulates hepatocarcinogenesis via PP2A and ERK signaling. Int J Cancer 137, 104-115.
Conte, D., Jr., MacNeil, L.T., Walhout, A.J.M., and Mello, C.C. (2015). RNA Interference in Caenorhabditis elegans. Curr Protoc Mol Biol 109, 26.23.21-26.23.30.
Corpas, F.J., and Barroso, J.B. (2014). NADPH-generating dehydrogenases: their role in the mechanism of protection against nitro-oxidative stress induced by adverse environmental conditions. Frontiers in Environmental Science 2.
Curtis, R., O'Connor, G., and DiStefano, P.S. (2006). Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5, 119-126.
Dai, C., Zhang, X., Xie, D., Tang, P., Li, C., Zuo, Y., Jiang, B., and Xue, C. (2017). Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells. Oncotarget 8, 95810-95823.
Das, K., and Roychoudhury, A. (2014). Reactive oxygen species (ROS) and response of antioxidants as ROS-scavengers during environmental stress in plants. Frontiers in Environmental Science 2.
Deng, J., Dai, Y., Tang, H., and Pang, S. (2020). SKN-1 Is a Negative Regulator of DAF-16 and Somatic Stress Resistance in Caenorhabditis elegans. G3 Genes|Genomes|Genetics 10, 1707-1712.
Dennis, P.B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S.C., and Thomas, G. (2001). Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102-1105.
Dienel, G.A. (2019). Brain Glucose Metabolism: Integration of Energetics with Function. Physiol Rev 99, 949-1045.
DuGoff, E.H., Canudas-Romo, V., Buttorff, C., Leff, B., and Anderson, G.F. (2014). Multiple Chronic Conditions and Life Expectancy: A Life Table Analysis. Medical Care 52.
Escobar, K.A., Cole, N.H., Mermier, C.M., and VanDusseldorp, T.A. (2019). Autophagy and aging: Maintaining the proteome through exercise and caloric restriction. Aging Cell 18, e12876.
Ewald, C.Y., Hourihan, J.M., Bland, M.S., Obieglo, C., Katic, I., Moronetti Mazzeo, L.E., Alcedo, J., Blackwell, T.K., and Hynes, N.E. (2017). NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans. eLife 6, e19493.
Farkas, R., Daniš, P., Medved'ová, L., Mechler, B.M., and Knopp, J. (2002). Regulation of cytosolic malate dehydrogenase by juvenile hormone in Drosophila melanogaster. Cell Biochemistry and Biophysics 37, 37-52.
Feser, J., Truong, D., Das, C., Carson, J.J., Kieft, J., Harkness, T., and Tyler, J.K. (2010). Elevated histone expression promotes life span extension. Mol Cell 39, 724-735.
Filer, D., Thompson, M., Takhaveev, V., Dobson, A., Kotronaki, I., Green, J., Heinemann, M., Tullet, J., and Alic, N. (2017). RNA polymerase III limits longevity downstream of TORC1. Nature 552.
Firnhaber, C., and Hammarlund, M. (2013). Neuron-specific feeding RNAi in C. elegans and its use in a screen for essential genes required for GABA neuron function. PLoS Genet 9, e1003921.
Forman, H.J., Ursini, F., and Maiorino, M. (2014). An overview of mechanisms of redox signaling. J Mol Cell Cardiol 73, 2-9.
Forman, H.J., and Zhang, H. (2021). Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 20, 689-709.
Galluzzi, L., Baehrecke, E.H., Ballabio, A., Boya, P., Bravo-San Pedro, J.M., Cecconi, F., Choi, A.M., Chu, C.T., Codogno, P., Colombo, M.I., et al. (2017). Molecular definitions of autophagy and related processes. Embo j 36, 1811-1836.
Gao, X., Zhao, L., Liu, S., Li, Y., Xia, S., Chen, D., Wang, M., Wu, S., Dai, Q., Vu, H., et al. (2019). γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate Pathway, Contributes to AMPK Activation through Inhibition of PP2A. Molecular Cell 76, 857-871.e859.
Ghoneum, A., Abdulfattah, A.Y., Warren, B.O., Shu, J., and Said, N. (2020). Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics. Int J Mol Sci 21.
Gkekas, I., Gioran, A., Boziki, M.K., Grigoriadis, N., Chondrogianni, N., and Petrakis, S. (2021). Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases. Antioxidants (Basel) 10.
Go, Y.M., and Jones, D.P. (2017). Redox theory of aging: implications for health and disease. Clin Sci (Lond) 131, 1669-1688.
Govindan, J.A., Jayamani, E., Zhang, X., Mylonakis, E., and Ruvkun, G. (2015). Dialogue between E. coli free radical pathways and the mitochondria of C. elegans. Proc Natl Acad Sci U S A 112, 12456-12461.
Hansen, M., Rubinsztein, D.C., and Walker, D.W. (2018). Autophagy as a promoter of longevity: insights from model organisms. Nature Reviews Molecular Cell Biology 19, 579-593.
Hardie, D.G., Ross, F.A., and Hawley, S.A. (2012). AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13, 251-262.
Heesbeen, H.J., Oerthel, L., Vries, P.M., Wagemans, M.R.J., and Smidt, M.P. (2021). Neuronal Dot1l is a broad mitochondrial gene-repressor associated with human brain aging via H3K79 hypermethylation.
Heintz, C., Doktor, T.K., Lanjuin, A., Escoubas, C., Zhang, Y., Weir, H.J., Dutta, S., Silva-García, C.G., Bruun, G.H., Morantte, I., et al. (2017). Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102-106.
Heintze, J., Costa, J.R., Weber, M., and Ketteler, R. (2016). Ribose 5-phosphate isomerase inhibits LC3 processing and basal autophagy. Cell Signal 28, 1380-1388.
Henderson, S.T., and Johnson, T.E. (2001). daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 11, 1975-1980.
Hobert, O., Glenwinkel, L., and White, J. (2016). Revisiting Neuronal Cell Type Classification in Caenorhabditis elegans. Current Biology 26, R1197-R1203.
Hofmeister, F., Baber, L., Ferrari, U., Hintze, S., Jarmusch, S., Krause, S., Meinke, P., Mehaffey, S., Neuerburg, C., Tangenelli, F., et al. (2021). Late-onset neuromuscular disorders in the differential diagnosis of sarcopenia. BMC Neurology 21, 241.
Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Géloën, A., Even, P.C., Cervera, P., and Le Bouc, Y. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187.
Inoki, K., Kim, J., and Guan, K.L. (2012). AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52, 381-400.
Jiang, P., Du, W., and Wu, M. (2014). Regulation of the pentose phosphate pathway in cancer. Protein Cell 5, 592-602.
Jones, D.P. (2015). Redox theory of aging. Redox Biol 5, 71-79.
Ju, H.-Q., Lin, J.-F., Tian, T., Xie, D., and Xu, R.-H. (2020). NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Signal Transduction and Targeted Therapy 5, 231.
Kapahi, P., Kaeberlein, M., and Hansen, M. (2017). Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Research Reviews 39, 3-14.
Karnewar, S., Neeli, P.K., Panuganti, D., Kotagiri, S., Mallappa, S., Jain, N., Jerald, M.K., and Kotamraju, S. (2018). Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1864, 1115-1128.
Kenyon, C., Chang, J., Gensch, E., Rudner, A., and Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature 366, 461-464.
Kilic, U., Gok, O., Erenberk, U., Dundaroz, M.R., Torun, E., Kucukardali, Y., Elibol-Can, B., Uysal, O., and Dundar, T. (2015). A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human. PLoS One 10, e0117954.
Kim, J., Kundu, M., Viollet, B., and Guan, K.-L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology 13, 132-141.
Kim, W., Kim, R., Park, G., Park, J.-W., and Kim, J.-E. (2012a). Deficiency of H3K79 histone methyltransferase Dot1-like protein (DOT1L) inhibits cell proliferation. J Biol Chem 287, 5588-5599.
Kim, Y., Kim, E.Y., Seo, Y.M., Yoon, T.K., Lee, W.S., and Lee, K.A. (2012b). Function of the pentose phosphate pathway and its key enzyme, transketolase, in the regulation of the meiotic cell cycle in oocytes. Clin Exp Reprod Med 39, 58-67.
Kim, Y., Park, Y., Hwang, J., and Kwack, K. (2018). Comparative genomic analysis of the human and nematode Caenorhabditis elegans uncovers potential reproductive genes and disease associations in humans. Physiological Genomics 50, 1002-1014.
Klionsky, D.J., Abdel-Aziz, A.K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M.H., Abudu, Y.P., Acevedo-Arozena, A., et al. (2021). Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Autophagy 17, 1-382.
Kumsta, C., Chang, J.T., Lee, R., Tan, E.P., Yang, Y., Loureiro, R., Choy, E.H., Lim, S.H.Y., Saez, I., Springhorn, A., et al. (2019). The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy. Nature Communications 10, 5648.
Kumsta, C., Chang, J.T., Schmalz, J., and Hansen, M. (2017). Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nature Communications 8, 14337.
López-Lluch, G., and Navas, P. (2016). Calorie restriction as an intervention in ageing. J Physiol 594, 2043-2060.
López-Otín, C., Galluzzi, L., Freije, J.M.P., Madeo, F., and Kroemer, G. (2016). Metabolic Control of Longevity. Cell 166, 802-821.
López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2013). The Hallmarks of Aging. Cell 153, 1194-1217.
Legan, S.K., Rebrin, I., Mockett, R.J., Radyuk, S.N., Klichko, V.I., Sohal, R.S., and Orr, W.C. (2008). Overexpression of Glucose-6-phosphate Dehydrogenase Extends the Life Span of <em>Drosophila melanogaster</em>*. Journal of Biological Chemistry 283, 32492-32499.
Leiers, B., Kampkötter, A., Grevelding, C.G., Link, C.D., Johnson, T.E., and Henkle-Dührsen, K. (2003). A stress-responsive glutathione S-transferase confers resistance to oxidative stress in Caenorhabditis elegans. Free Radical Biology and Medicine 34, 1405-1415.
Li, X., Wang, L., Zhou, X.E., Ke, J., de Waal, P.W., Gu, X., Tan, M.H., Wang, D., Wu, D., Xu, H.E., et al. (2015). Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res 25, 50-66.
Lin, K., Hsin, H., Libina, N., and Kenyon, C. (2001). Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nature Genetics 28, 139-145.
Lin, R., Elf, S., Shan, C., Kang, H.B., Ji, Q., Zhou, L., Hitosugi, T., Zhang, L., Zhang, S., Seo, J.H., et al. (2015). 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol 17, 1484-1496.
Lu, J.-Y., Lin, Y.-Y., Sheu, J.-C., Wu, J.-T., Lee, F.-J., Chen, Y., Lin, M.-I., Chiang, F.-T., Tai, T.-Y., Berger, Shelley L., et al. (2011). Acetylation of Yeast AMPK Controls Intrinsic Aging Independently of Caloric Restriction. Cell 146, 969-979.
Luckinbill, L.S., Riha, V., Rhine, S., and Grudzien, T.A. (1990). The role of glucose-6-phosphate dehydrogenase in the evolution of longevity in Drosophila melanogaster. Heredity 65, 29-38.
Mallick, A., Ranawade, A., van den Berg, W., and Gupta, B.P. (2020). Axin-Mediated Regulation of Lifespan and Muscle Health in C. elegans Requires AMPK-FOXO Signaling. iScience 23, 101843.
McCormick, M.A., Tsai, S.Y., and Kennedy, B.K. (2011). TOR and ageing: a complex pathway for a complex process. Philos Trans R Soc Lond B Biol Sci 366, 17-27.
Mirzaei, H., Suarez, J.A., and Longo, V.D. (2014). Protein and amino acid restriction, aging and disease: from yeast to humans. Trends Endocrinol Metab 25, 558-566.
Morselli, E., Maiuri, M.C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S.A., Vitale, I., et al. (2010). Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death & Disease 1, e10-e10.
Murphy, C.T., and Hu, P.J. (2013). Insulin/insulin-like growth factor signaling in C. elegans. WormBook, 1-43.
Muschiol, D., Schroeder, F., and Traunspurger, W. (2009). Life cycle and population growth rate of Caenorhabditis elegans studied by a new method. BMC ecology 9, 14.
Nóbrega-Pereira, S., Fernandez-Marcos, P.J., Brioche, T., Gomez-Cabrera, M.C., Salvador-Pascual, A., Flores, J.M., Viña, J., and Serrano, M. (2016). G6PD protects from oxidative damage and improves healthspan in mice. Nature Communications 7, 10894.
Nakatogawa, H., Suzuki, K., Kamada, Y., and Ohsumi, Y. (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10, 458-467.
Nhan, J., Turner, C., Anderson, S., Yen, C.-A., Dalton, H., Cheesman, H., Ruter, D., Uma Naresh, N., Haynes, C., Soukas, A., et al. (2019). Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection. Proceedings of the National Academy of Sciences 116, 201909666.
Nieh, Y.C., Chou, Y.T., Chou, Y.T., Wang, C.Y., Lin, S.X., Ciou, S.C., Yuh, C.H., and Wang, H.D. (2022). Suppression of Ribose-5-Phosphate Isomerase a Induces ROS to Activate Autophagy, Apoptosis, and Cellular Senescence in Lung Cancer. Int J Mol Sci 23.
Oeggl, R., Neumann, T., Gätgens, J., Romano, D., Noack, S., and Rother, D. (2018). Citrate as Cost-Efficient NADPH Regenerating Agent. Frontiers in Bioengineering and Biotechnology 6.
Omar, H. (2013). Mycotoxins-Induced Oxidative Stress and Disease. In, pp. 63-92.
Patra, K.C., and Hay, N. (2014). The pentose phosphate pathway and cancer. Trends Biochem Sci 39, 347-354.
Pitt, J.N., and Kaeberlein, M. (2015). Why Is Aging Conserved and What Can We Do about It? PLOS Biology 13, e1002131.
Porta-de-la-Riva, M., Fontrodona, L., Villanueva, A., and Cerón, J. (2012). Basic Caenorhabditis elegans methods: synchronization and observation. J Vis Exp, e4019.
Ristow, M., and Zarse, K. (2010). How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 45, 410-418.
Rose, H.R.a.M. (2019). Age Structure (Our World in Data), pp. https://ourworldindata.org/age-structure.
Rubinsztein, David C., Mariño, G., and Kroemer, G. (2011). Autophagy and Aging. Cell 146, 682-695.
Salminen, A., and Kaarniranta, K. (2012). AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Research Reviews 11, 230-241.
Santana-Codina, N., Roeth, A., Zhang, Y., Yang, A., Mashadova, O., Asara, J., Wang, X., Bronson, R., Lyssiotis, C., Ying, H., et al. (2018). Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nature Communications 9.
Satoh, A., Brace, C.S., Rensing, N., Cliften, P., Wozniak, D.F., Herzog, E.D., Yamada, K.A., and Imai, S. (2013). Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab 18, 416-430.
Schaar, C.E., Dues, D.J., Spielbauer, K.K., Machiela, E., Cooper, J.F., Senchuk, M., Hekimi, S., and Van Raamsdonk, J.M. (2015). Mitochondrial and Cytoplasmic ROS Have Opposing Effects on Lifespan. PLOS Genetics 11, e1004972.
Schmeisser, S., Li, S., Bouchard, B., Ruiz, M., Des Rosiers, C., and Roy, R. (2019). Muscle-Specific Lipid Hydrolysis Prolongs Lifespan through Global Lipidomic Remodeling. Cell Reports 29, 4540-4552.e4548.
Senchuk, M.M., Dues, D.J., and Van Raamsdonk, J.M. (2017). Measuring Oxidative Stress in Caenorhabditis elegans: Paraquat and Juglone Sensitivity Assays. Bio Protoc 7.
Silva, I., Lopes, C., and Liz, M. (2020). Transthyretin interacts with actin regulators in a Drosophila model of familial amyloid polyneuropathy. Scientific Reports 10, 13596.
Sohal, R.S., and Orr, W.C. (2012). The redox stress hypothesis of aging. Free Radic Biol Med 52, 539-555.
Spaans, S., Weusthuis, R., Van Der Oost, J., and Kengen, S. (2015). NADPH-generating systems in bacteria and archaea. Frontiers in Microbiology 6.
Stanton, R.C. (2012). Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life 64, 362-369.
Steinbaugh, M.J., Narasimhan, S.D., Robida-Stubbs, S., Moronetti Mazzeo, L.E., Dreyfuss, J.M., Hourihan, J.M., Raghavan, P., Operaña, T.N., Esmaillie, R., and Blackwell, T.K. (2015). Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence. eLife 4, e07836.
Stenesen, D., Suh, J.M., Seo, J., Yu, K., Lee, K.S., Kim, J.S., Min, K.J., and Graff, J.M. (2013). Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab 17, 101-112.
Stiernagle, T. (2006). Maintenance of C. elegans. WormBook, 1-11.
Suh, Y., Atzmon, G., Cho, M.-O., Hwang, D., Liu, B., Leahy, D.J., Barzilai, N., and Cohen, P. (2008). Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proceedings of the National Academy of Sciences 105, 3438-3442.
Sun, X., Chen, W.-D., and Wang, Y.-D. (2017). DAF-16/FOXO Transcription Factor in Aging and Longevity. Frontiers in Pharmacology 8.
Sural, S., Liang, C.Y., Wang, F.Y., Ching, T.T., and Hsu, A.L. (2020). HSB-1/HSF-1 pathway modulates histone H4 in mitochondria to control mtDNA transcription and longevity. Sci Adv 6.
Tan, B.L., Norhaizan, M.E., Liew, W.-P.-P., and Sulaiman Rahman, H. (2018). Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases. Frontiers in Pharmacology 9.
The, C.e.D.M.C. (2012). Large-Scale Screening for Targeted Knockouts in the Caenorhabditis elegans Genome. G3 Genes|Genomes|Genetics 2, 1415-1425.
Trefts, E., and Shaw, R.J. (2021). AMPK: restoring metabolic homeostasis over space and time. Mol Cell 81, 3677-3690.
Tullet, J.M., Hertweck, M., An, J.H., Baker, J., Hwang, J.Y., Liu, S., Oliveira, R.P., Baumeister, R., and Blackwell, T.K. (2008). Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132, 1025-1038.
Ulgherait, M., Rana, A., Rera, M., Graniel, J., and Walker, D.W. (2014). AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep 8, 1767-1780.
Uno, M., Tani, Y., Nono, M., Okabe, E., Kishimoto, S., Takahashi, C., Abe, R., Kurihara, T., and Nishida, E. (2021). Neuronal DAF-16-to-intestinal DAF-16 communication underlies organismal lifespan extension in C. elegans. iScience 24, 102706.
Wang, C.-T., Chen, Y.-C., Wang, Y.-Y., Huang, M.-H., Yen, T.-L., Li, H., Liang, C.-J., Sang, T.-K., Ciou, S.-C., Yuh, C.-H., et al. (2012). Reduced neuronal expression of ribose-5-phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila. Aging Cell 11, 93-103.
Weir, H.J., Yao, P., Huynh, F.K., Escoubas, C.C., Goncalves, R.L., Burkewitz, K., Laboy, R., Hirschey, M.D., and Mair, W.B. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metab 26, 884-896.e885.
Wong, S.Q., Kumar, A.V., Mills, J., and Lapierre, L.R. (2020). Autophagy in aging and longevity. Hum Genet 139, 277-290.
Wullschleger, S., Loewith, R., and Hall, M.N. (2006). TOR signaling in growth and metabolism. Cell 124, 471-484.
Yamamoto, K., Iwadate, D., Kato, H., Nakai, Y., Tateishi, K., and Fujishiro, M. (2022). Targeting autophagy as a therapeutic strategy against pancreatic cancer. Journal of Gastroenterology.
Yu, W., Dittenhafer-Reed, K.E., and Denu, J.M. (2012). SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status. J Biol Chem 287, 14078-14086.
Zhang, S., Li, F., Zhou, T., Wang, G., and Li, Z. (2020). Caenorhabditis elegans as a Useful Model for Studying Aging Mutations. Frontiers in Endocrinology 11.
Zullo, J.M., Drake, D., Aron, L., O’Hern, P., Dhamne, S.C., Davidsohn, N., Mao, C.-A., Klein, W.H., Rotenberg, A., Bennett, D.A., et al. (2019). Regulation of lifespan by neural excitation and REST. Nature 574, 359-364.