A list of interventions that are likely to be among the first officially recognized treatments for human lifespan extension
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Neff, Frauke, et al. "Rapamycin extends murine lifespan but has limited effects on aging." The Journal of clinical investigation 123.8 (2013): 3272-3291.
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.
Hyperbaric Oxygen Therapy (HBOT)
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]
- The TOR (nutrient sensing) pathway is activated by nutrients, insulin, and growth factors. TOR increases protein synthesis, inhibits autophagy, and may develop compensatory resistance to insulin, growth hormone, and growth factors. TOR drives geroconverison (from quiescence to senescence), which lasted 3-6 days in cell culture and takes decades in the human body. mTOR makes the cells hypertrophic and leads to SASP, which then causes age-related pathologies. There is no natural bodily inhibitor of TOR. Rapamycin inhibits TOR.
- Rapamycin is a natural anti-fungal produced by soil bacteria Streptomyces hygroscopicus.
- Rapamycin extends longevity (3-fold) in short-lived strain of mice, and prolongs life in normal mice, yeast, flies, and worms, and prevents age-related conditions, even in humans.
- Rapamycin is FDA-approved and is used as anti-aging drugs since 2006.
- Rapamycin improves immunity in cancer patients and the elderly, reduces CMV (Cytomegalovirus) infection in transplant patients. Rapamycin is indicated in almost all age-related disease like cancer, obesity, neurodegeneration, and atherosclerosis . No study has shown that Rapamycin causes cancer.
- Rapamycin in an effective anti-aging drug irrespective of age. It would be most effective if it is used early, before the disease manifests.
- Intermittent Rapamycin and calorie restriction (24-48 hours after) when combined, avoids hyperglycemia. Rapamycin both prevents and abrogates insulin resistance even in humans.
- Physical exercise, if started immediately after Rapamycin use, can take advantage of Rapamycin-induced lipolysis as fuel for the muscles. Chronic Rapamycin treatment does not reduce muscle endurance and prevents muscle loss.
- A daily 1 mg/day for several weeks in the elderly did not have side-effects.
- Rapamycin may interact with other drugs and that may lead to hyperglycemia.
- Rapamycin is required to activate or rejuvenate the stem cells. However, it needs to be withdrawn for the rejuvenated stem cells to induce regeneration and healing (Rapamycin impairs healing).
- At high doses in the elderly, Rapamycin may cause reversible thrombocytopenia, anemia, and leukopenia. However, a slight reduction in platelets is beneficial.
- Rapamycin may cause stomatitis and mycositis (ulceration and inflammation of the mucous membranes of the alimentary canal and the digestive tract), non-infectious interstitial pneumonitis, and it may increase the severity of bacterial infections (by inhibiting neutrophil function).
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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
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
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
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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
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
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
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
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
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
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
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
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
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
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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
- Resveratrol supplementation was shown to increase lifespan and improve the healthspan of various models.
- Resveratrol inhibits oxidative stress, inflammatory response, and much more.
- Improved cognitive function in postmenopausal women that took 75 mg trans-resveratrol two times a day for a year.
- Resveratrol hasn't got a good bioavailability.
- Genetic factors may impact the effectiveness of the treatment.
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.
Schultz, Michael B., and David A. Sinclair. "Why NAD+ declines during aging: it’s destroyed." Cell metabolism 23.6 (2016): 965-966.
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.
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.
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.
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.
Gonzalez-Freire, Marta, et al. "The road ahead for health and lifespan interventions." Ageing Research Reviews (2020): 101037.
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.
Walle, Thomas, et al. "High absorption but very low bioavailability of oral resveratrol in humans." Drug metabolism and disposition 32.12 (2004): 1377-1382.
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.
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
Metformin - more to improve the healthspan than lifespan
- Metformin has a safety and efficacy record not observed with any other diabetic drug.
- Metformin is already there. The production and distribution channels are set.
- The clinical cohort of male veterans with T2D who were >65 years old included 8,393 metformin users. After 9 years of follow-up, four distinct age-related comorbidity trajectory classes could be identified. In the healthy class, the odds ratio of mortality associated with metformin use was 0.53; in the high-cancer-risk class it was 0.72, in the high-CVD-risk class it was 0.58, and in the high-frailty class it was 0.39, indicating that the last group benefitted most from the drug concerning mortality.
- In observational studies (cohort, case-control, and cross-sectional studies), diabetics taking metformin had a lower rate of all-cause mortality and of developing any cancer even compared to the general non-diabetic control population.
- Metformin is contra-indicated to populations with abnormal kidney function.
- The cancer risk with T2D is either not lowered or decreased significantly for patients taking metformin in some studies.
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
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
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
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
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
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
The Gut Flora
Guarner, Francisco, and Juan-R. Malagelada. "Gut flora in health and disease." The Lancet 361.9356 (2003): 512-519.
Bárcena, Clea, et al. "Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice." Nature medicine 25.8 (2019): 1234-1242.
Haifer, Craig, Sudarshan Paramsothy, and Rupert W. Leong. "Faecal microbiota transplantation as an elixir of youth." Hepatobiliary Surgery and Nutrition 9.4 (2020): 488.
Booth, Lauren N., and Anne Brunet. "The aging epigenome." Molecular cell 62.5 (2016): 728-744.
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.
Cosentino, Claudia, and Raul Mostoslavsky. "Metabolism, longevity and epigenetics." Cellular and Molecular Life Sciences 70.9 (2013): 1525-1541.
Hardy, Tabitha M., and Trygve O. Tollefsbol. "Epigenetic diet: impact on the epigenome and cancer." Epigenomics 3.4 (2011): 503-518.
- Live reprogramming
- Nerve regeneration
- No carcinogenicity
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
 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).
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
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
PGE2-EP2 binding inhibitors/ blockers
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
Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) promotes healthspan and lifespan
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
NAD+ and nervous system, cancer, liver function, kidney function, skeletal muscle, heart function
Campisi, J., Kapahi, P., Lithgow, G.J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019).
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).
Senolytic drugs to remove senescent cells.
Collado, Manuel, Maria A. Blasco, and Manuel Serrano. "Cellular senescence in cancer and aging." Cell 130.2 (2007): 223-233.
Xu, Ming, et al. "Senolytics improve physical function and increase lifespan in old age." Nature medicine 24.8 (2018): 1246-1256.
Integrated stress response inhibitor drug reverses age-related cognitive decline
An increase in the levels of LB1 or a decrease in those of SUN1 to decline aging in neural stem cells
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