Investigational drugs and nutrients for human longevity. Recent clinical trials registered in ClinicalTrials.gov and clinicaltrialsregister.eu

References

• Roser M, Ortiz-Ospina E, Ritchie H. Life expectancy. cited 2020 Jul 21]. 2019. Available from: https://ourworldindata.org/life-expectancy
   Google Scholar
• Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010;5(1):e8758.
   PubMed Web of Science ®Google Scholar
• Cabreiro F, Au C, Leung KY, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153(1):228–239. .
   PubMed Web of Science ®Google Scholar
• De Haes W, Frooninckx L, Van Assche R, et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci U S A. 2014;111(24):E2501–2509. .
   PubMed Web of Science ®Google Scholar
• Wu L, Zhou B, Oshiro-Rapley N, et al. An ancient, unified mechanism for metformin growth inhibition in C elegans and cancer. Cell. 2016;167(7):1705–1718 e1713. .
   PubMed Web of Science ®Google Scholar
• Chen J, Ou Y, Li Y, et al. Metformin extends C. elegans lifespan through lysosomal pathway. Elife. 2017;6. DOI:10.7554/eLife.31268.
   Web of Science ®Google Scholar
• Powers RW 3rd, Kaeberlein M, Caldwell SD, et al. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006;20(2):174–184. .
   PubMed Web of Science ®Google Scholar
• Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–395. .
   PubMed Web of Science ®Google Scholar
• Kaeberlein M, Kennedy BK. Ageing: a midlife longevity drug? Nature. 2009;460(7253):331–332.
   PubMed Web of Science ®Google Scholar
• Harrison DE, Strong R, Allison DB, et al. Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell. 2014;13(2):273–282. .
   PubMed Web of Science ®Google Scholar
• Warner HR, Ingram D, Miller RA, et al. Program for testing biological interventions to promote healthy aging. Mech Ageing Dev. 2000;115(3):199–207. .
   PubMedGoogle Scholar
• Miller RA, Harrison DE, Astle CM, et al. An aging interventions testing program: study design and interim report. Aging Cell. 2007;6(4):565–575. .
   PubMed Web of Science ®Google Scholar
• Nadon NL, Strong R, Miller RA, et al. NIA interventions testing program: investigating putative aging intervention agents in a genetically heterogeneous mouse model. EBioMedicine. 2017;21:3–4.
   PubMed Web of Science ®Google Scholar
• Bakula D, Ablasser A, Aguzzi A, et al. Latest advances in aging research and drug discovery. Aging (Albany NY). 2019;11(22):9971–9981. .
   PubMedGoogle Scholar
• Cannella C, Savina C, Donini LM. Nutrition, longevity and behavior. Arch Gerontol Geriatr. 2009;49(Suppl 1):19–27.
   PubMedGoogle Scholar
• Weindruch R, Walford RL, Fligiel S, et al. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986;116(4):641–654. .
   PubMed Web of Science ®Google Scholar
• McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition. 1989;5(3): 155–171. discussion 172.
   PubMed Web of Science ®Google Scholar
• Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003;78(3):361–369.
   PubMed Web of Science ®Google Scholar
• Passarino G, De Rango F, Montesanto A. Human longevity: genetics or lifestyle? It takes two to tango. Immun Ageing. 2016;13(1):12.
   PubMedGoogle Scholar
• Garay RP, Citrome L, Grossberg GT, et al. Investigational drugs for treating agitation in persons with dementia. Expert Opin Investig Drugs. 2016;25(8):973–983.
   PubMed Web of Science ®Google Scholar
• Garay RP, Zarate CA Jr., Charpeaud T, et al. Investigational drugs in recent clinical trials for treatment-resistant depression. Expert Rev Neurother. 2017;17(6):593–609. .
   PubMed Web of Science ®Google Scholar
• Neale RE, Armstrong BK, Baxter C, et al. The D-Health trial: a randomized trial of vitamin D for prevention of mortality and cancer. Contemp Clin Trials. 2016;48:83–90.
   PubMed Web of Science ®Google Scholar
• Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003;35(3):7S–14S.
   PubMed Web of Science ®Google Scholar
• FDA. Food and Drug Administration. Rapamune. [ cited 2020 Jul 14]. 2020. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
   Google Scholar
• Vellai T, Takacs-Vellai K, Zhang Y, et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426(6967):620. .
   PubMed Web of Science ®Google Scholar
• AgelessRx. AgelessRx launches first large-scale placebo-controlled clinical trial into the effects of rapamycin on longevity. [ cited Nover 30, 2020]. 2020. Available from: https://www.agelessrx.com/pearl
   Google Scholar
• Slack C, Foley A, Partridge L. Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila. PLoS One. 2012;7(10):e47699.
   PubMed Web of Science ®Google Scholar
• Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7(17):2769–2773. .
   PubMed Web of Science ®Google Scholar
• Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4(1):2192. .
   PubMedGoogle Scholar
• Strong R, Miller RA, Antebi A, et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an alpha-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016;15(5):872–884. .
   PubMed Web of Science ®Google Scholar
• Kulkarni AS, Brutsaert EF, Anghel V, et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell. 2018;17(2):e12723. .
   PubMed Web of Science ®Google Scholar
• Harrison DE, Strong R, Alavez S, et al. Acarbose improves health and lifespan in aging HET3 mice. Aging Cell. 2019;18(2):e12898. .
   PubMed Web of Science ®Google Scholar
• Smith BJ, Miller RA, Ericsson AC, et al. Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice. BMC Microbiol. 2019;19(1):130. .
   PubMed Web of Science ®Google Scholar
• FDA. Food and Drug Administration. Acarbose. [ cited 2020 Jul 21] 2019. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=077532
   Google Scholar
• DiNicolantonio JJ, Bhutani J, O’Keefe JH. Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes. Open Heart. 2015;2(1):e000327.
   PubMed Web of Science ®Google Scholar
• Holick MF, MacLaughlin JA, Clark MB, et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science. 1980;210(4466):203–205. .
   PubMed Web of Science ®Google Scholar
• Luxwolda MF, Kuipers RS, Kema IP, et al. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012;108(9):1557–1561. .
   PubMed Web of Science ®Google Scholar
• Cashman KD. Vitamin D deficiency: defining, prevalence, causes, and strategies of addressing. Calcif Tissue Int. 2020;106(1):14–29.
   PubMed Web of Science ®Google Scholar
• Grossman DC, Curry SJ, Owens DK, et al. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: us preventive services task force recommendation statement. JAMA. 2018;319(15):1592–1599. .
   PubMed Web of Science ®Google Scholar
• Ramagopalan SV, Heger A, Berlanga AJ, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010;20(10):1352–1360. .
   PubMed Web of Science ®Google Scholar
• Heath AK, Kim IY, Hodge AM, et al. Vitamin D status and mortality: a systematic review of observational studies. Int J Environ Res Public Health. 2019;16(3):383. .
   PubMed Web of Science ®Google Scholar
• Zhang Y, Fang F, Tang J, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673.
   PubMedGoogle Scholar
• D-Health. D-Health Trial Newsletter. Vol. 7, Issue 1, 2020. [cited 2020 Nov 12. 2020. Available from: https://dhealth.qimrberghofer.edu.au/icms_docs/D-HealthNewsletterVolume7_Issue1.pdf
   Google Scholar
• Rake C, Gilham C, Bukasa L, et al. High-dose oral vitamin D supplementation and mortality in people aged 65-84 years: the VIDAL cluster feasibility RCT of open versus double-blind individual randomisation. Health Technol Assess. 2020;24(10):1–54. .
   PubMed Web of Science ®Google Scholar
• Bischoff-Ferrari HA, Molino C, Rival S, et al. DO-HEALTH: vitamin D3 - Omega3 - Home exercise - Healthy aging and longevity trial - Design of a multinational clinical trial on healthy aging among European seniors. Contemp Clin Trials. 2020;100:106124.
   PubMedGoogle Scholar
• Zheng J, Huang T, Yu Y, et al. Fish consumption and CHD mortality: an updated meta-analysis of seventeen cohort studies. Public Health Nutr. 2012;15(4):725–737. .
   PubMed Web of Science ®Google Scholar
• Wang C, Harris WS, Chung M, et al. n-3 fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84(1):5–17. .
   PubMed Web of Science ®Google Scholar
• Hu Y, Hu FB, Manson JE. Marine omega-3 supplementation and cardiovascular disease: an updated Meta-Analysis of 13 randomized controlled trials involving 127 477 participants. J Am Heart Assoc. 2019;8(19):e013543.
   PubMed Web of Science ®Google Scholar
• Kazeminia M, Daneshkhah A, Jalali R, et al. The effect of exercise on the older adult’s blood pressure suffering hypertension: systematic review and Meta-Analysis on clinical trial studies. Int J Hypertens. 2020;2020:2786120.
   PubMed Web of Science ®Google Scholar
• Sofi F, Valecchi D, Bacci D, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med. 2011;269(1):107–117. .
   PubMed Web of Science ®Google Scholar
• Chase JD, Phillips LJ, Brown M. Physical activity intervention effects on physical function among community-dwelling older adults: a systematic review and Meta-Analysis. J Aging Phys Act. 2017;25(1):149–170.
   PubMed Web of Science ®Google Scholar
• Bischoff-Ferrari HA, Dawson-Hughes B, Platz A, et al. Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial. Arch Intern Med. 2010;170(9):813–820. .
   PubMedGoogle Scholar
• Papadopoli D, Boulay K, Kazak L, et al. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8Papadopoli D, Boulay K, Kazak L et al mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8. DOI: 10.12688/f1000research.17196.1
   PubMedGoogle Scholar
• Hunter GR, Gower BA, Kane BL. Age related shift in visceral fat. Int J Body Compos Res. 2010;8(3):103–108.
   PubMedGoogle Scholar
• Holman R. Metformin as first choice in oral diabetes treatment: the UKPDS experience. Journ Annu Diabetol Hotel Dieu. 2007; 13–20:18613325.
   PubMedGoogle Scholar
• Tacutu R, Craig T, Budovsky A, et al. Human ageing genomic resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res. 2013;41(D1):D1027–1033. .
   PubMed Web of Science ®Google Scholar
• Khalili N, Safavipour A. Evaluation of the effects of acarbose on weight and metabolic, inflammatory, and cardiovascular markers in patients with obesity and overweight. Int J Prev Med. 2020;11(1):140.
   PubMed Web of Science ®Google Scholar
• NHS. National Health Institute (UK). How to get vitamin D from sunlight. [ cited April 1, 2021] 2018.
   Google Scholar
• NIH. National Institute of Health. Office of dietary supplements. Vitamin D. [ cited 2021 Apr 8]. 2021. Available from: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
   Google Scholar
• van der Velde RY, Brouwers JR, Geusens PP, et al. Calcium and vitamin D supplementation: state of the art for daily practice. Food Nutr Res. 2014;58(1):21796. .
   PubMedGoogle Scholar
• van den Bergh JP, van Geel TA, Geusens PP. Osteoporosis, frailty and fracture: implications for case finding and therapy. Nat Rev Rheumatol. 2012;8(3):163–172.
   PubMed Web of Science ®Google Scholar
• Bours SP, van Geel TA, Geusens PP, et al. Contributors to secondary osteoporosis and metabolic bone diseases in patients presenting with a clinical fracture. J Clin Endocrinol Metab. 2011;96(5):1360–1367. .
   PubMed Web of Science ®Google Scholar
• Liu J, Wang L, Wang Z, et al. Roles of telomere biology in cell senescence, replicative and chronological ageing. Cells. 2019;8(1):54. .
   Web of Science ®Google Scholar
• Zhu H, Guo D, Li K, et al. Increased telomerase activity and vitamin D supplementation in overweight African Americans. Int J Obes (Lond). 2012;36(6):805–809. .
   PubMed Web of Science ®Google Scholar
• Perez-Lopez FR, Fernandez-Alonso AM, Mannella P, et al. Vitamin D, sunlight and longevity. Minerva Endocrinol. 2011;36(3):257–266.
   PubMed Web of Science ®Google Scholar
• Autier P, Gandini S. Vitamin D supplementation and total mortality A Meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167(16):1730–1737.
   PubMedGoogle Scholar
• Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380(9859):2197–2223. .
   PubMed Web of Science ®Google Scholar
• GBD 2017 DALYs Hale Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2018;392:1859–1922.
   PubMed Web of Science ®Google Scholar
• Barzilai N, Crandall JP, Kritchevsky SB, et al. Metformin as a tool to target aging. Cell Metab. 2016;23(6):1060–1065. .
   PubMed Web of Science ®Google Scholar
• Glossmann HH, Lutz OMD. Metformin and aging: a review. Gerontology. 2019;65(6):581–590.
   PubMed Web of Science ®Google Scholar
• Strong R, Miller RA, Astle CM, et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell. 2008;7(5):641–650. .
   PubMed Web of Science ®Google Scholar
• Miller RA, Harrison DE, Astle CM, et al. Glycine supplementation extends lifespan of male and female mice. Aging Cell. 2019;18(3):e12953. .
   PubMed Web of Science ®Google Scholar
• McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379(16):1499–1508. .
   PubMed Web of Science ®Google Scholar
• Sekhar RV, Patel SG, Guthikonda AP, et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. 2011;94(3):847–853. .
   PubMed Web of Science ®Google Scholar
• Kumar P, Liu C, Hsu JW, et al. Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: results of a pilot clinical trial. Clin Transl Med. 2021;11(3):e372. .
   PubMed Web of Science ®Google Scholar
• Langley RE, Gilbert DC, Duong T, et al. Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. Lancet. 2021;397(10274):581–591. .
   PubMed Web of Science ®Google Scholar
• Ueberschlag SL, Seay JR, Roberts AH, et al. The effect of Protandim(R) supplementation on athletic performance and oxidative blood markers in runners. PLoS One. 2016;11(8):e0160559. .
   PubMed Web of Science ®Google Scholar
• Ueberschlag SL, Seay JR, Roberts AH, et al. Correction: the effect of Protandim(R) supplementation on athletic performance and oxidative blood markers in runners. PLoS One. 2020;15(10):e0241520. .
   PubMed Web of Science ®Google Scholar
• FDA. Food and Drug Administration. Protandim. [ cited 2021 May 31. 2017. Available from: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/lifevantage-corp-510546-04172017
   Google Scholar
• Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232–236. .
   PubMed Web of Science ®Google Scholar
• Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184–189. .
   PubMed Web of Science ®Google Scholar
• Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016;7(1):11190.
   PubMedGoogle Scholar
• Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518–536.
   PubMed 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
• Prieto-Oliveira P. Telomerase activation in the treatment of aging or degenerative diseases: a systematic review. Mol Cell Biochem. 2021;476(2):599–607.
   PubMed Web of Science ®Google Scholar
• NIH. National Institute of Health (USA). Evaluation of safety and tolerability of libella gene therapy for the treatment of aging: AAV- hTERT. ClinicalTrial.gov [ cited 2021 Apr 1] 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04133649?term=telomere&type=Intr&cond=aging&lupd_s=01%2F01%2F2017&lupd_e=04%2F01%2F2021&draw=2&rank=3
   Google Scholar
• Tompkins BA, DiFede DL, Khan A, et al. Allogeneic mesenchymal stem cells ameliorate aging frailty: a phase ii randomized, double-blind, Placebo-Controlled clinical trial. J Gerontol A Biol Sci Med Sci. 2017;72(11):1513–1522. .
   PubMed Web of Science ®Google Scholar
• Arriola Apelo SI, Neuman JC, Baar EL, et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell. 2016;15(1):28–38. .
   PubMed Web of Science ®Google Scholar
• Schumacher A. Anticorrelation & DNA methylation as biomarker for aging. Western University Lectures. [accessed 2021 Apr 9]. 2009. Available from: DOI: 10.13140/RG.2.2.12457.83042
   Google Scholar
• Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115.
   PubMed Web of Science ®Google Scholar
• Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019;11(2):303–327. .
   PubMedGoogle Scholar
• McCrory C, Fiorito G, Hernandez B, et al. GrimAge outperforms other epigenetic clocks in the prediction of age-related clinical phenotypes and all-cause mortality. J Gerontol A Biol Sci Med Sci. 2020;75(3):495–503. .
   PubMedGoogle Scholar
• Yaskolka Meir A, Keller M, Bernhart SH, et al. Lifestyle weight-loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial. Clin Epigenetics. 2021;13(1):48. .
   PubMed Web of Science ®Google Scholar
• Ferrucci L, Gonzalez-Freire M, Fabbri E, et al. Measuring biological aging in humans: a quest. Aging Cell. 2020;19(2):e13080. .
   PubMed Web of Science ®Google Scholar
• Fahy GM, Brooke RT, Watson JP, et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell. 2019;18(6):e13028. .
   PubMed Web of Science ®Google Scholar
• Kaeberlein M, Creevy KE, Promislow DE. The dog aging project: translational geroscience in companion animals. Mamm Genome. 2016;27(7–8):279–288.
   PubMed Web of Science ®Google Scholar
• 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):291–298.
   PubMed Web of Science ®Google Scholar
• Savage N. Growing up. Nature. 2017;552(7684):S57–S58.
   PubMed Web of Science ®Google Scholar
• 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):117–127. .
   PubMed Web of Science ®Google Scholar