An Updated Prioritization of Geroscience- Guided FDA-Approved Drugs Repurposed to Target Aging

Main Article Content

Michael Leone Nir Barzilai

Abstract

The biological mechanisms of aging drive the development of chronic diseases such as cardiovascular disease, diabetes, dementia, and cancer that dominate our current medical system. Geroscience-guided approaches seek to mitigate these pathological consequences of aging by targeting the fundamental hallmarks of aging. Using modalities that modulate these aging mechanisms to reinforce longevity we can prevent the onset of these diseases as well as target many of them at once. In this way, geroscience-guided approaches hope to extend both lifespan and healthspan in the near future. This article builds upon a previous paper which proposed a standardized process for evaluating FDA-approved medications for their geroscience potential and prioritized them to reflect preclinical and clinical evidence. In this article, we provide an update of the previous list of candidate gerotherapeutics to reflect the new and rapidly evolving evidence. We include the geroscience-guided evidence for three new FDA-approved drugs which did not have strong arguments for inclusion before: bisphosphonates, GLP-1 receptor agonists, beta blockers. This updated prioritization should help guide the efforts and financial investments for translating geroscience and allow immediate progress involving such candidate gerotherapeutics, especially the top 4 drugs: SGLT2 inhibitors, metformin, bisphosphonates, and GLP-1 receptor agonists. Since all of these drugs have been approved for safety and used extensively, repurposing them as gerotherapeutics should be considered in older adults.

Article Details

How to Cite
LEONE, Michael; BARZILAI, Nir. An Updated Prioritization of Geroscience- Guided FDA-Approved Drugs Repurposed to Target Aging. Medical Research Archives, [S.l.], v. 12, n. 2, feb. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5138>. Date accessed: 10 oct. 2024. doi: https://doi.org/10.18103/mra.v12i2.5138.
Section
Research Articles

References

1. Institute of Medicine Committee on Care at the End of L. In: Field MJ, Cassel CK, eds. Approaching Death: Improving Care at the End of Life. National Academies Press (US)
2. Copyright 1997 by the National Academy of Sciences. All rights reserved.; 1997.
3. Centers for Disease Control and Prevention. Leading Causes of Death. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
4. Kulkarni AS, Aleksic S, Berger DM, Sierra F, Kuchel GA, Barzilai N. Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization. Aging Cell. Apr 2022;21(4):e13596. doi:10.1111/acel.13596
5. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. Jun 14 2016;23(6):1060-1065. doi:10.1016/j.cmet.2016.05.011
6. Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E. Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2018;65(4):1225-1236. doi:10.3233/jad-180263
7. Novelle MG, Ali A, Diéguez C, Bernier M, de Cabo R. Metformin: A Hopeful Promise in Aging Research. Cold Spring Harb Perspect Med. Mar 1 2016;6(3):a025932. doi:10.1101/cshperspect.a025932 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. Sep 12 1998;352(9131):854-65.
8. Justice JN, Gubbi S, Kulkarni AS, Bartley JM, Kuchel GA, Barzilai N. A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin. Geroscience. Jun 2021;43(3):1093-1112. doi:10.1007/s11357-020-00261-6
9. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. Jun 6 2013;153(6):1194-217. doi:10.1016/j.cell.2013.05.039
10. Chen Z, Cordero J, Alqarni AM, Slack C, Zeidler MP, Bellantuono I. Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner. J Gerontol A Biol Sci Med Sci. Aug 12 2022;77(8):1494-1502. doi:10.1093/gerona/glab172
11. Polidoro S, Broccoletti R, Campanella G, et al. Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw. Mutat Res. Oct 9 2013;757(2):104-13. doi:10.1016/j.mrgentox.2013.07.003
12. Omoigui S. The Interleukin-6 inflammation pathway from cholesterol to aging--role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases. Immun Ageing. Mar 20 2007;4:1. doi:10.1186/1742-4933-4-1
13. Fernández-Martín S, López-Peña M, Muñoz F, Permuy M, González-Cantalapiedra A. Bisphosphonates as disease-modifying drugs in osteoarthritis preclinical studies: a systematic review from 2000 to 2020. Arthritis Res Ther. Feb 22 2021;23(1):60. doi:10.1186/s13075-021-02446-6
14. Misra J, Mohanty ST, Madan S, et al. Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function. Stem Cells. Mar 2016;34(3):756-67. doi:10.1002/stem.2255
15. Iannuzzo G, De Filippo G, Merlotti D, et al. Effects of Bisphosphonate Treatment on Circulating Lipid and Glucose Levels in Patients with Metabolic Bone Disorders. Calcif Tissue Int. Jun 2021;108(6):757-763. doi:10.1007/s00223-021-00811-w
16. Munoz MA, Fletcher EK, Skinner OP, et al. Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages. Elife. Dec 30 2021;10doi:10.7554/eLife.72430
17. Varela I, Pereira S, Ugalde AP, et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med. Jul 2008;14(7):767-72. doi:10.1038/nm1786
18. Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. Apr 2016;15(2):196-207. doi:10.1111/acel.12427
19. Papadopoli D, Boulay K, Kazak L, et al. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8doi:10.12688/f1000research.17196.1
20. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. Nov 1 2007;357(18):1799-809. doi:10.1056/NEJMoa074941
21. Bolland MJ, Grey AB, Gamble GD, Reid IR. Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab. Mar 2010;95(3):1174-81. doi:10.1210/jc.2009-0852
22. Cummings SR, Lui LY, Eastell R, Allen IE. Association Between Drug Treatments for Patients With Osteoporosis and Overall Mortality Rates: A Meta-analysis. JAMA Intern Med. Nov 1 2019;179(11):1491-1500. doi:10.1001/jamainternmed.2019.2779
23. Bondo L, Eiken P, Abrahamsen B. Analysis of the association between bisphosphonate treatment survival in Danish hip fracture patients-a nationwide register-based open cohort study. Osteoporos Int. Jan 2013;24(1):245-52. doi:10.1007/s00198-012-2024-8
24. Brozek W, Reichardt B, Zwerina J, Dimai HP, Klaushofer K, Zwettler E. Antiresorptive therapy and risk of mortality and refracture in osteoporosis-related hip fracture: a nationwide study. Osteoporos Int. Jan 2016;27(1):387-96. doi:10.1007/s00198-015-3415-4
25. Chen YC, Su FM, Cheng TT, Lin WC, Lui CC. Can antiosteoporotic therapy reduce mortality in MRI-proved acute osteoporotic vertebral fractures? J Bone Miner Metab. May 2016;34(3):325-30. doi:10.1007/s00774-015-0672-4
26. Lee P, Ng C, Slattery A, Nair P, Eisman JA, Center JR. Preadmission Bisphosphonate and Mortality in Critically Ill Patients. J Clin Endocrinol Metab. May 2016;101(5):1945-53. doi:10.1210/jc.2015-3467
27. Bliuc D, Tran T, van Geel T, et al. Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study. Osteoporos Int. Apr 2019;30(4):817-828. doi:10.1007/s00198-018-4806-0
28. Sing CW, Wong AY, Kiel DP, et al. Association of Alendronate and Risk of Cardiovascular Events in Patients With Hip Fracture. J Bone Miner Res. Aug 2018;33(8):1422-1434. doi:10.1002/jbmr.3448
29. Kang JH, Keller JJ, Lin HC. Bisphosphonates reduced the risk of acute myocardial infarction: a 2-year follow-up study. Osteoporos Int. Jan 2013;24(1):271-7. doi:10.1007/s00198-012-2213-5
30. Wolfe F, Bolster MB, O'Connor CM, Michaud K, Lyles KW, Colón-Emeric CS. Bisphosphonate use is associated with reduced risk of myocardial infarction in patients with rheumatoid arthritis. J Bone Miner Res. May 2013;28(5):984-91. doi:10.1002/jbmr.1792
31. Reid IR, Horne AM, Mihov B, et al. Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women. J Bone Miner Res. Jan 2020;35(1):20-27. doi:10.1002/jbmr.3860
32. Sing CW, Kiel DP, Hubbard RB, et al. Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture. J Bone Miner Res. Sep 2020;35(9):1676-1684. doi:10.1002/jbmr.4030
33. Li YY, Gao LJ, Zhang YX, et al. Bisphosphonates and risk of cancers: a systematic review and meta-analysis. Br J Cancer. Nov 2020;123(10):1570-1581. doi:10.1038/s41416-020-01043-9
34. Nian S, Mi Y, Ren K, Wang S, Li M, Yang D. The inhibitory effects of Dulaglutide on cellular senescence against high glucose in human retinal endothelial cells. Hum Cell. Jul 2022;35(4):995-1004. doi:10.1007/s13577-022-00703-7
35. Zhou H, Li D, Shi C, et al. Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro. Sci Rep. Aug 7 2015;5:12898. doi:10.1038/srep12898
36. Zummo FP, Cullen KS, Honkanen-Scott M, Shaw JAM, Lovat PE, Arden C. Glucagon-Like Peptide 1 Protects Pancreatic β-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function. Diabetes. May 2017;66(5):1272-1285. doi:10.2337/db16-1009
37. Morales PE, Torres G, Sotomayor-Flores C, et al. GLP-1 promotes mitochondrial metabolism in vascular smooth muscle cells by enhancing endoplasmic reticulum-mitochondria coupling. Biochem Biophys Res Commun. Mar 28 2014;446(1):410-6. doi:10.1016/j.bbrc.2014.03.004
38. Seppa K, Toots M, Reimets R, et al. GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome. Sci Rep. Oct 31 2019;9(1):15742. doi:10.1038/s41598-019-52295-2
39. Batista AF, Bodart-Santos V, De Felice FG, Ferreira ST. Neuroprotective Actions of Glucagon-Like Peptide-1 (GLP-1) Analogues in Alzheimer's and Parkinson's Diseases. CNS Drugs. Mar 2019;33(3):209-223. doi:10.1007/s40263-018-0593-6
40. Noyan-Ashraf MH, Momen MA, Ban K, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. Apr 2009;58(4):975-83. doi:10.2337/db08-1193
41. Helmstädter J, Frenis K, Filippou K, et al. Endothelial GLP-1 (Glucagon-Like Peptide-1) Receptor Mediates Cardiovascular Protection by Liraglutide In Mice With Experimental Arterial Hypertension. Arterioscler Thromb Vasc Biol. Jan 2020;40(1):145-158. doi:10.1161/atv.0000615456.97862.30
42. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. Oct 2019;7(10):776-785. doi:10.1016/s2213-8587(19)30249-9
43. Avgerinos I, Michailidis T, Liakos A, et al. Oral semaglutide for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. Mar 2020;22(3):335-345. doi:10.1111/dom.13899
44. Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. Jama. Apr 17 2018;319(15):1580-1591. doi:10.1001/jama.2018.3024
45. Herrera Comoglio R, Vidal Guitart X. Cardiovascular outcomes, heart failure and mortality in type 2 diabetic patients treated with glucagon-like peptide 1 receptor agonists (GLP-1 RAs): A systematic review and meta-analysis of observational cohort studies. Int J Clin Pract. Sep 2020;74(9):e13553. doi:10.1111/ijcp.13553
46. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. Nov 11 2023;doi:10.1056/NEJMoa2307563
47. Tang H, Shao H, Shaaban CE, et al. Newer glucose-lowering drugs and risk of dementia: A systematic review and meta-analysis of observational studies. J Am Geriatr Soc. Jul 2023;71(7):2096-2106. doi:10.1111/jgs.18306
48. Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. Bmj. Jan 13 2021;372:m4573. doi:10.1136/bmj.m4573
49. Cukierman-Yaffe T, Gerstein HC, Colhoun HM, et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. Jul 2020;19(7):582-590. doi:10.1016/s1474-4422(20)30173-3
50. Wang L, Wang W, Kaelber DC, Xu R, Berger NA. GLP-1 Receptor Agonists and Colorectal Cancer Risk in Drug-Naive Patients With Type 2 Diabetes, With and Without Overweight/Obesity. JAMA Oncol. Dec 7 2023;doi:10.1001/jamaoncol.2023.5573
51. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. Sep 21 2023;389(12):1069-1084. doi:10.1056/NEJMoa2306963
52. Xu C, Hu Y, Hou L, et al. β-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression. J Mol Cell Cardiol. Oct 2014;75:111-21. doi:10.1016/j.yjmcc.2014.07.009
53. Ushijima K, Maekawa T, Ishikawa-Kobayashi E, Ando H, Shiga T, Fujimura A. Influence of beta-blockers on the myocardial mRNA expressions of circadian clock- and metabolism-related genes. J Am Soc Hypertens. Mar-Apr 2013;7(2):107-17. doi:10.1016/j.jash.2012.12.007
54. Spindler SR, Mote PL, Li R, et al. β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice. Age (Dordr). Dec 2013;35(6):2099-109. doi:10.1007/s11357-012-9498-3
55. Bonnet N, Benhamou CL, Malaval L, et al. Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions. J Cell Physiol. Dec 2008;217(3):819-27. doi:10.1002/jcp.21564
56. Heidenreich PA, Lee TT, Massie BM. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. Jul 1997;30(1):27-34. doi:10.1016/s0735-1097(97)00104-6
57. Cleophas TJ, Zwinderman AH. Beta-blockers and heart failure: meta-analysis of mortality trials. Int J Clin Pharmacol Ther. Sep 2001;39(9):383-8. doi:10.5414/cpp39383
58. Mihai Gheorghiade WSC, Karl Swedberg. B-blockers in chronic heart failure. American Heart Association.
59. Etminan M, Jafari S, Carleton B, FitzGerald JM. Beta-blocker use and COPD mortality: a systematic review and meta-analysis. BMC Pulm Med. Sep 4 2012;12:48. doi:10.1186/1471-2466-12-48
60. Jin J, Guo X, Yu Q. Effects of Beta-Blockers on Cardiovascular Events and Mortality in Dialysis Patients: A Systematic Review and Meta-Analysis. Blood Purif. 2019;48(1):51-59. doi:10.1159/000496083
61. Shu de F, Dong BR, Lin XF, Wu TX, Liu GJ. Long-term beta blockers for stable angina: systematic review and meta-analysis. Eur J Prev Cardiol. Jun 2012;19(3):330-41. doi:10.1177/1741826711409325
62. Tsujimoto T, Kajio H, Shapiro MF, Sugiyama T. Risk of All-Cause Mortality in Diabetic Patients Taking β-Blockers. Mayo Clin Proc. Apr 2018;93(4):409-418. doi:10.1016/j.mayocp.2017.11.019
63. DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O'Keefe JH. Meta-analysis of carvedilol versus beta 1 selective beta-blockers (atenolol, bisoprolol, metoprolol, and nebivolol). Am J Cardiol. Mar 1 2013;111(5):765-9. doi:10.1016/j.amjcard.2012.11.031
64. Ding J, Davis-Plourde KL, Sedaghat S, et al. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies. Lancet Neurol. Jan 2020;19(1):61-70. doi:10.1016/s1474-4422(19)30393-x
65. Monami M, Filippi L, Ungar A, et al. Further data on beta-blockers and cancer risk: observational study and meta-analysis of randomized clinical trials. Curr Med Res Opin. Apr 2013;29(4):369-78. doi:10.1185/03007995.2013.772505
66. Popiolek-Kalisz J, Fornal E. The Effects of Quercetin Supplementation on Blood Pressure - Meta-Analysis. Curr Probl Cardiol. Nov 2022;47(11):101350. doi:10.1016/j.cpcardiol.2022.101350
67. Nakamura Y, Watanabe H, Tanaka A, Nishihira J, Murayama N. Effect of quercetin glycosides on cognitive functions and cerebral blood flow: a randomized, double-blind, and placebo-controlled study. Eur Rev Med Pharmacol Sci. Dec 2022;26(23):8700-8712. doi:10.26355/eurrev_202212_30541
68. Ma S, Guo C, Sun C, et al. Aspirin Use and Risk of Breast Cancer: A Meta-analysis of Observational Studies from 1989 to 2019. Clin Breast Cancer. Dec 2021;21(6):552-565. doi:10.1016/j.clbc.2021.02.005
69. Hurwitz LM, Townsend MK, Jordan SJ, et al. Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia. J Clin Oncol. Dec 20 2022;40(36):4207-4217. doi:10.1200/jco.21.01900
70. Seo SI, Park CH, Kim TJ, et al. Aspirin, metformin, and statin use on the risk of gastric cancer: A nationwide population-based cohort study in Korea with systematic review and meta-analysis. Cancer Med. Feb 2022;11(4):1217-1231. doi:10.1002/cam4.4514
71. Ryan J, Storey E, Murray AM, et al. Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline. Neurology. Jul 21 2020;95(3):e320-e331. doi:10.1212/wnl.0000000000009277
72. Parish S, Mafham M, Offer A, et al. Effects of aspirin on dementia and cognitive function in diabetic patients: the ASCEND trial. Eur Heart J. Jun 1 2022;43(21):2010-2019. doi:10.1093/eurheartj/ehac179
73. Kumar P, Osahon OW, Sekhar RV. GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage. Nutrients. Mar 7 2022;14(5)doi:10.3390/nu14051114
74. Maartens M, Kruger MJ, van de Vyver M. The Effect of N-Acetylcysteine and Ascorbic Acid-2-Phosphate Supplementation on Mesenchymal Stem Cell Function in B6.C-Lep(ob)/J Type 2 Diabetic Mice. Stem Cells Dev. Dec 1 2021;30(23):1179-1189. doi:10.1089/scd.2021.0139
75. Kawaguchi K, Hashimoto M, Sugimoto M. An antioxidant suppressed lung cellular senescence and enhanced pulmonary function in aged mice. Biochem Biophys Res Commun. Feb 19 2021;541:43-49. doi:10.1016/j.bbrc.2020.12.112
76. Nassar M, Abosheaishaa H, Singh AK, Misra A, Bloomgarden Z. Noninsulin-based antihyperglycemic medications in patients with diabetes and COVID-19: A systematic review and meta-analysis. J Diabetes. Feb 2023;15(2):86-96. doi:10.1111/1753-0407.13359
77. Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. Aug 18 2022;387(7):599-610. doi:10.1056/NEJMoa2201662
78. Li J, Wei Q, McCowen KC, et al. Inpatient use of metformin and acarbose is associated with reduced mortality of COVID-19 patients with type 2 diabetes mellitus. Endocrinol Diabetes Metab. Jan 2022;5(1):e00301. doi:10.1002/edm2.301
79. Alam MS, Hasan MN, Maowa Z, Khatun F, Nazir K, Alam MZ. N-acetylcysteine reduces severity and mortality in COVID-19 patients: A systematic review and meta-analysis. J Adv Vet Anim Res. Jun 2023;10(2):157-168. doi:10.5455/javar.2023.j665
80. Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Diabetes Endocrinol. Dec 2023;11(12):905-914. doi:10.1016/s2213-8587(23)00253-x
81. Permana H, Audi Yanto T, Ivan Hariyanto T. Pre-admission use of sodium glucose transporter-2 inhibitor (SGLT-2i) may significantly improves Covid-19 outcomes in patients with diabetes: A systematic review, meta-analysis, and meta-regression. Diabetes Res Clin Pract. Jan 2023;195:110205. doi:10.1016/j.diabres.2022.110205
82. Hamidi-Alamdari D, Hafizi-Lotfabadi S, Bagheri-Moghaddam A, et al. METHYLENE BLUE FOR TREATMENT OF HOSPITALIZED COVID-19 PATIENTS: A RANDOMIZED, CONTROLLED, OPEN-LABEL CLINICAL TRIAL, PHASE 2. Rev Invest Clin. 2021;73(3):190-198. doi:10.24875/ric.21000028
83. Dambha-Miller H, Hinton W, Wilcox CR, et al. Mortality from angiotensin-converting enzyme-inhibitors and angiotensin receptor blockers in people infected with COVID-19: a cohort study of 3.7 million people. Fam Pract. Mar 28 2023;40(2):330-337. doi:10.1093/fampra/cmac094
84. Khalaji A, Behnoush AH, Peiman S. Aspirin and P2Y12 inhibitors in treating COVID-19. Eur J Intern Med. Apr 2023;110:101-103. doi:10.1016/j.ejim.2022.11.027
85. Sierra F, Caspi A, Fortinsky RH, et al. Moving geroscience from the bench to clinical care and health policy. J Am Geriatr Soc. Sep 2021;69(9):2455-2463. doi:10.1111/jgs.17301
86. Rodrigues LP, Teixeira VR, Alencar-Silva T, et al. Hallmarks of aging and immunosenescence: Connecting the dots. Cytokine Growth Factor Rev. Jun 2021;59:9-21. doi:10.1016/j.cytogfr.2021.01.006
87. Phillips EJ, Simons MJP. Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis. Geroscience. Apr 2023;45(2):1263-1270. doi:10.1007/s11357-022-00691-4
88. Bowman L, Mafham M, Wallendszus K, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med. Oct 18 2018;379(16):1529-1539. doi:10.1056/NEJMoa1804988
89. Mannick JB, Del Giudice G, Lattanzi M, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. Dec 24 2014;6(268):268ra179. doi:10.1126/scitranslmed.3009892
90. Konopka AR, Laurin JL, Schoenberg HM, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. Feb 2019;18(1):e12880. doi:10.1111/acel.12880
91. Kulkarni AS, Peck BD, Walton RG, et al. Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults. Aging (Albany NY). Oct 18 2020;12(20):19852-19866. doi:10.18632/aging.104096
92. Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nat Aging. Jun 2023;3(6):642-660. doi:10.1038/s43587-023-00416-y
93. Olshansky SJ. Articulating the Case for the Longevity Dividend. Cold Spring Harb Perspect Med. Jan 8 2016;6(2):a025940. doi:10.1101/cshperspect.a025940
94. Scott AJ, Ellison M, Sinclair DA. The economic value of targeting aging. Nat Aging. Jul 2021;1(7):616-623. doi:10.1038/s43587-021-00080-0