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Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

Phillips, Eleanor J., Simons, Mirre J. P.·2023·GeroScience
DOI 10.1007/s11357-022-00691-4PMC PMC9886774

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Abstract

Dietary restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR, and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice ( n = 1223 from 23 studies comprising 46 effect sizes involving DR ( n = 17) and rapamycin treatment ( n = 29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR = − 0.72; CI = − 1.17, -0.28; p = 0.0015). In contrast, DR reduced post-infection survival (lnHR = 0.80; CI = 0.08, 1.52; p = 0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower ( p < 0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR, our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.

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Fig. 1 Forest plot of log hazard ratio estimates (circles) for DR and rapamycin post-infection survival curve pairings (n = 46) from Cox proportional hazard models. Squares indicate overall effect sizes as determined using meta-analysis controlling for interdependence of study and shared controls. Whiskers indicate 95% CIs
Fig. 1 Forest plot of log hazard ratio estimates (circles) for DR and rapamycin post-infection survival curve pairings (n = 46) from Cox proportional hazard models. Squares indicate overall effect sizes as determined using meta-analysis controlling for interdependence of study and shared controls. Whiskers indicate 95% CIsCC BY · PubMed Central

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Citations

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Research works printed but not linked: 53

  1. Chung HY, Kim HJ, Kim KW, Choi JS, Yu BP. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc Res Tech. 2002;59:264–72. https://doi.org/10.1002/jemt.10203. · DOI
  2. Gavazzi G, Krause K-H. Ageing and infection. Lancet Infect Dis. 2002;2:659–66. https://doi.org/10.1016/S1473-3099(02)00437-1. · DOI · Paper page
  3. Nikolich-Žugich J, Messaoudi I. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol, Metabolism, Aging and Longevity. 2005;40:884–93. https://doi.org/10.1016/j.exger.2005.06.007. · DOI
  4. Ritz BW, Gardner EM. Malnutrition and energy restriction differentially affect viral immunity. J Nutr. 2006;136:1141–4. https://doi.org/10.1093/jn/136.5.1141. · DOI
  5. Baylis D, Bartlett DB, Patel HP, Roberts HC. Understanding how we age: insights into inflammaging. Longev Heal. 2013;2:8. https://doi.org/10.1186/2046-2395-2-8. · DOI
  6. Foster AD, Sivarapatna A, Gress RE. The aging immune system and its relationship with cancer. Aging Health. 2011;7:707–18. https://doi.org/10.2217/ahe.11.56. · DOI
  7. Fontana L, Partridge L, Longo VD. Extending healthy life span—from yeast to humans. Science. 2010;328:321–6. https://doi.org/10.1126/science.1172539. · DOI · Paper page
  8. Katewa SD, Kapahi P. Dietary restriction and aging, 2009. Aging Cell. 2010;9:105–12. https://doi.org/10.1111/j.1474-9726.2010.00552.x. · DOI
  9. Garratt M, Nakagawa S, Simons MJP. Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction. Aging Cell. 2016;15:737–43. https://doi.org/10.1111/acel.12489. · DOI
  10. Cox LS, Mattison JA. Increasing longevity through caloric restriction or rapamycin feeding in mammals: common mechanisms for common outcomes? Aging Cell. 2009;8:607–13. https://doi.org/10.1111/j.1474-9726.2009.00509.x. · DOI
  11. Green CL, Lamming DW, Fontana L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol. 2022;23:56–73. https://doi.org/10.1038/s41580-021-00411-4. · DOI · Paper page
  12. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11:35–46. https://doi.org/10.1016/j.cmet.2009.11.010. · DOI · Paper page
  13. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13:468–77. https://doi.org/10.1111/acel.12194. · DOI
  14. Unnikrishnan A, Kurup K, Salmon AB, Richardson A. Is rapamycin a dietary restriction mimetic? J Gerontol Ser A. 2020;75:4–13. https://doi.org/10.1093/gerona/glz060. · DOI
  15. Jolly CA. Dietary restriction and immune function. J Nutr. 2004;134:1853–6. https://doi.org/10.1093/jn/134.8.1853. · DOI
  16. Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int. 2001;59:3–16. https://doi.org/10.1046/j.1523-1755.2001.00460.x. · DOI
  17. Speakman JR, Mitchell SE. Caloric restriction. Mol Aspects Med, Caloric Restriction. 2011;32:159–221. https://doi.org/10.1016/j.mam.2011.07.001. · DOI
  18. Camell CD, Yousefzadeh MJ, Zhu Y, Prata LGPL, Huggins MA, Pierson M, Zhang L, O’Kelly RD, Pirtskhalava T, Xun P, Ejima K, Xue A, Tripathi U, Espindola-Netto JM, Giorgadze N, Atkinson EJ, Inman CL, Johnson KO, Cholensky SH, Carlson TW, LeBrasseur NK, Khosla S, O’Sullivan MG, Allison DB, Jameson SC, Meves A, Li M, Prakash YS, Chiarella SE, Hamilton SE, Tchkonia T, Niedernhofer LJ, Kirkland JL, Robbins PD. Senolytics reduce coronavirus-related mortality in old mice. Science. 2021;373:eabe4832. https://doi.org/10.1126/science.abe4832. · DOI · Paper page
  19. Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Žugich J. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell. 2015;14:130–8. https://doi.org/10.1111/acel.12280. · DOI
  20. Castle SC. Clinical relevance of age-related immune dysfunction. Clin Infect Dis. 2000;31:578–85. https://doi.org/10.1086/313947. · DOI
  21. Mejia P, Treviño-Villarreal JH, Hine C, Harputlugil E, Lang S, Calay E, Rogers R, Wirth D, Duraisingh MT, Mitchell JR. Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression. Nat Commun. 2015;6:6050. https://doi.org/10.1038/ncomms7050. · DOI
  22. Canivet C, Menasria R, Rhéaume C, Piret J, Boivin G. Valacyclovir combined with artesunate or rapamycin improves the outcome of herpes simplex virus encephalitis in mice compared to antiviral therapy alone. Antiviral Res. 2015;123:105–13. https://doi.org/10.1016/j.antiviral.2015.09.007. · DOI
  23. Huang C-T, Hung C-Y, Chen T-C, Lin C-Y, Lin Y-C, Chang C-S, He Y-C, Huang Y-L, Dutta A. Rapamycin adjuvant and exacerbation of severe influenza in an experimental mouse model. Sci Rep. 2017;7:4136. https://doi.org/10.1038/s41598-017-04365-6. · DOI
  24. Birkisdóttir MB, Jaarsma D, Brandt RMC, Barnhoorn S, van Vliet N, Imholz S, van Oostrom CT, Nagarajah B, Portilla Fernández E, Roks AJM, Elgersma Y, van Steeg H, Ferreira JA, Pennings JLA, Hoeijmakers JHJ, Vermeij WP, Dollé MET. Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice. Aging Cell. 2021;20: e13302. https://doi.org/10.1111/acel.13302. · DOI · Paper page
  25. Messaoudi I, Fischer M, Warner J, Park B, Mattison J, Ingram DK, Totonchy T, Mori M, Nikolich-Žugich J. Optimal window of caloric restriction onset limits its beneficial impact on T-cell senescence in primates. Aging Cell. 2008;7:908–19. https://doi.org/10.1111/j.1474-9726.2008.00440.x. · DOI · Paper page
  26. Pae M, Meydani SN, Wu D. The role of nutrition in enhancing immunity in aging. Aging Dis. 2011;3:91–129.
  27. González O, Tobia C, Ebersole J, Novak M. Caloric restriction and chronic inflammatory diseases. Oral Dis. 2012;18:16–31. https://doi.org/10.1111/j.1601-0825.2011.01830.x. · DOI
  28. Abe T, Nakajima A, Satoh N, Ohkoshi M, Sakuragi S, Koizumi A. Suppression of experimental autoimmune uveoretinitis by dietary calorie restriction. Jpn J Ophthalmol. 2001;45:46–52. https://doi.org/10.1016/S0021-5155(00)00303-8. · DOI
  29. Chacón F, Cano P, Lopez-Varela S, Jiménez V, Marcos A, Esquifino AI. Chronobiological features of the immune system. Effect of calorie restriction. Eur J Clin Nutr. 2002;56:S69–72. https://doi.org/10.1038/sj.ejcn.1601491. · DOI
  30. Sun D, Muthukumar AR, Lawrence RA, Fernandes G. Effects of calorie restriction on polymicrobial peritonitis induced by cecum ligation and puncture in young C57BL/6 mice. Clin Diagn Lab Immunol 2001;8:1003–11. https://doi.org/10.1128/CDLI.8.5.1003-1011.2001 · DOI
  31. Clinthorne JF, Adams DJ, Fenton JI, Ritz BW, Gardner EM. Short-term re-feeding of previously energy-restricted C57BL/6 male mice restores body weight and body fat and attenuates the decline in natural killer cell function after primary influenza infection. J Nutr. 2010;140:1495–501. https://doi.org/10.3945/jn.110.122408. · DOI
  32. Clinthorne JF, Beli E, Duriancik DM, Gardner EM. NK cell maturation and function in C57BL/6 mice are altered by caloric restriction. J Immunol. 2013;190:712–22. https://doi.org/10.4049/jimmunol.1201837. · DOI
  33. Naylor C, Petri WA. Leptin regulation of immune responses. Trends Mol Med. 2016;22:88–98. https://doi.org/10.1016/j.molmed.2015.12.001. · DOI
  34. Goldberg EL, Smithey MJ, Lutes LK, Uhrlaub JL, Nikolich-Žugich J. Immune memory–boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J Immunol. 2014;193:757–63. https://doi.org/10.4049/jimmunol.1400188. · DOI · Paper page
  35. Liu Q, Zhou Y, Yang Z. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13:3–10. https://doi.org/10.1038/cmi.2015.74. · DOI
  36. Chen C, Liu Yu, Liu Yang, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2009; 2. https://doi.org/10.1126/scisignal.2000559 · DOI · Paper page
  37. Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, Brown SA, Surman S, Wilson ZS, Bradley P, Hurwitz J, Chi H, Doherty PC, Thomas PG, McGargill MA. The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol. 2013;14:1266–76. https://doi.org/10.1038/ni.2741. · DOI
  38. Liepkalns JS, Pandey A, Hofstetter AR, Kumar A, Jones EN, Cao W, Liu F, Levine MZ, Sambhara S, Gangappa S. Rapamycin does not impede survival or induction of antibody responses to primary and heterosubtypic influenza infections in mice. Viral Immunol. 2016;29:487–93. · DOI
  39. Bischof E, Siow RC, Zhavoronkov A, Kaeberlein M. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. Lancet Healthy Longev. 2021;2:e105–11. https://doi.org/10.1016/S2666-7568(20)30068-4. · DOI
  40. Hurez V, Dao V, Liu A, Pandeswara S, Gelfond J, Sun L, Bergman M, Orihuela CJ, Galvan V, Padrón Á, Drerup J, Liu Y, Hasty P, Sharp ZD, Curiel TJ. Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice. Aging Cell. 2015;14:945–56. https://doi.org/10.1111/acel.12380. · DOI
  41. Hinojosa CA, Mgbemena V, Van Roekel S, Austad SN, Miller RA, Bose S, Orihuela CJ. Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence. Exp Gerontol. 2012;47:958–65. https://doi.org/10.1016/j.exger.2012.08.013. · DOI
  42. Juricic P, Lu Y-X, Leech T, Drews LF, Paulitz J, Lu J, Nespital T, Azami S, Regan JC, Funk E, Fröhlich J, Grönke S, Partridge L. Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy. Nat Aging 2022; 1–13. https://doi.org/10.1038/s43587-022-00278-w · DOI · Paper page
  43. Simons MJP, Hartshorne L, Trooster S, Thomson J, Tatar M. 2019. Age-dependent effects of reduced mTor signalling on life expectancy through distinct physiology. preprint bioRxiv. https://doi.org/10.1101/719096 · DOI
  44. Shindyapina AV, Cho Y, Kaya A, Tyshkovskiy A, Castro JP, Gordevicius J, Poganik JR, Horvath S, Peshkin L, Gladyshev VN. Preprint bioRxiv. Rapamycin treatment during development extends lifespan and healthspan. 2022. https://doi.org/10.1101/2022.02.18.481092. · DOI
  45. Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, Tung H, Vizzini N, Chen B, Smith K, Meza D, Yajima M, Beyer RP, Kerr KF, Davis DJ, Gillespie CH, Snyder JM, Treuting PM, Kaeberlein M. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 2016;5:e16351. https://doi.org/10.7554/eLife.16351 · DOI · Paper page
  46. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;349:g7647. https://doi.org/10.1136/bmj.g7647. · DOI · Paper page
  47. Ohkusu-Tsukada K, Tsukada T, Isobe K. Accelerated development and aging of the immune system in p53-deficient mice. J Immunol Baltim Md. 1999;1950(163):1966–72.
  48. Davies WL, Smith SC, Pond WL, Rasmussen AF, Clark PF. Effect of dietary restriction on susceptibility of mice to infection with Theiler’s GDVII virus. Proc Soc Exp Biol Med. 1949;72:528–31. https://doi.org/10.3181/00379727-72-17488. · DOI
  49. Swindell WR. Meta-analysis of 29 experiments evaluating the effects of rapamycin on life span in the laboratory mouse. J Gerontol Ser A. 2017;72:1024–32. https://doi.org/10.1093/gerona/glw153. · DOI
  50. Therneau TM, Grambsch PM (2000) Modeling survival data: extending the cox model. Springer, New York · DOI · Paper page
  51. Swindell WR. Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan. Ageing Res Rev. 2012;11:254–70. https://doi.org/10.1016/j.arr.2011.12.006. · DOI
  52. Fornefett J, Krause J, Klose K, Fingas F, Hassert R, Eisenberg T, Schrödl W, Grunwald T, Müller U, Baums CG. Comparative analysis of clinics, pathologies and immune responses in BALB/c and C57BL/6 mice infected with Streptobacillus moniliformis. Microbes Infect. 2018;20:101–10. https://doi.org/10.1016/j.micinf.2017.10.001. · DOI
  53. Viechtbauer W. Conducting meta-analyses in R with the metafor Package. J Stat Softw. 2010;36:1–48. https://doi.org/10.18637/jss.v036.i03. · DOI · Paper page

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Metadata

Authors
Phillips, E. J., & Simons, M. J. P.
ORCID
Simons, Mirre J. P.
Venue
GeroScience
Publisher
Springer Science and Business Media LLC
Published
2022-11-18
Volume
45
Issue
2
Pages
1263-1270
ISSN
  • 2509-2715
  • 2509-2723
DOI
10.1007/s11357-022-00691-4
PMC
PMC9886774
Cited by
21
References
9
Language
en
Licence
Funders
  • Wellcome Trust (216405/Z/19/Z)
  • Academy of Medical Sciences (SBF004\1085)

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