{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:49:23Z","timestamp":1791316163908,"version":"4.3.1"},"reference-count":107,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["UI9AG057377"],"award-info":[{"award-number":["UI9AG057377"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["GeroScience"],"DOI":"10.1007\/s11357-024-01484-7","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T10:10:26Z","timestamp":1739527826000},"page":"2851-2877","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Test of Rapamycin in Aging Dogs (TRIAD): study design and rationale for a prospective, parallel-group, double-masked, randomized, placebo-controlled, multicenter trial of rapamycin in healthy middle-aged dogs from the Dog Aging Project"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5476-5963","authenticated-orcid":false,"given":"Amanda E.","family":"Coleman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Creevy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rozalyn","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May J.","family":"Reed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia R.","family":"Fajt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Aicher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genna","family":"Atiee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian G.","family":"Barnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Baumwart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Boudreau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne M.","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Dunbar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobbie","family":"Ditzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiersten K.","family":"Forsyth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya N.","family":"Gambino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya G.","family":"Gordon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hillary K.","family":"Hammond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney N.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary K.","family":"Iannaccone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Illing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saki","family":"Kadotani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby A.","family":"Knowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan L.","family":"MacLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A.","family":"Maran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Markovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"McGrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel L.","family":"Melvin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikaela S.","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. Lynne","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha J.","family":"Olby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa E.","family":"Pancotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Parsley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna M.","family":"Potter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jena O.","family":"Prescott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley B.","family":"Saunders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly M.","family":"Sawyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A.","family":"Scansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney C.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja S.","family":"Tjostheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Katherine","family":"Tolbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Tropf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance C.","family":"Visser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya R.","family":"Wesselowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C.","family":"Windsor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky K.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Ruple","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E. L.","family":"Promislow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Kaeberlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Dog Aging Project Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua M.","family":"Akey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Benton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elhanan","family":"Borenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta G.","family":"Castelhano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda E.","family":"Coleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Creevy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette L.","family":"Fitzpatrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Crowder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Dunbar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia R.","family":"Fajt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette L.","family":"Fitzpatrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unity","family":"Jeffery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica C.","family":"Jonlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Kaeberlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elinor K.","family":"Karlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen F.","family":"Kerr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Levine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn L.","family":"McClelland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E. L.","family":"Promislow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Ruple","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Schwartz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandi","family":"Shrager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah M.","family":"Snyder-Mackler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Katherine","family":"Tolbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvan R.","family":"Urfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin S.","family":"Wilfond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"issue":"21","key":"1484_CR1","doi-asserted-by":"publisher","first-page":"e2120887119","DOI":"10.1073\/pnas.2120887119","volume":"119","author":"S Horvath","year":"2022","unstructured":"Horvath S, Lu AT, Haghani A, Zoller JA, Li CZ, Lim AR, et al. DNA methylation clocks for dogs and humans. Proc Natl Acad Sci USA. 2022;119(21):e2120887119.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"1484_CR2","doi-asserted-by":"publisher","first-page":"a026633","DOI":"10.1101\/cshperspect.a026633","volume":"6","author":"KE Creevy","year":"2016","unstructured":"Creevy KE, Austad SN, Hoffman JM, O\u2019Neill DG, Promislow DE. The companion dog as a model for the longevity dividend. Cold Spring Harb Perspect Med. 2016;6(1):a026633.","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"7\u20138","key":"1484_CR3","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s00335-016-9638-7","volume":"27","author":"M Kaeberlein","year":"2016","unstructured":"Kaeberlein M, Creevy KE, Promislow DE. The dog aging project: translational geroscience in companion animals. Mammalian genome: official journal of the International Mammalian Genome Society. 2016;27(7\u20138):279\u201388.","journal-title":"Mammalian genome: official journal of the International Mammalian Genome Society"},{"issue":"6701","key":"1484_CR4","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1126\/science.adl0426","volume":"384","author":"C Sexton","year":"2024","unstructured":"Sexton C, Ruple A. Canine sentinels and our shared exposome. Science. 2024;384(6701):1170\u20132.","journal-title":"Science"},{"issue":"3","key":"1484_CR5","doi-asserted-by":"publisher","first-page":"M146","DOI":"10.1093\/gerona\/56.3.M146","volume":"56","author":"LP Fried","year":"2001","unstructured":"Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146\u201356.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"11","key":"1484_CR6","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1007\/s11136-020-02568-5","volume":"29","author":"MJ Kim","year":"2020","unstructured":"Kim MJ, Park S, Jung YI, Kim SH, Oh IH. Exploring health-related quality of life and frailty in older adults based on the Korean frailty and aging cohort study. Qual Life Res. 2020;29(11):2911\u20139.","journal-title":"Qual Life Res"},{"issue":"4","key":"1484_CR7","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1111\/jgs.12735","volume":"62","author":"TK Malmstrom","year":"2014","unstructured":"Malmstrom TK, Miller DK, Morley JE. A comparison of four frailty models. J Am Geriatr Soc. 2014;62(4):721\u20136.","journal-title":"J Am Geriatr Soc"},{"issue":"6","key":"1484_CR8","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.jamda.2013.03.022","volume":"14","author":"JE Morley","year":"2013","unstructured":"Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, et al. Frailty consensus: a call to action. J Am Med Dir Assoc. 2013;14(6):392\u20137.","journal-title":"J Am Med Dir Assoc"},{"key":"1484_CR9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/1471-2318-11-33","volume":"11","author":"J Vermeulen","year":"2011","unstructured":"Vermeulen J, Neyens JC, van Rossum E, Spreeuwenberg MD, de Witte LP. Predicting ADL disability in community-dwelling elderly people using physical frailty indicators: a systematic review. BMC Geriatr. 2011;11:33.","journal-title":"BMC Geriatr"},{"issue":"1","key":"1484_CR10","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/BF03324816","volume":"22","author":"CH Wong","year":"2010","unstructured":"Wong CH, Weiss D, Sourial N, Karunananthan S, Quail JM, Wolfson C, et al. Frailty and its association with disability and comorbidity in a community-dwelling sample of seniors in Montreal: a cross-sectional study. Aging Clin Exp Res. 2010;22(1):54\u201362.","journal-title":"Aging Clin Exp Res"},{"issue":"12","key":"1484_CR11","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.2460\/ajvr.77.12.1357","volume":"77","author":"J Hua","year":"2016","unstructured":"Hua J, Hoummady S, Muller C, Pouchelon JL, Blondot M, Gilbert C, et al. Assessment of frailty in aged dogs. Am J Vet Res. 2016;77(12):1357\u201365.","journal-title":"Am J Vet Res"},{"issue":"1","key":"1484_CR12","doi-asserted-by":"publisher","first-page":"16749","DOI":"10.1038\/s41598-019-52585-9","volume":"9","author":"T Banzato","year":"2019","unstructured":"Banzato T, Franzo G, Di Maggio R, Nicoletto E, Burti S, Cesari M, et al. A frailty index based on clinical data to quantify mortality risk in dogs. Sci Rep. 2019;9(1):16749.","journal-title":"Sci Rep"},{"issue":"308","key":"1484_CR13","doi-asserted-by":"publisher","first-page":"308ps21","DOI":"10.1126\/scitranslmed.aaa9116","volume":"7","author":"A Kol","year":"2015","unstructured":"Kol A, Arzi B, Athanasiou KA, Farmer DL, Nolta JA, Rebhun RB, et al. Companion animals: translational scientist\u2019s new best friends. Sci Transl Med. 2015;7(308):308ps21.","journal-title":"Sci Transl Med"},{"key":"1484_CR14","doi-asserted-by":"crossref","unstructured":"Creevy KE, Akey JM, Kaeberlein M, Promislow DEL, Dog aging project C. An open science study of ageing in companion dogs. Nature. 2022;602(7895):51\u20137","DOI":"10.1038\/s41586-021-04282-9"},{"issue":"6","key":"1484_CR15","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1016\/j.cmet.2016.05.009","volume":"23","author":"BK Kennedy","year":"2016","unstructured":"Kennedy BK, Lamming DW. The mechanistic target of rapamycin: the grand conductor of metabolism and aging. Cell Metab. 2016;23(6):990\u20131003.","journal-title":"Cell Metab"},{"issue":"7253","key":"1484_CR16","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nature08221","volume":"460","author":"DE Harrison","year":"2009","unstructured":"Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392\u20135.","journal-title":"Nature"},{"issue":"7","key":"1484_CR17","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1093\/gerona\/glw064","volume":"71","author":"SI Arriola Apelo","year":"2016","unstructured":"Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the life span of female C57BL\/6J Mice. J Gerontol A Biol Sci Med Sci. 2016;71(7):876\u201381.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"1484_CR18","doi-asserted-by":"crossref","unstructured":"Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. elife. 2016;5:e16351.","DOI":"10.7554\/eLife.16351"},{"issue":"6","key":"1484_CR19","doi-asserted-by":"publisher","first-page":"e13435","DOI":"10.1111\/cpr.13435","volume":"56","author":"Q Tang","year":"2023","unstructured":"Tang Q, Markby GR, MacNair AJ, Tang K, Tkacz M, Parys M, et al. TGF-beta-induced PI3K\/AKT\/mTOR pathway controls myofibroblast differentiation and secretory phenotype of valvular interstitial cells through the modulation of cellular senescence in a naturally occurring in vitro canine model of myxomatous mitral valve disease. Cell Prolif. 2023;56(6):e13435.","journal-title":"Cell Prolif"},{"key":"1484_CR20","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.rvsc.2018.11.006","volume":"122","author":"LG Rivera-Calderon","year":"2019","unstructured":"Rivera-Calderon LG, Fonseca-Alves CE, Kobayashi PE, Carvalho M, Vasconcelos RO, Laufer-Amorim R. p-mTOR, p-4EBP-1 and eIF4E expression in canine prostatic carcinoma. Res Vet Sci. 2019;122:86\u201392.","journal-title":"Res Vet Sci"},{"key":"1484_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.tma.2017.09.004","volume":"1","author":"M Kaeberlein","year":"2017","unstructured":"Kaeberlein M. Translational geroscience: a new paradigm for 21(st) century medicine. Transl Med Aging. 2017;1:1\u20134.","journal-title":"Transl Med Aging"},{"issue":"4","key":"1484_CR22","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.cell.2014.10.039","volume":"159","author":"BK Kennedy","year":"2014","unstructured":"Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709\u201313.","journal-title":"Cell"},{"issue":"7432","key":"1484_CR23","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/nature11861","volume":"493","author":"SC Johnson","year":"2013","unstructured":"Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338\u201345.","journal-title":"Nature"},{"key":"1484_CR24","first-page":"849186","volume":"2013","author":"M Kaeberlein","year":"2013","unstructured":"Kaeberlein M. mTOR inhibition: from aging to autism and beyond. Scientifica (Cairo). 2013;2013:849186.","journal-title":"Scientifica (Cairo)"},{"issue":"2","key":"1484_CR25","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1093\/gerona\/glq178","volume":"66","author":"RA Miller","year":"2011","unstructured":"Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011;66(2):191\u2013201.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"3","key":"1484_CR26","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1111\/acel.12194","volume":"13","author":"RA Miller","year":"2014","unstructured":"Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13(3):468\u201377.","journal-title":"Aging Cell"},{"issue":"98","key":"1484_CR27","doi-asserted-by":"publisher","first-page":"ra75","DOI":"10.1126\/scisignal.2000559","volume":"2","author":"C Chen","year":"2009","unstructured":"Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009;2(98):ra75.","journal-title":"Sci Signal"},{"issue":"2","key":"1484_CR28","doi-asserted-by":"publisher","first-page":"314","DOI":"10.18632\/aging.100881","volume":"8","author":"YA Chiao","year":"2016","unstructured":"Chiao YA, Kolwicz SC, Basisty N, Gagnidze A, Zhang J, Gu H, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY). 2016;8(2):314\u201327.","journal-title":"Aging (Albany NY)"},{"issue":"3","key":"1484_CR29","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1111\/acel.12203","volume":"13","author":"DF Dai","year":"2014","unstructured":"Dai DF, Karunadharma PP, Chiao YA, Basisty N, Crispin D, Hsieh EJ, et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell. 2014;13(3):529\u201339.","journal-title":"Aging Cell"},{"issue":"5","key":"1484_CR30","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1111\/acel.12109","volume":"12","author":"JM Flynn","year":"2013","unstructured":"Flynn JM, O\u2019Leary MN, Zambataro CA, Academia EC, Presley MP, Garrett BJ, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013;12(5):851\u201362.","journal-title":"Aging Cell"},{"key":"1484_CR31","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.neuroscience.2012.06.054","volume":"223","author":"J Halloran","year":"2012","unstructured":"Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, et al. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience. 2012;223:102\u201313.","journal-title":"Neuroscience"},{"issue":"7","key":"1484_CR32","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1093\/gerona\/glx249","volume":"73","author":"T Shavlakadze","year":"2018","unstructured":"Shavlakadze T, Zhu J, Wang S, Zhou W, Morin B, Egerman MA, et al. Short-term low-dose mTORC1 inhibition in aged rats counter-regulates age-related gene changes and blocks age-related kidney pathology. J Gerontol A Biol Sci Med Sci. 2018;73(7):845\u201352.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"7404","key":"1484_CR33","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nature11163","volume":"486","author":"OH Yilmaz","year":"2012","unstructured":"Yilmaz OH, Katajisto P, Lamming DW, Gultekin Y, Bauer-Rowe KE, Sengupta S, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature. 2012;486(7404):490\u20135.","journal-title":"Nature"},{"issue":"24","key":"1484_CR34","doi-asserted-by":"publisher","first-page":"3050","DOI":"10.1161\/01.CIR.0000130641.08705.45","volume":"109","author":"JR McMullen","year":"2004","unstructured":"McMullen JR, Sherwood MC, Tarnavski O, Zhang L, Dorfman AL, Shioi T, et al. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation. 2004;109(24):3050\u20135.","journal-title":"Circulation"},{"issue":"12","key":"1484_CR35","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1161\/01.CIR.0000057979.36322.88","volume":"107","author":"T Shioi","year":"2003","unstructured":"Shioi T, McMullen JR, Tarnavski O, Converso K, Sherwood MC, Manning WJ, et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation. 2003;107(12):1664\u201370.","journal-title":"Circulation"},{"issue":"7","key":"1484_CR36","doi-asserted-by":"publisher","first-page":"3477","DOI":"10.1210\/en.2007-0099","volume":"148","author":"JA Kuzman","year":"2007","unstructured":"Kuzman JA, O\u2019Connell TD, Gerdes AM. Rapamycin prevents thyroid hormone-induced cardiac hypertrophy. Endocrinology. 2007;148(7):3477\u201384.","journal-title":"Endocrinology"},{"issue":"6","key":"1484_CR37","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.yjmcc.2012.09.007","volume":"53","author":"A Das","year":"2012","unstructured":"Das A, Salloum FN, Durrant D, Ockaili R, Kukreja RC. Rapamycin protects against myocardial ischemia-reperfusion injury through JAK2-STAT3 signaling pathway. J Mol Cell Cardiol. 2012;53(6):858\u201369.","journal-title":"J Mol Cell Cardiol"},{"issue":"3","key":"1484_CR38","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1172\/JCI44972","volume":"121","author":"TM Marin","year":"2011","unstructured":"Marin TM, Keith K, Davies B, Conner DA, Guha P, Kalaitzidis D, et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Investig. 2011;121(3):1026\u201343.","journal-title":"J Clin Investig"},{"issue":"1","key":"1484_CR39","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1159\/000348308","volume":"125","author":"K Xie","year":"2013","unstructured":"Xie K, Jin B, Li Y, Luo X, Zhu J, Ma D, et al. Modulating autophagy improves cardiac function in a rat model of early-stage dilated cardiomyopathy. Cardiology. 2013;125(1):60\u20138.","journal-title":"Cardiology"},{"issue":"144","key":"1484_CR40","doi-asserted-by":"publisher","first-page":"144ra03","DOI":"10.1126\/scitranslmed.3003802","volume":"4","author":"FJ Ramos","year":"2012","unstructured":"Ramos FJ, Chen SC, Garelick MG, Dai DF, Liao CY, Schreiber KH, et al. Rapamycin reverses elevated mTORC1 signaling in lamin A\/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med. 2012;4(144):144ra03.","journal-title":"Sci Transl Med"},{"issue":"144","key":"1484_CR41","doi-asserted-by":"publisher","first-page":"14402","DOI":"10.1126\/scitranslmed.3003875","volume":"4","author":"JC Choi","year":"2012","unstructured":"Choi JC, Muchir A, Wu W, Iwata S, Homma S, Morrow JP, et al. Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A\/C gene mutation. Sci Transl Med. 2012;4(144):14402.","journal-title":"Sci Transl Med"},{"issue":"1","key":"1484_CR42","doi-asserted-by":"publisher","first-page":"110","DOI":"10.4161\/auto.22403","volume":"9","author":"JC Choi","year":"2013","unstructured":"Choi JC, Worman HJ. Reactivation of autophagy ameliorates LMNA cardiomyopathy. Autophagy. 2013;9(1):110\u20131.","journal-title":"Autophagy"},{"key":"1484_CR43","doi-asserted-by":"crossref","unstructured":"Kaplan JL, Rivas VN, Walker AL, Grubb L, Farrell A, Fitzgerald S, et al. Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial. Journal of the American Veterinary Medical Association. 2023;261(11):1628\u20131637.","DOI":"10.2460\/javma.23.04.0187"},{"key":"1484_CR44","doi-asserted-by":"crossref","unstructured":"Kaeberlein M, Galvan V. Rapamycin and alzheimer\u2019s disease: time for a clinical trial? Sci Transl Med. 2019;11(476):eaar4289.","DOI":"10.1126\/scitranslmed.aar4289"},{"issue":"11","key":"1484_CR45","doi-asserted-by":"publisher","first-page":"e0142340","DOI":"10.1371\/journal.pone.0142340","volume":"10","author":"R Siman","year":"2015","unstructured":"Siman R, Cocca R, Dong Y. The mTOR inhibitor rapamycin mitigates perforant pathway neurodegeneration and synapse loss in a mouse model of early-stage Alzheimer-type tauopathy. PLoS ONE. 2015;10(11):e0142340.","journal-title":"PLoS ONE"},{"issue":"1","key":"1484_CR46","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1177\/0271678X15621575","volume":"37","author":"AL Lin","year":"2017","unstructured":"Lin AL, Jahrling JB, Zhang W, DeRosa N, Bakshi V, Romero P, et al. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer\u2019s disease. J Cereb Blood Flow Metab. 2017;37(1):217\u201326.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"9","key":"1484_CR47","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1038\/jcbfm.2013.82","volume":"33","author":"AL Lin","year":"2013","unstructured":"Lin AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJ, et al. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer\u2019s disease. J Cereb Blood Flow Metab. 2013;33(9):1412\u201321.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"9","key":"1484_CR48","doi-asserted-by":"publisher","first-page":"e25416","DOI":"10.1371\/journal.pone.0025416","volume":"6","author":"S Majumder","year":"2011","unstructured":"Majumder S, Richardson A, Strong R, Oddo S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS ONE. 2011;6(9):e25416.","journal-title":"PLoS ONE"},{"issue":"3","key":"1484_CR49","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.tvjl.2009.11.007","volume":"184","author":"HE Salvin","year":"2010","unstructured":"Salvin HE, McGreevy PD, Sachdev PS, Valenzuela MJ. Under diagnosis of canine cognitive dysfunction: a cross-sectional survey of older companion dogs. Vet J. 2010;184(3):277\u201381.","journal-title":"Vet J"},{"issue":"6","key":"1484_CR50","first-page":"1569","volume":"29","author":"T Schutt","year":"2015","unstructured":"Schutt T, Toft N, Berendt M. Cognitive function, progression of age-related behavioral changes, biomarkers, and survival in dogs more than 8 years old. J Vet Int Med\/American College Vet Int Med. 2015;29(6):1569\u201377.","journal-title":"J Vet Int Med\/American College Vet Int Med"},{"issue":"9","key":"1484_CR51","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1016\/j.bbadis.2013.03.016","volume":"1832","author":"E Head","year":"2013","unstructured":"Head E. A canine model of human aging and Alzheimer\u2019s disease. Biochim Biophys Acta. 2013;1832(9):1384\u20139.","journal-title":"Biochim Biophys Acta"},{"issue":"6","key":"1484_CR52","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1007\/s00401-006-0052-1","volume":"111","author":"M Pugliese","year":"2006","unstructured":"Pugliese M, Geloso MC, Carrasco JL, Mascort J, Michetti F, Mahy N. Canine cognitive deficit correlates with diffuse plaque maturation and S100beta (-) astrocytosis but not with insulin cerebrospinal fluid level. Acta Neuropathol. 2006;111(6):519\u201328.","journal-title":"Acta Neuropathol"},{"key":"1484_CR53","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/S0079-6123(08)61218-2","volume":"106","author":"WW Ruehl","year":"1995","unstructured":"Ruehl WW, Bruyette DS, DePaoli A, Cotman CW, Head E, Milgram NW, et al. Canine cognitive dysfunction as a model for human age-related cognitive decline, dementia and Alzheimer\u2019s disease: clinical presentation, cognitive testing, pathology and response to 1-deprenyl therapy. Prog Brain Res. 1995;106:217\u201325.","journal-title":"Prog Brain Res"},{"issue":"5","key":"1484_CR54","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/S0197-4580(00)00113-5","volume":"21","author":"MA Colle","year":"2000","unstructured":"Colle MA, Hauw JJ, Crespeau F, Uchihara T, Akiyama H, Checler F, et al. Vascular and parenchymal Abeta deposition in the aging dog: correlation with behavior. Neurobiol Aging. 2000;21(5):695\u2013704.","journal-title":"Neurobiol Aging"},{"issue":"9","key":"1484_CR55","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1097\/NEN.0000000000000230","volume":"74","author":"F Schmidt","year":"2015","unstructured":"Schmidt F, Boltze J, Jager C, Hofmann S, Willems N, Seeger J, et al. Detection and quantification of beta-amyloid, pyroglutamyl abeta, and tau in aged canines. J Neuropathol Exp Neurol. 2015;74(9):912\u201323.","journal-title":"J Neuropathol Exp Neurol"},{"issue":"5","key":"1484_CR56","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/S0278-5846(00)00107-X","volume":"24","author":"R Torp","year":"2000","unstructured":"Torp R, Head E, Cotman CW. Ultrastructural analyses of beta-amyloid in the aged dog brain: neuronal beta-amyloid is localized to the plasma membrane. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(5):801\u201310.","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"issue":"2","key":"1484_CR57","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1177\/0300985815623997","volume":"53","author":"SA Youssef","year":"2016","unstructured":"Youssef SA, Capucchio MT, Rofina JE, Chambers JK, Uchida K, Nakayama H, et al. Pathology of the aging brain in domestic and laboratory animals, and animal models of human neurodegenerative diseases. Vet Pathol. 2016;53(2):327\u201348.","journal-title":"Vet Pathol"},{"issue":"1","key":"1484_CR58","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1006\/nlme.1996.0039","volume":"66","author":"BJ Cummings","year":"1996","unstructured":"Cummings BJ, Head E, Afagh AJ, Milgram NW, Cotman CW. Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol Learn Mem. 1996;66(1):11\u201323.","journal-title":"Neurobiol Learn Mem"},{"issue":"2","key":"1484_CR59","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1159\/000481621","volume":"64","author":"D Chapagain","year":"2018","unstructured":"Chapagain D, Range F, Huber L, Viranyi Z. Cognitive aging in dogs. Gerontology. 2018;64(2):165\u201371.","journal-title":"Gerontology"},{"issue":"6","key":"1484_CR60","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1007\/s00109-014-1127-4","volume":"92","author":"H Yi","year":"2014","unstructured":"Yi H, Brooks ED, Thurberg BL, Fyfe JC, Kishnani PS, Sun B. Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med (Berl). 2014;92(6):641\u201350.","journal-title":"J Mol Med (Berl)"},{"issue":"6","key":"1484_CR61","doi-asserted-by":"publisher","first-page":"e11013","DOI":"10.1371\/journal.pone.0011013","volume":"5","author":"MC Paoloni","year":"2010","unstructured":"Paoloni MC, Mazcko C, Fox E, Fan T, Lana S, Kisseberth W, et al. Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs. PLoS ONE. 2010;5(6):e11013.","journal-title":"PLoS ONE"},{"issue":"2","key":"1484_CR62","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s11357-017-9972-z","volume":"39","author":"SR Urfer","year":"2017","unstructured":"Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, Promislow DEL, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience. 2017;39(2):117\u201327.","journal-title":"Geroscience"},{"key":"1484_CR63","doi-asserted-by":"publisher","first-page":"1168711","DOI":"10.3389\/fvets.2023.1168711","volume":"10","author":"BG Barnett","year":"2023","unstructured":"Barnett BG, Wesselowski SR, Gordon SG, Saunders AB, Promislow DEL, Schwartz SM, et al. A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs. Front Vet Sci. 2023;10:1168711.","journal-title":"Front Vet Sci"},{"issue":"11","key":"1484_CR64","doi-asserted-by":"publisher","first-page":"3005","DOI":"10.1158\/1078-0432.CCR-21-0315","volume":"27","author":"AK LeBlanc","year":"2021","unstructured":"LeBlanc AK, Mazcko CN, Cherukuri A, Berger EP, Kisseberth WC, Brown ME, et al. Adjuvant sirolimus does not improve outcome in pet dogs receiving standard-of-care therapy for appendicular osteosarcoma: a prospective, randomized trial of 324 Dogs. Clin Cancer Res. 2021;27(11):3005\u201316.","journal-title":"Clin Cancer Res"},{"key":"1484_CR65","doi-asserted-by":"crossref","unstructured":"Rivas VN, Kaplan JL, Kennedy SA, Fitzgerald S, Crofton AE, Farrell A, et al. Multi-omic, histopathologic, and clinicopathologic effects of once-weekly oral rapamycin in a naturally occurring feline model of hypertrophic cardiomyopathy: a pilot study. Animals. 2023;13:3184.","DOI":"10.3390\/ani13203184"},{"issue":"11","key":"1484_CR66","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.2460\/javma.23.04.0187","volume":"261","author":"JL Kaplan","year":"2023","unstructured":"Kaplan JL, Rivas VN, Walker AL, Grubb L, Farrell A, Fitzgerald S, et al. Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial. J Am Vet Med Assoc. 2023;261(11):1628\u201337.","journal-title":"J Am Vet Med Assoc"},{"issue":"268","key":"1484_CR67","doi-asserted-by":"publisher","first-page":"268ra179","DOI":"10.1126\/scitranslmed.3009892","volume":"6","author":"JB Mannick","year":"2014","unstructured":"Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179.","journal-title":"Sci Transl Med"},{"issue":"5","key":"1484_CR68","doi-asserted-by":"publisher","first-page":"2757","DOI":"10.1007\/s11357-023-00818-1","volume":"45","author":"TL Kaeberlein","year":"2023","unstructured":"Kaeberlein TL, Green AS, Haddad G, Hudson J, Isman A, Nyquist A, et al. Evaluation of off-label rapamycin use to promote healthspan in 333 adults. Geroscience. 2023;45(5):2757\u201368.","journal-title":"Geroscience"},{"issue":"6","key":"1484_CR69","doi-asserted-by":"publisher","first-page":"267","DOI":"10.5326\/JAAHA-MS-6999","volume":"55","author":"KE Creevy","year":"2019","unstructured":"Creevy KE, Grady J, Little SE, Moore GE, Strickler BG, Thompson S, et al. 2019 AAHA Canine Life Stage Guidelines. J Am Anim Hosp Assoc. 2019;55(6):267\u201390.","journal-title":"J Am Anim Hosp Assoc"},{"key":"1484_CR70","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.neuroimage.2018.10.009","volume":"185","author":"SY Bookheimer","year":"2019","unstructured":"Bookheimer SY, Salat DH, Terpstra M, Ances BM, Barch DM, Buckner RL, et al. The lifespan human connectome project in aging: an overview. Neuroimage. 2019;185:335\u201348.","journal-title":"Neuroimage"},{"issue":"5","key":"1484_CR71","doi-asserted-by":"publisher","first-page":"213","DOI":"10.5326\/JAAHA-MS-Canine-Vaccination-Guidelines","volume":"58","author":"J Ellis","year":"2022","unstructured":"Ellis J, Marziani E, Aziz C, Brown CM, Cohn LA, Lea C, et al. 2022 AAHA canine vaccination guidelines. J Am Anim Hosp Assoc. 2022;58(5):213\u201330.","journal-title":"J Am Anim Hosp Assoc"},{"key":"1484_CR72","unstructured":"Rapamune (sirolimus) [package insert]. Philadelphia: Pfizer, Inc.; 2017."},{"key":"1484_CR73","unstructured":"WHO good manufacturing practices for pharmaceutical products: main principles. World Health Organization.\u00a0Document number 986. 2014."},{"key":"1484_CR74","unstructured":"Brennan T, Grubb L, Byrne L, Fitzgerald S, inventor. Veterinary formulations comprising rapamycin and methods of using the same for treating animal disease. 2022."},{"key":"1484_CR75","doi-asserted-by":"crossref","unstructured":"Veterinary cooperative oncology group\u2014common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol. 2016;14(4):417\u201346.","DOI":"10.1111\/vco.283"},{"issue":"Suppl 1","key":"1484_CR76","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1093\/gerona\/glu057","volume":"69","author":"C Franceschi","year":"2014","unstructured":"Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69(Suppl 1):S4-9.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"9","key":"1484_CR77","first-page":"1675","volume":"19","author":"S Salvioli","year":"2013","unstructured":"Salvioli S, Monti D, Lanzarini C, Conte M, Pirazzini C, Bacalini MG, et al. Immune system, cell senescence, aging and longevity\u2014inflamm-aging reappraised. Curr Pharm Des. 2013;19(9):1675\u20139.","journal-title":"Curr Pharm Des"},{"issue":"6","key":"1484_CR78","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/j.ceb.2011.09.003","volume":"23","author":"E Dazert","year":"2011","unstructured":"Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. 2011;23(6):744\u201355.","journal-title":"Curr Opin Cell Biol"},{"key":"1484_CR79","first-page":"107","volume":"40","author":"SC Johnson","year":"2015","unstructured":"Johnson SC, Sangesland M, Kaeberlein M, Rabinovitch PS. Modulating mTOR in aging and health. Interdiscip Top Gerontol. 2015;40:107\u201327.","journal-title":"Interdiscip Top Gerontol"},{"issue":"Suppl 2","key":"1484_CR80","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1111\/j.1467-789X.2012.01038.x","volume":"13","author":"Z Yang","year":"2012","unstructured":"Yang Z, Ming XF. mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases. Obes Rev. 2012;13(Suppl 2):58\u201368.","journal-title":"Obes Rev"},{"key":"1484_CR81","doi-asserted-by":"publisher","first-page":"819135","DOI":"10.3389\/fvets.2021.819135","volume":"8","author":"JA Hoel","year":"2021","unstructured":"Hoel JA, Templeton GB, Fefer G, Case BC, Shah A, Gruen ME, et al. Sustained gaze is a reliable in-home test of attention for aging pet dogs. Front Vet Sci. 2021;8:819135.","journal-title":"Front Vet Sci"},{"key":"1484_CR82","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.applanim.2015.08.034","volume":"171","author":"A Madari","year":"2015","unstructured":"Madari A, Farbakova J, Katina S, Smolek T, Novak P, Weissova T, et al. Assessment of severity and progression of canine cognitive dysfunction syndrome using the CAnine DEmentia Scale (CADES). Appl Anim Behav Sci. 2015;171:138\u201345.","journal-title":"Appl Anim Behav Sci"},{"key":"1484_CR83","doi-asserted-by":"crossref","unstructured":"Vikartovska Z, Farbakova J, Smolek T, Hanes J, Zilka N, Hornakova L, et al. Novel diagnostic tools for identifying cognitive impairment in dogs: behavior, biomarkers, and pathology. Front Vet Sci. 2021;7:551895.","DOI":"10.3389\/fvets.2020.551895"},{"issue":"3","key":"1484_CR84","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.3233\/JAD-215562","volume":"87","author":"G Fefer","year":"2022","unstructured":"Fefer G, Panek WK, Khan MZ, Singer M, Westermeyer HD, Mowat FM, et al. Use of cognitive testing, questionnaires, and plasma biomarkers to quantify cognitive impairment in an aging pet dog population. J Alzheimers Dis. 2022;87(3):1367\u201378.","journal-title":"J Alzheimers Dis"},{"issue":"3","key":"1484_CR85","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.tvjl.2010.05.014","volume":"188","author":"HE Salvin","year":"2011","unstructured":"Salvin HE, McGreevy PD, Sachdev PS, Valenzuela MJ. The canine cognitive dysfunction rating scale (CCDR): a data-driven and ecologically relevant assessment tool. Vet J. 2011;188(3):331\u20136.","journal-title":"Vet J"},{"issue":"3","key":"1484_CR86","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.tvjl.2013.03.021","volume":"197","author":"RP Lavan","year":"2013","unstructured":"Lavan RP. Development and validation of a survey for quality of life assessment by owners of healthy dogs. Vet J. 2013;197(3):578\u201382.","journal-title":"Vet J"},{"issue":"6","key":"1484_CR87","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1111\/jvim.15331","volume":"32","author":"MJ Acierno","year":"2018","unstructured":"Acierno MJ, Brown S, Coleman AE, Jepson RE, Papich M, Stepien RL, et al. ACVIM consensus statement: guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Internal Med \/ American College Vet Internal Med. 2018;32(6):1803\u201322.","journal-title":"J Vet Internal Med \/ American College Vet Internal Med"},{"issue":"6","key":"1484_CR88","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1111\/j.1740-8261.2003.tb00533.x","volume":"44","author":"JA Abbott","year":"2003","unstructured":"Abbott JA, MacLean HN. Comparison of Doppler-derived peak aortic velocities obtained from subcostal and apical transducer sites in healthy dogs. Vet Radiol Ultrasound: Off J American College Vet Radiol Int Vet Radiol Assoc. 2003;44(6):695\u20138.","journal-title":"Vet Radiol Ultrasound: Off J American College Vet Radiol Int Vet Radiol Assoc"},{"key":"1484_CR89","doi-asserted-by":"crossref","unstructured":"Thomas WP, Gaber CE, Jacobs GJ, Kaplan PM, Lombard CW, Moise NS, et al. Recommendations for standards in transthoracic two-dimensional echocardiography in the dog and cat. Echocardiography Committee of the Specialty of Cardiology, American College of Veterinary Internal Medicine. J Vet Internal Med \/ American College Vet Int Med 1993 7(4):247\u201352","DOI":"10.1111\/j.1939-1676.1993.tb01015.x"},{"issue":"5","key":"1484_CR90","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.jvc.2018.07.008","volume":"20","author":"LE Strohm","year":"2018","unstructured":"Strohm LE, Visser LC, Chapel EH, Drost WT, Bonagura JD. Two-dimensional, long-axis echocardiographic ratios for assessment of left atrial and ventricular size in dogs. J Vet Cardiol\u202f: official J European Soc Vet Cardiol. 2018;20(5):330\u201342.","journal-title":"J Vet Cardiol : official J European Soc Vet Cardiol"},{"issue":"5","key":"1484_CR91","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1111\/jvim.15562","volume":"33","author":"LC Visser","year":"2019","unstructured":"Visser LC, Ciccozzi MM, Sintov DJ, Sharpe AN. Echocardiographic quantitation of left heart size and function in 122 healthy dogs: a prospective study proposing reference intervals and assessing repeatability. J Vet Internal Med\/American College Vet Internal Med. 2019;33(5):1909\u201320.","journal-title":"J Vet Internal Med\/American College Vet Internal Med"},{"issue":"3","key":"1484_CR92","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1111\/j.1740-8261.2007.00234.x","volume":"48","author":"V Bavegems","year":"2007","unstructured":"Bavegems V, Duchateau L, Sys SU, De Rick A. Echocardiographic reference values in whippets. Vet Radiol Ultrasound: Off J American College Vet Radiol Int Vet Radiol Assoc. 2007;48(3):230\u20138.","journal-title":"Vet Radiol Ultrasound: Off J American College Vet Radiol Int Vet Radiol Assoc"},{"key":"1484_CR93","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.jvc.2020.10.003","volume":"33","author":"C Bourguignon","year":"2021","unstructured":"Bourguignon C, Caivano D, Dickson D, Vatne L, Harris J, Rishniw M, et al. Two-dimensional echocardiographic estimates of left ventricular volumes obtained in different views in dogs provide similar measurements but are not interchangeable. J Vet Cardiol: Official J European Soc Vet Cardiol. 2021;33:13\u201324.","journal-title":"J Vet Cardiol: Official J European Soc Vet Cardiol"},{"issue":"6","key":"1484_CR94","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1007\/s10071-012-0529-3","volume":"15","author":"K Fujita","year":"2012","unstructured":"Fujita K, Morisaki A, Takaoka A, Maeda T, Hori Y. Incidental memory in dogs (Canis familiaris): adaptive behavioral solution at an unexpected memory test. Anim Cogn. 2012;15(6):1055\u201363.","journal-title":"Anim Cogn"},{"issue":"2","key":"1484_CR95","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s10071-020-01443-7","volume":"24","author":"EE Bray","year":"2021","unstructured":"Bray EE, Gruen ME, Gnanadesikan GE, Horschler DJ, Levy KM, Kennedy BS, et al. Dog cognitive development: a longitudinal study across the first 2 years of life. Anim Cogn. 2021;24(2):311\u201328.","journal-title":"Anim Cogn"},{"issue":"4","key":"1484_CR96","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1007\/s10071-020-01385-0","volume":"23","author":"MM Watowich","year":"2020","unstructured":"Watowich MM, MacLean EL, Hare B, Call J, Kaminski J, Miklosi A, et al. Age influences domestic dog cognitive performance independent of average breed lifespan. Anim Cogn. 2020;23(4):795\u2013805.","journal-title":"Anim Cogn"},{"issue":"7","key":"1484_CR97","doi-asserted-by":"publisher","first-page":"670","DOI":"10.2460\/ajvr.80.7.670","volume":"80","author":"EM Morgan","year":"2019","unstructured":"Morgan EM, Heseltine JC, Levine GJ, Promislow DEL, Creevy KE. Evaluation of a low-technology system to obtain morphological and mobility trial measurements in dogs and investigation of potential predictors of canine mobility. Am J Vet Res. 2019;80(7):670\u20139.","journal-title":"Am J Vet Res"},{"issue":"8","key":"1484_CR98","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1093\/aje\/kwy041","volume":"187","author":"C Wu","year":"2018","unstructured":"Wu C, Geldhof GJ, Xue QL, Kim DH, Newman AB, Odden MC. Development, construct validity, and predictive validity of a continuous frailty scale: results from 2 large US cohorts. Am J Epidemiol. 2018;187(8):1752\u201362.","journal-title":"Am J Epidemiol"},{"issue":"2","key":"1484_CR99","doi-asserted-by":"publisher","first-page":"100","DOI":"10.18632\/aging.100533","volume":"5","author":"CB Livi","year":"2013","unstructured":"Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, et al. Rapamycin extends life span of Rb1+\/- mice by inhibiting neuroendocrine tumors. Aging (Albany NY). 2013;5(2):100\u201310.","journal-title":"Aging (Albany NY)"},{"key":"1484_CR100","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.12659\/MSM.900742","volume":"23","author":"H Zeng","year":"2017","unstructured":"Zeng H, Fu R, Yan L, Huang J. Lycorine induces apoptosis of A549 Cells via AMPK-mammalian target of rapamycin (mTOR)-S6K signaling pathway. Med Sci Monit. 2017;23:2035\u201341.","journal-title":"Med Sci Monit"},{"key":"1484_CR101","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/1471-2288-13-61","volume":"13","author":"N Wongpakaran","year":"2013","unstructured":"Wongpakaran N, Wongpakaran T, Wedding D, Gwet KL. A comparison of Cohen\u2019s Kappa and Gwet\u2019s AC1 when calculating inter-rater reliability coefficients: a study conducted with personality disorder samples. BMC Med Res Methodol. 2013;13:61.","journal-title":"BMC Med Res Methodol"},{"issue":"Pt 1","key":"1484_CR102","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1348\/000711006X126600","volume":"61","author":"KL Gwet","year":"2008","unstructured":"Gwet KL. Computing inter-rater reliability and its variance in the presence of high agreement. Br J Math Stat Psychol. 2008;61(Pt 1):29\u201348.","journal-title":"Br J Math Stat Psychol"},{"key":"1484_CR103","doi-asserted-by":"crossref","unstructured":"McNulty KE, Creevy KE, Fitzpatrick A, Wilkins V, Barnett BG, Dog aging project Consortium, et al. Development and validation of a novel instrument to capture companion dog mortality data: the Dog Aging Project End of Life Survey. J American Vet Med Assoc 2023;261(9):1326\u20131336.","DOI":"10.2460\/javma.23.02.0078"},{"key":"1484_CR104","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s40575-020-00086-8","volume":"7","author":"SR Urfer","year":"2020","unstructured":"Urfer SR, Kaeberlein M, Promislow DEL, Creevy KE. Lifespan of companion dogs seen in three independent primary care veterinary clinics in the United States. Canine Med Genet. 2020;7:7.","journal-title":"Canine Med Genet"},{"key":"1484_CR105","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2019.103208","volume":"95","author":"PA Harris","year":"2019","unstructured":"Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O\u2019Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95: 103208.","journal-title":"J Biomed Inform"},{"issue":"2","key":"1484_CR106","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","volume":"42","author":"PA Harris","year":"2009","unstructured":"Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)\u2014a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377\u201381.","journal-title":"J Biomed Inform"},{"key":"1484_CR107","doi-asserted-by":"publisher","first-page":"117727192211372","DOI":"10.1177\/11772719221137217","volume":"17","author":"L Mouttham","year":"2022","unstructured":"Mouttham L, Castelhano MG. Purpose, Partnership, and possibilities: the implementation of the dog aging project biobank. Biomarker insights. 2022;17:11772719221137216.","journal-title":"Biomarker insights"}],"container-title":["GeroScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-024-01484-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11357-024-01484-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-024-01484-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T13:02:07Z","timestamp":1750510927000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11357-024-01484-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,14]]},"references-count":107,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["1484"],"URL":"https:\/\/doi.org\/10.1007\/s11357-024-01484-7","relation":{},"ISSN":["2509-2723"],"issn-type":[{"value":"2509-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,14]]},"assertion":[{"value":"23 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The University of Washington IRB deemed that recruitment of dog owners for the Dog Aging Project and the administration and content of the DAP surveys are human subjects research that qualifies for category 2 exempt status (IRB ID no. 5988, effective 10\/30\/2018). All study-related procedures involving privately owned dogs were approved by the Texas A&M University IACUC, under animal use protocols 2021-0317 CAM (effective 12\/8\/2021 to present) and 2018-0368 CA (effective 12\/19\/2018 to 12\/18\/2021).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"IACUC approval declaration"}},{"value":"The authors declare the following conflicts of interest: MK is a scientific advisor for TriviumVet; DELP is a consultant for WndrHLTH.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimer"}}]}}