Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.

Aging and Neurodegeneration Lab German Center for Neurodegenerative Diseases Venusberg Campus 1 99 53127 Bonn Germany

Center of Allergy and Environment Technische Universität München and Helmholtz Zentrum München 85764 Neuherberg Germany

Chair of Developmental Genetics TUM School of Life Sciences Technische Universität München Freising Germany

Chair of Experimental Genetics TUM School of Life Sciences Technische Universität München 85354 Freising Germany

Department of Neurology Faculty of Medicine University of Bonn Bonn Germany

DZNE German Center for Neurodegenerative Diseases 80336 Munich Germany

Friedrich Baur Institut Department of Neurology Ludwig Maximilians University Munich 80336 Munich Germany

GEMoaB GmbH Tatzberg 47 01307 Dresden Germany

Institute for Medical Biometry Informatics and Epidemiology Faculty of Medicine University of Bonn Venusberg Campus 1 53127 Bonn Germany

Institute for Medical Microbiology Immunology and Hygiene Technische Universität München 81675 Munich Germany

Institute of Developmental Genetics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Institute of Experimental Genetics German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany

Institute of Molecular Animal Breeding and Biotechnology Gene Center Ludwig Maximilians University Munich Munich Germany

Institute of Molecular Genetics of the Czech Academy of Sciences Czech Centre for Phenogenomics Prumyslova 595 Vestec 252 50 Czech Republic

Laboratory of Cancer Biology and Genetics CCR NCI NIH Bethesda MD 20892 USA

Mailman School of Public Health Columbia University 630W 168th St New York NY 10032 USA

Member of German Center for Diabetes Research 85764 Neuherberg Germany

Molecular Nutritional Medicine Else Kröner Fresenius Center Technische Universität München 85350 Freising Weihenstephan Germany

Munich Cluster for Systems Neurology 80336 Munich Germany

Nuclear Function Lab German Center for Neurodegenerative Diseases Venusberg Campus 1 99 53127 Bonn Germany

Population Health Sciences German Center for Neurodegenerative Diseases Venusberg Campus 1 99 53127 Bonn Germany

Research Group Experimental Neuropsychopharmacology Federal Institute for Drugs and Medical Devices 53175 Bonn Germany

Translational Biogerontology Lab German Center for Neurodegenerative Diseases Venusberg Campus 1 99 53127 Bonn Germany

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Tacutu R, et al. Human Ageing Genomic Resources: new and updated databases. Nucleic Acids Res. 2018;46:D1083–D1090. doi: 10.1093/nar/gkx1042. PubMed DOI PMC

Barardo D, et al. The DrugAge database of aging-related drugs. Aging Cell. 2017;16:594–597. doi: 10.1111/acel.12585. PubMed DOI PMC

Miller, R.A. Biology of Aging and Longevity. In: Hazzard’s Geriatric Medicine and Gerontology (eds. Halter, J.B. et al.) (McGraw Hill, 2009).

Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–1217. doi: 10.1016/j.cell.2013.05.039. PubMed DOI PMC

Blackwell BN, Bucci TJ, Hart RW, Turturro A. Longevity, body weight, and neoplasia in ad libitum-fed and diet-restricted C57BL6 mice fed NIH-31 open formula diet. Toxicol. Pathol. 1995;23:570–582. doi: 10.1177/019262339502300503. PubMed DOI

Pettan-Brewer C, Treuting PM. Practical pathology of aging mice. Pathobiol. Aging Age-Relat. Dis. 2011;1:7202. doi: 10.3402/pba.v1i0.7202. PubMed DOI PMC

Brayton CF, Treuting PM, Ward JM. Pathobiology of aging mice and GEM: background strains and experimental design. Vet. Pathol. 2012;49:85–105. doi: 10.1177/0300985811430696. PubMed DOI

Lipman R, Galecki A, Burke DT, Miller RA. Genetic loci that influence cause of death in a heterogeneous mouse stock. J. Gerontol. A Biol. Sci. Med Sci. 2004;59:977–983. doi: 10.1093/gerona/59.10.B977. PubMed DOI PMC

Miller RA, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med Sci. 2011;66:191–201. doi: 10.1093/gerona/glq178. PubMed DOI PMC

Xie K, et al. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice. Nat. Commun. 2017;8:155. doi: 10.1038/s41467-017-00178-3. PubMed DOI PMC

Rose, M. R. Evolutionary biology of aging, (Oxford University Press, Oxford, 1991).

Rockstein, M., Chesky, J. A. & Sussman, M. Comparative biology and evolution of aging. In: Handbook of the biology of aging 3-34 (Van Nostrand Reinhold Company, New York, 1977).

Aspinall, R. Aging of the Organs and Systems, (Kluwer Academic Publishers, 2003).

Abdulla, A. & Rai, G.S. The biology of ageing and its clinical implications, (Radcliffe Publishing, London, 2013).

Freund A. Untangling Aging Using Dynamic, Organism-Level Phenotypic Networks. Cell Syst. 2019;8:172–181. doi: 10.1016/j.cels.2019.02.005. PubMed DOI

Neff F, et al. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 2013;123:3272–3291. doi: 10.1172/JCI67674. PubMed DOI PMC

Bellantuono I, et al. A toolbox for the longitudinal assessment of healthspan in aging mice. Nat. Protoc. 2020;15:540–574. doi: 10.1038/s41596-019-0256-1. PubMed DOI PMC

Ehninger D, Neff F, Xie K. Longevity, aging and rapamycin. Cell Mol. Life Sci. 2014;71:4325–4346. doi: 10.1007/s00018-014-1677-1. PubMed DOI PMC

Richardson, A. & McCarter, R. Mechanism of food restriction: change of rate or change of set point. In: The potential for nutritional modulation of aging processes (eds. Ingram, D. K., Baker, G. T. & Shock, N. W.) 177–192 (Food & Nutrition Press, Inc., 1992).

Meszaros, L., Hoffmann, A., Wihan, J. & Winkler, J. Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy. Int. J. Mol. Sci.21, 2775 (2020). PubMed PMC

Hampel H, et al. Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives. Nat. Rev. Drug Disco. 2010;9:560–574. doi: 10.1038/nrd3115. PubMed DOI

Cummings J, Fox N. Defining Disease Modifying Therapy for Alzheimer’s Disease. J. Prev. Alzheimers Dis. 2017;4:109–115. PubMed PMC

Espay, A. & Stecher, B. Symptomatic vs. Disease-Modifying Therapies. in Brain Fables: The Hidden History of Neurodegenerative Diseases and a Blueprint to Conquer Them 87–93 (Cambridge University Press, 2020).

Vellai T, et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426:620. doi: 10.1038/426620a. PubMed DOI

Kapahi P, et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 2004;14:885–890. doi: 10.1016/j.cub.2004.03.059. PubMed DOI PMC

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;131:3897–3906. doi: 10.1242/dev.01255. PubMed DOI

Pan KZ, et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell. 2007;6:111–119. doi: 10.1111/j.1474-9726.2006.00266.x. PubMed DOI PMC

Harrison DE, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–395. doi: 10.1038/nature08221. PubMed DOI PMC

Chen C, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2009;2:ra75. doi: 10.1126/scisignal.2000559. PubMed DOI PMC

Bjedov I, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11:35–46. doi: 10.1016/j.cmet.2009.11.010. PubMed DOI PMC

Anisimov VN, et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011;10:4230–4236. doi: 10.4161/cc.10.24.18486. PubMed DOI

Robida-Stubbs S, et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 2012;15:713–724. doi: 10.1016/j.cmet.2012.04.007. PubMed DOI PMC

Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338–345. doi: 10.1038/nature11861. PubMed DOI PMC

Zhang Y, et al. Rapamycin Extends Life and Health in C57BL/6 Mice. J. Gerontol. A Biol. Sci. Med Sci. 2014;69:119–130. doi: 10.1093/gerona/glt056. PubMed DOI PMC

Wu JJ, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 2013;4:913–920. doi: 10.1016/j.celrep.2013.07.030. PubMed DOI PMC

Miller RA, et al. Rapamycin-Mediated Lifespan Increase in Mice is Dose and Sex-Dependent and Appears Metabolically Distinct from Dietary Restriction. Aging Cell. 2014;13:468–477. doi: 10.1111/acel.12194. PubMed DOI PMC

Fok WC, et al. Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS One. 2014;9:e83988. doi: 10.1371/journal.pone.0083988. PubMed DOI PMC

Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J. Gerontol. A Biol. Sci. Med Sci. 2016;71:876–881. doi: 10.1093/gerona/glw064. PubMed DOI PMC

Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife5, e16351 (2016). PubMed PMC

Wang T, et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 2017;18:57. doi: 10.1186/s13059-017-1186-2. PubMed DOI PMC

Schinaman JM, Rana A, Ja WW, Clark RI, Walker DW. Rapamycin modulates tissue aging and lifespan independently of the gut microbiota in Drosophila. Sci. Rep. 2019;9:7824. doi: 10.1038/s41598-019-44106-5. PubMed DOI PMC

Ferrara-Romeo I, et al. The mTOR pathway is necessary for survival of mice with short telomeres. Nat. Commun. 2020;11:1168. doi: 10.1038/s41467-020-14962-1. PubMed DOI PMC

Strong R, et al. Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects. Aging Cell. 2020;19:e13269. doi: 10.1111/acel.13269. PubMed DOI PMC

Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461–464. doi: 10.1038/366461a0. PubMed DOI

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. doi: 10.1093/genetics/118.1.75. PubMed DOI PMC

Flurkey K, Papaconstantinou J, Harrison DE. The Snell dwarf mutation Pit1(dw) can increase life span in mice. Mech. Ageing Dev. 2002;123:121–130. doi: 10.1016/S0047-6374(01)00339-6. PubMed DOI

Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A. Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J. Gerontol. A Biol. Sci. Med Sci. 2003;58:291–296. doi: 10.1093/gerona/58.4.B291. PubMed DOI

Ikeno Y, et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A Biol. Sci. Med Sci. 2009;64:522–529. doi: 10.1093/gerona/glp017. PubMed DOI PMC

Masternak MM, Panici JA, Bonkowski MS, Hughes LF, Bartke A. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J. Gerontol. A Biol. Sci. Med Sci. 2009;64:516–521. doi: 10.1093/gerona/glp024. PubMed DOI PMC

Sun, L.Y. et al. Longevity is impacted by growth hormone action during early postnatal period. Elife6, e24059 (2017). PubMed PMC

Mattison JA, et al. Studies of aging in ames dwarf mice: Effects of caloric restriction. J. Am. Aging Assoc. 2000;23:9–16. PubMed PMC

Brown-Borg HM, et al. Growth hormone signaling is necessary for lifespan extension by dietary methionine. Aging Cell. 2014;13:1019–1027. doi: 10.1111/acel.12269. PubMed DOI PMC

Aguiar-Oliveira MH, Bartke A. Growth Hormone Deficiency: Health and Longevity. Endocr. Rev. 2019;40:575–601. doi: 10.1210/er.2018-00216. PubMed DOI PMC

Vitale G, Pellegrino G, Vollery M, Hofland LJ. ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians’ Perspective. Front Endocrinol. (Lausanne) 2019;10:27. doi: 10.3389/fendo.2019.00027. PubMed DOI PMC

Duran-Ortiz S, et al. Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan. Aging Cell. 2021;20:e13506. doi: 10.1111/acel.13506. PubMed DOI PMC

Lamming, D. W. Extending Lifespan by Inhibiting the Mechanistic Target of Rapamycin (mTOR). In: Anti-aging Drugs: From Basic Research to Clinical Practice (ed. Vaiserman, A.M.) 352-375 (The Royal Society of Chemistry, 2017).

Zhang S, et al. Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production. Blood. 2011;117:1228–1238. doi: 10.1182/blood-2010-05-287821. PubMed DOI PMC

Zhang S, et al. B cell-specific deficiencies in mTOR limit humoral immune responses. J. Immunol. 2013;191:1692–1703. doi: 10.4049/jimmunol.1201767. PubMed DOI PMC

Eicher EM, Beamer WG. Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. J. Hered. 1976;67:87–91. doi: 10.1093/oxfordjournals.jhered.a108682. PubMed DOI

Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA. 2001;98:6736–6741. doi: 10.1073/pnas.111158898. PubMed DOI PMC

Ward DD, et al. Association of retinal layer measurements and adult cognitive function: A population-based study. Neurology. 2020;95:e1144–e1152. doi: 10.1212/WNL.0000000000010146. PubMed DOI

McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J. Nutr. 1935;10:63–79. doi: 10.1093/jn/10.1.63. PubMed DOI

Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N. Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech. Ageing Dev. 1990;55:69–87. doi: 10.1016/0047-6374(90)90107-Q. PubMed DOI

Someya S, et al. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc. Natl Acad. Sci. USA. 2009;106:19432–19437. doi: 10.1073/pnas.0908786106. PubMed DOI PMC

Henson, S. M. & Aspinall, R. Aging and the Immune System. In: Aging of Organs and Systems (ed. Aspinall, R.) 225-242 (Kluwer Academic Publishers, 2003).

Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat. Immunol. 2004;5:133–139. doi: 10.1038/ni1033. PubMed DOI

Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 2009;9:57–62. doi: 10.1038/nri2471. PubMed DOI

Bonda TA, et al. Remodeling of the intercalated disc related to aging in the mouse heart. J. Cardiol. 2016;68:261–268. doi: 10.1016/j.jjcc.2015.10.001. PubMed DOI

Mason JW, et al. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J. Electrocardiol. 2007;40:228–234. doi: 10.1016/j.jelectrocard.2006.09.003. PubMed DOI

Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell11, 675–682 (2012). PubMed PMC

Bartke A. Growth Hormone and Aging: Updated Review. World J. Mens. Health. 2019;37:19–30. doi: 10.5534/wjmh.180018. PubMed DOI PMC

Bartke A, Quainoo N. Impact of Growth Hormone-Related Mutations on Mammalian Aging. Front Genet. 2018;9:586. doi: 10.3389/fgene.2018.00586. PubMed DOI PMC

Garcia, J. M., Merriam, G. R. & Kargi, A. Y. Growth Hormone in Aging. In: Endotext (eds. Feingold, K. R. et al.) (South Dartmouth (MA), 2000).

Kim SS, Lee CK. Growth signaling and longevity in mouse models. BMB Rep. 2019;52:70–85. doi: 10.5483/BMBRep.2019.52.1.299. PubMed DOI PMC

Carrie I, Debray M, Bourre JM, Frances H. Age-induced cognitive alterations in OF1 mice. Physiol. Behav. 1999;66:651–656. doi: 10.1016/S0031-9384(99)00003-7. PubMed DOI

GTEx-Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369:1318–1330. doi: 10.1126/science.aaz1776. PubMed DOI PMC

Shan T, et al. Adipocyte-specific deletion of mTOR inhibits adipose tissue development and causes insulin resistance in mice. Diabetologia. 2016;59:1995–2004. doi: 10.1007/s00125-016-4006-4. PubMed DOI PMC

Selman C. Dietary restriction and the pursuit of effective mimetics. Proc. Nutr. Soc. 2014;73:260–270. doi: 10.1017/S0029665113003832. PubMed DOI

Speakman JR, Mitchell SE. Caloric restriction. Mol. Asp. Med. 2011;32:159–221. doi: 10.1016/j.mam.2011.07.001. PubMed DOI

Bordner KA, et al. Parallel declines in cognition, motivation, and locomotion in aging mice: association with immune gene upregulation in the medial prefrontal cortex. Exp. Gerontol. 2011;46:643–659. PubMed PMC

Sprott RL, Eleftheriou BE. Open-field behavior in aging inbred mice. Gerontologia. 1974;20:155–162. doi: 10.1159/000212009. PubMed DOI

Alderman JM, et al. Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp. Gerontol. 2009;44:26–33. doi: 10.1016/j.exger.2008.05.014. PubMed DOI PMC

Keshavarz, M., Xie, K., Schaaf, K., Bano, D. & Ehninger, D. Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction? Mol. Psychiatry10.1038/s41380-022-01680-x (2022). PubMed PMC

Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging. 2009;1:281–288. doi: 10.18632/aging.100034. PubMed DOI PMC

Blagosklonny MV. Rapamycin and quasi-programmed aging: four years later. Cell Cycle. 2010;9:1859–1862. doi: 10.4161/cc.9.10.11872. PubMed DOI

Xiang L, He G. Caloric restriction and antiaging effects. Ann. Nutr. Metab. 2011;58:42–48. doi: 10.1159/000323748. PubMed DOI

Blagosklonny MV. Prospective treatment of age-related diseases by slowing down aging. Am. J. Pathol. 2012;181:1142–1146. doi: 10.1016/j.ajpath.2012.06.024. PubMed DOI

Sohal RS, Forster MJ. Caloric restriction and the aging process: a critique. Free Radic. Biol. Med. 2014;73:366–382. doi: 10.1016/j.freeradbiomed.2014.05.015. PubMed DOI PMC

Blagosklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017;8:35492–35507. doi: 10.18632/oncotarget.18033. PubMed DOI PMC

Klimova B, Novotny M, Kuca K. Anti-Aging Drugs - Prospect of Longer Life? Curr. Med Chem. 2018;25:1946–1953. doi: 10.2174/0929867325666171129215251. PubMed DOI

Flanagan EW, Most J, Mey JT, Redman LM. Calorie Restriction and Aging in Humans. Annu Rev. Nutr. 2020;40:105–133. doi: 10.1146/annurev-nutr-122319-034601. PubMed DOI PMC

Mueller, L. D., Rauser, C. L. & Rose, M. R. Aging Stops: Late Life, Evolutionary Biology, and Gerontology. In: Does Aging Stop? (Oxford University Press, New York, 2011).

Petr, M. A. et al. A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice. Elife10, e62952 (2021). PubMed PMC

Yang AC, et al. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature. 2020;583:425–430. doi: 10.1038/s41586-020-2453-z. PubMed DOI PMC

Schaum N, et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature. 2020;583:596–602. doi: 10.1038/s41586-020-2499-y. PubMed DOI PMC

Tabula Muris C. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature. 2020;583:590–595. doi: 10.1038/s41586-020-2496-1. PubMed DOI PMC

Ximerakis M, et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat. Neurosci. 2019;22:1696–1708. doi: 10.1038/s41593-019-0491-3. PubMed DOI

Fischer KE, et al. A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging (Albany NY) 2016;8:2370–2391. doi: 10.18632/aging.101059. PubMed DOI PMC

Hayflick L. When does aging begin? Res Aging. 1984;6:99–103. doi: 10.1177/0164027584006001005. PubMed DOI

Papadopoli, D. et al. mTOR as a central regulator of lifespan and aging. F1000Res.810.12688/f1000research.17196.1 (2019). PubMed PMC

Martineau CN, Brown AEX, Laurent P. Multidimensional phenotyping predicts lifespan and quantifies health in Caenorhabditis elegans. PLoS Comput Biol. 2020;16:e1008002. doi: 10.1371/journal.pcbi.1008002. PubMed DOI PMC

Zhang WB, et al. Extended Twilight among Isogenic C. elegans Causes a Disproportionate Scaling between Lifespan and Health. Cell Syst. 2016;3:333–345 e334. doi: 10.1016/j.cels.2016.09.003. PubMed DOI PMC

Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J. Gerontol. A Biol. Sci. Med Sci. 2007;62:722–727. doi: 10.1093/gerona/62.7.722. PubMed DOI

Fried LP, et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med Sci. 2001;56:M146–M156. doi: 10.1093/gerona/56.3.M146. PubMed DOI

Bell CG, et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 2019;20:249. doi: 10.1186/s13059-019-1824-y. PubMed DOI PMC

Xie K, et al. Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice. Proc. Natl Acad. Sci. USA. 2018;115:E2348–E2357. doi: 10.1073/pnas.1707337115. PubMed DOI PMC

Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med Sci. 2014;69(Suppl 1):S4–S9. doi: 10.1093/gerona/glu057. PubMed DOI

Shavlakadze T, et al. Age-Related Gene Expression Signature in Rats Demonstrate Early, Late, and Linear Transcriptional Changes from Multiple Tissues. Cell Rep. 2019;28:3263–3273 e3263. doi: 10.1016/j.celrep.2019.08.043. PubMed DOI

Mair W, Goymer P, Pletcher SD, Partridge L. Demography of dietary restriction and death in Drosophila. Science. 2003;301:1731–1733. doi: 10.1126/science.1086016. PubMed DOI

Hughes BG, Hekimi S. Different Mechanisms of Longevity in Long-Lived Mouse and Caenorhabditis elegans Mutants Revealed by Statistical Analysis of Mortality Rates. Genetics. 2016;204:905–920. doi: 10.1534/genetics.116.192369. PubMed DOI PMC

Hahm JH, et al. C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation. Nat. Commun. 2015;6:8919. doi: 10.1038/ncomms9919. PubMed DOI PMC

Zhao Y, et al. Two forms of death in ageing Caenorhabditis elegans. Nat. Commun. 2017;8:15458. doi: 10.1038/ncomms15458. PubMed DOI PMC

Podshivalova K, Kerr RA, Kenyon C. How a Mutation that Slows Aging Can Also Disproportionately Extend End-of-Life Decrepitude. Cell Rep. 2017;19:441–450. doi: 10.1016/j.celrep.2017.03.062. PubMed DOI PMC

Stroustrup N, et al. The temporal scaling of Caenorhabditis elegans ageing. Nature. 2016;530:103–107. doi: 10.1038/nature16550. PubMed DOI PMC

Cohen AA, Levasseur M, Raina P, Fried LP, Fulop T. Is Aging Biology Ageist? J. Gerontol. A Biol. Sci. Med Sci. 2020;75:1653–1655. doi: 10.1093/gerona/glz190. PubMed DOI

Le Couteur DG, Simpson SJ. Adaptive senectitude: the prolongevity effects of aging. J. Gerontol. A Biol. Sci. Med Sci. 2011;66:179–182. doi: 10.1093/gerona/glq171. PubMed DOI

Fuchs H, et al. Mouse phenotyping. Methods. 2011;53:120–135. doi: 10.1016/j.ymeth.2010.08.006. PubMed DOI

Gailus-Durner V, et al. Systemic first-line phenotyping. Methods Mol. Biol. 2009;530:463–509. doi: 10.1007/978-1-59745-471-1_25. PubMed DOI

Rogers DC, et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome. 1997;8:711–713. doi: 10.1007/s003359900551. PubMed DOI

Jones BJ, Roberts DJ. A rotarod suitable for quantitative measurements of motor incoordination in naive mice. Naunyn Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1968;259:211. doi: 10.1007/BF00537801. PubMed DOI

Schoensiegel F, et al. High throughput echocardiography in conscious mice: training and primary screens. Ultraschall Med. 2011;32(Suppl 1):S124–S129. PubMed

Roth DM, Swaney JS, Dalton ND, Gilpin EA, Ross J., Jr. Impact of anesthesia on cardiac function during echocardiography in mice. Am. J. Physiol. Heart Circ. Physiol. 2002;282:H2134–H2140. doi: 10.1152/ajpheart.00845.2001. PubMed DOI

Fischer MD, et al. Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography. PLoS One. 2009;4:e7507. doi: 10.1371/journal.pone.0007507. PubMed DOI PMC

Schmucker C, Schaeffel F. In vivo biometry in the mouse eye with low coherence interferometry. Vis. Res. 2004;44:2445–2456. doi: 10.1016/j.visres.2004.05.018. PubMed DOI

Prusky GT, Alam NM, Beekman S, Douglas RM. Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system. Invest Ophthalmol. Vis. Sci. 2004;45:4611–4616. doi: 10.1167/iovs.04-0541. PubMed DOI

Rathkolb B, et al. Blood Collection from Mice and Hematological Analyses on Mouse Blood. Curr. Protoc. Mouse Biol. 2013;3:101–119. doi: 10.1002/9780470942390.mo130054. PubMed DOI

Weaver JL, Broud DD, McKinnon K, Germolec DR. Serial phenotypic analysis of mouse peripheral blood leukocytes. Toxicol. Mech. Methods. 2002;12:95–118. doi: 10.1080/10517230290075341. PubMed DOI

Roederer M, Nozzi JL, Nason MC. SPICE: exploration and analysis of post-cytometric complex multivariate datasets. Cytom. A. 2011;79:167–174. doi: 10.1002/cyto.a.21015. PubMed DOI PMC

Baumgarth N, Roederer M. A practical approach to multicolor flow cytometry for immunophenotyping. J. Immunol. Methods. 2000;243:77–97. doi: 10.1016/S0022-1759(00)00229-5. PubMed DOI

Hou Z, et al. A cost-effective RNA sequencing protocol for large-scale gene expression studies. Sci. Rep. 2015;5:9570. doi: 10.1038/srep09570. PubMed DOI PMC

Lawrence M, Gentleman R, Carey V. rtracklayer: an R package for interfacing with genome browsers. Bioinformatics. 2009;25:1841–1842. doi: 10.1093/bioinformatics/btp328. PubMed DOI PMC

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. doi: 10.1186/s13059-014-0550-8. PubMed DOI PMC

Li Y, Tomko RJ, Jr., Hochstrasser M. Proteasomes: Isolation and Activity Assays. Curr. Protoc. Cell Biol. 2015;67:3 43 41–43 43 20. doi: 10.1002/0471143030.cb0343s67. PubMed DOI PMC

Driver AS, Kodavanti PR, Mundy WR. Age-related changes in reactive oxygen species production in rat brain homogenates. Neurotoxicol Teratol. 2000;22:175–181. doi: 10.1016/S0892-0362(99)00069-0. PubMed DOI

Aziz, N. A. et al. Seroprevalence and correlates of SARS-CoV-2 neutralizing antibodies: Results from a population-based study in Bonn, Germany. Nat. Commun.12, 2117 (2020). PubMed PMC

Estrada S, et al. FatSegNet: A fully automated deep learning pipeline for adipose tissue segmentation on abdominal dixon MRI. Magn. Reson Med. 2020;83:1471–1483. doi: 10.1002/mrm.28022. PubMed DOI PMC

Ehninger, D. Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice. Zenodo10.5281/zenodo.7142629 (2022). PubMed PMC

A review of standardized high-throughput cardiovascular phenotyping with a link to metabolism in mice

Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice