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The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery

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Abstract

Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the “million-molecule challenge”, an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested.

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References

  1. Admasu TD, Chaithanya Batchu K, Barardo D, Ng LF, Lam VYM, et al. Drug synergy slows aging and improves healthspan through IGF and SREBP lipid signaling. Dev Cell. 2018;47:67-79.e65.

    Article  CAS  PubMed  Google Scholar 

  2. Ahmad W, Ebert PR. Metformin attenuates Aβ Pathology mediated through levamisole sensitive nicotinic acetylcholine receptors in a C. elegans model of Alzheimer’s Disease. Mol Neurobiol. 2017;54:5427–39.

    Article  CAS  PubMed  Google Scholar 

  3. Alique M, Sánchez-López E, Bodega G, Giannarelli C, Carracedo J, et al. Hypoxia-Inducible Factor-1α: the master regulator of endothelial cell senescence in vascular aging. Cells. 2020;9(1):195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Almotayri A, Thomas J, Munasinghe M, Jois M. The Effect of mianserin on Lifespan of Caenorhabditis elegan is Abolished by Glucose. Curr Aging Sci. 2021;14:118–23.

    Article  CAS  PubMed  Google Scholar 

  5. Alsaqati M, Thomas RS, Kidd EJ. Proteins involved in endocytosis are upregulated by ageing in the normal human brain: implications for the development of Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci. 2018;73:289–98.

    Article  CAS  PubMed  Google Scholar 

  6. Alvarez J, Alvarez-Illera P, García-Casas P, Fonteriz RI, Montero M. The role of Ca(2+) signaling in aging and neurodegeneration: insights from Caenorhabditis elegans models. Cells. 2020;9(1):204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, et al. Autophagy in healthy aging and disease. Nature Aging. 2021;1:634–50.

    Article  PubMed  PubMed Central  Google Scholar 

  8. An JY, Kerns KA, Ouellette A, Robinson L, Morris HD, et al. Rapamycin rejuvenates oral health in aging mice. Elife. 2020;9:e54318.

  9. Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab. 2020;32:447-456.e446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Athar F, Templeman NM. C. elegans as a model organism to study female reproductive health. Comp Biochem Physiol A Mol Integr Physiol. 2022;266:111152.

    Article  CAS  PubMed  Google Scholar 

  11. Barardo D, Thornton D, Thoppil H, Walsh M, Sharifi S, et al. The DrugAge database of aging-related drugs. Aging Cell. 2017;16:594–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bene M, Salmon AB. Testing the evidence that lifespan-extending compound interventions are conserved across laboratory animal model species. Geroscience. 2023. https://doi.org/10.1007/s11357-022-00722-0.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Berry BJ, Vodičková A, Müller-Eigner A, Meng C, Ludwig C, et al. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan. Nature Aging. 2023;3:157–61.

    Article  PubMed  Google Scholar 

  14. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11:35–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Blagosklonny MV. Cancer prevention with rapamycin. Oncotarget. 2023;14:342–50.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Burtner CR, Murakami CJ, Olsen B, Kennedy BK, Kaeberlein M. A genomic analysis of chronological longevity factors in budding yeast. Cell Cycle. 2011;10:1385–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Caldwell KA, Willicott CW, Caldwell GA. Modeling neurodegeneration in Caenorhabditiselegans. Dis Model Mech. 2020;13:dmm046110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Carretero M, Gomez-Amaro RL, Petrascheck M. Pharmacological classes that extend lifespan of Caenorhabditis elegans. Frontiers in Genetics. 2015;6:77.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Castillo-Quan JI, Tain LS, Kinghorn KJ, Li L, Grönke S, et al. A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. Proc Natl Acad Sci. 2019;116:20817–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022;28:1556–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chang GR, Chiu YS, Wu YY, Chen WY, Liao JW, et al. Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J Pharmacol Sci. 2009;109:496–503.

    Article  CAS  PubMed  Google Scholar 

  22. Chen C-H, Patel R, Bortolami A, Sesti F. A novel assay for drug screening that utilizes the heat shock response of Caenorhabditis elegans nematodes. PLoS One. 2020;15: e0240255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Christian CJ, Benian GM. Animal models of sarcopenia. Aging Cell. 2020;19: e13223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Churgin MA, Jung SK, Yu CC, Chen X, Raizen DM, et al. Longitudinal imaging of Caenorhabditis elegans in a microfabricated device reveals variation in behavioral decline during aging. Elife. 2017;6:e26652.

  25. D’Amico D, Andreux PA, Valdés P, Singh A, Rinsch C, et al. Impact of the Natural Compound Urolithin A on health, disease, and aging. Trends Mol Med. 2021;27:687–99.

    Article  PubMed  Google Scholar 

  26. Dall KB, Færgeman NJ. Metabolic regulation of lifespan from a C. elegans perspective. Genes Nutr. 2019;14:25.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Dancy BM, Sedensky MM, Morgan PG. Effects of the mitochondrial respiratory chain on longevity in C. elegans. Exp Gerontol. 2014;56:245–55.

    Article  CAS  PubMed  Google Scholar 

  28. de Magalhães JP. Longevity pharmacology comes of age. Drug Discov Today. 2021;26:1559–62.

    Article  PubMed  Google Scholar 

  29. Debès C, Papadakis A, Grönke S, Karalay Ö, Tain LS, et al. Ageing-associated changes in transcriptional elongation influence longevity. Nature. 2023;616:814–21.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, et al. Rates of behavior and aging specified by mitochondrial function during development. Science. 2002;298:2398–401.

    Article  CAS  PubMed  Google Scholar 

  31. Dimov I, Maduro MF. The C. elegans intestine: organogenesis, digestion, and physiology. Cell Tissue Res. 2019;377:383–96.

    Article  PubMed  Google Scholar 

  32. Epstein HF, Benian GM. Paradigm shifts in cardiovascular research from Caenorhabditis elegans muscle. Trends Cardiovasc Med. 2012;22:201–9.

    Article  PubMed  Google Scholar 

  33. Evason K, Collins JJ, Huang C, Hughes S, Kornfeld K. Valproic acid extends Caenorhabditis elegans lifespan. Aging Cell. 2008;7:305–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Flynn JM, O’Leary MN, Zambataro CA, Academia EC, Presley MP, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013;12:851–62.

    Article  CAS  PubMed  Google Scholar 

  35. Friedman DB, Johnson TE. A mutation in the AGE-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics. 1988;118:75–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ganner A, Neumann-Haefelin E. Genetic kidney diseases: Caenorhabditis elegans as model system. Cell Tissue Res. 2017;369:105–18.

    Article  CAS  PubMed  Google Scholar 

  37. Geiger RS, Cope D, Ip J, Lotosh M, Shah A, et al. “Garbage in, garbage out” revisited: What do machine learning application papers report about human-labeled training data? Quant Sci Stud. 2021;2:795–827.

    Article  Google Scholar 

  38. Gieseler K, Qadota H, Benian GM. Development, structure, and maintenance of C. elegans body wall muscle. WormBook: The Online Review of C. elegans Biology. 2018.

  39. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature. 2011;479:365–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gureev AP, Shaforostova EA, Popov VN. Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Front Genet. 2019;10:435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Haçariz O, Viau C, Karimian F, Xia J. The symbiotic relationship between Caenorhabditis elegans and members of its microbiome contributes to worm fitness and lifespan extension. BMC Genomics. 2021;22:364.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hamilton B, Dong Y, Shindo M, Liu W, Odell I, et al. A systematic RNAi screen for longevity genes in C. elegans. Genes Dev. 2005;19:1544–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hansen M, Hsu AL, Dillin A, Kenyon C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet. 2005;1:119–28.

    Article  CAS  PubMed  Google Scholar 

  44. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hodge F, Bajuszova V, van Oosten-Hawle P. The Intestine as a lifespan- and proteostasis-promoting signaling tissue. Front Aging. 2022;3: 897741.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hofer SJ, Simon AK, Bergmann M, Eisenberg T, Kroemer G, et al. Mechanisms of spermidine-induced autophagy and geroprotection. Nature Aging. 2022;2:1112–29.

    Article  PubMed  Google Scholar 

  47. Hyun M, Lee J, Lee K, May A, Bohr VA, et al. Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans. Nucleic Acids Res. 2008;36:1380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development. 2004;131:3897–906.

    Article  CAS  PubMed  Google Scholar 

  49. Jin K, Wilson KA, Beck JN, Nelson CS, Brownridge GW 3rd, et al. Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila. PLoS Genet. 2020;16: e1008835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol. 2013;9:366–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kaeberlein M. Translational geroscience: a new paradigm for 21st century medicine. Transl Med Aging. 2017;1:1–4.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Kaeberlein M. It is time to embrace 21st-century medicine. Public Policy & Aging Report. 2019;29:111–5.

    Article  Google Scholar 

  54. Kaeberlein M, Galvan V. Rapamycin and Alzheimer’s disease: Time for a clinical trial? Sci Transl Med. 2019;11:5.

    Article  Google Scholar 

  55. Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005;310:1193–6.

    Article  CAS  PubMed  Google Scholar 

  56. Kaeberlein TL, Smith ED, Tsuchiya M, Welton KL, Thomas JH, et al. Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell. 2006;5:487–94.

    Article  CAS  PubMed  Google Scholar 

  57. Kajiwara M, Masuda S. Role of mTOR inhibitors in kidney disease. Int J Mol Sci. 2016;17:975.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kaya A, Ma S, Wasko B, Lee M, Kaeberlein M, et al. Defining molecular basis for longevity traits in natural yeast isolates. NPJ Aging Mech Dis. 2015;1:15001.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kaya A, Phua CZJ, Lee M, Wang L, Tyshkovskiy A, et al. Evolution of natural lifespan variation and molecular strategies of extended lifespan in yeast. eLife. 2021;10:e64860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ke W, Reed JN, Yang C, Higgason N, Rayyan L, et al. Genes in human obesity loci are causal obesity genes in C. elegans. Plos Genet. 2021;17:e1009736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159:709–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kennedy BK, Lamming DW. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab. 2016;23:990–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kenyon C. The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Philos Trans R Soc Lond B Biol Sci. 2011;366:9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild-type. Nature. 1993;366:461–4.

    Article  CAS  PubMed  Google Scholar 

  65. Kerr RA, Roux AE, Goudeau J, Kenyon C. The C. elegans observatory: high-throughput exploration of behavioral aging. Front Aging. 2022;3:932656.

  66. Komura T, Yamanaka M, Nishimura K, Hara K, Nishikawa Y. Autofluorescence as a noninvasive biomarker of senescence and advanced glycation end products in Caenorhabditis elegans. NPJ Aging Mech Dis. 2021;7:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kropp PA, Bauer R, Zafra I, Graham C, Golden A. Caenorhabditis elegans for rare disease modeling and drug discovery: strategies and strengths. Dis Model Mech. 2021;14:8.

    Article  Google Scholar 

  68. Kyriakakis E, Markaki M, Tavernarakis N. Caenorhabditis elegans as a model for cancer research. Mol Cell Oncol. 2015;2: e975027.

    Article  PubMed  Google Scholar 

  69. Lagunas-Rangel FA. G protein-coupled receptors that influence lifespan of human and animal models. Biogerontology. 2022;23:1–19.

    Article  PubMed  Google Scholar 

  70. Lee HJ, Noormohammadi A, Koyuncu S, Calculli G, Simic MS, et al. Prostaglandin signals from adult germline stem cells delay somatic ageing of Caenorhabditis elegans. Nat Metab. 2019;1:790–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee MB, Hill CM, Bitto A, Kaeberlein M. Antiaging diets: separating fact from fiction. Science. 2021;374:eabe7365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lee MB, Kaeberlein M. Translational Geroscience: From invertebrate models to companion animal and human interventions. Transl Med Aging. 2018;2:15–29.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Lee MB, Kiflezghi MG, Tsuchiya M, Wasko B, Carr DT, et al. Pterocarpus marsupium extract extends replicative lifespan in budding yeast. Geroscience. 2021;43:2595–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet. 2003;33:40–8.

    Article  CAS  PubMed  Google Scholar 

  75. Lee TW-S, David HS, Engstrom AK, Carpenter BS, Katz DJ. Repressive H3K9me2 protects lifespan against the transgenerational burden of COMPASS activity in C. elegans. eLife. 2019;8:e48498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Leiser SF, Miller H, Rossner R, Fletcher M, Leonard A, et al. Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span. Science. 2015;350:1375–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186:243–78.

    Article  PubMed  Google Scholar 

  78. Lucanic M, Garrett T, Yu I, Calahorro F, Asadi Shahmirzadi A, et al. Chemical activation of a food deprivation signal extends lifespan. Aging Cell. 2016;15:832–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, et al. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nat Commun. 2017;8:14256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Maglioni S, Ventura N. C. elegans as a model organism for human mitochondrial associated disorders. Mitochondrion. 2016;30:117–25.

    Article  CAS  PubMed  Google Scholar 

  81. Martins F, Sousa J, Pereira CD, da Cruz ESOAB, Rebelo S. Nuclear envelope dysfunction and its contribution to the aging process. Aging Cell. 2020;19: e13143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Matsunami K. Frailty and Caenorhabditis elegans as a benchtop animal model for screening drugs including natural herbs. Front Nutr. 2018;5:111.

    Article  PubMed  PubMed Central  Google Scholar 

  83. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life and upon ultimate size. J Nutr. 1935;10:63–79.

    Article  CAS  Google Scholar 

  84. McColl G, Roberts BR, Pukala TL, Kenche VB, Roberts CM, et al. Utility of an improved model of amyloid-beta (Aβ1-42) toxicity in Caenorhabditis elegansfor drug screening for Alzheimer’s disease. Mol Neurodegener. 2012;7:57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. McCormick MA, Delaney JR, Tsuchiya M, Tsuchiyama S, Shemorry A, et al. A Comprehensive analysis of replicative lifespan in 4,698 single-gene deletion strains uncovers conserved mechanisms of aging. Cell Metab. 2015;22:895–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Meléndez A, Tallóczy Z, Seaman M, Eskelinen EL, Hall DH, et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science. 2003;301:1387–91.

    Article  PubMed  Google Scholar 

  87. Meneely PM, Dahlberg CL, Rose JK. Working with worms: Caenorhabditis elegans as a model organism. Curr Protoc Essent Lab Tech. 2019;19: e35.

    Article  Google Scholar 

  88. Meng H, Minjie H, Chengming Z, Di C, Xiangyang C et al. H3K9me1/2 methylation limits the lifespan of C. elegans. bioRxiv. 2021;2021.2010.2027.466082.

  89. Miller HA, Dean ES, Pletcher SD, Leiser SF. Cell non-autonomous regulation of health and longevity. eLife. 2020;9:e62659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Miller HA, Huang S, Dean ES, Schaller ML, Tuckowski AM, et al. Serotonin and dopamine modulate aging in response to food odor and availability. Nat Commun. 2022;13:3271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Miller RA, Harrison DE, Astle CM, Bogue MA, Brind J, et al. Glycine supplementation extends lifespan of male and female mice. Aging Cell. 2019;18: e12953.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Miller RA, Harrison DE, Astle CM, Floyd RA, Flurkey K, et al. An aging interventions testing program: study design and interim report. Aging Cell. 2007;6:565–75.

    Article  CAS  PubMed  Google Scholar 

  93. Mitchell SJ, Bernier M, Aon MA, Cortassa S, Kim EY, et al. Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab. 2018;27:667-676.e664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mohammed I, Hollenberg MD, Ding H, Triggle CR. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol. 2021;12:718942.

  95. Morcos M, Hutter H. The model Caenorhabditis elegans in diabetes mellitus and Alzheimer’s disease. J Alzheimers Dis. 2009;16:897–908.

    Article  PubMed  Google Scholar 

  96. Moreno-Arriola E, Cárdenas-Rodríguez N, Coballase-Urrutia E, Pedraza-Chaverri J, Carmona-Aparicio L, et al. Caenorhabditis elegans: a useful model for studying metabolic disorders in which oxidative stress is a contributing factor. Oxidative Med Cell Longev. 2014;2014:705253.

  97. Nadon NL, Strong R, Miller RA, Harrison DE. NIA Interventions testing program: investigating putative aging intervention agents in a genetically heterogeneous mouse model. EBioMedicine. 2017;21:3–4.

    Article  PubMed  Google Scholar 

  98. Nadon NL, Strong R, Miller RA, Nelson J, Javors M, et al. Design of aging intervention studies: the NIA interventions testing program. Age (Dordr). 2008;30:187–99.

    Article  CAS  PubMed  Google Scholar 

  99. Naranjo-Galindo FJ, Ai R, Fang EF, Nilsen HL, SenGupta T. C. elegans as an animal model to study the intersection of DNA repair, aging and neurodegeneration. Front Aging. 2022;3:916118.

  100. Oikonomou G, Shaham S. The glia of Caenorhabditis elegans. Glia. 2011;59:1253–63.

    Article  PubMed  Google Scholar 

  101. Onken B, Sedore CA, Coleman-Hulbert AL, Hall D, Johnson E, et al. Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes. Aging Cell. 2022;21: e13488.

    Article  CAS  PubMed  Google Scholar 

  102. Oz N, Vayndorf EM, Tsuchiya M, McLean S, Turcios-Hernandez L, et al. Evidence that conserved essential genes are enriched for pro-longevity factors. GeroScience. 2022;44:1995–2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Palmer AK, Jensen MD. Metabolic changes in aging humans: current evidence and therapeutic strategies. J Clin Invest. 2022;132:16.

    Article  Google Scholar 

  104. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, et al. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8:998.

    Article  CAS  Google Scholar 

  105. Park S, Kim BK, Park SK. Effects of fisetin, a plant-derived flavonoid, on response to oxidative stress, aging, and age-related diseases in Caenorhabditis elegans. Pharmaceuticals (Basel). 2022;15:1528.

    Article  CAS  PubMed  Google Scholar 

  106. Park SK, Link CD, Johnson TE. Life-span extension by dietary restriction is mediated by NLP-7 signaling and coelomocyte endocytosis in C. elegans. Faseb J. 2010;24:383–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Peleg S, Feller C, Ladurner AG, Imhof A. The metabolic impact on histone acetylation and transcription in ageing. Trends Biochem Sci. 2016;41:700–11.

    Article  CAS  PubMed  Google Scholar 

  108. Pereira L, Kratsios P, Serrano-Saiz E, Sheftel H, Mayo AE, et al. A cellular and regulatory map of the cholinergic nervous system of C. elegans. eLife. 2015;4:e12432.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Petrascheck M, Ye X, Buck LB. An antidepressant that extends lifespan in adult Caenorhabditis elegans. Nature. 2007;450:553–6.

    Article  CAS  PubMed  Google Scholar 

  110. Pincus Z, Mazer TC, Slack FJ. Autofluorescence as a measure of senescence in C. elegans: look to red, not blue or green. Aging-Us. 2016;8:889–98.

    Article  CAS  Google Scholar 

  111. Piskovatska V, Storey KB, Vaiserman AM, Lushchak O. The use of metformin to increase the human healthspan. In: Guest PC, editor. Reviews on new drug targets in age-related disorders Springer International Publishing. Cham; 2020. p. 319–32.

    Chapter  Google Scholar 

  112. Pitt JN, Strait NL, Vayndorf EM, Blue BW, Tran CH, et al. WormBot, an open-source robotics platform for survival and behavior analysis in C. elegans. Geroscience. 2019;41:961–73.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Pittman WE, Sinha DB, Zhang WB, Kinser HE, Pincus Z. A simple culture system for long-term imaging of individual C. elegans. Lab Chip. 2017;17:3909–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Porte D Jr, Baskin DG, Schwartz MW. Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes. 2005;54:1264–76.

    Article  CAS  PubMed  Google Scholar 

  115. Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006;20:174–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Quarles E, Basisty N, Chiao YA, Merrihew G, Gu H, et al. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell. 2020;19: e13086.

    Article  CAS  PubMed  Google Scholar 

  117. Querfurth H, Lee H-K. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol Neurodegener. 2021;16:44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Radulescu CI, Cerar V, Haslehurst P, Kopanitsa M, Barnes SJ. The aging mouse brain: cognition, connectivity and calcium. Cell Calcium. 2021;94: 102358.

    Article  CAS  PubMed  Google Scholar 

  119. Redmon J, Divvala S, Girshick R, Farhadi A. You only look once: unified, real-time object detection, pp. 779–788 in 2016 IEEE Conference on Computer Vision and Pattern Recognition (CVPR). 2016.

  120. Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 2012;15:713–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rohde PD, Bøcker A, Jensen CAB, Bergstrøm AL, Madsen MIJ, et al. Genotype and trait specific responses to rapamycin intake in Drosophila melanogaster. Insects. 2021;12:474.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Salameh Y, Bejaoui Y, El Hajj N. DNA methylation biomarkers in aging and age-related diseases. Front Gen. 2020;11:171.

    Article  CAS  Google Scholar 

  123. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012;11:230–41.

    Article  CAS  PubMed  Google Scholar 

  124. Sánchez-Blanco A, Rodríguez-Matellán A, González-Paramás A, González-Manzano S, Kim SK, et al. Dietary and microbiome factors determine longevity in Caenorhabditis elegans. Aging (Albany NY). 2016;8:1513–39.

    Article  PubMed  Google Scholar 

  125. Schlotterer A, Kukudov G, Bozorgmehr F, Hutter H, Du X, et al. C. elegans as model for the study of high glucose–mediated life span reduction. Diabetes. 2009;58:2450–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Schuske K, Beg AA, Jorgensen EM. The GABA nervous system in C. elegans. Trends Neurosci. 2004;27:407–14.

    Article  CAS  PubMed  Google Scholar 

  127. Shaposhnikov MV, Guvatova ZG, Zemskaya NV, Koval LA, Schegoleva EV, et al. Molecular mechanisms of exceptional lifespan increase of Drosophila melanogaster with different genotypes after combinations of pro-longevity interventions. Commun Biol. 2022;5:566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shin E-Y, Soung N-K, Schwartz MA, Kim E-G. Altered endocytosis in cellular senescence. Ageing Res Rev. 2021;68: 101332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Smith ED, Tsuchiya M, Fox LA, Dang N, Hu D, et al. Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res. 2008;18:564–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Statzer C, Jongsma E, Liu SX, Dakhovnik A, Wandrey F, et al. Youthful and age-related matreotypes predict drugs promoting longevity. Aging Cell. 2021;20: e13441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Strong R, Miller RA, Antebi A, Astle CM, Bogue M, 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;15:872–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Stroustrup N, Ulmschneider BE, Nash ZM, López-Moyado IF, Apfeld J, et al. The Caenorhabditis elegans lifespan machine. Nat Methods. 2013;10:665–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Teno JM. Garbage in, garbage out—words of caution on big data and machine learning in medical practice. JAMA Health Forum. 2023;4:e230397–e230397.

    Article  PubMed  Google Scholar 

  134. Teterina AA, Coleman-Hulbert AL, Banse SA, Willis JH, Perez VI et al. Genetic diversity estimates for the Caenorhabditis Intervention Testing Program screening panel. MicroPublication Biology. 2022;2022:10.17912.

  135. Tolkin T, Hubbard EJA. Germline stem and progenitor cell aging in C. elegans. Front Cell Dev Biol. 2021;9:699671.

  136. Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience. 2017;39:117–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Vakkayil KL, Hoppe T. Temperature-dependent regulation of proteostasis and longevity. Front Aging. 2022;3: 853588.

    Article  PubMed  PubMed Central  Google Scholar 

  138. van der Bliek AM, Sedensky MM, Morgan PG. Cell biology of the mitochondrion. Genetics. 2017;207:843–71.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, et al. Influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426:620–620.

    Article  CAS  PubMed  Google Scholar 

  140. Watts JL, Ristow M. Lipid and carbohydrate metabolism in Caenorhabditis elegans. Genetics. 2017;207:413–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986;116:641–54.

    Article  CAS  PubMed  Google Scholar 

  142. Wilson KA, Beck JN, Nelson CS, Hilsabeck TA, Promislow D, et al. GWAS for lifespan and decline in climbing ability in flies upon dietary restriction reveal decima as a mediator of insulin-like peptide production. Curr Biol. 2020;30:2749-2760.e2743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wodrich APK, Scott AW, Shukla AK, Harris BT, Giniger E. The unfolded protein responses in health, aging, and neurodegeneration: recent advances and future considerations. Front Mol Neurosci. 2022;15: 831116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Woodward K, Shirokikh NE. Translational control in cell ageing: an update. Biochem Soc Trans. 2021;49:2853–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wu N, Ma Y-C, Gong X-Q, Zhao P-J, Jia Y-J, et al. The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans. Nat Commun. 2023;14:240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Xian B, Shen J, Chen W, Sun N, Qiao N, et al. WormFarm: a quantitative control and measurement device toward automated Caenorhabditis elegans aging analysis. Aging Cell. 2013;12:398–409.

    Article  CAS  PubMed  Google Scholar 

  147. Ye X, Linton JM, Schork NJ, Buck LB, Petrascheck M. A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell. 2014;13:206–15.

    Article  CAS  PubMed  Google Scholar 

  148. Yousefzadeh M, Henpita C, Vyas R, Soto-Palma C, Robbins P et al. DNA damage-how and why we age? eLife. 2021;10:e62852.

  149. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yu G, Wu Q, Gao Y, Chen M, Yang M. The epigenetics of aging in invertebrates. Int J Mol Sci. 2019;20:4535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Zarse K, Ristow M. Antidepressants of the serotonin-antagonist type increase body fat and decrease lifespan of adult Caenorhabditis elegans. PLoS One. 2008;3: e4062.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Zhang H, Meltzer P, Davis S. RCircos: an R package for Circos 2D track plots. BMC Bioinformatics. 2013;14:244.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Zhang WH, Koyuncu S, Vilchez D. Insights into the links between proteostasis and aging from C. elegans. Front Aging. 2022;3:854157.

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Ora Biomedical, Inc., 12101 Tukwila International Blvd Suite 210, Seattle, WA, 98168, USA

    Mitchell B. Lee, Benjamin Blue, Michael Muir & Matt Kaeberlein

  2. Optispan Geroscience, Seattle, WA, USA

    Matt Kaeberlein

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M.L., B.B., and M.K. are co-founders of Ora Biomedical, Inc., a for-profit company that specializes in longevity drug discovery and development. M.L., B.B., and M.M. are employed by Ora Biomedical, Inc. All authors hold equity stake in Ora Biomedical, Inc.

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Lee, M.B., Blue, B., Muir, M. et al. The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery. GeroScience 45, 3103–3113 (2023). https://doi.org/10.1007/s11357-023-00867-6

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