Candidate molecular targets uncovered in mouse lifespan extension studies

References

• World Health Organization: WHO. Ageing. World Health Organization: WHO; Published 2020 Feb 5cited 2023 Feb 5. https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
   Google Scholar
• Vanhooren V, Libert C. The mouse as a model organism in aging research: usefulness, pitfalls and possibilities. Ageing Res Rev. 2013;12(1):8–21. doi: 10.1016/j.arr.2012.03.010
   PubMed Web of Science ®Google Scholar
• Jaramillo-Rangel G, Chávez-Briones MDL, Ancer-Arellano A, et al. Back to the basics: usefulness of naturally aged mouse models and immunohistochemical and quantitative morphologic methods in studying mechanisms of lung aging and associated diseases. Biomedicines. 2023;11(7):2075. doi: 10.3390/biomedicines11072075
   PubMed Web of Science ®Google Scholar
• Anczuków O, Airhart S, Chuang JH, et al. Challenges and opportunities for modeling aging and cancer. Cancer Cell. 2023;41(4):641–645. doi: 10.1016/j.ccell.2023.03.006
   PubMed Web of Science ®Google Scholar
• Daneshjoo S, Young Park J, Moreno J. A mouse model of naturally occurring age-related cognitive impairment. Aging Pathobiol Ther. 2022;4(3):87–89. doi: 10.31491/apt.2022.09.090
   PubMedGoogle Scholar
• Seluanov A, Gladyshev VN, Vijg J, et al. Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer. 2018;18(7):433–441. doi: 10.1038/s41568-018-0004-9
   PubMed Web of Science ®Google Scholar
• Snyder JM, Ward JM, Treuting PM. Cause-of-death analysis in rodent aging studies. Vet Pathol. 2015;53(2):233–243. doi: 10.1177/0300985815610391
   PubMed Web of Science ®Google Scholar
• Palliyaguru DL, Vieira Ligo Teixeira C, Duregon E, et al. Study of longitudinal aging in mice: presentation of experimental techniques. J Gerontol A. 2020;76(4):552–560.
   Google Scholar
• Mekada K, Yoshiki A. Substrains matter in phenotyping of C57BL/6 mice. Exp Anim. 2021;70(2):145–160. doi: 10.1538/expanim.20-0158
   PubMed Web of Science ®Google Scholar
• Spiridonova O, Kriukov D, Nemirovich-Danchenko N, et al. On standardization of controls in lifespan studies. Cold Spring Harbor Laboratory; 2023. cited 2023 Nov 23. doi: 10.1101/2023.08.17.552381
   Google Scholar
• Lee J, Purello C, Booth SL, et al. Chow diet in mouse aging studies: nothing regular about it. Geroscience. 2023;45(3):2079–2084. doi: 10.1007/s11357-023-00775-9
   PubMed Web of Science ®Google Scholar
• Seyhan AA. Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Transl Med Commun. 2019;4(1). doi: 10.1186/s41231-019-0050-7
   Google Scholar
• Moskalev A, Chernyagina E, Tsvetkov V, et al. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell. 2016;15(3):407–415. doi: 10.1111/acel.12463
   PubMed Web of Science ®Google Scholar
• Sun LY, Spong A, Swindell WR, et al. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. Elife. 2013;2. doi: 10.7554/elife.01098
   Web of Science ®Google Scholar
• Pathak S, Stewart WCL, Burd CE, et al. Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice. PLOS ONE. 2020;15(6):e0234910. doi: 10.1371/journal.pone.0234910
   PubMed Web of Science ®Google Scholar
• Bartke A, Wright JC, Mattison JA, et al. Extending the lifespan of long-lived mice. Nature. 2001;414(6862):412–412. doi: 10.1038/35106646
   PubMed Web of Science ®Google Scholar
• Shyu Y, Liao P, Huang T, et al. Genetic disruption of KLF1 K74 SUMOylation in hematopoietic system promotes healthy longevity in mice. Adv Sci. 2022;9(25). doi: 10.1002/advs.202201409
   Web of Science ®Google Scholar
• Zhang Y, Xie Y, Berglund ED, et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife. 2012;1. doi: 10.7554/elife.00065
   Web of Science ®Google Scholar
• Bernardes de Jesus B, Vera E, Schneeberger K, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012;4(8):691–704.
   PubMed Web of Science ®Google Scholar
• Oh E, Miller RA, Thurmond DC. Syntaxin 4 overexpression ameliorates effects of aging and high-fat diet on glucose control and extends lifespan. Cell Metab. 2015;22(3):499–507. doi: 10.1016/j.cmet.2015.07.023
   PubMed Web of Science ®Google Scholar
• Harper JM, Wilkinson JE, Miller RA. Macrophage migration inhibitory factor‐knockout mice are long lived and respond to caloric restriction. Faseb J. 2010;24(7):2436–2442. doi: 10.1096/fj.09-152223
   PubMed Web of Science ®Google Scholar
• Strong R, Miller RA, Cheng CJ, et al. Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice. Aging Cell. 2022;21(12). doi: 10.1111/acel.13724
   PubMed Web of Science ®Google Scholar
• Mitchell SJ, Madrigal-Matute J, Scheibye-Knudsen M, et al. Effects of sex, strain, and energy intake on hallmarks of aging in mice. Cell Metab. 2016;23(6):1093–1112. doi: 10.1016/j.cmet.2016.05.027
   PubMed Web of Science ®Google Scholar
• Selman C, Lingard S, Choudhury AI, et al. Evidence for lifespan extension and delayed age–related biomarkers in insulin receptor substrate 1 null mice. Faseb J. 2007;22(3):807–818.
   PubMed Web of Science ®Google Scholar
• Canaan A, DeFuria J, Perelman E, et al. Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. Proc Nat Acad Sci. 2014;111(14):5313–5318. doi: 10.1073/pnas.1323426111
   PubMed Web of Science ®Google Scholar
• Mitchell SJ, Bernier M, Mattison JA, et al. Daily fasting improves health and survival in male mice Independent of diet composition and calories. Cell Metab. 2019;29(1):221–228.e3.
   PubMed Web of Science ®Google Scholar
• Acosta-Rodríguez V, Rijo-Ferreira F, Izumo M, et al. Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice. Science. 2022;376(6598):1192–1202. doi: 10.1126/science.abk0297
   PubMed Web of Science ®Google Scholar
• 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(3):468–477. doi: 10.1111/acel.12194
   PubMed Web of Science ®Google Scholar
• Dang Y, An Y, He J, et al. Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression. Aging Cell. 2019;19(1): doi: 10.1111/acel.13060
   PubMed Web of Science ®Google Scholar
• 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(5):913–920. doi: 10.1016/j.celrep.2013.07.030
   PubMed Web of Science ®Google Scholar
• Unnikrishnan A, Kurup K, Salmon AB, et al. Is rapamycin a dietary restriction mimetic? J Gerontol A. 2019;75(1):4–13.
   Google Scholar
• Most J, Tosti V, Redman LM, et al. Calorie restriction in humans: an update. Ageing Res Rev. 2017;39:36–45. doi: 10.1016/j.arr.2016.08.005
   PubMed Web of Science ®Google Scholar
• Waziry R, Corcoran D, Huffman K, et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults: cALERIETM Trial Analysis. Cold Spring Harbor Laboratory; 2021 [cited 2023 Nov 23]. doi: 10.1101/2021.09.21.21263912
   Google Scholar
• Nielsen JL, Bakula D, Scheibye-Knudsen M. Clinical trials targeting aging. Front Aging. 2022;3:3. doi: 10.3389/fragi.2022.820215
   Google Scholar
• Yu D, Tomasiewicz JL, Yang SE, et al. Calorie-restriction-induced insulin sensitivity is mediated by adipose mTORC2 and not required for lifespan extension. Cell Rep. 2019;29(1):236–248.e3.
   PubMed Web of Science ®Google Scholar
• Chellappa K, Brinkman JA, Mukherjee S, et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell. 2019;18(5). doi: 10.1111/acel.13014
   Web of Science ®Google Scholar
• Arriola Apelo SI, Lin A, Brinkman JA, et al. Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging. Elife. 2020;9. doi: 10.7554/elife.56177
   PubMed Web of Science ®Google Scholar
• Lamming DW, Mihaylova MM, Katajisto P, et al. Depletion of Rictor, an essential protein component of mTORC 2, decreases male lifespan. Aging Cell. 2014;13(5):911–917. doi: 10.1111/acel.12256
   PubMed Web of Science ®Google Scholar
• Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nature Aging. 2023;3(6):642–660. doi: 10.1038/s43587-023-00416-y
   PubMedGoogle Scholar
• Vogelzang NJ, Bhor M, Liu Z, et al. Everolimus vs. Temsirolimus for advanced renal cell carcinoma: use and use of resources in the US oncology network. Clin Genitourin Cancer. 2013;11(2):115–120. doi: 10.1016/j.clgc.2012.09.008
   PubMed Web of Science ®Google Scholar
• Lamming DW, Ye L, Sabatini DM, et al. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Investig. 2013;123(3):980–989. doi: 10.1172/jci64099
   PubMed Web of Science ®Google Scholar
• Huyghe E, Zairi A, Nohra J, et al. Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. Transplant Int. 2007;20(4):305–311. doi: 10.1111/j.1432-2277.2006.00423.x
   PubMed Web of Science ®Google Scholar
• Mannick JB, Morris M, Hockey HP, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 2018;10(449):eaaq1564.
   PubMed Web of Science ®Google Scholar
• Mannick JB, Teo G, Bernardo P, et al. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2021;2(5):e250–e262. doi: 10.1016/s2666-7568(21)00062-3
   PubMedGoogle Scholar
• Cummings J, Lee G, Nahed P, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimer’s & Dementia: Transl Res Clin Interventions. 2022;8(1): doi: 10.1002/trc2.12295
   Google Scholar
• Chung CL, Lawrence I, Hoffman M, et al. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. Geroscience. 2019;41(6):861–869. doi: 10.1007/s11357-019-00113-y
   PubMed Web of Science ®Google Scholar
• Kim J, Yang G, Kim Y, et al. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016;48(4):e224–e224. doi: 10.1038/emm.2016.16
   PubMed Web of Science ®Google Scholar
• Ulgherait M, Rana A, Rera M, et al. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 2014;8(6):1767–1780. doi: 10.1016/j.celrep.2014.08.006
   PubMed Web of Science ®Google Scholar
• Fang X, Wu H, Wei J, et al. Research progress on the pharmacological effects of berberine targeting mitochondria. Front Endocrinol. 2022;13:13. doi: 10.3389/fendo.2022.982145
   Web of Science ®Google Scholar
• Miller RA, Harrison DE, Allison DB, et al. Canagliflozin extends life span in genetically heterogeneous male but not female mice. JCI Insight. 2020;5(21). doi: 10.1172/jci.insight.140019
   Web of Science ®Google Scholar
• Feng J, Wang X, Ye X, et al. Mitochondria as an important target of metformin: the mechanism of action, toxic and side effects, and new therapeutic applications. Pharmacol Res. 2022;177:106114. doi: 10.1016/j.phrs.2022.106114
   PubMed Web of Science ®Google Scholar
• Steinberg GR, Carling D. AMP-activated protein kinase: the current landscape for drug development. Nat Rev Drug Discov. 2019;18(7):527–551. doi: 10.1038/s41573-019-0019-2
   PubMed Web of Science ®Google Scholar
• Steneberg P, Lindahl E, Dahl U, et al. PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI Insight. 2018;3(12). doi: 10.1172/jci.insight.99114
   PubMed Web of Science ®Google Scholar
• Mofidifar S, Sohraby F, Bagheri M, et al. Repurposing existing drugs for new AMPK activators as a strategy to extend lifespan: a computer-aided drug discovery study. Biogerontology. 2018;19(2):133–143. doi: 10.1007/s10522-018-9744-x
   PubMed Web of Science ®Google Scholar
• Viollet B. AMPK: lessons from transgenic and knockout animals. Front Biosci. 2009;14:19. doi: 10.2741/3229
   PubMed Web of Science ®Google Scholar
• Entezari M, Hashemi D, Taheriazam A, et al. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: a pre-clinical and clinical investigation. Biomed Pharmacother. 2022;146:112563. doi: 10.1016/j.biopha.2021.112563
   PubMed Web of Science ®Google Scholar
• Li T, Mu N, Yin Y, et al. Targeting AMP-Activated protein kinase in aging-related cardiovascular diseases. Aging Dis. 2020;11(4):967. doi: 10.14336/ad.2019.0901
   PubMed Web of Science ®Google Scholar
• Wang Q, Sun J, Liu M, et al. The new role of AMP-Activated protein kinase in regulating fat metabolism and energy expenditure in adipose tissue. Biomolecules. 2021;11(12):1757. doi: 10.3390/biom11121757
   PubMed Web of Science ®Google Scholar
• Lu Y, Yuan T, Min X, et al. AMPK: potential therapeutic target for vascular calcification. Front Cardiovasc Med. 2021;8:8. doi: 10.3389/fcvm.2021.670222
   Web of Science ®Google Scholar
• Neumann NR, Thompson DC, Vasiliou V. AMPK activators for the prevention and treatment of neurodegenerative diseases. Expert Opin Drug Metab Toxicol. 2021;17(10):1199–1210. doi: 10.1080/17425255.2021.1991308
   PubMed Web of Science ®Google Scholar
• Rey V, Tamargo-Gómez I. From kinases to diseases: investigating the role of AMPK in human pathologies. Kinases and Phosphatases. 2023;1(3):181–205. doi: 10.3390/kinasesphosphatases1030012
   Google Scholar
• Zhang Z, Cheng X, Yue L, et al. Molecular pathogenesis in chronic obstructive pulmonary disease and therapeutic potential by targeting AMP‐activated protein kinase. J Cell Physiol. 2017;233(3):1999–2006.
   PubMed Web of Science ®Google Scholar
• Padki MM, Stambler I. Targeting aging with metformin (TAME). Springer International Publishing; cited 2021 Jan 1. doi: 10.1007/978-3-030-22009-9_400
   Google Scholar
• Myers RW, Guan HP, Ehrhart J, et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science. 2017;357(6350):507–511. doi: 10.1126/science.aah5582
   PubMed Web of Science ®Google Scholar
• Keerthana CK, Rayginia TP, Shifana SC, et al. The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment. Front Immunol. 2023;14:14. doi: 10.3389/fimmu.2023.1114582
   Web of Science ®Google Scholar
• Sadria M, Seo D, Layton AT. The mixed blessing of AMPK signaling in cancer treatments. BMC Cancer. 2022;22(1). doi: 10.1186/s12885-022-09211-1
   PubMed Web of Science ®Google Scholar
• Bartke A. Growth hormone and aging. Rev Endocr Metab Disord. 2020;22(1):71–80. doi: 10.1007/s11154-020-09593-2
   PubMed Web of Science ®Google Scholar
• Merriam GR, Schwartz RS, Vitiello MV. Growth hormone-releasing hormone and growth hormone secretagogues in normal aging. Endocrine. 2003;22(1):41–48. doi: 10.1385/endo:22:1:41
   PubMed Web of Science ®Google Scholar
• Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med. 1990;323(1):1–6. doi: 10.1056/nejm199007053230101
   PubMed Web of Science ®Google Scholar
• Perls TT, Reisman NR, Olshansky SJ. Provision or distribution of growth hormone for “antiaging. JAMA. 2005;294(16):2086. doi: 10.1001/jama.294.16.2086
   PubMed Web of Science ®Google Scholar
• Luo YY, Zeng X, Zhu L, et al. Growth hormone reduces aneuploidy and improves oocytes quality by JAK2-MAPK3/1 pathway in aged mice. J Transl Med. 2023;21(1): doi: 10.1186/s12967-023-04296-z
   Web of Science ®Google Scholar
• Masternak MM, Darcy J, Victoria B, et al. Dwarf mice and aging. In: Progress in molecular biology and translational science. Elsevier; 2018 [cited 2023 Nov 23]; p. 69–83. doi: 10.1016/bs.pmbts.2017.12.002
   Google Scholar
• Brown-Borg HM, Borg KE, Meliska CJ, et al. Dwarf mice and the ageing process. Nature. 1996;384(6604):33–33. doi: 10.1038/384033a0
   PubMed Web of Science ®Google Scholar
• Panici JA, Harper JM, Miller RA, et al. Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. Faseb J. 2010;24(12):5073–5079. doi: 10.1096/fj.10.163253
   PubMed Web of Science ®Google Scholar
• Bartke A, Wright JC, Mattison JA, et al. Extending the lifespan of long-lived mice. Nature. 2001;414(6862):412–412.
   PubMed Web of Science ®Google Scholar
• Miller RA. Kleemeier Award Lecture: Are There Genes for Aging? J Gerontol Ser A. 1999;54(7):B297–B307. doi: 10.1093/gerona/54.7.b297
   PubMed Web of Science ®Google Scholar
• Flurkey K, Papaconstantinou J, Harrison DE. The Snell dwarf mutation Pit1dw can increase life span in mice. Mech Ageing Dev. 2002;123(2–3):121–130. doi: 10.1016/s0047-6374(01)00339-6
   PubMed Web of Science ®Google Scholar
• Flurkey K, Papaconstantinou J, Miller RA, et al. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Nat Acad Sci. 2001;98(12):6736–6741. doi: 10.1073/pnas.111158898
   PubMed Web of Science ®Google Scholar
• Duran-Ortiz S, List EO, Basu R, et al. Extending lifespan by modulating the growth hormone/insulin-like growth factor-1 axis: coming of age. Pituitary. 2021;24(3):438–456. doi: 10.1007/s11102-020-01117-0
   PubMed Web of Science ®Google Scholar
• Conover CA, Bale LK, Mader JR, et al. Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A. J Gerontol A. 2010;65A(6):590–599. doi: 10.1093/gerona/glq032
   Google Scholar
• Mohrin M, Liu J, Zavala‐Solorio J, et al. Inhibition of longevity regulator PAPP‐A modulates tissue homeostasis via restraint of mesenchymal stromal cells. Aging Cell. 2021;20(3). doi: 10.1111/acel.13313
   PubMed Web of Science ®Google Scholar
• Coschigano KT, Clemmons D, Bellush LL, et al. Assessment of growth parameters and life span of GHR/BP gene-disrupted Mice1. Endocrinology. 2000;141(7):2608–2613. doi: 10.1210/endo.141.7.7586
   PubMed Web of Science ®Google Scholar
• Kim SS, Lee CK. Growth signaling and longevity in mouse models. BMB Rep. 2019;52(1):70–85. doi: 10.5483/bmbrep.2019.52.1.299
   PubMed Web of Science ®Google Scholar
• Geiger BC, Wang S, Padera RF Jr, et al. Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis. Sci, trans med. 2018;10(469): doi: 10.1126/scitranslmed.aat8800
   PubMed Web of Science ®Google Scholar
• Loffredo FS, Pancoast JR, Cai L, et al. Targeted delivery to cartilage is critical for in vivo efficacy of Insulin‐like growth factor 1 in a rat model of osteoarthritis. Arthritis Rheumatol. 2014;66(5):1247–1255. doi: 10.1002/art.38357
   PubMed Web of Science ®Google Scholar
• Abdellatif M, Trummer-Herbst V, Heberle AM, et al. Fine-tuning cardiac insulin-like growth factor 1 receptor signaling to promote health and longevity. Circulation. 2022;145(25):1853–1866. doi: 10.1161/circulationaha.122.059863
   PubMed Web of Science ®Google Scholar
• Koffi KA, Doublier S, Ricort JM, et al. The Role of GH/IGF Axis in dento-alveolar complex from development to aging and therapeutics: a narrative review. Cells. 2021;10(5):1181. doi: 10.3390/cells10051181
   PubMed Web of Science ®Google Scholar
• Gungor O, Ulu S, Hasbal NB, et al. Effects of hormonal changes on sarcopenia in chronic kidney disease: where are we now and what can we do? J Cachexia Sarcopenia Muscle. 2021;12(6):1380–1392.
   PubMed Web of Science ®Google Scholar
• Kopple JD, Cheung AK, Christiansen JS, et al. OPPORTUNITYTM. Clin J Am Soc Nephrol. 2008;3(6):1741–1751.
   PubMedGoogle Scholar
• Gomez J. Growth hormone and insulin-like growth factor-I as an endocrine axis in Alzheimer's disease. Endocr Metab Immune Disord Drug Target. 2008;8(2):143–151. doi: 10.2174/187153008784534367
   PubMedGoogle Scholar
• Manuel Gomez Saez J. Possible usefulness of growth hormone/Insulin-like growth factor-I axis in Alzheimer’s disease treatment. Endocr Metab Immune Disord Drug. 2012;12(3):274–286. doi: 10.2174/187153012802002857
   PubMedGoogle Scholar
• Basu T, Bertrand H, Karantzelis N, et al. Pharmacological inhibition of insulin growth factor-1 receptor (IGF-1R) alone or in combination with ruxolitinib shows therapeutic efficacy in preclinical myeloproliferative neoplasm models. Hemasphere. 2021;5(5):e565. doi: 10.1097/hs9.0000000000000565
   PubMed Web of Science ®Google Scholar
• Melmed S, Bronstein MD, Chanson P, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552–561. doi: 10.1038/s41574-018-0058-5
   PubMed Web of Science ®Google Scholar
• Werner H, Sarfstein R, Bruchim I. Investigational IGF1R inhibitors in early stage clinical trials for cancer therapy. Expert Opin Investig Drugs. 2019;28(12):1101–1112. doi: 10.1080/13543784.2019.1694660
   PubMed Web of Science ®Google Scholar
• Siatecka M, Xue L, Bieker JJ. Sumoylation of EKLF promotes transcriptional repression and is involved in inhibition of Megakaryopoiesis. Mol Cell Biol. 2007;27(24):8547–8560. doi: 10.1128/mcb.00589-07
   PubMed Web of Science ®Google Scholar
• Paikari A, Sheehan VA. Fetal haemoglobin induction in sickle cell disease. Br J Haematol. 2017;180(2):189–200. doi: 10.1111/bjh.15021
   PubMed Web of Science ®Google Scholar
• Liu D, Zhang X, Yu L, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of β-thalassemia. Blood. 2014;124(5):803–811. doi: 10.1182/blood-2014-03-561779
   PubMed Web of Science ®Google Scholar
• Spurlin BA, Park SY, Nevins AK, et al. Syntaxin 4 transgenic mice exhibit enhanced insulin-mediated glucose uptake in skeletal muscle. Diabetes. 2004;53(9):2223–2231. doi: 10.2337/diabetes.53.9.2223
   PubMed Web of Science ®Google Scholar
• Yang C, Coker KJ, Kim JK, et al. Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance. J Clin Investig. 2001;107(10):1311–1318. doi: 10.1172/jci12274
   PubMed Web of Science ®Google Scholar
• Oh E, Stull ND, Mirmira RG, et al. Syntaxin 4 Up-Regulation Increases Efficiency of Insulin Release in pancreatic islets from humans with and without type 2 diabetes mellitus. J Clin Endocrinol Metab. 2014;99(5):E866–E870. doi: 10.1210/jc.2013-2221
   PubMed Web of Science ®Google Scholar
• Livingstone R, Bryant NJ, Boyle JG, et al. Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle. Endocrinol Diabetes Metabol. 2022;5(5): doi: 10.1002/edm2.361
   PubMedGoogle Scholar
• Dratwa M, Wysoczańska B, Łacina P, et al. TERT—Regulation and roles in cancer formation. Front Immunol. 2020;11:11. doi: 10.3389/fimmu.2020.589929
   PubMed Web of Science ®Google Scholar
• Altamura G, Degli Uberti B, Galiero G, et al. The Small molecule BIBR1532 exerts potential anti-cancer activities in preclinical models of feline oral squamous cell carcinoma through inhibition of telomerase activity and down-regulation of TERT. Front Vet Sci. 2021 [cited 2021 Jan 20];7:620776.
   PubMed Web of Science ®Google Scholar
• Guterres AN, Villanueva J. Targeting telomerase for cancer therapy. Oncogene. 2020;39(36):5811–5824. doi: 10.1038/s41388-020-01405-w
   PubMed Web of Science ®Google Scholar
• Zheng Q, Huang J, Wang WG. Mitochondria, telomeres and telomerase subunits. Front Cell Dev Biol. 2019;7:7. doi: 10.3389/fcell.2019.00274
   PubMed Web of Science ®Google Scholar
• de Jesus B B, Schneeberger K, Vera E, et al. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell. 2011;10(4):604–621. doi: 10.1111/j.1474-9726.2011.00700.x
   PubMed Web of Science ®Google Scholar
• Yu X, Liu MM, Zheng CY, et al. Telomerase reverse transcriptase and neurodegenerative diseases. Front Immunol. 2023;14:14. doi: 10.3389/fimmu.2023.1165632
   Web of Science ®Google Scholar
• Wan T, Weir EJ, Johnson M, et al. Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson’s disease associated with enhanced autophagy. Prog Neurobiol. 2021;199:101953. doi: 10.1016/j.pneurobio.2020.101953
   PubMed Web of Science ®Google Scholar
• Bawamia B, Spray L, Wangsaputra VK, et al. Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction. Geroscience. 2023;45(4):2689–2705. doi: 10.1007/s11357-023-00794-6
   PubMed Web of Science ®Google Scholar
• Jaijyan DK, Selariu A, Cruz-Cosme R, et al. New intranasal and injectable gene therapy for healthy life extension. Proc Nat Acad Sci. 2022;119(20): doi: 10.1073/pnas.2121499119
   PubMed Web of Science ®Google Scholar
• Sewell PE. Safety study of AAV hTert and klotho gene transfer therapy for dementia. J Regenerative Bio Med. cited 2021 Nov 8. doi: 10.37191/mapsci-2582-385x-3(6)-097
   Google Scholar
• Liu C, Schönke M, Zhou E, et al. Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis. Cardiovasc Res. 2021;118(2):489–502.
   Web of Science ®Google Scholar
• Szczepańska E, Gietka-Czernel M. FGF21: a novel regulator of glucose and lipid metabolism and whole-body energy balance. Hormone Metab Res. 2022;54(4):203–211. doi: 10.1055/a-1778-4159
   PubMedGoogle Scholar
• Kilkenny DM, Rocheleau JV. The FGF21 receptor signaling complex. In: Klotho. 2016 [cited 2023 Nov 23]:17–58. doi: 10.1016/bs.vh.2016.02.008.
   Google Scholar
• Shao W, Jin T. Hepatic hormone FGF21 and its analogues in clinical trials. Chronic Dis Transl Med. 2022;8(1):19–25. doi: 10.1016/j.cdtm.2021.08.005
   PubMedGoogle Scholar
• Talukdar S, Zhou Y, Li D, et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 2016;23(3):427–440. doi: 10.1016/j.cmet.2016.02.001
   PubMed Web of Science ®Google Scholar
• Sanyal A, Charles ED, Neuschwander-Tetri BA, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2018;392(10165):2705–2717. doi: 10.1016/s0140-6736(18)31785-9
   PubMed Web of Science ®Google Scholar
• Gaich G, Chien JY, Fu H, et al. The Effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18(3):333–340. doi: 10.1016/j.cmet.2013.08.005
   PubMed Web of Science ®Google Scholar
• Dong JQ, Rossulek M, Somayaji VR, et al. Pharmacokinetics and pharmacodynamics of PF‐05231023, a novel long‐acting FGF21 mimetic, in a first‐in‐human study. Br J Clin Pharmacol. 2015;80(5):1051–1063.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Ruane PJ, Freilich BL, et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial. Nature Med. 2021;27(7):1262–1271. doi: 10.1038/s41591-021-01425-3
   PubMed Web of Science ®Google Scholar
• Cui A, Li J, Ji S, et al. The Effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates. Diabetes. 2020;69(8):1611–1623. doi: 10.2337/db20-0209
   PubMed Web of Science ®Google Scholar
• Wong C, Dash A, Fredrickson J, et al. Fibroblast growth factor receptor 1/Klothoβ agonist BFKB8488A improves lipids and liver health markers in patients with diabetes or NAFLD: a phase 1b randomized trial. Hepatology. 2022;78(3):847–862.
   PubMed Web of Science ®Google Scholar
• Davidsohn N, Pezone M, Vernet A, et al. A single combination gene therapy treats multiple age-related diseases. Proc Nat Acad Sci. 2019;116(47):23505–23511. doi: 10.1073/pnas.1910073116
   PubMed Web of Science ®Google Scholar
• Florez-Sampedro L, Soto-Gamez A, Poelarends GJ, et al. The role of MIF in chronic lung diseases: looking beyond inflammation. Am J Physiol Lung Cell Mol Physiol. 2020;318(6):L1183–L1197. doi: 10.1152/ajplung.00521.2019
   PubMed Web of Science ®Google Scholar
• Oda S, Oda T, Nishi K, et al. Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner. PLOS ONE. 2008;3(5):e2215. doi: 10.1371/journal.pone.0002215
   PubMed Web of Science ®Google Scholar
• Sinitski D, Kontos C, Krammer C, et al. Macrophage migration inhibitory factor (MIF)-based therapeutic concepts in atherosclerosis and inflammation. Thromb Haemost. 2019;119(4):553–566.
   PubMed Web of Science ®Google Scholar
• Sauler M, Bucala R, Lee PJ. Role of macrophage migration inhibitory factor in age-related lung disease. Am J Physiol Lung Cell Mol Physiol. 2015;309(1):L1–L10. doi: 10.1152/ajplung.00339.2014
   PubMed Web of Science ®Google Scholar
• Bilsborrow JB, Doherty E, Tilstam PV, et al. Macrophage migration inhibitory factor (MIF) as a therapeutic target for rheumatoid arthritis and systemic lupus erythematosus. Expert Opin Ther Targets. 2019;23(9):733–744. doi: 10.1080/14728222.2019.1656718
   PubMed Web of Science ®Google Scholar
• Mahalingam D, Patel MR, Sachdev JC, et al. Phase I study of imalumab (BAX69), a fully human recombinant antioxidized macrophage migration inhibitory factor antibody in advanced solid tumours. Br J Clin Pharmacol. 2020;86(9):1836–1848.
   PubMed Web of Science ®Google Scholar
• Sumaiya K, Langford D, Natarajaseenivasan K, et al. Macrophage migration inhibitory factor (MIF): a multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther. 2022;233:108024. doi: 10.1016/j.pharmthera.2021.108024
   PubMed Web of Science ®Google Scholar
• Gokani S, Bhatt LK. Bromodomains: a novel target for the anticancer therapy. Eur J Pharmacol. 2021;911:174523. doi: 10.1016/j.ejphar.2021.174523
   PubMed Web of Science ®Google Scholar
• Liu L, Yang C, Candelario-Jalil E. Role of BET Proteins in inflammation and CNS diseases. Front Mol Biosci. 2021;8:8. doi: 10.3389/fmolb.2021.748449
   Web of Science ®Google Scholar
• Kokkola T, Suuronen T, Pesonen M, et al. BET inhibition upregulates SIRT1 and alleviates inflammatory responses. Chembiochem. 2015;16(14):1997–2001. doi: 10.1002/cbic.201500272
   PubMed Web of Science ®Google Scholar
• Zhou S, Zhang S, Wang L, et al. BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling. Oncogenesis. 2020;9(3). doi: 10.1038/s41389-020-0218-z
   Web of Science ®Google Scholar
• Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067–1073. doi: 10.1038/nature09504
   PubMed Web of Science ®Google Scholar
• Piquereau J, Boet A, Péchoux C, et al. The BET bromodomain inhibitor I-BET-151 induces structural and functional alterations of the heart mitochondria in healthy male mice and rats. Int J Mol Sci. 2019;20(7):1527. doi: 10.3390/ijms20071527
   PubMed Web of Science ®Google Scholar
• Zhang X, Lee HC, Shirazi F, et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia. 2018;32(10):2224–2239. doi: 10.1038/s41375-018-0044-x
   PubMed Web of Science ®Google Scholar
• Braun T, Gardin C. Investigational BET bromodomain protein inhibitors in early stage clinical trials for acute myelogenous leukemia (AML). Expert Opin Investig Drugs. 2017;26(7):803–811. doi: 10.1080/13543784.2017.1335711
   PubMed Web of Science ®Google Scholar
• Roverato ND, Sailer C, Catone N, et al. Parkin is an E3 ligase for the ubiquitin-like modifier FAT10, which inhibits Parkin activation and mitophagy. Cell Rep. 2021;34(11):108857. doi: 10.1016/j.celrep.2021.108857
   PubMed Web of Science ®Google Scholar
• Bakula D, Scheibye-Knudsen M. MitophAging: mitophagy in aging and disease. Front Cell Dev Biol. 2020;8:8. doi: 10.3389/fcell.2020.00239
   PubMed Web of Science ®Google Scholar
• Aichem A, Groettrup M. The ubiquitin-like modifier FAT10 – much more than a proteasome-targeting signal. J Cell Sci. 2020;133(14). doi: 10.1242/jcs.246041
   PubMed Web of Science ®Google Scholar
• Michaud M, Balardy L, Moulis G, et al. Proinflammatory cytokines, aging, and Age-Related diseases. J Am Med Dir Assoc. 2013;14(12):877–882. doi: 10.1016/j.jamda.2013.05.009
   PubMed Web of Science ®Google Scholar
• Jia Y, Ji P, French SW. The role of FAT10 in alcoholic hepatitis pathogenesis. Biomedicines. 2020;8(7):189. doi: 10.3390/biomedicines8070189
   PubMed Web of Science ®Google Scholar
• Zhang Y, Zuo Z, Liu B, et al. FAT10 promotes hepatocellular carcinoma (HCC) carcinogenesis by mediating P53 degradation and acts as a prognostic indicator of HCC. J Gastrointest Oncol. 2021;12(4):1823–1837.
   PubMed Web of Science ®Google Scholar
• Iourov IY, Yurov YB, Vorsanova SG, et al. Chromosome instability, aging and brain diseases. Cells. 2021;10(5):1256. doi: 10.3390/cells10051256
   PubMed Web of Science ®Google Scholar
• Morice S, Danieau G, Rédini F, et al. Hippo/YAP signaling pathway: a promising therapeutic target in bone paediatric cancers? Cancers (Basel). 2020;12(3):645. doi: 10.3390/cancers12030645
   PubMed Web of Science ®Google Scholar
• Sladitschek-Martens HL, Guarnieri A, Brumana G, et al. YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS–STING. Nature. 2022;607(7920):790–798. doi: 10.1038/s41586-022-04924-6
   PubMed Web of Science ®Google Scholar
• Yi X, Deng X, Zhao Y, et al. Ubiquitin-like protein FAT10 promotes osteosarcoma growth by modifying the ubiquitination and degradation of YAP1. Exp Cell Res. 2020;387(2):111804. doi: 10.1016/j.yexcr.2019.111804
   PubMed Web of Science ®Google Scholar
• Zhang K, Chen L, Zhang Z, et al. Ubiquitin-like protein FAT10: a potential cardioprotective factor and novel therapeutic target in cancer. Clinica Chimica Acta. 2020;510:802–811. doi: 10.1016/j.cca.2020.09.016
   PubMed Web of Science ®Google Scholar
• Gao Y, Theng SS, Mah WC, et al. Silibinin down-regulates FAT10 and modulate TNF-α/IFN-γ-induced chromosomal instability and apoptosis sensitivity. Biol Open. 2015;4(8):961–969. doi: 10.1242/bio.011189
   PubMed Web of Science ®Google Scholar
• Knufinke M, MacArthur MR, Ewald CY, et al. Sex differences in pharmacological interventions and their effects on lifespan and healthspan outcomes: a systematic review. Front Aging. 2023;4:4. doi: 10.3389/fragi.2023.1172789
   Google Scholar
• Bitto A, Ito TK, Pineda VV, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016;5. doi: 10.7554/elife.16351
   PubMed Web of Science ®Google Scholar
• Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28. doi: 10.1016/j.ebiom.2018.09.015
   PubMed Web of Science ®Google Scholar
• Sabini E, O’Mahony A, Caturegli P. MyMD-1 improves health span and prolongs life span in old mice: a noninferiority study to rapamycin. J Gerontol A. 2022;78(2):227–235. doi: 10.1093/gerona/glac142
   Google Scholar
• Junnila RK, Duran-Ortiz S, Suer O, et al. Disruption of the GH receptor gene in adult mice increases maximal lifespan in females. Endocrinology. 2016;157(12):4502–4513. doi: 10.1210/en.2016-1649
   PubMed Web of Science ®Google Scholar
• Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003;299(5606):572–574. doi: 10.1126/science.1078223
   PubMed Web of Science ®Google Scholar
• Lee HY, Jeon Y, Kim YK, et al. Identifying molecular targets for reverse aging using integrated network analysis of transcriptomic and epigenomic changes during aging. Sci Rep. 2021;11(1): doi: 10.1038/s41598-021-91811-1
   Web of Science ®Google Scholar
• Sen P. High-throughput chromatin screens to identify targets of senescence and aging. Transl Med Aging. 2020;4:73–75. doi: 10.1016/j.tma.2020.06.002
   PubMedGoogle Scholar
• Mo C, Zhang W, Liu L, et al. High throughput screening technology and the small molecules modulating aging related signals. Comb Chem High Throughput Screen. 2012;15(3):242–252.
   PubMed Web of Science ®Google Scholar
• Aliper A, Belikov AV, Garazha A, et al. In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aging. 2016;8(9):2127–2152. doi: 10.18632/aging.101047
   PubMedGoogle Scholar
• Moskalev A, Chernyagina E, Kudryavtseva A, et al. Geroprotectors: a unified concept and screening approaches. Aging Dis. 2017;8(3):354. doi: 10.14336/ad.2016.1022
   PubMed Web of Science ®Google Scholar
• Center for Drug Evaluation, Research. Codevelopment of two or more new investigational drugs for use in combination. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/codevelopment-two-or-more-new-investigational-drugs-use-combination.
   Google Scholar
• Kim SK, Goughnour PC, Lee EJ, et al. Identification of drug combinations on the basis of machine learning to maximize anti-aging effects. PLOS ONE. 2021;16(1):e0246106. doi: 10.1371/journal.pone.0246106
   PubMed Web of Science ®Google Scholar