Abstract
It is now widely recognised that ageing and its associated functional decline are regulated by a wide range of molecules that fit into specific cellular pathways. Here, we describe several of the evolutionary conserved cellular signalling pathways that govern organismal ageing and discuss how their identification, and work on the individual molecules that contribute to them, has aided in the design of therapeutic strategies to alleviate the adverse effects of ageing and age-related disease.
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References
Alic N et al (2011a) Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling. Mol Syst Biol 7:502–502
Alic N, Hoddinott MP, Vinti G, Partridge L (2011b) Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor. Aging Cell 10:137–147
Alic N, Giannakou ME, Papatheodorou I, Hoddinott MP, Andrews TD, Bolukbasi E, Partridge L (2014a) Interplay of dFOXO and two ETS-family transcription factors determines lifespan in Drosophila melanogaster. PLoS Genet 10:e1004619
Alic N et al (2014b) Cell-nonautonomous effects of dFOXO/DAF-16 in aging. Cell Rep 6:608–616
Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8:450–461
An JH, Blackwell TK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17:1882–1893
An JH, Vranas K, Lucke M, Inoue H, Hisamoto N, Matsumoto K, Blackwell TK (2005) Regulation of the caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proc Natl Acad Sci U S A 102:16275–16280
Andziak B, Buffenstein R (2006) Disparate patterns of age-related changes in lipid peroxidation in long-lived naked mole-rats and shorter-lived mice. Aging Cell 5:525–532
Anisimov VN et al (2011) Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10:4230–4236
Apfeld J, O’Connor G, McDonagh T, DiStefano PS, Curtis R (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18:3004–3009
Bakker WJ et al (2007) Differential regulation of Foxo3a target genes in erythropoiesis. Mol Cell Biol 27:3839–3854
Bansal A et al (2014) Transcriptional regulation of caenorhabditis elegans FOXO/DAF-16 modulates lifespan. Longev Healthspan 3:5–5
Bartke A et al (2000) Growth hormone and aging. Age 23:219–225
Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (2016) Metformin as a tool to target aging. Cell Metab 23:1060–1065
Ben-Sahra I, Manning BD (2017) mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol 45:72–82
Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev Cell 12:487–502
Bishop NA, Guarente L (2007) Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447:545–549
Biteau B, Hochmuth CE, Jasper H (2008) JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3:442–455
Biteau B, Karpac J, Supoyo S, DeGennaro M, Lehmann R, Jasper H (2010) Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet 6:e1001159
Bitto A et al (2016) Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. elife 5:e16351
Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L (2010) Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11:35–46
Blackwell TK, Steinbaugh MJ, Hourihan JM, Ewald CY, Isik M (2015) SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic Biol Med 88:1–12
Blagosklonny MV (2006) Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle 5:2087–2102
Blagosklonny MV (2007) Paradoxes of aging. Cell Cycle 6:2997–3003
Blagosklonny MV (2008) Aging: ROS or TOR. Cell Cycle 7:3344–3354
Blagosklonny MV (2012) Answering the ultimate question “what is the proximal cause of aging?”. Aging 4:861–877
Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572–574
Borras C et al (2011) RasGrf1 deficiency delays aging in mice. Aging 3:262–276
Broughton SJ et al (2005) Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A 102:3105–3110
Brown-Borg HM, Rakoczy SG, Sharma S, Bartke A (2009) Long-living growth hormone receptor knockout mice: potential mechanisms of altered stress resistance. Exp Gerontol 44:10–19
Brunner D, Ducker K, Oellers N, Hafen E, Scholz H, Klambt C (1994) The ETS domain protein pointed-P2 is a target of MAP kinase in the sevenless signal transduction pathway. Nature 370:386–389
Bruns DR, Drake JC, Biela LM, Peelor FF, Miller BF, Hamilton KL (2015) Nrf2 Signaling and the slowed aging phenotype: evidence from long-lived models. Oxid Med Cell Longev 2015:1–15
Budanov AV, Karin M (2008) The p53-regulated Sestrin gene products inhibit mTOR signaling. Cell 134:451–460
Buffenstein R (2008) Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B 178:439–445
Carling D (2017) AMPK signalling in health and disease. Curr Opin Cell Biol 45:31–37
Carriere A et al (2011) ERK1/2 phosphorylate raptor to promote ras-dependent activation of mTOR complex 1 (mTORC1). J Biol Chem 286:567–577
Castellano E, Downward J (2011) RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2:261–274
Chandarlapaty S et al (2011) AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19:58–71
Chen C, Liu Y, Liu Y, Zheng P (2009) mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2:ra75
Chen C-C et al (2010) FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and rictor. Dev Cell 18:592–604
Chen D et al (2013) Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell Rep 5:1600–1610
Christensen K, Johnson TE, Vaupel JW (2006) The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet 7:436–448
Clancy DJ et al (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104–106
Conover CA, Bale LK (2007) Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6:727–729
Costanzo-Garvey DL et al (2009) KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab 10:366–378
Csiszar A et al (2014) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. AJP Heart Circ Physiol 307:H292–H306
Curtis R, O’Connor G, DiStefano PS (2006) Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5:119–126
Davinelli S, Willcox DC, Scapagnini G (2012) Extending healthy ageing: nutrient sensitive pathway and centenarian population. Immun Ageing 9:9–9
Demontis F, Perrimon N (2010) FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143:813–825
Dodson M, Redmann M, Rajasekaran Namakkal S, Darley-Usmar V, Zhang J (2015) KEAP1–NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem J 469:347–355
Edrey YH et al (2012) Sustained high levels of neuregulin-1 in the longest-lived rodents; a key determinant of rodent longevity. Aging Cell 11:213–222
Eijkelenboom A et al (2013) Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling. Mol Syst Biol 9:638–638
Elbourkadi N, Austad SN, Miller RA (2014) Fibroblasts from long-lived species of mammals and birds show delayed, but prolonged, phosphorylation of ERK. Aging Cell 13:283–291
Erdogan CS, Hansen BW, Vang O (2016) Are invertebrates relevant models in ageing research? Focus on the effects of rapamycin on TOR. Mech Ageing Dev 153:22–29
Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB, Longo VD (2003) SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163:35–46
Fernandes de Abreu DA et al (2014) An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PLoS Genet 10:e1004225
Fernandez-Medarde A, Santos E (2011) The RasGrf family of mammalian guanine nucleotide exchange factors. Biochim Biophys Acta 1815:170–188
Flynn JM et al (2013) Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 12:851–862
Foukas LC et al (2013) Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism. EMBO Mol Med 5:563–571
Friedman DB, Johnson TE (1988) A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118:75–86
Funakoshi M, Tsuda M, Muramatsu K, Hatsuda H, Morishita S, Aigaki T (2011) A gain-of-function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila. Biochem Biophys Res Commun 405:667–672
Gaubitz C, Prouteau M, Kusmider B, Loewith R (2016) TORC2 structure and function. Trends Biochem Sci 41:532–545
Gems D, de la Guardia Y (2013) Alternative perspectives on aging in caenorhabditis elegans: reactive oxygen species or hyperfunction? Antioxid Redox Signal 19:321–329
Gems D, Partridge L (2013) Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol 75:621–644
Gems D, Pletcher S, Partridge L (2002) Interpreting interactions between treatments that slow aging. Aging Cell 1:1–9
Giannakou ME, Goss M, Jünger MA, Hafen E, Leevers SJ, Partridge L (2004) Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science 305:361–361
Golden TR, Beckman KB, Lee AHJ, Dudek N, Hubbard A, Samper E, Melov S (2007) Dramatic age-related changes in nuclear and genome copy number in the nematode Caenorhabditis elegans. Aging Cell 6:179–188
Greer EL et al (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17:1646–1656
Grönke S, Clarke D-F, Broughton S, Andrews TD, Partridge L (2010) Molecular evolution and functional characterization of Drosophila insulin-like peptides. PLoS Genet 6:e1000857
Gwinn DM et al (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226
Halfon MS, Carmena A, Gisselbrecht S, Sackerson CM, Jimenez F, Baylies MK, Michelson AM (2000) Ras pathway specificity is determined by the integration of multiple signal-activated and tissue-restricted transcription factors. Cell 103:63–74
Halloran J et al (2012) Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 223:102–113
Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C (2007) Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6:95–110
Hardie DG (2014) AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu Rev Nutr 34:31–55
Hardie DG (2016) Regulation of AMP-activated protein kinase by natural and synthetic activators. Acta Pharm Sin B 6:1–19
Harrison DE et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–395
Hay N (2011) Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta 1813:1965–1970
Henderson ST, Johnson TE (2001) daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 11:1975–1980
Herndon LA et al (2002) Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419:808–814
Holzenberger M et al (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187
Honegger B, Galic M, Köhler K, Wittwer F, Brogiolo W, Hafen E, Stocker H (2008) Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. J Biol 7:10–10
Huang J, Manning BD (2009) A complex interplay between Akt, TSC2, and the two mTOR complexes. Biochem Soc Trans 37:217–222
Hutter D, Yo Y, Chen W, Liu P, Holbrook NJ, Roth GS, Liu Y (2000) Age-related decline in Ras/ERK mitogen-activated protein kinase cascade is linked to a reduced association between Shc and EGF receptor. J Gerontol Ser A Biol Med Sci 55:B125–B134
Hwangbo DS, Gersham B, Tu M-P, Palmer M, Tatar M, Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429:562–566
Inoki K, Zhu T, Guan K-L (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590
Itoh K et al (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322
Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86
Jazwinski SM (1999) The RAS genes: a homeostatic device in Saccharomyces cerevisiae longevity☆. Neurobiol Aging 20:471–478
Jazwinski SM et al (2010) HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging. Aging Cell 9:698–708
Jia K (2004) The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131:3897–3906
Jud M, Razelun J, Bickel J, Czerwinski M, Schisa JA (2007) Conservation of large foci formation in arrested oocytes of Caenorhabditis nematodes. Dev Genes Evol 217:221–226
Junger MA et al (2003) The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol 2:20–20
Kaeberlein M et al (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310:1193–1196
Kansanen E, Kuosmanen SM, Leinonen H, Levonen A-L (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1:45–49
Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14:885–890
Katsuoka F, Motohashi H, Engel JD, Yamamoto M (2005a) Nrf2 transcriptionally activates the mafG Gene through an antioxidant response element. J Biol Chem 280:4483–4490
Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M (2005b) Genetic evidence that small Maf proteins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol 25:8044–8051
Kenyon C (2010) A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Ann N Y Acad Sci 1204:156–162
Kenyon C (2011) The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Philos Trans R Soc Lond Ser B Biol Sci 366:9–16
Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464
Kerr F et al (2017) Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease. PLoS Genet 13:e1006593
Kim J, Cha Y-N, Surh Y-J (2010) A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res Fundam Mol Mech Mutagen 690:12–23
Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946
Kodiha M, Rassi JG, Brown CM, Stochaj U (2007) Localization of AMP kinase is regulated by stress, cell density, and signaling through the MEK→ERK1/2 pathway. Am J Physiol Cell Physiol 293:C1427–C1436
Kurosu H et al (2005) Suppression of aging in mice by the Hormone Klotho. Science 309:1829–1833
Kwak M-K, Itoh K, Yamamoto M, Kensler TW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22:2883–2892
Kwon ES, Narasimhan SD, Yen K, Tissenbaum HA (2010) A new DAF-16 isoform regulates longevity. Nature 466:498–502
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293
Lee JH et al (2010) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327:1223–1228
Liang S, Mele J, Wu Y, Buffenstein R, Hornsby PJ (2010) Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 9:626–635
Lin K, Hsin H, Libina N, Kenyon C (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28:139–145
Long X, Spycher C, Han ZS, Rose AM, Müller F, Avruch J (2002) TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol 12:1448–1461
Lopez-Cotarelo P et al (2015) A novel MEK-ERK-AMPK signaling axis controls chemokine receptor CCR7-dependent survival in human mature dendritic cells. J Biol Chem 290:827–840
Mair W, Morantte I, Rodrigues APC, Manning G, Montminy M, Shaw RJ, Dillin A (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470:404–408
Majumder S et al (2012) Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell 11:326–335
Mannick JB et al (2014) mTOR inhibition improves immune function in the elderly. Sci Transl Med 6:268ra179
McGinnis N, Ragnhildstveit E, Veraksa A, McGinnis W (1998) A cap ‘n’ collar protein isoform contains a selective Hox repressor function. Development 125:4553–4564
Mirisola MG, Longo VD (2011) Conserved role of Ras-GEFs in promoting aging: from yeast to mice. Aging 3:340–343
Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382:536–539
Motohashi H, Yamamoto M (2004) Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 10:549–557
Murphy CT et al (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424:277–283
Murphy CT, Lee S-J, Kenyon C (2007) Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc Natl Acad Sci U S A 104:19046–19050
Muthusamy VR et al (2012) Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium. Free Radic Biol Med 52:366–376
Nanji M, Hopper NA, Gems D (2005) LET-60 RAS modulates effects of insulin/IGF-1 signaling on development and aging in Caenorhabditis elegans. Aging Cell 4:235–245
Nojima A et al (2013) Haploinsufficiency of akt1 prolongs the lifespan of mice. PLoS One 8:e69178
O’Neill EM, Rebay I, Tjian R, Rubin GM (1994) The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell 78:137–147
Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999
Orme MH, Alrubaie S, Bradley GL, Walker CD, Leevers SJ (2006) Input from Ras is required for maximal PI(3)K signalling in Drosophila. Nat Cell Biol 8:1298–1302
Ortega-Molina A et al (2012) Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab 15:382–394
Paik JH et al (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128:309–323
Pan KZ, Palter JE, Rogers AN, Olsen A, Chen D, Lithgow GJ, Kapahi P (2007) Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6:111–119
Pan CL, Peng CY, Chen CH, McIntire S (2011) Genetic analysis of age-dependent defects of the Caenorhabditis elegans touch receptor neurons. Proc Natl Acad Sci U S A 108:9274–9279
Pawlikowska L et al (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8:460–472
Pearson KJ et al (2008) Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci U S A 105:2325–2330
Plowman SJ et al (2006) The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice. Exp Cell Res 312:16–26
Puig O, Tjian R (2005) Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev 19:2435–2446
Puig O, Marr MTM, Ruhf ML, Tjian R (2003) Control of cell number by Drosophila FOXO : downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17:2006–2020
Qi W, Huang X, Neumann-Haefelin E, Schulze E, Baumeister R (2012) Cell-nonautonomous signaling of FOXO/DAF-16 to the stem cells of Caenorhabditis elegans. PLoS Genet 8:e1002836
Rauen KA (2007) HRAS and the costello syndrome. Clin Genet 71:101–108
Riera CE et al (2014) TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 157:1023–1036
Ritter AD et al (2013) Complex expression dynamics and robustness in C. elegans insulin networks. Genome Res 23:954–965
Robida-Stubbs S et al (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15:713–724
Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11:230–241
Salomon RN, Rob Jackson F (2008) Tumors of testis and midgut in aging flies. Fly 2:265–268
Sarbassov DD et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168
Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976
Schuster E et al (2010) DamID in C. elegans reveals longevity-associated targets of DAF-16/FoxO. Mol Syst Biol 6:399–399
Selman C et al (2007) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22:807–818
Selman C et al (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326:140–144
Sheaffer KL, Updike DL, Mango SE (2008) The target of rapamycin (TOR) pathway antagonizes pha-4/FoxA to control development and aging. Curr Biol 18:1355–1364
Showkat M, Beigh MA, Andrabi KI (2014) mTOR signaling in protein translation regulation: implications in cancer genesis and therapeutic interventions. Mol Biol Int 2014:686984
Slack C, Giannakou ME, Foley A, Goss M, Partridge L (2011) dFOXO-independent effects of reduced insulin-like signaling in Drosophila. Aging Cell 10:735–748
Slack C, Alic N, Foley A, Cabecinha M, Hoddinott MP, Partridge L (2015) The Ras-Erk-ETS-signaling pathway is a drug target for longevity. Cell 162:72–83
Steelman LS et al (2011) Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging 3:192–222
Stenesen D et al (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
Sternberg PW, Han M (1998) Genetics of RAS signaling in C. elegans. Trends Genet 14:466–472
Sun J, Kale SP, Childress AM, Pinswasdi C, Jazwinski SM (1994) Divergent roles of RAS1 and RAS2 in yeast longevity. J Biol Chem 269:18638–18645
Sun LY, Steinbaugh MJ, Masternak MM, Bartke A, Miller RA (2009) Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes. Free Radic Biol Med 47:1753–1761
Sun L et al (2015) FOXO3 variants are beneficial for longevity in Southern Chinese living in the Red River Basin: a case-control study and meta-analysis. Sci Rep 5:9852–9852
Sykiotis GP, Bohmann D (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell 14:76–85
Sykiotis GP, Bohmann D (2010) Stress-activated cap‘n’collar transcription factors in aging and human disease. Sci Signal 3:re3
Taguchi A, Wartschow LM, White MF (2007) Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317:369–372
Tan PB, Lackner MR, Kim SK (1998) MAP kinase signaling specificity mediated by the LIN-1 Ets/LIN-31 WH transcription factor complex during C. elegans vulval induction. Cell 93:569–580
Tank EMH, Rodgers KE, Kenyon C (2011) Spontaneous age-related neurite branching in caenorhabditis elegans. J Neurosci 31:9279–9288
Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110
Teleman AA, Chen YW, Cohen SM (2005) Drosophila melted modulates FOXO and TOR activity. Dev Cell 9:271–281
Tothova Z, Gilliland DG (2007) FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 1:140–152
Tsai S et al (2015) Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity. J Clin Investig 125:2952–2964
Tsunekawa S, Demozay D, Briaud I, McCuaig J, Accili D, Stein R, Rhodes CJ (2011) FoxO feedback control of basal IRS-2 expression in pancreatic β-cells is distinct from that in hepatocytes. Diabetes 60:2883–2891
Tullet JMA et al (2008) Direct Inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132:1025–1038
Tullet JM et al (2014) DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in caenorhabditis elegans. PLoS Genet 10:e1004109
Tullet JMA et al (2017) The SKN-1/Nrf2 transcription factor can protect against oxidative stress and increase lifespan in C. elegans by distinct mechanisms. Aging Cell 16:1191–1194
Ulgherait M, Rana A, Rera M, Graniel J, Walker DW (2014) AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep 8:1767–1780
Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, Promislow DEL, Kaeberlein M (2017) A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. GeroScience 39:117–127
Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426:620–620
White MF (1997) The insulin signalling system and the IRS proteins. Diabetologia 40:S2–S17
Wilkinson JE et al (2012) Rapamycin slows aging in mice. Aging Cell 11:675–682
Willcox BJ et al (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A 105:13987–13992
Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–398
Yang J-Y et al (2008) ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10:138–148
Zhao S-C et al (2014) Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis. Asian J Androl 16:446–446
Zimmermann S, Moelling K (1999) Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286:1741–1744
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Slack, C., Tullet, J. (2018). Signal Transduction Pathways in Ageing. In: Harris, J., Korolchuk, V. (eds) Biochemistry and Cell Biology of Ageing: Part I Biomedical Science. Subcellular Biochemistry, vol 90. Springer, Singapore. https://doi.org/10.1007/978-981-13-2835-0_11
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