{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:12:07Z","timestamp":1790845927795,"version":"4.1.0"},"reference-count":71,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A 2018 report from the American Heart Association shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin\u2013angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, and heart failure, among others. It has been suggested that ACE inhibitors can alleviate the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that genetic variants of the ACE gene are risk factors for Alzheimer\u2019s disease (AD) and other neurological diseases, while other variants are associated with reduced risk of AD. In mice, ACE overexpression in the brain reduces symptoms of the AD model systems. Thus, we find two opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin\u2013angiotensin system; (2) amyloid-degrading enzyme that hydrolyzes beta-amyloid, reducing amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to AD to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during midlife, leading to age-related later events.<\/jats:p>","DOI":"10.3390\/ijms222413178","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T09:52:29Z","timestamp":1638870749000},"page":"13178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Two Opposing Functions of Angiotensin-Converting Enzyme (ACE) That Links Hypertension, Dementia, and Aging"],"prefix":"10.3390","volume":"22","author":[{"given":"Duc","family":"Le","sequence":"first","affiliation":[{"name":"Department of Basic Sciences, Master of Science in Medical Health Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Master of Science in Medical Health Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kundan","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Master of Science in Medical Health Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8806-0611","authenticated-orcid":false,"given":"Shin","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Master of Science in Medical Health Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1084\/jem.103.3.295","article-title":"The preparation and function of the hypertensin-converting enzyme","volume":"103","author":"Skeggs","year":"1956","journal-title":"J. Exp. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.127.3292.242.b","article-title":"Suggested Revision of Nomenclature\u2014Angiotensin","volume":"127","author":"Page","year":"1958","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1056\/NEJM197410172911603","article-title":"An Angiotensin Converting-Enzyme Inhibitor to Identify and Treat Vasoconstrictor and Volume Factors in Hypertensive Patients","volume":"291","author":"Gavras","year":"1974","journal-title":"N. Engl. J. Med."},{"key":"ref_4","first-page":"16","article-title":"Experimental and clinical studies with converting enzyme inhibitor","volume":"12","author":"Haber","year":"1976","journal-title":"Prog. Biochem. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1016\/j.peptides.2009.07.003","article-title":"Seven decades of angiotensin (1939\u20132009)","volume":"30","author":"Skrbic","year":"2009","journal-title":"Peptides"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7741","DOI":"10.1073\/pnas.86.20.7741","article-title":"Molecular cloning of human testicular angiotensin-converting enzyme: The testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme","volume":"86","author":"Ehlers","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","first-page":"CD001841","article-title":"First-line drugs for hypertension","volume":"4","author":"Wright","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/S0011-5029(96)90019-X","article-title":"Secondary hypertension: Evaluation and treatment","volume":"42","author":"Akpunonu","year":"1996","journal-title":"Disease-a-Month"},{"key":"ref_9","first-page":"67","article-title":"Diagnosing Secondary Hypertension","volume":"67","author":"Onusko","year":"2003","journal-title":"Am. Fam. Physician"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3389\/fgene.2017.00055","article-title":"Meta Analysis of Human AlzGene Database: Benefits and Limitations of Using C. elegans for the Study of Alzheimer\u2019s Disease and Co-morbid Conditions","volume":"8","author":"Nia","year":"2017","journal-title":"Front. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.17756\/jnen.2020-069","article-title":"Evidence-based geneti5 Editorial Board, cs and identification of key human Alzheimer\u2019s disease alleles with co-morbidities","volume":"6","author":"Le","year":"2020","journal-title":"J. Neurol. Exp. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"The Brainstorm Consortium, Anttila, V., Bulik-Sullivan, B., Finucane, H.K., Walters, R.K., Bras, J., Duncan, L., Escott-Price, V., Falcone, G.J., and Gormley, P. (2018). Analysis of shared heritability in common disorders of the brain. Science, 360, eaap8757.","DOI":"10.1126\/science.aap8757"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3389\/fphar.2018.00440","article-title":"Targeting Renin\u2013Angiotensin System Against Alzheimer\u2019s Disease","volume":"9","author":"Gebre","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tadic, M., Cuspidi, C., and Hering, D. (2016). Hypertension and cognitive dysfunction in elderly: Blood pressure management for this global burden. BMC Cardiovasc. Disord., 16.","DOI":"10.1186\/s12872-016-0386-0"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"700","DOI":"10.3390\/idr13030065","article-title":"Unusually High Risks of COVID-19 Mortality with Age-Related Comorbidities: An Adjusted Meta-Analysis Method to Improve the Risk Assessment of Mortality Using the Comorbid Mortality Data","volume":"13","author":"Antos","year":"2021","journal-title":"Infect. Dis. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1081\/IAS-100102895","article-title":"Development of an enzyme immunoassay for a stable amidated analog of the hemoregulatory peptide acetyl-ser-asp-lys-pro","volume":"22","author":"Junot","year":"2001","journal-title":"J. Immunoass. Immunochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1161\/01.HYP.0000151323.93372.f5","article-title":"Selective Angiotensin-Converting Enzyme C-Domain Inhibition Is Sufficient to Prevent Angiotensin I\u2013Induced Vasoconstriction","volume":"45","author":"Tom","year":"2005","journal-title":"Hypertension"},{"key":"ref_18","first-page":"91","article-title":"Update on angiotensin AT2 receptors","volume":"26","author":"Carey","year":"2017","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14109","DOI":"10.1073\/pnas.1612668113","article-title":"Role of the receptor Mas in macrophage-mediated inflammation in vivo","volume":"113","author":"Hammer","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s11906-020-01071-z","article-title":"Age of Hypertension Onset: Overview of Research and How to Apply in Practice","volume":"22","author":"Suvila","year":"2020","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ki.2011.142","article-title":"Combination inhibition of the renin\u2013angiotensin system: Is more better?","volume":"80","author":"Krause","year":"2011","journal-title":"Kidney Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1056\/NEJM200105033441802","article-title":"Lesser Response to Angiotensin-Converting\u2013Enzyme Inhibitor Therapy in Black as Compared with White Patients with Left Ventricular Dysfunction","volume":"344","author":"Exner","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18014","DOI":"10.1038\/nrdp.2018.14","article-title":"Hypertension","volume":"4","author":"Oparil","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease and Stroke Statistics\u20142021 Update: A Report From the American Heart Association","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0304-3940(99)00827-7","article-title":"Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population","volume":"277","author":"Hu","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/5009","article-title":"Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease","volume":"21","author":"Kehoe","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_27","unstructured":"(2021, October 01). AlzGene.org. Available online: https:\/\/www.alzgene.org\/geneoverview.asp?geneid=125."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1212\/01.WNL.0000106823.72493.FF","article-title":"Alzheimer disease risk and genetic variation in ACE: A meta-analysis","volume":"62","author":"Elkins","year":"2004","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1093\/aje\/kwi202","article-title":"Large Meta-Analysis Establishes the ACE Insertion-Deletion Polymorphism as a Marker of Alzheimer\u2019s Disease","volume":"162","author":"Lehmann","year":"2005","journal-title":"Am. J. Epidemiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ng1934","article-title":"Systematic meta-analyses of Alzheimer disease genetic association studies: The AlzGene database","volume":"39","author":"Bertram","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neulet.2009.06.006","article-title":"An age effect on the association of common variants of ACE with Alzheimer\u2019s disease","volume":"461","author":"Helbecque","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nrneurol.2016.84","article-title":"Genetic variants in Alzheimer disease\u2014Molecular and brain network approaches","volume":"12","author":"Gaiteri","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2147\/VHRM.S75306","article-title":"Cognitive impairment and stroke in elderly patients","volume":"12","author":"Corrao","year":"2016","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s12974-018-1313-3","article-title":"Inflammation: The link between comorbidities, genetics, and Alzheimer\u2019s disease","volume":"15","author":"Newcombe","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s10571-020-00796-4","article-title":"Caveolin: A New Link between Diabetes and AD","volume":"40","author":"Surguchov","year":"2020","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/8760","article-title":"Sequence variation in the human angiotensin converting enzyme","volume":"22","author":"Rieder","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.neulet.2004.11.062","article-title":"ACE I\/D polymorphism is a risk factor of Alzheimer\u2019s disease but not of vascular dementia","volume":"377","author":"Jessen","year":"2005","journal-title":"Neurosci. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.neurobiolaging.2004.09.011","article-title":"ACE gene is associated with Alzheimer\u2019s disease and atrophy of hippocampus and amygdala","volume":"26","author":"Sleegers","year":"2005","journal-title":"Neurobiol. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1093\/hmg\/ddg094","article-title":"Haplotypes extending across ACE are associated with Alzheimer\u2019s disease","volume":"12","author":"Kehoe","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kauwe, J.S.K., Bailey, M.H., Ridge, P.G., Perry, R., Wadsworth, M.E., Hoyt, K.L., Staley, L.A., Karch, C., Harari, O., and Cruchaga, C. (2014). Genome-Wide Association Study of CSF Levels of 59 Alzheimer\u2019s Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004758"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8628","DOI":"10.1523\/JNEUROSCI.1549-07.2007","article-title":"Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition en-hances brain Abeta deposition","volume":"27","author":"Zou","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"eaaz2541","DOI":"10.1126\/scitranslmed.aaz2541","article-title":"A\u03b2-accelerated neurodegeneration caused by Alzheimer\u2019s-associated ACE variant R1279Q is rescued by angiotensin system inhibition in mice","volume":"12","author":"Cuddy","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_44","first-page":"163","article-title":"Angiotensin-converting enzyme levels and activity in Alzheimer\u2019s disease: Differences in brain and CSF ACE and association with ACE1 genotypes","volume":"1","author":"Miners","year":"2009","journal-title":"Am. J. Transl. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/bcp.14141","article-title":"Risk factors associated with biochemically detected and hospitalised acute kidney injury in patients prescribed renin angiotensin system inhibitors","volume":"86","author":"Mark","year":"2020","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16917","DOI":"10.3390\/ijms140816917","article-title":"ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer\u2019s Disease","volume":"14","author":"Abdalla","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1471-4159.2011.07510.x","article-title":"Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer\u2019s disease?","volume":"120","author":"Nalivaeva","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1111\/bph.14593","article-title":"Targeting amyloid clearance in Alzheimer\u2019s disease as a therapeutic strategy","volume":"176","author":"Nalivaeva","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"47863","DOI":"10.1074\/jbc.M104068200","article-title":"Angiotensin-converting Enzyme Degrades Alzheimer Amyloid \u03b2-Peptide (A\u03b2); Retards A\u03b2 Aggregation, Deposition, Fibril Formation; and Inhibits Cytotoxicity","volume":"276","author":"Hu","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/j.1460-9568.2005.03912.x","article-title":"The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid \u03b2-peptide","volume":"21","author":"Oba","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"37644","DOI":"10.1074\/jbc.M508460200","article-title":"Amyloid \u03b2-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor","volume":"280","author":"Hemming","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1172\/JCI66541","article-title":"Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer\u2019s-like cognitive decline","volume":"124","author":"Bernstein","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/brain\/awz364","article-title":"Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease","volume":"143","author":"Sheyn","year":"2020","journal-title":"Brain"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.peptides.2003.12.010","article-title":"Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: A brief history, the beginning and follow-ups to early studies","volume":"25","year":"2004","journal-title":"Peptides"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1042\/bj2620125","article-title":"Novel activity of angiotensin-converting enzyme. Hydrolysis of cholecystokinin and gastrin analogues with release of the amidated C-terminal dipeptide","volume":"262","author":"Dubreuil","year":"1989","journal-title":"Biochem. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"9496","DOI":"10.1016\/S0021-9258(18)98378-X","article-title":"Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides","volume":"268","author":"Jaspard","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Kumar, S., Dietrich, N., and Kornfeld, K. (2016). Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005866"},{"key":"ref_58","first-page":"1844","article-title":"Lisinopril Preserves Physical Resilience and Extends Life Span in a Genotype-Specific Manner in Drosophila melanogaster","volume":"74","author":"Gabrawy","year":"2019","journal-title":"J. Gerontol. Ser. A Boil. Sci. Med. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s11357-016-9948-4","article-title":"Combined statin and angiotensin-converting enzyme (ACE) inhibitor treatment increases the lifespan of long-lived F1 male mice","volume":"38","author":"Spindler","year":"2016","journal-title":"AGE"},{"key":"ref_60","first-page":"B392","article-title":"Hypothesis: Interventions That Increase the Response to Stress Offer the Potential for Effective Life Prolongation and Increased Health","volume":"51","author":"Johnson","year":"1996","journal-title":"J. Gerontol. Ser. A Boil. Sci. Med. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1093\/genetics\/143.3.1207","article-title":"A Genetic Pathway Conferring Life Extension and Resistance to UV Stress in Caenorhabditis elegans","volume":"143","author":"Murakami","year":"1996","journal-title":"Genetics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1096\/fj.02-1092fje","article-title":"Multiplex stress resistance in cells from long-lived dwarf mice","volume":"17","author":"Murakami","year":"2003","journal-title":"FASEB J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.exger.2006.06.061","article-title":"Stress resistance in long-lived mouse models","volume":"41","author":"Murakami","year":"2006","journal-title":"Exp. Gerontol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.mam.2011.10.007","article-title":"Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity","volume":"32","author":"Calabrese","year":"2011","journal-title":"Mol. Asp. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1152\/physrev.00006.2012","article-title":"Somatotropic Signaling: Trade-Offs Between Growth, Reproductive Development, and Longevity","volume":"93","author":"Bartke","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fgene.2014.00202","article-title":"A semi-automated motion-tracking analysis of locomotion speed in the C. elegans transgenics overexpressing beta-amyloid in neurons","volume":"5","author":"Machino","year":"2014","journal-title":"Front. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"20200916","DOI":"10.1098\/rsbl.2020.0916","article-title":"Genes implicated in Caenorhabditis elegans and human health regulate stress resistance and physical abilities in aged Caenorhabditis elegans","volume":"17","author":"Dysarz","year":"2021","journal-title":"Biol. Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF02700625","article-title":"Caenorhabditis elegans as a model system to study aging of learning and memory","volume":"35","author":"Murakami","year":"2007","journal-title":"Mol. Neurobiol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Farooqui, T. (2011). Current advances in the study of oxidative stress and age-related memory impairment in C. elegans. Molecular Aspects of Oxidative Stress on Cell Signaling in Verte-Brates and Invertebrates, Wiley-Blackwell Publisher.","DOI":"10.1002\/9781118148143"},{"key":"ref_70","unstructured":"Menzel, R., and Benjamin, P.R. (2013). Age-dependent modulation of learning and memory in C. elegans. Handbook of Behavioral Neuroscience, Elsevier. Chapter 12."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1080\/14737175.2020.1708195","article-title":"Antihypertensive agents in Alzheimer\u2019s disease: Beyond vascular protection","volume":"20","author":"Lebouvier","year":"2020","journal-title":"Expert Rev. Neurother."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:42:17Z","timestamp":1760168537000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,7]]},"references-count":71,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222413178"],"URL":"https:\/\/doi.org\/10.3390\/ijms222413178","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202110.0197.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,7]]}}}