Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.
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Niccoli, T. & Partridge, L. Ageing as a risk factor for disease. Curr. Biol. 22, R741–R752 (2012).
Niccoli, T., Partridge, L. & Isaacs, A. M. Ageing as a risk factor for ALS/FTD. Hum. Mol. Genet. 26, R105–R113 (2017).
Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).
Hurst, J. R. et al. Global Alliance for Chronic Disease researchers’ statement on multimorbidity. Lancet Glob. Health 6, e1270–e1271 (2018).
Evangelista, L., Steinhubl, S. R. & Topol, E. J. Digital health care for older adults. Lancet 393, 1493 (2019).
Hardy, J. & De Strooper, B. Alzheimer’s disease: where next for anti-amyloid therapies? Brain 140, 853–855 (2017).
Tarakad, A. & Jankovic, J. Diagnosis and management of Parkinson’s disease. Semin. Neurol. 37, 118–126 (2017).
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span-from yeast to humans. Science 328, 321–326 (2010).
Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–118 (2015).
Longo, V. D. et al. Interventions to slow aging in humans: are we ready? Aging Cell 14, 497–510 (2015).
Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018).
Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546.e5 (2017).
Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 5, e16351 (2016).
Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012).
Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).
Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14063 (2017).
Goldman, D. The economic promise of delayed aging. Cold Spring Harb. Perspect. Med. 6, a025072 (2015).
Olshansky, S. J. Articulating the case for the longevity dividend. Cold Spring Harb. Perspect. Med. 6, a025940 (2016).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
de Magalhaes, J. P., Stevens, M. & Thornton, D. The business of anti-aging science. Trends Biotechnol. 35, 1062–1073 (2017).
Brown, A. S. & Patel, C. J. A standard database for drug repositioning. Sci. Data 4, 170029 (2017).
Himmelstein, D. S. et al. Systematic integration of biomedical knowledge prioritizes drugs for repurposing. eLife 6, e26726 (2017).
Schubert, D. et al. Geroneuroprotectors: effective geroprotectors for the brain. Trends Pharmacol. Sci. 39, 1004–1007 (2018).
Figueira, I. et al. Interventions for age-related diseases: shifting the paradigm. Mech. Ageing Dev. 160, 69–92 (2016).
Moskalev, A. et al. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell 15, 407–415 (2016).
Moskalev, A., Chernyagina, E., Kudryavtseva, A. & Shaposhnikov, M. Geroprotectors: a unified concept and screening approaches. Aging Dis. 8, 354–363 (2017).
Trendelenburg, A. U., Scheuren, A. C., Potter, P., Muller, R. & Bellantuono, I. Geroprotectors: a role in the treatment of frailty. Mech. Ageing Dev. 180, 11–20 (2019).
Moskalev, A. et al. Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging 7, 616–628 (2015).
Kumar, S. & Lombard, D. B. Finding Ponce de Leon’s Pill: challenges in screening for anti-aging molecules. F1000Res 5, 406 (2016).
Vaiserman, A. M., Lushchak, O. V. & Koliada, A. K. Anti-aging pharmacology: promises and pitfalls. Ageing Res. Rev. 31, 9–35 (2016).
de Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M. N. & Madeo, F. The search for antiaging interventions: from elixirs to fasting regimens. Cell 157, 1515–1526 (2014).
Mallikarjun, V. & Swift, J. Therapeutic manipulation of ageing: repurposing old dogs and discovering new tricks. EBioMedicine 14, 24–31 (2016).
Arriola Apelo, S. I. & Lamming, D. W. Rapamycin: an inhibiTOR of aging emerges from the soil of Easter Island. J. Gerontol. A Biol. Sci. Med. Sci. 71, 841–849 (2016).
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Li, J., Kim, S. G. & Blenis, J. Rapamycin: one drug, many effects. Cell Metab. 19, 373–379 (2014).
Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).
Powers, R. W. 3rd, Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006).
Ha, C. W. & Huh, W. K. Rapamycin increases rDNA stability by enhancing association of Sir2 with rDNA in Saccharomyces cerevisiae. Nucleic Acids Res. 39, 1336–1350 (2011).
Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004).
Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).
Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).
Robida-Stubbs, S. et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012).
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Miller, R. A. et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 66, 191–201 (2011).
Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).
Wu, J. J. et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 4, 913–920 (2013).
Anisimov, V. N. et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10, 4230–4236 (2011).
Popovich, I. G. et al. Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin. Cancer Biol. Ther. 15, 586–592 (2014).
Grabiner, B. C. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4, 554–563 (2014).
Xu, J. et al. Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin. J. Clin. Invest. 126, 3526–3540 (2016).
Neff, F. et al. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 123, 3272–3291 (2013).
Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012).
Lesniewski, L. A. et al. Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell 16, 17–26 (2017).
Halloran, J. et al. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 223, 102–113 (2012).
Majumder, S. et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling. Aging Cell 11, 326–335 (2012).
Flynn, J. M. et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 12, 851–862 (2013).
Dai, D. F. et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13, 529–539 (2014).
An, J. Y. et al. Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience 39, 457–463 (2017).
Dou, X. et al. Short-term rapamycin treatment increases ovarian lifespan in young and middle-aged female mice. Aging Cell 16, 825–836 (2017).
Reifsnyder, P. C., Flurkey, K., Te, A. & Harrison, D. E. Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging 8, 3120–3130 (2016).
Menzies, F. M. & Rubinsztein, D. C. Broadening the therapeutic scope for rapamycin treatment. Autophagy 6, 286–287 (2010).
Bove, J., Martinez-Vicente, M. & Vila, M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat. Rev. Neurosci. 12, 437–452 (2011).
Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One 5, e9979 (2010).
Ozcelik, S. et al. Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PLoS One 8, e62459 (2013).
Lin, A. L. et al. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease. J. Cereb. Blood Flow. Metab. 37, 217–226 (2017).
Richardson, A., Galvan, V., Lin, A. L. & Oddo, S. How longevity research can lead to therapies for Alzheimer’s disease: the rapamycin story. Exp. Gerontol. 68, 51–58 (2015).
Bai, X. et al. Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy. Pathobiol. Aging Age Relat. Dis. 5, 28743 (2015).
Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).
Sarkar, S. et al. A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum. Mol. Genet. 17, 170–178 (2008).
Johnson, S. C. et al. Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Front. Genet. 6, 247 (2015).
Kennedy, B. K. & Pennypacker, J. K. Mammalian target of rapamycin: a target for (lung) diseases and aging. Ann. Am. Thorac. Soc. 13 (Suppl. 5), S398–S401 (2016).
Sciarretta, S., Forte, M., Frati, G. & Sadoshima, J. New insights into the role of mTOR signaling in the cardiovascular system. Circ. Res. 122, 489–505 (2018).
Walters, H. E. & Cox, L. S. mTORC inhibitors as broad-spectrum therapeutics for age-related diseases. Int. J. Mol. Sci. 19, 2325 (2018).
University of Washington. Dog Aging Project https://dogagingproject.org/ (2019).
Urfer, S. R. et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39, 117–127 (2017).
Tardif, S. et al. Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. J. Gerontol. A Biol. Sci. Med. Sci. 70, 577–587 (2015).
Ross, C. et al. Metabolic consequences of long-term rapamycin exposure on common Marmoset monkeys (Callithrix jacchus). Aging 7, 964–973 (2015).
Lelegren, M., Liu, Y., Ross, C., Tardif, S. & Salmon, A. B. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol. Aging Age Relat. Dis. 6, 31793 (2016).
Kennedy, B. K. & Lamming, D. W. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab. 23, 990–1003 (2016).
Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).
Haller, S. et al. mTORC1 activation during repeated regeneration impairs somatic stem cell maintenance. Cell Stem Cell 21, 806–818.e5 (2017).
Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
Fan, X. et al. Rapamycin preserves gut homeostasis during Drosophila aging. Oncotarget 6, 35274–35283 (2015).
Sung, J. Y., Lee, K. Y., Kim, J. R. & Choi, H. C. Interaction between mTOR pathway inhibition and autophagy induction attenuates adriamycin-induced vascular smooth muscle cell senescence through decreased expressions of p53/p21/p16. Exp. Gerontol. 109, 51–58 (2018).
Wang, R., Sunchu, B. & Perez, V. I. Rapamycin and the inhibition of the secretory phenotype. Exp. Gerontol. 94, 89–92 (2017).
Hine, C. Rapamycin keeps the reproductive clock ticking. Sci. Transl Med. 9, eaan4296 (2017).
Wang, R. et al. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell 16, 564–574 (2017).
Augustine, J. J., Bodziak, K. A. & Hricik, D. E. Use of sirolimus in solid organ transplantation. Drugs 67, 369–391 (2007).
de Oliveira, M. A. et al. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral. Oncol. 47, 998–1003 (2011).
Schreiber, K. H. et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14, 265–273 (2015).
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).
Zheng, Y. et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J. Immunol. 178, 2163–2170 (2007).
Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).
Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
Haxhinasto, S., Mathis, D. & Benoist, C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565–574 (2008).
Pollizzi, K. N. & Powell, J. D. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 36, 13–20 (2015).
Pollizzi, K. N. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17, 704–711 (2016).
Verbist, K. C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389–393 (2016).
Murphy, S. L., Jiaquan, X. & Kochnanek, K. D. Deaths: Final Data for 2010. Natl Vital Stat. Rep. 61, 1–117 (2013).
Goodwin, K., Viboud, C. & Simonsen, L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24, 1159–1169 (2006).
Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl Med. 6, 268ra179 (2014).
Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl Med. 10, eaaq1564 (2018).
resTORbio. resTORbio announces that the phase 3 PROTECTOR 1 trial of RTB101 in clinically symptomatic respiratory illness did not meet the primary endpoint. resTORbio https://ir.restorbio.com/news-releases/news-release-details/restorbio-announces-phase-3-protector-1-trial-rtb101-clinically (2019).
Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).
Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).
Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).
Collado, M. & Serrano, M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer 10, 51–57 (2010).
Anestakis, D. et al. Mechanisms and applications of interleukins in cancer immunotherapy. Int. J. Mol. Sci. 16, 1691–1710 (2015).
Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).
Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2017).
van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).
Yanai, H. & Fraifeld, V. E. The role of cellular senescence in aging through the prism of Koch-like criteria. Ageing Res. Rev. 41, 18–33 (2018).
Khosla, S., Farr, J. N. & Kirkland, J. L. Inhibiting cellular senescence: a new therapeutic paradigm for age-related osteoporosis. J. Clin. Endocrinol. Metab. 103, 1282–1290 (2018).
Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).
Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017).
Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).
Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016).
Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017).
Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).
Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).
Jeon, O. H., David, N., Campisi, J. & Elisseeff, J. H. Senescent cells and osteoarthritis: a painful connection. J. Clin. Invest. 128, 1229–1237 (2018).
Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
Palmer, A. K. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18, e12950 (2019).
Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).
Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).
Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018).
Cavalcante, M. B. et al. Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice. Aging 12, 2711–2722 (2020).
Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147.e16 (2017).
Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017).
Fuhrmann-Stroissnigg, H., Niedernhofer, L. J. & Robbins, P. D. Hsp90 inhibitors as senolytic drugs to extend healthy aging. Cell Cycle 17, 1048–1055 (2018).
Kashyap, D. et al. Fisetin and quercetin: promising flavonoids with chemopreventive potential. Biomolecules 9, 174 (2019).
Triana-Martinez, F. et al. Identification and characterization of cardiac glycosides as senolytic compounds. Nat. Commun. 10, 4731 (2019).
Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metabolism 1, 1074–1088 (2019).
NIH U.S. National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03513016 (2018).
Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019).
Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017).
Herranz, N. & Gil, J. Mechanisms and functions of cellular senescence. J. Clin. Invest. 128, 1238–1246 (2018).
Marshall, S. M. 60 years of metformin use: a glance at the past and a look to the future. Diabetologia 60, 1561–1565 (2017).
Adak, T., Samadi, A., Unal, A. Z. & Sabuncuoglu, S. A reappraisal on metformin. Regul. Toxicol. Pharmacol. 92, 324–332 (2018).
Nathan, D. M. et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 29, 1963–1972 (2006).
Sharma, M., Nazareth, I. & Petersen, I. Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study. BMJ Open 6, e010210 (2016).
IMS Institute for Healthcare Informatics. National prescription audit December 2012 (IMS Institute for Healthcare Informatics, 2012).
Le, S. & Lee, G. C. Emerging trends in metformin prescribing in the United States from 2000 to 2015. Clin. Drug Invest. 39, 757–763 (2019).
Witters, L. A. The blooming of the French lilac. J. Clin. Invest. 108, 1105–1107 (2001).
He, L. et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137, 635–646 (2009).
Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013).
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 5, e8758 (2010).
De Haes, W. et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc. Natl Acad. Sci. USA 111, E2501–E2509 (2014).
Chen, J. et al. Metformin extends C. elegans lifespan through lysosomal pathway. eLife 6, e31268 (2017).
Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017).
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 7, e47699 (2012).
Anisimov, V. N. Metformin: do we finally have an anti-aging drug? Cell Cycle 12, 3483–3489 (2013).
Strong, R. et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15, 872–884 (2016).
Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192 (2013).
Dhahbi, J. M., Mote, P. L., Fahy, G. M. & Spindler, S. R. Identification of potential caloric restriction mimetics by microarray profiling. Physiol. Genomics 23, 343–350 (2005).
Rena, G., Hardie, D. G. & Pearson, E. R. The mechanisms of action of metformin. Diabetologia 60, 1577–1585 (2017).
Stein, B. D. et al. Quantitative in vivo proteomics of metformin response in liver reveals AMPK-dependent and -independent signaling networks. Cell Rep. 29, 3331–3348.e7 (2019).
Shin, N. R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014).
Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).
Zhou, Z. Y. et al. Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling. Acta Pharmacol. Sin. 37, 1063–1075 (2016).
Zhang, X. et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci. Rep. 5, 14405 (2015).
Cameron, A. R. et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ. Res. 119, 652–665 (2016).
Cacicedo, J. M., Yagihashi, N., Keaney, J. F. Jr., Ruderman, N. B. & Ido, Y. AMPK inhibits fatty acid-induced increases in NF-κB transactivation in cultured human umbilical vein endothelial cells. Biochem. Biophys. Res. Commun. 324, 1204–1209 (2004).
Ibanez, L., Valls, C. & de Zegher, F. Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-α and the neutrophil/lymphocyte ratio. Hum. Reprod. 21, 451–456 (2006).
Hattori, Y., Suzuki, K., Hattori, S. & Kasai, K. Metformin inhibits cytokine-induced nuclear factor κB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 47, 1183–1188 (2006).
Ren, T. et al. Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-alpha or isoproterenol. J. Mol. Endocrinol. 37, 175–183 (2006).
Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 12, 489–498 (2013).
Horiuchi, T. et al. Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. J. Biol. Chem. 292, 8436–8446 (2017).
Cuyas, E. et al. Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging Cell 17, e12772 (2018).
Kirpichnikov, D., McFarlane, S. & Sowers, J. Metformin: an update. Ann. Intern. Med. 137, 25–33 (2002).
Beisswenger, P., Howell, S., Touchette, A., Lal, S. & Szwergold, B. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 48, 198–202 (1999).
Kooy, A. et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch. Intern. Med. 169, 616–625 (2009).
Wang, C. P., Lorenzo, C., Habib, S. L., Jo, B. & Espinoza, S. E. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J. Diabetes Complicat. 31, 679–686 (2017).
Currie, C., Poole, C. & Gale, E. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777 (2009).
Franciosi, M. et al. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One 8, e71583 (2013).
Qiu, H., Rhoads, G., Berlin, J., Marcella, S. & Demissie, K. Initial metformin or sulphonylurea exposure and cancer occurrence among patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 15, 349–357 (2013).
Hsieh, M. et al. The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. Exp. Diabetes Res. 2012, 413782 (2012).
Bowker, S., Yasui, Y., Veugelers, P. & Johnson, J. Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia 53, 1631–1637 (2010).
Ruiter, R. et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 35, 119–124 (2012).
Libby, G. et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32, 1620–1625 (2009).
Gandini, S. et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev. Res. 7, 867–885 (2014).
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 352, 854–865 (1998).
Bannister, C. 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. 16, 1165–1173 (2014).
Claesen, M. et al. Mortality in individuals treated with glucose-lowering agents: a large, controlled cohort study. J. Clin. Endocrinol. Metab. 101, 461–469 (2016).
Campbell, J. M., Bellman, S. M., Stephenson, M. D. & 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. 40, 31–44 (2017).
Palmer, S. C. et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 316, 313–324 (2016).
Hayden, E. C. Anti-ageing pill pushed as bona fide drug. Nature 522, 265–266 (2015).
Justice, J. N. et al. Development of clinical trials to extend healthy lifespan. Cardiovasc. Endocrinol. Metab. 7, 80–83 (2018).
Barzilai, N., Crandall, J. P., Kritchevsky, S. B. & Espeland, M. A. Metformin as a tool to target aging. Cell Metab. 23, 1060–1065 (2016).
Kulkarni, A. S. et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 17, e12723 (2018).
Konopka, A. R. et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell 18, e12880 (2019).
Brewer, R. A., Gibbs, V. K. & Smith, D. L. Jr. Targeting glucose metabolism for healthy aging. Nutr. Healthy Aging 4, 31–46 (2016).
Balfour, J. A. & McTavish, D. Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 46, 1025–1054 (1993).
Yamamoto, M. & Otsuki, M. Effect of inhibition of alpha-glucosidase on age-related glucose intolerance and pancreatic atrophy in rats. Metabolism 55, 533–540 (2006).
Harrison, D. E. et al. Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13, 273–282 (2014).
Harrison, D. E. et al. Acarbose improves health and lifespan in aging HET3 mice. Aging Cell 18, e12898 (2019).
Sadagurski, M., Cady, G. & Miller, R. A. Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner. Aging Cell 16, 652–660 (2017).
Garratt, M., Bower, B., Garcia, G. G. & Miller, R. A. Sex differences in lifespan extension with acarbose and 17-α estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling. Aging Cell 16, 1256–1266 (2017).
Smith, B. J. et al. Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice. BMC Microbiol. 19, 130 (2019).
Rosak, C. & Mertes, G. Critical evaluation of the role of acarbose in the treatment of diabetes: patient considerations. Diabetes Metab. Syndr. Obes. 5, 357–367 (2012).
Pegg, A. E. Functions of polyamines in mammals. J. Biol. Chem. 291, 14904–14912 (2016).
Scalabrino, G. & Ferioli, M. E. Polyamines in mammalian ageing: an oncological problem, too? A review. Mech. Ageing Dev. 26, 149–164 (1984).
Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).
Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).
Yue, F. et al. Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. 77, 2938–2951 (2017).
Tain, L. S. et al. Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production. Aging Cell 19, e13043 (2020).
Kiechl, S. et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am. J. Clin. Nutr. 108, 371–380 (2018).
Pietrocola, F. et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516 (2015).
Marino, G. et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725 (2014).
Wang, J. et al. Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function. Aging 12, 650–671 (2020).
Zhang, H. et al. Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence. Mol. Cell 76, 110–125.e9 (2019).
Sacitharan, P. K., Gharios, G. B. & Edwards, J. R. Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300: response to correspondence by Borzi et al. Exp. Mol. Med. 51, 1–2 (2019).
Garcia-Prat, L., Munoz-Canoves, P. & Martinez-Vicente, M. Dysfunctional autophagy is a driver of muscle stem cell functional decline with aging. Autophagy 12, 612–613 (2016).
Bhukel, A., Madeo, F. & Sigrist, S. J. Spermidine boosts autophagy to protect from synapse aging. Autophagy 13, 444–445 (2017).
Noro, T. et al. Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury. Cell Death Dis. 6, e1720 (2015).
Maglione, M. et al. Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses. Sci. Rep. 9, 19616 (2019).
Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).
Murray-Stewart, T. R., Woster, P. M. & Casero, R. A. Jr. Targeting polyamine metabolism for cancer therapy and prevention. Biochem. J. 473, 2937–2953 (2016).
Rajman, L., Chwalek, K. & Sinclair, D. A. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 27, 529–547 (2018).
Hikosaka, K., Yaku, K., Okabe, K. & Nakagawa, T. Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases. Nutr. Neurosci. https://doi.org/10.1080/1028415X.2019.1637504 (2019).
Yoshino, J., Baur, J. A. & Imai, S. I. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 27, 513–528 (2018).
Ramsey, K. M., Mills, K. F., Satoh, A. & Imai, S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 7, 78–88 (2008).
Massudi, H. et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7, e42357 (2012).
Zhu, X. H., Lu, M., Lee, B. Y., Ugurbil, K. & Chen, W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc. Natl Acad. Sci. USA 112, 2876–2881 (2015).
Zhang, H. et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).
Mills, K. F. et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806 (2016).
Belenky, P. et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell 129, 473–484 (2007).
Mouchiroud, L. et al. The NAD+/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).
de Picciotto, N. E. et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15, 522–530 (2016).
Bertoldo, M. J. et al. NAD+ repletion rescues female fertility during reproductive aging. Cell Rep. 30, 1670–1681.e7 (2020).
Trammell, S. A. et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun. 7, 12948 (2016).
Airhart, S. E. et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One 12, e0186459 (2017).
Dellinger, R. W. et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech. Dis. 3, 17 (2017).
Conze, D. B., Crespo-Barreto, J. & Kruger, C. L. Safety assessment of nicotinamide riboside, a form of vitamin B3. Hum. Exp. Toxicol. 35, 1149–1160 (2016).
Elhassan, Y. S. et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 28, 1717–1728.e6 (2019).
Dollerup, O. L. et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am. J. Clin. Nutr. 108, 343–353 (2018).
Sofola-Adesakin, O. et al. Lithium suppresses Aβ pathology by inhibiting translation in an adult Drosophila model of Alzheimer’s disease. Front. Aging Neurosci. 6, 190 (2014).
McColl, G. et al. Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J. Biol. Chem. 283, 350–357 (2008).
Zarse, K. et al. Low-dose lithium uptake promotes longevity in humans and metazoans. Eur. J. Nutr. 50, 387–389 (2011).
Tam, Z. Y., Gruber, J., Ng, L. F., Halliwell, B. & Gunawan, R. Effects of lithium on age-related decline in mitochondrial turnover and function in Caenorhabditis elegans. J. Gerontol. A Biol. Sci. Med. Sci. 69, 810–820 (2014).
Castillo-Quan, J. I. et al. Lithium promotes longevity through GSK3/NRF2-dependent Hormesis. Cell Rep. 15, 638–650 (2016).
Martinsson, L. et al. Long-term lithium treatment in bipolar disorder is associated with longer leukocyte telomeres. Transl. Psychiat. 3, e261 (2013).
Schrauzer, G. N. & Shrestha, K. P. Lithium in drinking water. Br. J. Psychiatry 196, 159–160 (2010).
Ohgami, H., Terao, T., Shiotsuki, I., Ishii, N. & Iwata, N. Lithium levels in drinking water and risk of suicide. Br. J. Psychiatry 194, 464–465 (2009).
Brunt, K. R. et al. Role of WNT/β-catenin signaling in rejuvenating myogenic differentiation of aged mesenchymal stem cells from cardiac patients. Am. J. Pathol. 181, 2067–2078 (2012).
Quiroz, J. A., Machado-Vieira, R., Zarate, C. A. Jr. & Manji, H. K. Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 62, 50–60 (2010).
Forlenza, O. V., De-Paula, V. J. & Diniz, B. S. Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem. Neurosci. 5, 443–450 (2014).
Chiu, C. T. & Chuang, D. M. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol. Ther. 128, 281–304 (2010).
Farina, F. et al. The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease. Sci. Rep. 7, 4014 (2017).
Zhang, X. et al. Long-term treatment with lithium alleviates memory deficits and reduces amyloid-β production in an aged Alzheimer’s disease transgenic mouse model. J. Alzheimers Dis. 24, 739–749 (2011).
Sarkar, S. et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101–1111 (2005).
Renna, M., Jimenez-Sanchez, M., Sarkar, S. & Rubinsztein, D. C. Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. J. Biol. Chem. 285, 11061–11067 (2010).
Rome, L. H. & Lands, W. E. Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs. Proc. Natl Acad. Sci. USA 72, 4863–4865 (1975).
Vane, S. J. Aspirin and other anti-inflammatory drugs. Thorax 55 (Suppl. 2), S3–S9 (2000).
Wan, Q. L., Zheng, S. Q., Wu, G. S. & Luo, H. R. Aspirin extends the lifespan of Caenorhabditis elegans via AMPK and DAF-16/FOXO in dietary restriction pathway. Exp. Gerontol. 48, 499–506 (2013).
Danilov, A. et al. Influence of non-steroidal anti-inflammatory drugs on Drosophila melanogaster longevity. Oncotarget 6, 19428–19444 (2015).
Song, C. et al. Metabolome analysis of effect of aspirin on Drosophila lifespan extension. Exp. Gerontol. 95, 54–62 (2017).
Strong, R. et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7, 641–650 (2008).
Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).
Yin, M. J., Yamamoto, Y. & Gaynor, R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396, 77–80 (1998).
Bos, C. L. et al. Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A. Oncogene 25, 6447–6456 (2006).
He, C. et al. Enhanced longevity by ibuprofen, conserved in multiple species, occurs in yeast through inhibition of tryptophan import. PLoS Genet. 10, e1004860 (2014).
Ching, T. T., Chiang, W. C., Chen, C. S. & Hsu, A. L. Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity. Aging Cell 10, 506–519 (2011).
Cao, Y. et al. Population-wide impact of long-term use of aspirin and the risk for cancer. JAMA Oncol. 2, 762–769 (2016).
Cuzick, J. Preventive therapy for cancer. Lancet Oncol. 18, e472–e482 (2017).
Sun, D. et al. Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition. Cancer Lett. 406, 105–115 (2017).
Rothwell, P. M. et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376, 1741–1750 (2010).
Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379, 1591–1601 (2012).
Guirguis-Blake, J. M. et al. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force (Agency for Healthcare Research and Quality, 2015).
Vlad, S. C., Miller, D. R., Kowall, N. W. & Felson, D. T. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70, 1672–1677 (2008).
Poly, T. N., Islam, M. M. R., Yang, H. C. & Li, Y. J. Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur. J. Clin. Pharmacol. 75, 99–108 (2019).
McNeil, J. J. et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N. Engl. J. Med. 379, 1509–1518 (2018).
Group, A. S. C. et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N. Engl. J. Med. 379, 1529–1539 (2018).
McNeil, J. J. et al. Effect of aspirin on disability-free survival in the healthy elderly. N. Engl. J. Med. 379, 1499–1508 (2018).
McNeil, J. J. et al. Effect of aspirin on all-cause mortality in the healthy elderly. N. Engl. J. Med. 379, 1519–1528 (2018).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Mouse Genome Sequencing Consortium et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).
Gilbert, N., Lutz-Prigge, S. & Moran, J. V. Genomic deletions created upon LINE-1 retrotransposition. Cell 110, 315–325 (2002).
Gasior, S. L., Wakeman, T. P., Xu, B. & Deininger, P. L. The human LINE-1 retrotransposon creates DNA double-strand breaks. J. Mol. Biol. 357, 1383–1393 (2006).
Iskow, R. C. et al. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141, 1253–1261 (2010).
Reilly, M. T., Faulkner, G. J., Dubnau, J., Ponomarev, I. & Gage, F. H. The role of transposable elements in health and diseases of the central nervous system. J. Neurosci. 33, 17577–17586 (2013).
Hancks, D. C. & Kazazian, H. H. Jr. Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 22, 191–203 (2012).
Van Meter, M. et al. SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat. Commun. 5, 5011 (2014).
Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).
Dai, L., Huang, Q. & Boeke, J. D. Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. BMC Biochem. 12, 18 (2011).
Jones, R. B. et al. Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition. PLoS One 3, e1547 (2008).
Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885.e5 (2019).
De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).
Margolis, A. M., Heverling, H., Pham, P. A. & Stolbach, A. A review of the toxicity of HIV medications. J. Med. Toxicol. 10, 26–39 (2014).
Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).
Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).
Wyss-Coray, T. Ageing, neurodegeneration and brain rejuvenation. Nature 539, 180–186 (2016).
Horowitz, A. M. & Villeda, S. A. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease. F1000Res 6, 1291 (2017).
Conboy, M. J., Conboy, I. M. & Rando, T. A. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell 12, 525–530 (2013).
Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).
Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).
Ruckh, J. M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012).
Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).
Huang, Q. et al. A young blood environment decreases aging of senile mice kidneys. J. Gerontol. A Biol. Sci. Med. Sci. 73, 421–428 (2018).
Salpeter, S. J. et al. Systemic regulation of the age-related decline of pancreatic β-cell replication. Diabetes 62, 2843–2848 (2013).
Baht, G. S. et al. Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nat. Commun. 6, 7131 (2015).
Castellano, J. M. et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492 (2017).
Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).
Smith, L. K. et al. 2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat. Med. 21, 932–937 (2015).
Gontier, G. et al. Tet2 rescues age-related regenerative decline and enhances cognitive function in the adult mouse brain. Cell Rep. 22, 1974–1981 (2018).
Loffredo, F. S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013).
Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014).
Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).
Hinken, A. C. et al. Lack of evidence for GDF11 as a rejuvenator of aged skeletal muscle satellite cells. Aging Cell 15, 582–584 (2016).
Egerman, M. A. et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 22, 164–174 (2015).
Yousef, H. et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat. Med. 25, 988–1000 (2019).
Middeldorp, J. et al. Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol. 73, 1325–1333 (2016).
Sha, S. J. et al. Safety, tolerability, and feasibility of young plasma infusion in the plasma for Alzheimer symptom amelioration study: a randomized clinical trial. JAMA Neurol. 76, 35–40 (2019).
Clark, R. I. et al. Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep. 12, 1656–1667 (2015).
Langille, M. G. et al. Microbial shifts in the aging mouse gut. Microbiome 2, 50 (2014).
O’Toole, P. W. & Jeffery, I. B. Gut microbiota and aging. Science 350, 1214–1215 (2015).
Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016).
Fabbiano, S. et al. Functional gut microbiota remodeling contributes to the caloric restriction-induced metabolic improvements. Cell Metab. 28, 907–921.e7 (2018).
Hara, T. & Miyajima, A. Two distinct functional high affinity receptors for mouse interleukin-3 (IL-3). EMBO J. 11, 1875–1884 (1992).
Dalirfardouei, R., Karimi, G. & Jamialahmadi, K. Molecular mechanisms and biomedical applications of glucosamine as a potential multifunctional therapeutic agent. Life Sci. 152, 21–29 (2016).
Weimer, S. et al. D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat. Commun. 5, 3563 (2014).
Yang, W. & Hekimi, S. A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol. 8, e1000556 (2010).
Hwang, A. B. et al. Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 111, E4458–E4467 (2014).
Banerjee, P. S., Lagerlof, O. & Hart, G. W. Roles of O-GlcNAc in chronic diseases of aging. Mol. Asp. Med. 51, 1–15 (2016).
Miller, R. A. et al. Glycine supplementation extends lifespan of male and female mice. Aging Cell 18, e12953 (2019).
Brind, J. et al. Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats. FASEB J. 25 (Suppl. 1), 528.522–528.522 (2011).
Liu, Y. J. et al. Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion. PLoS Genet. 15, e1007633 (2019).
Edwards, C. et al. Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC Genet. 16, 8 (2015).
Alarcon-Aguilar, F. J. et al. Glycine regulates the production of pro-inflammatory cytokines in lean and monosodium glutamate-obese mice. Eur. J. Pharmacol. 599, 152–158 (2008).
Wang, W. et al. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids 45, 463–477 (2013).
Zhong, Z. et al. L-glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Curr. Opin. Clin. Nutr. Metab. Care 6, 229–240 (2003).
Alves, A., Bassot, A., Bulteau, A. L., Pirola, L. & Morio, B. Glycine metabolism and its alterations in obesity and metabolic diseases. Nutrients 11, 1356 (2019).
Stekovic, S. et al. Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans. Cell Metab. 30, 462–476.e6 (2019).
Kitada, M., Ogura, Y., Monno, I. & Koya, D. The impact of dietary protein intake on longevity and metabolic health. EBioMedicine 43, 632–640 (2019).
Simpson, S. J. et al. Dietary protein, aging and nutritional geometry. Ageing Res. Rev. 39, 78–86 (2017).
Piper, M. D. W. et al. Matching dietary amino acid balance to the in silico-translated exome optimizes growth and reproduction without cost to lifespan. Cell Metab. 25, 1206 (2017).
Parkhitko, A. A., Jouandin, P., Mohr, S. E. & Perrimon, N. Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species. Aging Cell 18, e13034 (2019).
Strong, R. et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15, 872–884 (2016).
Stout, M. B. et al. 17α-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. J. Gerontol. A Biol. Sci. Med. Sci. 72, 3–15 (2017).
Garratt, M. et al. 17-α estradiol ameliorates age-associated sarcopenia and improves late-life physical function in male mice but not in females or castrated males. Aging Cell 18, e12920 (2019).
Green, P. S., Bishop, J. & Simpkins, J. W. 17α-estradiol exerts neuroprotective effects on SK-N-SH cells. J. Neurosci. 17, 511–515 (1997).
Green, P. S., Gridley, K. E. & Simpkins, J. W. Estradiol protects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neurosci. Lett. 218, 165–168 (1996).
Cordey, M., Gundimeda, U., Gopalakrishna, R. & Pike, C. J. The synthetic estrogen 4-estren-3 alpha,17 beta-diol (estren) induces estrogen-like neuroprotection. Neurobiol. Dis. 19, 331–339 (2005).
Gelinas, S. et al. Alpha and beta estradiol protect neuronal but not native PC12 cells from paraquat-induced oxidative stress. Neurotox. Res. 6, 141–148 (2004).
Steyn, F. J. et al. 17alpha-estradiol acts through hypothalamic pro-opiomelanocortin expressing neurons to reduce feeding behavior. Aging Cell 17, e12703 (2018).
Dai, H., Sinclair, D. A., Ellis, J. L. & Steegborn, C. Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol. Ther. 188, 140–154 (2018).
Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
Fransquet, P. D., Wrigglesworth, J., Woods, R. L., Ernst, M. E. & Ryan, J. The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis. Clin. Epigenetics 11, 62 (2019).
Wang, T. et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 18, 57 (2017).
Chen, W. et al. Three-dimensional human facial morphologies as robust aging markers. Cell Res. 25, 574–587 (2015).
Chen, D. et al. Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell Rep. 5, 1600–1610 (2013).
Sagi, D. & Kim, S. K. An engineering approach to extending lifespan in C. elegans. PLoS Genet. 8, e1002780 (2012).
Hou, L. et al. A systems approach to reverse engineer lifespan extension by dietary restriction. Cell Metab. 23, 529–540 (2016).
Dakik, P. et al. Pairwise combinations of chemical compounds that delay yeast chronological aging through different signaling pathways display synergistic effects on the extent of aging delay. Oncotarget 10, 313–338 (2019).
Admasu, T. D. et al. Drug synergy slows aging and improves healthspan through IGF and SREBP lipid signaling. Dev. Cell 47, 67–79.e5 (2018).
Castillo-Quan, J. I. et al. A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. Proc. Natl Acad. Sci. USA 116, 20817–20819 (2019).
Petrascheck, M., Ye, X. & Buck, L. B. An antidepressant that extends lifespan in adult Caenorhabditis elegans. Nature 450, 553–556 (2007).
Ye, X., Linton, J. M., Schork, N. J., Buck, L. B. & Petrascheck, M. A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell 13, 206–215 (2014).
Benedetti, M. G. et al. Compounds that confer thermal stress resistance and extended lifespan. Exp. Gerontol. 43, 882–891 (2008).
Hoose, S. A. et al. Systematic analysis of cell cycle effects of common drugs leads to the discovery of a suppressive interaction between gemfibrozil and fluoxetine. PLoS One 7, e36503 (2012).
Sarnoski, E. A., Liu, P. & Acar, M. A high-throughput screen for yeast replicative lifespan identifies lifespan-extending compounds. Cell Rep. 21, 2639–2646 (2017).
Zimmermann, A. et al. Yeast as a tool to identify anti-aging compounds. FEMS Yeast Res. 18, foy020 (2018).
Vatolin, S., Radivoyevitch, T. & Maciejewski, J. P. New drugs for pharmacological extension of replicative life span in normal and progeroid cells. NPJ Aging Mech. Dis. 5, 2 (2019).
Donertas, H. M., Fuentealba, M., Partridge, L. & Thornton, J. M. Identifying potential ageing-modulating drugs in silico. Trends Endocrinol. Metab. 30, 118–131 (2019).
Craig, T. et al. The digital ageing atlas: integrating the diversity of age-related changes into a unified resource. Nucleic Acids Res. 43, D873–D878 (2015).
Digital Aging Atlas. DAA http://ageing-map.org (2015).
Tacutu, R. et al. Human ageing genomic resources: new and updated databases. Nucleic Acids Res. 46, D1083–D1090 (2018).
Human Ageing Genomic Resources. senescence.info http://genomics.senescence.info (2018).
Blankenburg, H., Pramstaller, P. P. & Domingues, F. S. A network-based meta-analysis for characterizing the genetic landscape of human aging. Biogerontology 19, 81–94 (2018).
Kim, S. et al. PubChem substance and compound databases. Nucleic Acids Res. 44, D1202–D1213 (2016).
National Center for Biotechnology Information. PubChem https://pubchem.ncbi.nlm.nih.gov/ (2016).
Royal Society of Chemistry. ChemSpider http://www.chemspider.com (2015).
Stitch Consortium. Stitch http://stitch.embl.de (2016).
Liu, H. et al. Screening lifespan-extending drugs in Caenorhabditis elegans via label propagation on drug-protein networks. BMC Syst. Biol. 10, 131 (2016).
Snell, T. W. et al. Repurposed FDA-approved drugs targeting genes influencing aging can extend lifespan and healthspan in rotifers. Biogerontology 19, 145–157 (2018).
Barardo, D. G. et al. Machine learning for predicting lifespan-extending chemical compounds. Aging 9, 1721–1737 (2017).
Aliper, A. et al. In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aging 8, 2127–2152 (2016).
Donertas, H. M., Fuentealba Valenzuela, M., Partridge, L. & Thornton, J. M. Gene expression-based drug repurposing to target aging. Aging Cell 17, e12819 (2018).
Janssens, G. E. et al. Transcriptomics-based screening identifies pharmacological inhibition of Hsp90 as a means to defer aging. Cell Rep. 27, 467–480 e466 (2019).
Yang, J. et al. Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases. GeroScience https://doi.org/10.1007/s11357-019-00106-x (2020).
Fuentealba, M. et al. Using the drug-protein interactome to identify anti-ageing compounds for humans. PLoS Comput. Biol. 15, e1006639 (2019).
Broad Institute. Connectivity map (CMap). Broad Institute https://www.broadinstitute.org/connectivity-map-cmap (2018).
Lamb, J. et al. The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935 (2006).
Subramanian, A. et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171, 1437–1452.e17 (2017).
Calvert, S. et al. A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans. Aging Cell 15, 256–266 (2016).
National Institute on Aging. Interventions Testing Program (ITP). NIA https://www.nia.nih.gov/research/dab/interventions-testing-program-itp (2019).
L.P. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 741989), and from the Wellcome Trust (UK). M.F. has received funding from the Comisión Nacional de Investigación Científica y Tecnológica-Government of Chile (CONICYT scholarship).
B.K.K. is board chair of Torcept Therapeutics, a board member and scientific adviser for PDL Pharma, a scientific adviser for AFFIRMATIVhealth, and a board member of L-Nutra. B.K.K. is named on patents held by PDL Pharma related to ageing interventions and performs corporate-sponsored research for Gero LLC. L.P. and M.F. declare no competing interests.
The time in a person’s life when they are in general good health.
Decline in function of the immune system with age.
Chemicals that prevent senescent cells from producing the senescence-associated secretory phenotype, which can damage surrounding tissue and cause systemic inflammation.
- Dietary restriction
(DR). Reduced food intake from its voluntary level while avoiding malnutrition.
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Partridge, L., Fuentealba, M. & Kennedy, B.K. The quest to slow ageing through drug discovery. Nat Rev Drug Discov 19, 513–532 (2020). https://doi.org/10.1038/s41573-020-0067-7
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