Skip to main content

Advertisement

SpringerLink
Log in

Blazing a trail for the clinical use of rapamycin as a geroprotecTOR

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with “off-target” inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Burch JB, Augustine AD, Frieden LA, et al. Advances in geroscience: impact on healthspan and chronic disease. The Journals of Gerontology: Series A. 2014;69(Suppl_1):S1–3. https://doi.org/10.1093/gerona/glu041.

    Article  Google Scholar 

  2. Ageing in the twenty-first century. Accessed May 10, 2021. /publications/ageing-twenty-first-century

  3. Kaeberlein M. The biology of aging: citizen scientists and their pets as a bridge between research on model organisms and human subjects. Vet Pathol. 2016;53(2):291–8. https://doi.org/10.1177/0300985815591082.

    Article  CAS  PubMed  Google Scholar 

  4. Barr P. The boomer challenge. As baby boomers age, they will strain the system’s ability to care for them. Trustee. 2014;67(2):13–6.

    PubMed  Google Scholar 

  5. Olshansky SJ. Pursuing longevity: delay vs elimination of degenerative diseases. Am J Public Health. 1985;75(7):754–7. https://doi.org/10.2105/ajph.75.7.754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004;14(10):885–90. https://doi.org/10.1016/j.cub.2004.03.059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lamming DW, Ye L, Katajisto P, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335(6076):1638–43. https://doi.org/10.1126/science.1215135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Selman C, Tullet JMA, Wieser D, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009;326(5949):140–4. https://doi.org/10.1126/science.1177221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426(6967):620. https://doi.org/10.1038/426620a.

    Article  CAS  PubMed  Google Scholar 

  10. Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020;21(4):183–203. https://doi.org/10.1038/s41580-019-0199-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kennedy BK, Lamming DW. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab. 2016;23(6):990–1003. https://doi.org/10.1016/j.cmet.2016.05.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nat Aging. 2023;3(6):642–60. https://doi.org/10.1038/s43587-023-00416-y.

    Article  CAS  PubMed  Google Scholar 

  13. Cole JJ, Robertson NA, Rather MI, et al. Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol. 2017;18:58. https://doi.org/10.1186/s13059-017-1185-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang R, Yu Z, Sunchu B, et al. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell. 2017;16(3):564–74. https://doi.org/10.1111/acel.12587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Krebs M, Brunmair B, Brehm A, et al. The mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes. 2007;56(6):1600–7. https://doi.org/10.2337/db06-1016.

    Article  CAS  PubMed  Google Scholar 

  16. Drummond MJ, Fry CS, Glynn EL, et al. Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. J Physiol. 2009;587(Pt 7):1535–46. https://doi.org/10.1113/jphysiol.2008.163816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gundermann DM, Walker DK, Reidy PT, et al. Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by rapamycin. American Journal of Physiology - Endocrinology and Metabolism. 2014;306(10):E1198. https://doi.org/10.1152/ajpendo.00600.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mannick JB, Del Giudice G, Lattanzi M, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179. https://doi.org/10.1126/scitranslmed.3009892.

    Article  CAS  PubMed  Google Scholar 

  19. Mannick JB, Morris M, Hockey HUP, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Science Translational Medicine. 2018;10(449):eaaq1564. https://doi.org/10.1126/scitranslmed.aaq1564.

    Article  CAS  PubMed  Google Scholar 

  20. Kraig E, Linehan LA, Liang H, et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018;105:53–69. https://doi.org/10.1016/j.exger.2017.12.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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):861–9. https://doi.org/10.1007/s11357-019-00113-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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. The Lancet Healthy Longevity. 2021;2(5):e250–62. https://doi.org/10.1016/S2666-7568(21)00062-3.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. The Journal of Clinical Endocrinology & Metabolism. 2001;86(8):3574–8. https://doi.org/10.1210/jcem.86.8.7763.

    Article  CAS  Google Scholar 

  24. Hoscheidt SM, Kellawan JM, Berman SE, et al. Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. J Cereb Blood Flow Metab. 2017;37(6):2249–61. https://doi.org/10.1177/0271678X16663214.

    Article  CAS  PubMed  Google Scholar 

  25. Willette AA, Xu G, Johnson SC, et al. Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care. 2013;36(2):443–9. https://doi.org/10.2337/dc12-0922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barzilay JI, Cotsonis GA, Walston J, et al. Insulin resistance is associated with decreased quadriceps muscle strength in nondiabetic adults aged ≥70 years. Diabetes Care. 2009;32(4):736–8. https://doi.org/10.2337/dc08-1781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zaslavsky O, Walker RL, Crane PK, Gray SL, Larson EB. Glucose levels and risk of frailty. The Journals of Gerontology: Series A. 2016;71(9):1223–9. https://doi.org/10.1093/gerona/glw024.

    Article  CAS  Google Scholar 

  28. Hsu PP, Kang SA, Rameseder J, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332(6035):1317–22. https://doi.org/10.1126/science.1199498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tremblay F, Brûlé S, Hee Um S, et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2007;104(35):14056–61. https://doi.org/10.1073/pnas.0706517104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Harrington LS, Findlay GM, Gray A, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166(2):213–23. https://doi.org/10.1083/jcb.200403069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Um SH, Frigerio F, Watanabe M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431(7005):200–5. https://doi.org/10.1038/nature02866.

    Article  CAS  PubMed  Google Scholar 

  32. Deepa SS, Walsh ME, Hamilton RT, et al. Rapamycin modulates markers of mitochondrial biogenesis and fatty acid oxidation in the adipose tissue of db/db mice. J Biochem Pharmacol Res. 2013;1(2):114–23.

    PubMed  PubMed Central  Google Scholar 

  33. Leontieva OV, Paszkiewicz GM, Blagosklonny MV. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging Cell. 2014;13(4):616–22. https://doi.org/10.1111/acel.12211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhou W, Ye S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biology International. 2018;42(10):1282–91. https://doi.org/10.1002/cbin.11015.

    Article  CAS  PubMed  Google Scholar 

  35. Lamming DW, Ye L, Astle M, Baur JA, Sabatini DM, Harrison DE. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell. 2013;12(4):712–8. https://doi.org/10.1111/acel.12097.

    Article  CAS  PubMed  Google Scholar 

  36. Schreiber KH, Arriola Apelo SI, Yu D, et al. A novel rapamycin analog is highly selective for mTORC1 in vivo. Nat Commun. 2019;10(1):3194. https://doi.org/10.1038/s41467-019-11174-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Minton DM, Elliehausen CJ, Javors MA, Santangelo KS, Konopka AR. Rapamycin-induced hyperglycemia is associated with exacerbated age-related osteoarthritis. Arthritis Research & Therapy. 2021;23(1):253. https://doi.org/10.1186/s13075-021-02637-1.

    Article  CAS  Google Scholar 

  38. Birdsill AC, Carlsson CM, Willette AA, et al. Low cerebral blood flow is associated with lower memory function in metabolic syndrome. Obesity (Silver Spring). 2013;21(7):1313–20. https://doi.org/10.1002/oby.20170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Biagi L, Abbruzzese A, Bianchi MC, Alsop DC, Del Guerra A, Tosetti M. Age dependence of cerebral perfusion assessed by magnetic resonance continuous arterial spin labeling. J Magn Reson Imaging. 2007;25(4):696–702. https://doi.org/10.1002/jmri.20839.

    Article  PubMed  Google Scholar 

  40. Halloran J, Hussong SA, Burbank R, 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;223:102–13. https://doi.org/10.1016/j.neuroscience.2012.06.054.

    Article  CAS  PubMed  Google Scholar 

  41. Jahrling JB, Lin AL, DeRosa N, et al. mTOR drives cerebral blood flow and memory deficits in LDLR−/− mice modeling atherosclerosis and vascular cognitive impairment. J Cereb Blood Flow Metab. 2018;38(1):58–74. https://doi.org/10.1177/0271678X17705973.

    Article  CAS  PubMed  Google Scholar 

  42. Lin AL, Zheng W, Halloran JJ, et al. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. J Cereb Blood Flow Metab. 2013;33(9):1412–21. https://doi.org/10.1038/jcbfm.2013.82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Skike CEV, Lin AL, Burbank RR, et al. mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging. Aging Cell. 2020;19(1):e13057. https://doi.org/10.1111/acel.13057.

    Article  CAS  PubMed  Google Scholar 

  44. Dai X, Hummel SL, Salazar JB, Taffet GE, Zieman S, Schwartz JB. Cardiovascular physiology in the older adults. J Geriatr Cardiol. 2015;12(3):196–201. https://doi.org/10.11909/j.issn.1671-5411.2015.03.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dai DF, Karunadharma PP, Chiao YA, et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell. 2014;13(3):529–39. https://doi.org/10.1111/acel.12203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Flynn JM, O’Leary MN, Zambataro CA, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013;12(5):851–62. https://doi.org/10.1111/acel.12109.

    Article  CAS  PubMed  Google Scholar 

  47. Quarles E, Basisty N, Chiao YA, et al. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell. 2020;19(2):e13086. https://doi.org/10.1111/acel.13086.

    Article  CAS  PubMed  Google Scholar 

  48. Urfer SR, Kaeberlein TL, Mailheau S, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience. 2017;39(2):117–27. https://doi.org/10.1007/s11357-017-9972-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Izumiya Y, Hopkins T, Morris C, et al. Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 2008;7(2):159–72. https://doi.org/10.1016/j.cmet.2007.11.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Seguin R, Nelson ME. The benefits of strength training for older adults. Am J Prev Med. 2003;25(3 Suppl 2):141–9. https://doi.org/10.1016/s0749-3797(03)00177-6.

    Article  PubMed  Google Scholar 

  51. Konopka AR, Harber MP. Skeletal muscle hypertrophy after aerobic exercise training. Exerc Sport Sci Rev. 2014;42(2):53–61. https://doi.org/10.1249/JES.0000000000000007.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Robinson MM, Dasari S, Konopka AR, et al. Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans. Cell Metab. 2017;25(3):581–92. https://doi.org/10.1016/j.cmet.2017.02.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med. 2002;346(11):793–801. https://doi.org/10.1056/NEJMoa011858.

    Article  PubMed  Google Scholar 

  54. Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc. 2002;50(5):889–96. https://doi.org/10.1046/j.1532-5415.2002.50216.x.

    Article  PubMed  Google Scholar 

  55. Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc. 2004;52(1):80–5. https://doi.org/10.1111/j.1532-5415.2004.52014.x.

    Article  PubMed  Google Scholar 

  56. Proctor DN, Balagopal P, Nair KS. Age-related sarcopenia in humans is associated with reduced synthetic rates of specific muscle proteins. J Nutr. 1998;128(2 Suppl):351S–5S. https://doi.org/10.1093/jn/128.2.351S.

    Article  CAS  PubMed  Google Scholar 

  57. Blair SN, Kohl HW III, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA. 1989;262(17):2395–401. https://doi.org/10.1001/jama.1989.03430170057028.

    Article  CAS  PubMed  Google Scholar 

  58. Blair SN, Kohl HW, Barlow CE, Paffenbarger RS, Gibbons LW, Macera CA. Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. JAMA. 1995;273(14):1093–8.

    Article  CAS  PubMed  Google Scholar 

  59. Wei M, Gibbons LW, Mitchell TL, Kampert JB, Lee CD, Blair SN. The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men. Ann Intern Med. 1999;130(2):89–96. https://doi.org/10.7326/0003-4819-130-2-199901190-00002.

    Article  CAS  PubMed  Google Scholar 

  60. Imboden MT, Harber MP, Whaley MH, Finch WH, Bishop DL, Kaminsky LA. Cardiorespiratory fitness and mortality in healthy men and women. J Am Coll Cardiol. 2018;72(19):2283–92. https://doi.org/10.1016/j.jacc.2018.08.2166.

    Article  PubMed  Google Scholar 

  61. Ham DJ, Börsch A, Lin S, et al. The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia. Nat Commun. 2020;11(1):4510. https://doi.org/10.1038/s41467-020-18140-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Baar EL, Carbajal KA, Ong IM, Lamming DW. Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell. 2016;15(1):155–66. https://doi.org/10.1111/acel.12425.

    Article  CAS  PubMed  Google Scholar 

  63. Markofski MM, Dickinson JM, Drummond MJ, et al. Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women. Exp Gerontol. 2015;65:1–7. https://doi.org/10.1016/j.exger.2015.02.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tang H, Inoki K, Brooks SV, et al. mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism. Aging Cell. 2019;18(3):e12943. https://doi.org/10.1111/acel.12943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Joseph GA, Wang SX, Jacobs CE, et al. Partial inhibition of mTORC1 in aged rats counteracts the decline in muscle mass and reverses molecular signaling associated with sarcopenia. Mol Cell Biol. 2019;39(19) https://doi.org/10.1128/MCB.00141-19.

  66. Barns M, Gondro C, Tellam RL, Radley-Crabb HG, Grounds MD, Shavlakadze T. Molecular analyses provide insight into mechanisms underlying sarcopenia and myofibre denervation in old skeletal muscles of mice. Int J Biochem Cell Biol. 2014;53:174–85. https://doi.org/10.1016/j.biocel.2014.04.025.

    Article  CAS  PubMed  Google Scholar 

  67. White Z, White RB, McMahon C, Grounds MD, Shavlakadze T. High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. Int J Biochem Cell Biol. 2016;78:10–21. https://doi.org/10.1016/j.biocel.2016.06.012.

    Article  CAS  PubMed  Google Scholar 

  68. Breen L, Phillips SM. Skeletal muscle protein metabolism in the elderly: interventions to counteract the “anabolic resistance” of ageing. Nutrition & Metabolism. 2011;8(1):68. https://doi.org/10.1186/1743-7075-8-68.

    Article  CAS  Google Scholar 

  69. Kaiser MS, Milan G, Ham DJ, et al. Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis. Commun Biol. 2022;5(1):1141. https://doi.org/10.1038/s42003-022-04097-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Castets P, Lin S, Rion N, et al. Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy. Cell Metabolism. 2013;17(5):731–44. https://doi.org/10.1016/j.cmet.2013.03.015.

    Article  CAS  PubMed  Google Scholar 

  71. Bitto A, Ito TK, Pineda VV, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016;5:e16351. https://doi.org/10.7554/eLife.16351.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009;2(98):ra75. https://doi.org/10.1126/scisignal.2000559.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anticancer Drugs. 2015;26(4):437–42. https://doi.org/10.1097/cad.0000000000000207.

    Article  CAS  PubMed  Google Scholar 

  74. Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol. 2008;19(7):1411–8. https://doi.org/10.1681/ASN.2007111202.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Krueger DA, Wilfong AA, Mays M, et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology. 2016;87(23):2408–15. https://doi.org/10.1212/WNL.0000000000003400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus long-term use in patients with tuberous sclerosis complex: four-year update of the EXIST-2 study. PLoS One. 2017;12(8):e0180939. https://doi.org/10.1371/journal.pone.0180939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Firpi RJ, Tran TT, Flores P, et al. Sirolimus-induced hyperlipidaemia in liver transplant recipients is not dose-dependent. Aliment Pharmacol Ther. 2004;19(9):1033–9. https://doi.org/10.1111/j.1365-2036.2004.01923.x.

    Article  CAS  PubMed  Google Scholar 

  78. Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. Journal of the American Society of Nephrology. 2005;16(10):3128. https://doi.org/10.1681/ASN.2005050487.

    Article  CAS  PubMed  Google Scholar 

  79. Kaeberlein TL, Green AS, Haddad G, et al. Evaluation of off-label rapamycin use to promote healthspan in 333 adults. GeroScience. 2023;16:1–12. https://doi.org/10.1007/s11357-023-00818-1.

    Article  Google Scholar 

  80. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell. 2006;22(2):159–68. https://doi.org/10.1016/j.molcel.2006.03.029.

    Article  CAS  PubMed  Google Scholar 

  81. 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):876–81. https://doi.org/10.1093/gerona/glw064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chen J, Zheng XF, Brown EJ, Schreiber SL. Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci U S A. 1995;92(11):4947–51. https://doi.org/10.1073/pnas.92.11.4947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell. 2010;38(5):768–74. https://doi.org/10.1016/j.molcel.2010.05.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liang J, Choi J, Clardy J. Refined structure of the FKBP12–rapamycin–FRB ternary complex at 2.2 Å resolution. Acta Cryst D. 1999;55(4):736–44. https://doi.org/10.1107/S0907444998014747.

    Article  CAS  Google Scholar 

  85. Chen X, Liu M, Tian Y, et al. Cryo-EM structure of human mTOR complex 2. Cell Res. 2018;28(5):518–28. https://doi.org/10.1038/s41422-018-0029-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Scaiola A, Mangia F, Imseng S, et al. The 3.2-Å resolution structure of human mTORC2. Sci Adv. 2020;6(45):eabc1251. https://doi.org/10.1126/sciadv.abc1251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296–302. https://doi.org/10.1016/j.cub.2004.06.054.

    Article  CAS  PubMed  Google Scholar 

  88. Schreiber KH, Ortiz D, Academia EC, Anies AC, Liao CY, Kennedy BK. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell. 2015;14(2):265–73. https://doi.org/10.1111/acel.12313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lamming DW, Mihaylova MM, Katajisto P, et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell. 2014;13(5):911–7. https://doi.org/10.1111/acel.12256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lamming DW, Demirkan G, Boylan JM, et al. Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2). FASEB J. 2014;28(1):300–15. https://doi.org/10.1096/fj.13-237743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 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:e56177. https://doi.org/10.7554/eLife.56177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chellappa K, Brinkman JA, Mukherjee S, et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell. 2019;18(5):e13014. https://doi.org/10.1111/acel.13014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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. https://doi.org/10.1016/j.celrep.2019.08.084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chang K, Kang P, Liu Y, et al. TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy. 2020;16(10):1807–22. https://doi.org/10.1080/15548627.2019.1704117.

    Article  CAS  PubMed  Google Scholar 

  95. Liu P, Chang K, Requejo G, Bai H. mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila. Front Cell Dev Biol. 2022;10:866210. https://doi.org/10.3389/fcell.2022.866210.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Yi HS, Kim SY, Kim JT, et al. T-cell senescence contributes to abnormal glucose homeostasis in humans and mice. Cell Death & Disease. 2019;10(3):1–15. https://doi.org/10.1038/s41419-019-1494-4.

    Article  CAS  Google Scholar 

  97. Spilman P, Podlutskaya N, Hart MJ, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One. 2010;5(4):e9979. https://doi.org/10.1371/journal.pone.0009979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Caccamo A, Branca C, Talboom JS, et al. Reducing ribosomal protein S6 kinase 1 expression improves spatial memory and synaptic plasticity in a mouse model of Alzheimer’s disease. J Neurosci. 2015;35(41):14042–56. https://doi.org/10.1523/JNEUROSCI.2781-15.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dou X, Sun Y, Li J, et al. Short-term rapamycin treatment increases ovarian lifespan in young and middle-aged female mice. Aging Cell. 2017;16(4):825–36. https://doi.org/10.1111/acel.12617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang XM, Li L, Xu JJ, et al. Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression. Gene. 2013;523(1):82–7. https://doi.org/10.1016/j.gene.2013.03.039.

    Article  CAS  PubMed  Google Scholar 

  101. An JY, Quarles EK, Mekvanich S, et al. Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience. 2017;39(4):457–63. https://doi.org/10.1007/s11357-017-9994-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. An JY, Kerns KA, Ouellette A, et al. Rapamycin rejuvenates oral health in aging mice. Elife. 2020;9:e54318. https://doi.org/10.7554/eLife.54318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We appreciate Drs. Jonathan An, Philip Atherton, Mitzi Gonzales, Joan Mannick, Mandeep Singh, Samuel Williams, Sajad Zalzala and Jørgen Wojtaszewski for sharing information about their studies. We thank Jacob Rome, JD for his assistance in navigating the submission process for FDA Investigational New Drug Applications (161611 and 166577). For EVERLAST, we thank Dr. Lindsay Clark for her input on cognitive assessments, Dr. Adrian Vella for assistance with the design and calculations to determine glucose kinetics during the dual isotope oral glucose tolerance test, Dr. Scott Bauer for the suggestion to include sex-specific lower urinary tract symptoms (LUTS) questionnaires, and Mihaela Teodorescu for sleep quality questionnaires. We also thank the faculty and staff within the Clinical Research Unit and the Pharmaceutical Research Center for initiating EVERLAST and RAP PAC which are supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR002373. EVERLAST is supported by NIH/NIA U01-AG076941 (to ARK), EVERLAST Biomarker Study is supported by the Impetus Longevity Grant by the Norn Group (to ARK), miEpiAge is supported by R21-AG083782 (to AT), RAP PAC is supported by U01-AG081482 (to ARK and DWL), and RAP-PROTECT is supported by the Impetus Longevity Grant by the Norn Group (to DWL). The Konopka Laboratory is also supported in part by NIH/NIA R21-AG067464 and New Investigator Award from AFAR/Hevolution. The Lamming laboratory is also supported in part by the NIH/NIA (AG056771, AG062328, and AG061635) and the NIH/NIDDK (DK125859 and DK133479). Both Konopka and Lamming Laboratories are also supported by startup and other funds from the University of Wisconsin-Madison School of Medicine and Public Health and Department of Medicine. This work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital.

Consortium authors

EVERLAST Investigators

Amanjot K. Yadev1, Rebecca C. Marrah1, Brittany A. Grasso1, Sara Decker2, Samantha Pabich3, Didier Mandelbrot4, Thomas R. Wallhaus5, Oliver Wieben6, Fay Osman7, Richard J. Chappell8, Irene M. Ong8, Reid S. Alisch9, Judith A. Simcox11, Christian J. Elliehausen1, Dennis M. Minton1, Michaela E. Trautman1, Alma Spahic6, Barbara B. Bendlin1, Sanjay Asthana1, Alexey Terskikh12

RAP PAC Investigators

Brittany A. Grasso1, Rebecca C. Marrah1, Sara Decker2, Neetika Garg4, Yeonhee Park8, Sin Yin Lim10, Judith A. Simcox11, Cara L. Green3, Isaac Grunow3

1Division of Geriatrics, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA

2Clinical Research Unit, University of Wisconsin Health System, Madison, WI, USA

3Division of Endocrinology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA

4Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA

5Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA

6Department of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, WI, USA

7Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA

8Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA

9 Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI, USA

10School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA

11Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA

12Development, Aging, and Regeneration Program, Sanford Burnham Prebys, San Diego, CA, USA

Author information

Authors and Affiliations

  1. Division of Geriatrics, Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Adam R. Konopka

  2. William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA

    Adam R. Konopka & Dudley W. Lamming

  3. Division of Geriatrics and Gerontology, Department of Medicine, Geriatric Research Education and Clinical Center (GRECC), William S. Middleton Memorial Veterans Hospital, University of Wisconsin-Madison, 2500 Overlook Terrace, Madison, WI, 53705, USA

    Adam R. Konopka

  4. Division of Endocrinology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Dudley W. Lamming

Authors
  1. Adam R. Konopka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dudley W. Lamming
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

RAP PAC Investigators

  • Brittany A. Grasso
  • , Rebecca C. Marrah
  • , Sara Decker
  • , Neetika Garg
  • , Yeonhee Park
  • , Sin Yin Lim
  • , Judith A. Simcox
  • , Cara L. Green
  •  & Isaac Grunow

EVERLAST Investigators

  • Amanjot K. Yadev
  • , Rebecca C. Marrah
  • , Brittany A. Grasso
  • , Sara Decker
  • , Samantha Pabich
  • , Didier Mandelbrot
  • , Thomas R. Wallhaus
  • , Oliver Wieben
  • , Fay Osman
  • , Richard J. Chappell
  • , Irene M. Ong
  • , Reid S. Alisch
  • , Judith A. Simcox
  • , Christian J. Elliehausen
  • , Dennis M. Minton
  • , Michaela E. Trautman
  • , Alma Spahic
  • , Barbara B. Bendlin
  • , Sanjay Asthana
  •  & Alexey Terskikh

Corresponding author

Correspondence to Adam R. Konopka.

Ethics declarations

Conflict of interest

DWL has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. Aeovian Pharmaceutical mTOR inhibitors will not be used in the clinical trials discussed within this manuscript.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the Department of Veterans Affairs, or the US Government.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Konopka, A.R., Lamming, D.W., RAP PAC Investigators. et al. Blazing a trail for the clinical use of rapamycin as a geroprotecTOR. GeroScience 45, 2769–2783 (2023). https://doi.org/10.1007/s11357-023-00935-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-023-00935-x

Keywords

Search

Navigation