A list of interventions that are likely to be among the first officially recognized treatments for human lifespan extension
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[1]Neff, Frauke, et al. "Rapamycin extends murine lifespan but has limited effects on aging." The Journal of clinical investigation 123.8 (2013): 3272-3291.
[2]De Haes, Wouter, et al. "Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2." Proceedings of the National Academy of Sciences 111.24 (2014): E2501-E2509.
Creative contributions
Hyperbaric Oxygen Therapy (HBOT)
[1]Hachmo Y, Hadanny A, Abu Hamed R, Daniel-Kotovsky M, Catalogna M, Fishlev G, Lang E, Polak N, Doenyas K, Friedman M, Zemel Y, Bechor Y, Efrati S. Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial. Aging (Albany NY). 2020; . https://doi.org/10.18632/aging.202188 [Epub ahead of print]
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Rapamycin
[1]Demidenko ZN, Blagosklonny M V. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle [Internet]. 2008 Nov 5;7(21):3355–61. Available from: http://www.tandfonline.com/doi/abs/10.4161/cc.7.21.6919
[2]Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR Is Essential for Growth and Proliferation in Early Mouse Embryos and Embryonic Stem Cells. Mol Cell Biol [Internet]. 2004 Aug 1;24(15):6710–8. Available from: https://mcb.asm.org/content/24/15/6710
[3]Blagosklonny M V. Rapamycin for longevity: opinion article. Aging (Albany NY) [Internet]. 2019 Oct 4;11(19):8048–67. Available from: http://www.aging-us.com/article/102355/text
[4]Johnson SC, Yanos ME, Kayser E-B, Quintana A, Sangesland M, Castanza A, et al. mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome. Science (80- ) [Internet]. 2013 Dec 20;342(6165):1524–8. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1244360
[5]Blagosklonny M V. Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. Cell Cycle [Internet]. 2006 Sep 15;5(18):2087–102. Available from: https://www.tandfonline.com/doi/full/10.4161/cc.5.18.3288
[6]Svatek RS, Ji N, de Leon E, Mukherjee NZ, Kabra A, Hurez V, et al. Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer. Cancer Immunol Res [Internet]. 2018 Dec 18; Available from: http://cancerimmunolres.aacrjournals.org/lookup/doi/10.1158/2326-6066.CIR-18-0336
[7]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 [Internet]. 2014 Dec 24;6(268):268ra179-268ra179. Available from: https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.3009892
[8]Pascual J, Royuela A, Fernández AM, Herrero I, Delgado JF, Solé A, et al. Role of mTOR inhibitors for the control of viral infection in solid organ transplant recipients. Transpl Infect Dis [Internet]. 2016 Dec;18(6):819–31. Available from: http://doi.wiley.com/10.1111/tid.12601
[9]Carosi JM, Sargeant TJ. Rapamycin and Alzheimer disease: a double-edged sword? Autophagy [Internet]. 2019 Aug 3;15(8):1460–2. Available from: https://www.tandfonline.com/doi/full/10.1080/15548627.2019.1615823
[10]Whyte LS, Lau AA, Hemsley KM, Hopwood JJ, Sargeant TJ. Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer’s disease? J Neurochem [Internet]. 2017 Mar;140(5):703–17. Available from: http://doi.wiley.com/10.1111/jnc.13935
[11]Makki K, Taront S, Molendi-Coste O, Bouchaert E, Neve B, Eury E, et al. Beneficial Metabolic Effects of Rapamycin Are Associated with Enhanced Regulatory Cells in Diet-Induced Obese Mice. Chavakis T, editor. PLoS One [Internet]. 2014 Apr 7;9(4):e92684. Available from: https://dx.plos.org/10.1371/journal.pone.0092684
[12]Zhou W, Ye S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol Int [Internet]. 2018 Sep;42(10):1282–91. Available from: http://doi.wiley.com/10.1002/cbin.11015
[13]Ye L, Widlund AL, Sims CA, Lamming DW, Guan Y, Davis JG, et al. Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging (Albany NY) [Internet]. 2013 Jul 16;5(7):539–50. Available from: http://www.aging-us.com/article/100576
[14]Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, 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 [Internet]. 2018 May;105:53–69. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0531556517309130
[15]Pavlakis M, Goldfarb-Rumyantzev AS. Diabetes after Transplantation and Sirolimus: What’s the Connection? J Am Soc Nephrol [Internet]. 2008 Jul;19(7):1255–6. Available from: http://www.jasn.org/lookup/doi/10.1681/ASN.2008050474
[16]Blagosklonny M V. Aging, Stem Cells, and Mammalian Target of Rapamycin: A Prospect of Pharmacologic Rejuvenation of Aging Stem Cells. Rejuvenation Res [Internet]. 2008 Aug;11(4):801–8. Available from: https://www.liebertpub.com/doi/10.1089/rej.2008.0722
[17]Weiner SM, Sellin L, Vonend O, Schenker P, Buchner NJ, Flecken M, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome a single-centre experience and review of the literature. Nephrol Dial Transplant [Internet]. 2007 Aug 25;22(12):3631–7. Available from: https://academic.oup.com/ndt/article-lookup/doi/10.1093/ndt/gfm420
[18]Dunn JLM, Kartchner LB, Gast K, Sessions M, Hunter RA, Thurlow L, et al. Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury. J Leukoc Biol [Internet]. 2018 May;103(5):909–18. Available from: http://doi.wiley.com/10.1002/JLB.3AB0616-251RRR
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Resveratrol
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[1]Bhullar, Khushwant S., and Basil P. Hubbard. "Lifespan and healthspan extension by resveratrol." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1852.6 (2015): 1209-1218.
[2]Schultz, Michael B., and David A. Sinclair. "Why NAD+ declines during aging: it’s destroyed." Cell metabolism 23.6 (2016): 965-966.
[3]McCormack, Shana, et al. "Pharmacologic targeting of sirtuin and PPAR signaling improves longevity and mitochondrial physiology in respiratory chain complex I mutant Caenorhabditis elegans." Mitochondrion 22 (2015): 45-59.
[4]Jimenez-Gomez, Yolanda, et al. "Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet." Cell metabolism 18.4 (2013): 533-545.
[5]Valenzano, Dario R., et al. "Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate." Current biology 16.3 (2006): 296-300.
[6]Rascón, Brenda, et al. "The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction." Aging (Albany NY) 4.7 (2012): 499.
[7]Gonzalez-Freire, Marta, et al. "The road ahead for health and lifespan interventions." Ageing Research Reviews (2020): 101037.
[8]Zaw, Jay Jay Thaung, Peter RC Howe, and Rachel HX Wong. "Sustained Cerebrovascular and Cognitive Benefits of Resveratrol in Postmenopausal Women." Nutrients 12.3 (2020): 828.
[9]Walle, Thomas, et al. "High absorption but very low bioavailability of oral resveratrol in humans." Drug metabolism and disposition 32.12 (2004): 1377-1382.
[10]Chang, Thomas KH, Jie Chen, and Wendy BK Lee. "Differential Inhibition and Inactivation of Human CYP1 Enzymes bytrans-Resveratrol: Evidence for Mechanism-Based Inactivation of CYP1A2." Journal of Pharmacology and Experimental Therapeutics 299.3 (2001): 874-882.
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Calorie restriction
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[1][1]Ma Shuai,Sun Shuhui,Geng Lingling,Song Moshi,Wang Wei,Ye Yanxia,Ji Qianzhao,Zou Zhiran,Wang Si,He Xiaojuan,Li Wei,Esteban Concepcion Rodriguez,Long Xiao,Guo Guoji,Chan Piu,Zhou Qi,Belmonte Juan Carlos Izpisua,Zhang Weiqi,Liu Guang-Hui. Caloric Restriction Reprograms the Single-Cell Transcriptional Landscape of Rattus Norvegicus Aging[J]. Cell,2020, 180(5).DOI:https://doi.org/10.1016/j.cell.2020.02.008
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Integrated stress response inhibitor drug reverses age-related cognitive decline
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Metformin - more to improve the healthspan than lifespan
[1]Glossmann HH, Lutz OMD. Metformin and Aging: A Review. Gerontology [Internet]. 2019;65(6):581–90. Available from: https://www.karger.com/Article/FullText/502257
[2]Wang C-P, Lorenzo C, Habib SL, Jo B, Espinoza SE. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complications [Internet]. 2017 Apr;31(4):679–86. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1056872716308005
[3]Campbell JM, Bellman SM, Stephenson MD, Lisy. K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev [Internet]. 2017 Nov;40:31–44. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1568163717301472
[4]Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obes Metab [Internet]. 2014 Nov;16(11):1165–73. Available from: http://doi.wiley.com/10.1111/dom.12354
[5]Xu H, Aldrich MC, Chen Q, Liu H, Peterson NB, Dai Q, et al. Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality. J Am Med Informatics Assoc [Internet]. 2014 Jul 22; Available from: https://academic.oup.com/jamia/article-lookup/doi/10.1136/amiajnl-2014-002649
[6]Noto H, Goto A, Tsujimoto T, Noda M. Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-analysis. Biondi-Zoccai G, editor. PLoS One [Internet]. 2012 Mar 20;7(3):e33411. Available from: https://dx.plos.org/10.1371/journal.pone.0033411
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The Gut Flora
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[1]Guarner, Francisco, and Juan-R. Malagelada. "Gut flora in health and disease." The Lancet 361.9356 (2003): 512-519.
[2]Bárcena, Clea, et al. "Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice." Nature medicine 25.8 (2019): 1234-1242.
[3]Haifer, Craig, Sudarshan Paramsothy, and Rupert W. Leong. "Faecal microbiota transplantation as an elixir of youth." Hepatobiliary Surgery and Nutrition 9.4 (2020): 488.
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Epigenetic Diet
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[1]Booth, Lauren N., and Anne Brunet. "The aging epigenome." Molecular cell 62.5 (2016): 728-744.
[2]Gallou-Kabani, Catherine, et al. "Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond." Clinical Chemistry and Laboratory Medicine (CCLM) 45.3 (2007): 321-327.
[3]Cosentino, Claudia, and Raul Mostoslavsky. "Metabolism, longevity and epigenetics." Cellular and Molecular Life Sciences 70.9 (2013): 1525-1541.
[4]Hardy, Tabitha M., and Trygve O. Tollefsbol. "Epigenetic diet: impact on the epigenome and cancer." Epigenomics 3.4 (2011): 503-518.
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OSK Treatment
![Deru Xu](https://cdn.brainstorming.com/s43exj1600067867651.jpg)
[1]Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., . . . Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature, 588(7836), 124-129. doi:10.1038/s41586-020-2975-4
[2] Sarkar, T.J., Quarta, M., Mukherjee, S. et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun 11, 1545 (2020).
[3]Goldberg, Jeffrey L et al. “Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity.” Neuron vol. 33,5 (2002): 689-702. doi:10.1016/s0896-6273(02)00602-5
[4]Park, Kevin Kyungsuk et al. “Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.” Science (New York, N.Y.) vol. 322,5903 (2008): 963-6. doi:10.1126/science.1161566
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PGE2-EP2 binding inhibitors/ blockers
[1]Minhas, P.S., Latif-Hernandez, A., McReynolds, M.R. et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature (2021). https://doi.org/10.1038/s41586-020-03160-0
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Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) promotes healthspan and lifespan
[1]Reynolds, J.C., Lai, R.W., Woodhead, J.S.T. et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 12, 470 (2021). https://doi.org/10.1038/s41467-020-20790-0
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NAD+ and nervous system, cancer, liver function, kidney function, skeletal muscle, heart function
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[1]Campisi, J., Kapahi, P., Lithgow, G.J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019).
[2]Mitsukuni Yoshida,Akiko Satoh,Jonathan B. Lin,Kathryn F. Mills,Yo Sasaki,Nicholas Rensing,Michael Wong,Rajendra S. Apte,Shin-ichiro Imai. Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice[J]. Cell Metabolism,2019,30(2).
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Senolytic drugs to remove senescent cells.
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[1]Collado, Manuel, Maria A. Blasco, and Manuel Serrano. "Cellular senescence in cancer and aging." Cell 130.2 (2007): 223-233.
[2]Xu, Ming, et al. "Senolytics improve physical function and increase lifespan in old age." Nature medicine 24.8 (2018): 1246-1256.
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An increase in the levels of LB1 or a decrease in those of SUN1 to decline aging in neural stem cells
[1]Muhammad Khadeesh bin Imtiaz, Baptiste N. Jaeger, Sara Bottes, Raquel A.C. Machado, Mojca Vidmar, Darcie L. Moore, Sebastian Jessberger. Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity, Cell Stem Cell, 2021, ISSN 1934-5909, https://doi.org/10.1016/j.stem.2021.01.015. https://www.sciencedirect.com/science/article/pii/S1934590921000151