REFERENCES
1. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991;253:905-9.
2. Wang L, Rhodes CJ, Lawrence JC Jr. Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex I. J Biol Chem 2006;281:24293-303.
3. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell 2010;38:768-74.
4. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013;493:338-45.
5. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005;15:702-13.
6. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-90.
7. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-26.
8. Efeyan A, Zoncu R, Chang S, et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 2013;493:679-83.
9. Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11:390-401.
10. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017;168:960-76.
11. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by rag GTPases in nutrient response. Nat Cell Biol 2008;10:935-45.
12. Sancak Y, Peterson TR, Shaul YD, et al. The rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008;320:1496-501.
13. Bar-Peled L, Chantranupong L, Cherniack AD, et al. A tumor suppressor complex with GAP activity for the rag GTPases that signal amino acid sufficiency to mTORC1. Science 2013;340:1100-6.
14. Zhenyukh O, Civantos E, Ruiz-Ortega M, et al. High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. Free Radic Biol Med 2017;104:165-77.
15. Brugarolas J, Lei K, Hurley RL, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004;18:2893-904.
16. Ma Y, Vassetzky Y, Dokudovskaya S. mTORC1 pathway in DNA damage response. Biochim Biophys Acta Mol Cell Res 2018;1865:1293-311.
17. Deldicque L, Theisen D, Francaux M. Regulation of mTOR by amino acids and resistance exercise in skeletal muscle. Eur J Appl Physiol 2005;94:1-10.
18. Kim M, Sujkowski A, Namkoong S, et al. Sestrins are evolutionarily conserved mediators of exercise benefits. Nat Commun 2020;11:190.
19. Sujkowski A, Wessells R. Exercise and sestrin mediate speed and lysosomal activity in drosophila by partially overlapping mechanisms. Cells 2021;10:2479.
20. Lee JH, Budanov AV, Park EJ, et al. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 2010;327:1223-8.
21. Chen CC, Jeon SM, Bhaskar PT, et al. FoxOs inhibit mTORC1 and activate akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 2010;18:592-604.
22. Liu P, Gan W, Chin YR, et al. PtdIns(3,4,5)P3-Dependent activation of the mTORC2 kinase complex. Cancer Discov 2015;5:1194-209.
23. Hsu PP, Kang SA, Rameseder J, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011;332:1317-22.
24. Harrington LS, Findlay GM, Gray A, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004;166:213-23.
25. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004;14:1650-6.
26. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-84.
27. López-Maury L, Marguerat S, Bähler J. Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nat Rev Genet 2008;9:583-93.
28. Hannan KM, Brandenburger Y, Jenkins A, et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol 2003;23:8862-77.
29. Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 2006;25:6384-91.
30. Candiracci J, Migeot V, Chionh YH, et al. Reciprocal regulation of TORC signaling and tRNA modifications by Elongator enforces nutrient-dependent cell fate. Sci Adv 2019;5:eaav0184.
31. Lee J, Moir RD, McIntosh KB, Willis IM. TOR signaling regulates ribosome and tRNA synthesis via LAMMER/Clk and GSK-3 family kinases. Mol Cell 2012;45:836-43.
33. Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 2006;314:467-71.
34. Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. Mammalian TOR: a homeostatic ATP sensor. Science 2001;294:1102-5.
35. Um SH, D'Alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 2006;3:393-402.
36. Aguilar V, Alliouachene S, Sotiropoulos A, et al. S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. Cell Metab 2007;5:476-87.
37. Zid BM, Rogers AN, Katewa SD, et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 2009;139:149-60.
38. Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 2005;433:477-80.
39. Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 2018;19:579-93.
40. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93.
41. Chang JT, Kumsta C, Hellman AB, Adams LM, Hansen M. Spatiotemporal regulation of autophagy during
42. Kaushik S, Arias E, Kwon H, et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep 2012;13:258-65.
43. Del Roso A, Vittorini S, Cavallini G, et al. Ageing-related changes in the
44. Demontis F, Perrimon N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 2010;143:813-25.
45. Chang K, Kang P, Liu Y, et al. TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy 2020;16:1807-22.
46. Taneike M, Yamaguchi O, Nakai A, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 2010;6:600-6.
47. Meléndez A, Tallóczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Autophagy genes are essential for dauer development and life-span extension in
48. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. A role for autophagy in the extension of lifespan by dietary restriction in
49. Bjedov I, Toivonen JM, Kerr F, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 2010;11:35-46.
50. Fernández ÁF, Sebti S, Wei Y, et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 2018;558:136-40.
52. Morselli E, Maiuri MC, Markaki M, et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis 2010;1:e10.
53. Hosokawa N, Hara T, Kaizuka T, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009;20:1981-91.
54. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 2012;8:903-14.
55. Roczniak-Ferguson A, Petit CS, Froehlich F, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 2012;5:ra42.
56. Ho TT, Warr MR, Adelman ER, et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 2017;543:205-10.
57. Baar EL, Carbajal KA, Ong IM, Lamming DW. Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell 2016;15:155-66.
58. Lapierre LR, Gelino S, Meléndez A, Hansen M. Autophagy and lipid metabolism coordinately modulate life span in germline-less
59. Lapierre LR, De Magalhaes Filho CD, McQuary PR, et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in
60. Wang RC, Wei Y, An Z, et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 2012;338:956-9.
61. Ozturk DG, Kocak M, Akcay A, et al. MITF-MIR211 axis is a novel autophagy amplifier system during cellular stress. Autophagy 2019;15:375-90.
62. Bartolomé A, García-Aguilar A, Asahara SI, et al. MTORC1 regulates both general autophagy and mitophagy induction after oxidative phosphorylation uncoupling. Mol Cell Biol 2017;37:e00441-17.
64. Ouwens DM, Boer C, Fodor M, et al. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 2005;48:1229-37.
67. Birse RT, Choi J, Reardon K, et al. High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metab 2010;12:533-44.
68. Diop SB, Bisharat-Kernizan J, Birse RT, Oldham S, Ocorr K, Bodmer R. PGC-1/Spargel counteracts high-fat-diet-induced obesity and cardiac lipotoxicity downstream of TOR and brummer ATGL lipase. Cell Rep 2015;10:1572-84.
69. Caron A, Richard D, Laplante M. The roles of mTOR complexes in lipid metabolism. Annu Rev Nutr 2015;35:321-48.
70. Lamming DW, Sabatini DM. A central role for mTOR in lipid homeostasis. Cell Metab 2013;18:465-9.
71. Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev 2021;101:1371-426.
72. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010;468:1100-4.
73. Zhang HH, Huang J, Düvel K, et al. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS One 2009;4:e6189.
74. Carnevalli LS, Masuda K, Frigerio F, et al. S6K1 plays a critical role in early adipocyte differentiation. Dev Cell 2010;18:763-74.
75. Porstmann T, Santos CR, Griffiths B, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008;8:224-36.
76. Owen JL, Zhang Y, Bae SH, et al. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci USA 2012;109:16184-9.
77. Peterson TR, Sengupta SS, Harris TE, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011;146:408-20.
78. Viscarra JA, Wang Y, Nguyen HP, Choi YG, Sul HS. Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis. Nat Commun 2020;11:796.
79. Lee G, Zheng Y, Cho S, et al. Post-transcriptional regulation of de novo lipogenesis by mTORC1-S6K1-SRPK2 signaling. Cell 2017;171:1545-58.e18.
80. Hagiwara A, Cornu M, Cybulski N, et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 2012;15:725-38.
81. Kumar A, Lawrence JC Jr, Jung DY, et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 2010;59:1397-406.
82. Sciarretta S, Zhai P, Shao D, et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 2012;125:1134-46.
83. Guo R, Zhang Y, Turdi S, Ren J. Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy. Biochim Biophys Acta 2013;1832:1136-48.
84. Das A, Durrant D, Koka S, Salloum FN, Xi L, Kukreja RC. Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem 2014;289:4145-60.
85. Völkers M, Doroudgar S, Nguyen N, et al. PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. EMBO Mol Med 2014;6:57-65.
86. Lakatta EG, Yin FC. Myocardial aging: functional alterations and related cellular mechanisms. Am J Physiol 1982;242:H927-41.
87. Liu P, Chang K, Requejo G, Bai H. mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila. Front Cell Dev Biol 2022;10:866210.
88. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: influence of TOR kinase on lifespan in
89. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate
90. Kaeberlein M, Powers RW 3rd, Steffen KK, et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005;310:1193-6.
91. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 2004;14:885-90.
92. Lamming DW, Ye L, Katajisto P, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012;335:1638-43.
93. Wu JJ, Liu J, Chen EB, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep 2013;4:913-20.
94. Henderson ST, Bonafè M, Johnson TE. daf-16 protects the nematode
95. Selman C, Tullet JM, Wieser D, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009;326:140-4.
97. Dai DF, Karunadharma PP, Chiao YA, et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 2014;13:529-39.
98. Hursting SD, Dunlap SM, Ford NA, Hursting MJ, Lashinger LM. Calorie restriction and cancer prevention: a mechanistic perspective. Cancer Metab 2013;1:10.
99. Obin M, Pike A, Halbleib M, Lipman R, Taylor A, Bronson R. Calorie restriction modulates age-dependent changes in the retinas of brown norway rats. Mech Ageing Dev 2000;114:133-47.
100. Izuta Y, Imada T, Hisamura R, et al. Ketone body 3-hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina. Aging Cell 2018;17:e12699.
101. Someya S, Yamasoba T, Weindruch R, Prolla TA, Tanokura M. Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis. Neurobiol Aging 2007;28:1613-22.
102. Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009;325:201-4.
103. Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C. Lifespan extension by conditions that inhibit translation in
104. Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392-5.
105. Robida-Stubbs S, Glover-Cutter K, Lamming DW, et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 2012;15:713-24.
106. Quarles EK, Rabinovitch PS. Transient and late-life rapamycin for healthspan extension. Aging 2020;12:4050-1.
107. Miller RA, Harrison DE, Astle CM, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 2014;13:468-77.
108. Fok WC, Bokov A, Gelfond J, et al. Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver. Aging Cell 2014;13:311-9.
109. Yu Z, Wang R, Fok WC, Coles A, Salmon AB, Pérez VI. Rapamycin and dietary restriction induce metabolically distinctive changes in mouse liver. J Gerontol A Biol Sci Med Sci 2015;70:410-20.
110. Fok WC, Zhang Y, Salmon AB, et al. Short-term treatment with rapamycin and dietary restriction have overlapping and distinctive effects in young mice. J Gerontol A Biol Sci Med Sci 2013;68:108-16.
111. Karunadharma PP, Basisty N, Dai DF, et al. Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. Aging Cell 2015;14:547-57.
113. Blice-Baum AC, Guida MC, Hartley PS, Adams PD, Bodmer R, Cammarato A. As time flies by: investigating cardiac aging in the short-lived Drosophila model. Biochim Biophys Acta Mol Basis Dis 2019;1865:1831-44.
114. Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 1993;119:419-31.
115. Komuro I, Izumo S. Csx: a murine homeobox-containing gene specifically expressed in the developing heart. Proc Natl Acad Sci USA 1993;90:8145-9.
116. Rotstein B, Paululat A. On the morphology of the drosophila heart. J Cardiovasc Dev Dis 2016;3:15.
117. Bodmer R. The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development 1993;118:719-29.
118. Tonissen KF, Drysdale TA, Lints TJ, Harvey RP, Krieg PA. XNkx-2.5, a Xenopus gene related to Nkx-2.5 and tinman: evidence for a conserved role in cardiac development. Dev Biol 1994;162:325-8.
119. Evans SM, Yan W, Murillo MP, Ponce J, Papalopulu N. Tinman, a drosophila homeobox gene required for heart and visceral mesoderm specification, may be represented by a family of genes in vertebrates: XNkx-2.3, a second vertebrate homologue of tinman. Development 1995;121:3889-99.
120. Fink M, Callol-Massot C, Chu A, et al. A new method for detection and quantification of heartbeat parameters in Drosophila, zebrafish, and embryonic mouse hearts. Biotechniques 2009;46:101-13.
121. Ocorr K, Fink M, Cammarato A, Bernstein S, Bodmer R. Semi-automated optical heartbeat analysis of small hearts. J Vis Exp ;2009:1435.
122. Lalevée N, Monier B, Sénatore S, Perrin L, Sémériva M. Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel. Curr Biol 2006;16:1502-8.
123. Monnier V, Iché-Torres M, Rera M, et al. dJun and Vri/dNFIL3 are major regulators of cardiac aging in Drosophila. PLoS Genet 2012;8:e1003081.
124. Klassen MP, Peters CJ, Zhou S, Williams HH, Jan LY, Jan YN. Age-dependent diastolic heart failure in an
125. Wolf MJ, Amrein H, Izatt JA, Choma MA, Reedy MC, Rockman HA. Drosophila as a model for the identification of genes causing adult human heart disease. Proc Natl Acad Sci USA 2006;103:1394-9.
126. Viswanathan MC, Kaushik G, Engler AJ, Lehman W, Cammarato A. A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function. Circ Res 2014;114:e6-17.
127. Kaushik G, Fuhrmann A, Cammarato A, Engler AJ.
128. Kaushik G, Zambon AC, Fuhrmann A, et al. Measuring passive myocardial stiffness in Drosophila melanogaster to investigate diastolic dysfunction. J Cell Mol Med 2012;16:1656-62.
129. Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R. Insulin regulation of heart function in aging fruit flies. Nat Genet 2004;36:1275-81.
130. Wessells R, Fitzgerald E, Piazza N, et al. d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila. Aging Cell 2009;8:542-52.
131. Cannon L, Zambon AC, Cammarato A, et al. Expression patterns of cardiac aging in Drosophila. Aging Cell 2017;16:82-92.
132. Zheng F, Plati AR, Potier M, et al. Resistance to glomerulosclerosis in B6 mice disappears after menopause. Am J Pathol 2003;162:1339-48.
133. Dai DF, Santana LF, Vermulst M, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009;119:2789-97.
134. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 2003;107:139-46.
135. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 2003;107:346-54.
136. Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal 2012;16:1492-526.
137. Treuting PM, Linford NJ, Knoblaugh SE, et al. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J Gerontol A Biol Sci Med Sci 2008;63:813-22.
138. Yan L, Vatner DE, O'Connor JP, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 2007;130:247-58.
139. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014;2:113-22.
140. Westermark P, Johansson B, Natvig JB. Senile cardiac amyloidosis: evidence of two different amyloid substances in the ageing heart. Scand J Immunol 1979;10:303-8.
141. Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 2005;165:1425-9.
142. Flynn JM, O'Leary MN, Zambataro CA, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 2013;12:851-62.
143. Dai DF, Hsieh EJ, Liu Y, et al. Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res 2012;93:79-88.
144. Dai DF, Johnson SC, Villarin JJ, et al. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 2011;108:837-46.
145. Dai DF, Chen T, Szeto H, et al. Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 2011;58:73-82.
146. Dai DF, Hsieh EJ, Chen T, et al. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail 2013;6:1067-76.
147. Triplett JC, Tramutola A, Swomley A, et al. Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity. Biochim Biophys Acta 2015;1852:2213-24.
148. Azpurua J, Ke Z, Chen IX, et al. Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage. Proc Natl Acad Sci USA 2013;110:17350-5.
149. Faulkes CG, Eykyn TR, Aksentijevic D. Cardiac metabolomic profile of the naked mole-rat-glycogen to the rescue. Biol Lett 2019;15:20190710.
150. Hilton HG, Rubinstein ND, Janki P, et al. Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity. PLoS Biol 2019;17:e3000528.
151. Can E, Smith M, Boukens BJ, Coronel R, Buffenstein R, Riegler J. Naked mole-rats maintain cardiac function and body composition well into their fourth decade of life. Geroscience 2022;44:731-46.
152. Eichelberg H, Seine R. Life expectancy and cause of death in dogs. I. The situation in mixed breeds and various dog breeds. Berl Munch Tierarztl Wochenschr 1996;109:292-303.
153. Van Vleet JF. Age-related non-neoplastic lesions of the heart. In: Mohr U, Patholbiology of the ageing dog; 2001. pp. 101-7.
154. Templeton GH, Platt MR, Willerson JT, Weisfeldt ML. Influence of aging on left ventricular hemodynamics and stiffness in beagles. Circ Res 1979;44:189-94.
155. Templeton GH, Willerson JT, Platt MR, Weisfeldt M. Contraction duration and diastolic stiffness in aged canine left ventricle. Recent Adv Stud Cardiac Struct Metab 1976;11:169-73.
156. Guglielmini C. Cardiovascular diseases in the ageing dog: diagnostic and therapeutic problems. Vet Res Commun 2003;27 Suppl 1:555-60.
157. Kaeberlein M, Creevy KE, Promislow DE. The dog aging project: translational geroscience in companion animals. Mamm Genome 2016;27:279-88.
158. Urfer SR, Kaeberlein TL, Mailheau S, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 2017;39:117-27.
159. Chiao YA, Kolwicz SC, Basisty N, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging 2016;8:314-27.
160. Lowenstine LJ, McManamon R, Terio KA. Comparative pathology of aging great apes: bonobos, chimpanzees, gorillas, and orangutans. Vet Pathol 2016;53:250-76.
161. Lane MA, Ingram DK, Roth GS. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicol Sci 1999;52:41-8.
162. Lane MA, Mattison J, Ingram DK, Roth GS. Caloric restriction and aging in primates: relevance to humans and possible CR mimetics. Microsc Res Technol 2002;59:335-8.
163. Mattison JA, Lane MA, Roth GS, Ingram DK. Calorie restriction in rhesus monkeys. Exp Gerontol 2003;38:35-46.
164. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK. Aging in rhesus monkeys: relevance to human health interventions. Science 2004;305:1423-6.
165. Tardif SD, Mansfield KG, Ratnam R, Ross CN, Ziegler TE. The marmoset as a model of aging and age-related diseases. ILAR J 2011;52:54-65.
166. Ross CN, Davis K, Dobek G, Tardif SD. Aging phenotypes of common marmosets (
167. Mota-Martorell N, Jove M, Pradas I, et al. Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity. Geroscience 2020;42:1157-73.
168. Luong N, Davies CR, Wessells RJ, et al. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab 2006;4:133-42.
169. McMullen JR, Shioi T, Zhang L, et al. Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy. Mol Cell Biol 2004;24:6231-40.
170. Lachance PE, Miron M, Raught B, Sonenberg N, Lasko P. Phosphorylation of eukaryotic translation initiation factor 4E is critical for growth. Mol Cell Biol 2002;22:1656-63.
171. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 1990;345:544-7.
172. Zhu Y, Pires KM, Whitehead KJ, et al. Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. PLoS One 2013;8:e54221.
173. Murakami M, Ichisaka T, Maeda M, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004;24:6710-8.
174. Zhang D, Contu R, Latronico MV, et al. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 2010;120:2805-16.
175. Garbern JC, Helman A, Sereda R, et al. Inhibition of mTOR signaling enhances maturation of cardiomyocytes derived from human-induced pluripotent stem cells via p53-induced quiescence. Circulation 2020;141:285-300.
176. Shende P, Plaisance I, Morandi C, et al. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation 2011;123:1073-82.
177. Shen WH, Chen Z, Shi S, et al. Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function. J Biol Chem 2008;283:13842-9.
178. McMullen JR, Sherwood MC, Tarnavski O, et al. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 2004;109:3050-5.
179. Yu SY, Liu L, Li P, Li J. Rapamycin inhibits the mTOR/p70S6K pathway and attenuates cardiac fibrosis in adriamycin-induced dilated cardiomyopathy. Thorac Cardiovasc Surg 2013;61:223-8.
180. Haller ST, Yan Y, Drummond CA, et al. Rapamycin attenuates cardiac fibrosis in experimental uremic cardiomyopathy by reducing marinobufagenin levels and inhibiting downstream pro-fibrotic signaling. J Am Heart Assoc 2016;5:e004106.
181. Tu X, Wang C, Ru X, Jing L, Zhou L, Jing L. Therapeutic effects of rapamycin on alcoholic cardiomyopathy. Exp Ther Med 2017;14:2763-70.
182. Gu S, Tan J, Li Q, et al. Downregulation of LAPTM4B contributes to the impairment of the autophagic flux via unopposed activation of mTORC1 signaling during myocardial ischemia/reperfusion injury. Circ Res 2020;127:e148-65.
183. Packer M. Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure. Eur Heart J 2020;41:3856-61.
184. Gao XM, Wong G, Wang B, et al. Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens 2006;24:1663-70.
185. Dai DF, Liu Y, Basisty N, et al. Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure. Geroscience 2019;41:847-60.
186. Moreira-Gonçalves D, Henriques-Coelho T, Fonseca H, et al. Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult. J Physiol 2015;593:3885-97.
187. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 2016;97:245-62.
188. Gangloff YG, Mueller M, Dann SG, et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 2004;24:9508-16.
189. Ranek MJ, Kokkonen-Simon KM, Chen A, et al. PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress. Nature 2019;566:264-9.
190. Oeing CU, Jun S, Mishra S, et al. MTORC1-regulated metabolism controlled by TSC2 limits cardiac reperfusion injury. Circ Res 2021;128:639-51.
191. Quarles E, Basisty N, Chiao YA, et al. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell 2020;19:e13086.
192. Bitto A, Ito TK, Pineda VV, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife 2016;5:e16351.
193. Juricic P, Lu Y, Leech T, et al. Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy. Nat Aging 2022;2:824-36.
194. Sciarretta S, Zhai P, Maejima Y, et al. mTORC2 regulates cardiac response to stress by inhibiting MST1. Cell Rep 2015;11:125-36.
195. Shende P, Xu L, Morandi C, et al. Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy. Cardiovasc Res 2016;109:103-14.
196. Völkers M, Konstandin MH, Doroudgar S, et al. Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation 2013;128:2132-44.
197. Jevtov I, Zacharogianni M, van Oorschot MM, et al. TORC2 mediates the heat stress response in Drosophila by promoting the formation of stress granules. J Cell Sci 2015;128:2497-508.
198. Cai W, Andres DA. mTORC2 is required for rit-mediated oxidative stress resistance. PLoS One 2014;9:e115602.
199. Chen CH, Shaikenov T, Peterson TR, et al. ER stress inhibits mTORC2 and Akt signaling through GSK-3β-mediated phosphorylation of rictor. Sci Signal 2011;4:ra10.
200. Wu Z, Sawada T, Shiba K, et al. Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance. Genes Dev 2013;27:157-62.
201. Murata H, Sakaguchi M, Jin Y, et al. A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: activation of AKT via mTORC2. J Biol Chem 2011;286:7182-9.
202. Ballesteros-Álvarez J, Andersen JK. mTORC2: The other mTOR in autophagy regulation. Aging Cell 2021;20:e13431.
203. Lamming DW, Mihaylova MM, Katajisto P, et al. Depletion of rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 2014;13:911-7.
