Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 11 2022
11 11 2022
Historique:
received:
25
03
2022
accepted:
27
10
2022
pubmed:
13
11
2022
medline:
16
11
2022
entrez:
12
11
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36369285
doi: 10.1038/s41467-022-34515-y
pii: 10.1038/s41467-022-34515-y
pmc: PMC9652467
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6830Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
Références
Tacutu, R. et al. Human Ageing Genomic Resources: new and updated databases. Nucleic Acids Res. 46, D1083–D1090 (2018).
doi: 10.1093/nar/gkx1042
Barardo, D. et al. The DrugAge database of aging-related drugs. Aging Cell 16, 594–597 (2017).
doi: 10.1111/acel.12585
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, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
doi: 10.1016/j.cell.2013.05.039
Blackwell, B. N., Bucci, T. J., Hart, R. W. & Turturro, A. Longevity, body weight, and neoplasia in ad libitum-fed and diet-restricted C57BL6 mice fed NIH-31 open formula diet. Toxicol. Pathol. 23, 570–582 (1995).
doi: 10.1177/019262339502300503
Pettan-Brewer, C. & Treuting, P. M. Practical pathology of aging mice. Pathobiol. Aging Age-Relat. Dis. 1, 7202 (2011).
doi: 10.3402/pba.v1i0.7202
Brayton, C. F., Treuting, P. M. & Ward, J. M. Pathobiology of aging mice and GEM: background strains and experimental design. Vet. Pathol. 49, 85–105 (2012).
doi: 10.1177/0300985811430696
Lipman, R., Galecki, A., Burke, D. T. & Miller, R. A. Genetic loci that influence cause of death in a heterogeneous mouse stock. J. Gerontol. A Biol. Sci. Med Sci. 59, 977–983 (2004).
doi: 10.1093/gerona/59.10.B977
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).
doi: 10.1093/gerona/glq178
Xie, K. et al. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice. Nat. Commun. 8, 155 (2017).
doi: 10.1038/s41467-017-00178-3
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. 8, 172–181 (2019).
doi: 10.1016/j.cels.2019.02.005
Neff, F. et al. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest 123, 3272–3291 (2013).
doi: 10.1172/JCI67674
Bellantuono, I. et al. A toolbox for the longitudinal assessment of healthspan in aging mice. Nat. Protoc. 15, 540–574 (2020).
doi: 10.1038/s41596-019-0256-1
Ehninger, D., Neff, F. & Xie, K. Longevity, aging and rapamycin. Cell Mol. Life Sci. 71, 4325–4346 (2014).
doi: 10.1007/s00018-014-1677-1
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).
Hampel, H. et al. Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives. Nat. Rev. Drug Disco. 9, 560–574 (2010).
doi: 10.1038/nrd3115
Cummings, J. & Fox, N. Defining Disease Modifying Therapy for Alzheimer’s Disease. J. Prev. Alzheimers Dis. 4, 109–115 (2017).
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 426, 620 (2003).
doi: 10.1038/426620a
Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).
doi: 10.1016/j.cub.2004.03.059
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).
doi: 10.1242/dev.01255
Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6, 111–119 (2007).
doi: 10.1111/j.1474-9726.2006.00266.x
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
doi: 10.1038/nature08221
Chen, C., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal 2, ra75 (2009).
doi: 10.1126/scisignal.2000559
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
doi: 10.1016/j.cmet.2009.11.010
Anisimov, V. N. et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10, 4230–4236 (2011).
doi: 10.4161/cc.10.24.18486
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).
doi: 10.1016/j.cmet.2012.04.007
Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).
doi: 10.1038/nature11861
Zhang, Y. et al. Rapamycin Extends Life and Health in C57BL/6 Mice. J. Gerontol. A Biol. Sci. Med Sci. 69, 119–130 (2014).
doi: 10.1093/gerona/glt056
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).
doi: 10.1016/j.celrep.2013.07.030
Miller, R. A. et al. Rapamycin-Mediated Lifespan Increase in Mice is Dose and Sex-Dependent and Appears Metabolically Distinct from Dietary Restriction. Aging Cell 13, 468–477 (2014).
doi: 10.1111/acel.12194
Fok, W. C. et al. Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS One 9, e83988 (2014).
doi: 10.1371/journal.pone.0083988
Arriola Apelo, S. I., Pumper, C. P., Baar, E. L., Cummings, N. E. & Lamming, D. W. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J. Gerontol. A Biol. Sci. Med Sci. 71, 876–881 (2016).
doi: 10.1093/gerona/glw064
Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife 5, e16351 (2016).
Wang, T. et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 18, 57 (2017).
doi: 10.1186/s13059-017-1186-2
Schinaman, J. M., Rana, A., Ja, W. W., Clark, R. I. & Walker, D. W. Rapamycin modulates tissue aging and lifespan independently of the gut microbiota in Drosophila. Sci. Rep. 9, 7824 (2019).
doi: 10.1038/s41598-019-44106-5
Ferrara-Romeo, I. et al. The mTOR pathway is necessary for survival of mice with short telomeres. Nat. Commun. 11, 1168 (2020).
doi: 10.1038/s41467-020-14962-1
Strong, R. et al. Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects. Aging Cell 19, e13269 (2020).
doi: 10.1111/acel.13269
Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).
doi: 10.1038/366461a0
Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).
doi: 10.1093/genetics/118.1.75
Flurkey, K., Papaconstantinou, J. & Harrison, D. E. The Snell dwarf mutation Pit1(dw) can increase life span in mice. Mech. Ageing Dev. 123, 121–130 (2002).
doi: 10.1016/S0047-6374(01)00339-6
Ikeno, Y., Bronson, R. T., Hubbard, G. B., 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. 58, 291–296 (2003).
doi: 10.1093/gerona/58.4.B291
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. 64, 522–529 (2009).
doi: 10.1093/gerona/glp017
Masternak, M. M., Panici, J. A., Bonkowski, M. S., Hughes, L. F. & Bartke, A. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J. Gerontol. A Biol. Sci. Med Sci. 64, 516–521 (2009).
doi: 10.1093/gerona/glp024
Sun, L.Y. et al. Longevity is impacted by growth hormone action during early postnatal period. Elife 6, e24059 (2017).
Mattison, J. A. et al. Studies of aging in ames dwarf mice: Effects of caloric restriction. J. Am. Aging Assoc. 23, 9–16 (2000).
Brown-Borg, H. M. et al. Growth hormone signaling is necessary for lifespan extension by dietary methionine. Aging Cell 13, 1019–1027 (2014).
doi: 10.1111/acel.12269
Aguiar-Oliveira, M. H. & Bartke, A. Growth Hormone Deficiency: Health and Longevity. Endocr. Rev. 40, 575–601 (2019).
doi: 10.1210/er.2018-00216
Vitale, G., Pellegrino, G., Vollery, M. & Hofland, L. J. ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians’ Perspective. Front Endocrinol. (Lausanne) 10, 27 (2019).
doi: 10.3389/fendo.2019.00027
Duran-Ortiz, S. et al. Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan. Aging Cell 20, e13506 (2021).
doi: 10.1111/acel.13506
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 117, 1228–1238 (2011).
doi: 10.1182/blood-2010-05-287821
Zhang, S. et al. B cell-specific deficiencies in mTOR limit humoral immune responses. J. Immunol. 191, 1692–1703 (2013).
doi: 10.4049/jimmunol.1201767
Eicher, E. M. & Beamer, W. G. Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. J. Hered. 67, 87–91 (1976).
doi: 10.1093/oxfordjournals.jhered.a108682
Flurkey, K., Papaconstantinou, J., Miller, R. A. & Harrison, D. E. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc. Natl Acad. Sci. USA 98, 6736–6741 (2001).
doi: 10.1073/pnas.111158898
Ward, D. D. et al. Association of retinal layer measurements and adult cognitive function: A population-based study. Neurology 95, e1144–e1152 (2020).
doi: 10.1212/WNL.0000000000010146
McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon the ultimate body size. J. Nutr. 10, 63–79 (1935).
doi: 10.1093/jn/10.1.63
Goodrick, C. L., Ingram, D. K., Reynolds, M. A., Freeman, J. R. & Cider, N. Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech. Ageing Dev. 55, 69–87 (1990).
doi: 10.1016/0047-6374(90)90107-Q
Someya, S. et al. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc. Natl Acad. Sci. USA 106, 19432–19437 (2009).
doi: 10.1073/pnas.0908786106
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, P. J. & Dorshkind, K. Age-related changes in lymphocyte development and function. Nat. Immunol. 5, 133–139 (2004).
doi: 10.1038/ni1033
Dorshkind, K., Montecino-Rodriguez, E. & Signer, R. A. The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 9, 57–62 (2009).
doi: 10.1038/nri2471
Bonda, T. A. et al. Remodeling of the intercalated disc related to aging in the mouse heart. J. Cardiol. 68, 261–268 (2016).
doi: 10.1016/j.jjcc.2015.10.001
Mason, J. W. et al. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J. Electrocardiol. 40, 228–234 (2007).
doi: 10.1016/j.jelectrocard.2006.09.003
Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012).
Bartke, A. Growth Hormone and Aging: Updated Review. World J. Mens. Health 37, 19–30 (2019).
doi: 10.5534/wjmh.180018
Bartke, A. & Quainoo, N. Impact of Growth Hormone-Related Mutations on Mammalian Aging. Front Genet 9, 586 (2018).
doi: 10.3389/fgene.2018.00586
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, S. S. & Lee, C. K. Growth signaling and longevity in mouse models. BMB Rep. 52, 70–85 (2019).
doi: 10.5483/BMBRep.2019.52.1.299
Carrie, I., Debray, M., Bourre, J. M. & Frances, H. Age-induced cognitive alterations in OF1 mice. Physiol. Behav. 66, 651–656 (1999).
doi: 10.1016/S0031-9384(99)00003-7
GTEx-Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020).
doi: 10.1126/science.aaz1776
Shan, T. et al. Adipocyte-specific deletion of mTOR inhibits adipose tissue development and causes insulin resistance in mice. Diabetologia 59, 1995–2004 (2016).
doi: 10.1007/s00125-016-4006-4
Selman, C. Dietary restriction and the pursuit of effective mimetics. Proc. Nutr. Soc. 73, 260–270 (2014).
doi: 10.1017/S0029665113003832
Speakman, J. R. & Mitchell, S. E. Caloric restriction. Mol. Asp. Med 32, 159–221 (2011).
doi: 10.1016/j.mam.2011.07.001
Bordner, K. A. et al. Parallel declines in cognition, motivation, and locomotion in aging mice: association with immune gene upregulation in the medial prefrontal cortex. Exp. Gerontol. 46, 643–659 (2011).
Sprott, R. L. & Eleftheriou, B. E. Open-field behavior in aging inbred mice. Gerontologia 20, 155–162 (1974).
doi: 10.1159/000212009
Alderman, J. M. et al. Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp. Gerontol. 44, 26–33 (2009).
doi: 10.1016/j.exger.2008.05.014
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. Psychiatry https://doi.org/10.1038/s41380-022-01680-x (2022).
Blagosklonny, M. V. Validation of anti-aging drugs by treating age-related diseases. Aging 1, 281–288 (2009).
doi: 10.18632/aging.100034
Blagosklonny, M. V. Rapamycin and quasi-programmed aging: four years later. Cell Cycle 9, 1859–1862 (2010).
doi: 10.4161/cc.9.10.11872
Xiang, L. & He, G. Caloric restriction and antiaging effects. Ann. Nutr. Metab. 58, 42–48 (2011).
doi: 10.1159/000323748
Blagosklonny, M. V. Prospective treatment of age-related diseases by slowing down aging. Am. J. Pathol. 181, 1142–1146 (2012).
doi: 10.1016/j.ajpath.2012.06.024
Sohal, R. S. & Forster, M. J. Caloric restriction and the aging process: a critique. Free Radic. Biol. Med 73, 366–382 (2014).
doi: 10.1016/j.freeradbiomed.2014.05.015
Blagosklonny, M. V. From rapalogs to anti-aging formula. Oncotarget 8, 35492–35507 (2017).
doi: 10.18632/oncotarget.18033
Klimova, B., Novotny, M. & Kuca, K. Anti-Aging Drugs - Prospect of Longer Life? Curr. Med Chem. 25, 1946–1953 (2018).
doi: 10.2174/0929867325666171129215251
Flanagan, E. W., Most, J., Mey, J. T. & Redman, L. M. Calorie Restriction and Aging in Humans. Annu Rev. Nutr. 40, 105–133 (2020).
doi: 10.1146/annurev-nutr-122319-034601
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. Elife 10, e62952 (2021).
Yang, A. C. et al. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 583, 425–430 (2020).
doi: 10.1038/s41586-020-2453-z
Schaum, N. et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature 583, 596–602 (2020).
doi: 10.1038/s41586-020-2499-y
Tabula Muris, C. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020).
doi: 10.1038/s41586-020-2496-1
Ximerakis, M. et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat. Neurosci. 22, 1696–1708 (2019).
doi: 10.1038/s41593-019-0491-3
Fischer, K. E. et al. A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging (Albany NY) 8, 2370–2391 (2016).
doi: 10.18632/aging.101059
Hayflick, L. When does aging begin? Res Aging 6, 99–103 (1984).
doi: 10.1177/0164027584006001005
Papadopoli, D. et al. mTOR as a central regulator of lifespan and aging. F1000Res. 8 https://doi.org/10.12688/f1000research.17196.1 (2019).
Martineau, C. N., Brown, A. E. X. & Laurent, P. Multidimensional phenotyping predicts lifespan and quantifies health in Caenorhabditis elegans. PLoS Comput Biol. 16, e1008002 (2020).
doi: 10.1371/journal.pcbi.1008002
Zhang, W. B. et al. Extended Twilight among Isogenic C. elegans Causes a Disproportionate Scaling between Lifespan and Health. Cell Syst. 3, 333–345 e334 (2016).
doi: 10.1016/j.cels.2016.09.003
Rockwood, K. & Mitnitski, A. Frailty in relation to the accumulation of deficits. J. Gerontol. A Biol. Sci. Med Sci. 62, 722–727 (2007).
doi: 10.1093/gerona/62.7.722
Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med Sci. 56, M146–M156 (2001).
doi: 10.1093/gerona/56.3.M146
Bell, C. G. et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 20, 249 (2019).
doi: 10.1186/s13059-019-1824-y
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 115, E2348–E2357 (2018).
doi: 10.1073/pnas.1707337115
Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med Sci. 69(Suppl 1), S4–S9 (2014).
doi: 10.1093/gerona/glu057
Shavlakadze, T. et al. Age-Related Gene Expression Signature in Rats Demonstrate Early, Late, and Linear Transcriptional Changes from Multiple Tissues. Cell Rep. 28, 3263–3273 e3263 (2019).
doi: 10.1016/j.celrep.2019.08.043
Mair, W., Goymer, P., Pletcher, S. D. & Partridge, L. Demography of dietary restriction and death in Drosophila. Science 301, 1731–1733 (2003).
doi: 10.1126/science.1086016
Hughes, B. G. & Hekimi, S. Different Mechanisms of Longevity in Long-Lived Mouse and Caenorhabditis elegans Mutants Revealed by Statistical Analysis of Mortality Rates. Genetics 204, 905–920 (2016).
doi: 10.1534/genetics.116.192369
Hahm, J. H. et al. C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation. Nat. Commun. 6, 8919 (2015).
doi: 10.1038/ncomms9919
Zhao, Y. et al. Two forms of death in ageing Caenorhabditis elegans. Nat. Commun. 8, 15458 (2017).
doi: 10.1038/ncomms15458
Podshivalova, K., Kerr, R. A. & Kenyon, C. How a Mutation that Slows Aging Can Also Disproportionately Extend End-of-Life Decrepitude. Cell Rep. 19, 441–450 (2017).
doi: 10.1016/j.celrep.2017.03.062
Stroustrup, N. et al. The temporal scaling of Caenorhabditis elegans ageing. Nature 530, 103–107 (2016).
doi: 10.1038/nature16550
Cohen, A. A., Levasseur, M., Raina, P., Fried, L. P. & Fulop, T. Is Aging Biology Ageist? J. Gerontol. A Biol. Sci. Med Sci. 75, 1653–1655 (2020).
doi: 10.1093/gerona/glz190
Le Couteur, D. G. & Simpson, S. J. Adaptive senectitude: the prolongevity effects of aging. J. Gerontol. A Biol. Sci. Med Sci. 66, 179–182 (2011).
doi: 10.1093/gerona/glq171
Fuchs, H. et al. Mouse phenotyping. Methods 53, 120–135 (2011).
doi: 10.1016/j.ymeth.2010.08.006
Gailus-Durner, V. et al. Systemic first-line phenotyping. Methods Mol. Biol. 530, 463–509 (2009).
doi: 10.1007/978-1-59745-471-1_25
Rogers, D. C. et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome 8, 711–713 (1997).
doi: 10.1007/s003359900551
Jones, B. J. & Roberts, D. J. A rotarod suitable for quantitative measurements of motor incoordination in naive mice. Naunyn Schmiedebergs Arch. Exp. Pathol. Pharmakol. 259, 211 (1968).
doi: 10.1007/BF00537801
Schoensiegel, F. et al. High throughput echocardiography in conscious mice: training and primary screens. Ultraschall Med 32(Suppl 1), S124–S129 (2011).
Roth, D. M., Swaney, J. S., Dalton, N. D., Gilpin, E. A. & Ross, J. Jr. Impact of anesthesia on cardiac function during echocardiography in mice. Am. J. Physiol. Heart Circ. Physiol. 282, H2134–H2140 (2002).
doi: 10.1152/ajpheart.00845.2001
Fischer, M. D. et al. Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography. PLoS One 4, e7507 (2009).
doi: 10.1371/journal.pone.0007507
Schmucker, C. & Schaeffel, F. In vivo biometry in the mouse eye with low coherence interferometry. Vis. Res 44, 2445–2456 (2004).
doi: 10.1016/j.visres.2004.05.018
Prusky, G. T., Alam, N. M., Beekman, S. & Douglas, R. M. Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system. Invest Ophthalmol. Vis. Sci. 45, 4611–4616 (2004).
doi: 10.1167/iovs.04-0541
Rathkolb, B. et al. Blood Collection from Mice and Hematological Analyses on Mouse Blood. Curr. Protoc. Mouse Biol. 3, 101–119 (2013).
doi: 10.1002/9780470942390.mo130054
Weaver, J. L., Broud, D. D., McKinnon, K. & Germolec, D. R. Serial phenotypic analysis of mouse peripheral blood leukocytes. Toxicol. Mech. Methods 12, 95–118 (2002).
doi: 10.1080/10517230290075341
Roederer, M., Nozzi, J. L. & Nason, M. C. SPICE: exploration and analysis of post-cytometric complex multivariate datasets. Cytom. A 79, 167–174 (2011).
doi: 10.1002/cyto.a.21015
Baumgarth, N. & Roederer, M. A practical approach to multicolor flow cytometry for immunophenotyping. J. Immunol. Methods 243, 77–97 (2000).
doi: 10.1016/S0022-1759(00)00229-5
Hou, Z. et al. A cost-effective RNA sequencing protocol for large-scale gene expression studies. Sci. Rep. 5, 9570 (2015).
doi: 10.1038/srep09570
Lawrence, M., Gentleman, R. & Carey, V. rtracklayer: an R package for interfacing with genome browsers. Bioinformatics 25, 1841–1842 (2009).
doi: 10.1093/bioinformatics/btp328
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
doi: 10.1186/s13059-014-0550-8
Li, Y., Tomko, R. J. Jr. & Hochstrasser, M. Proteasomes: Isolation and Activity Assays. Curr. Protoc. Cell Biol. 67, 3 43 41–43 43 20 (2015).
doi: 10.1002/0471143030.cb0343s67
Driver, A. S., Kodavanti, P. R. & Mundy, W. R. Age-related changes in reactive oxygen species production in rat brain homogenates. Neurotoxicol Teratol. 22, 175–181 (2000).
doi: 10.1016/S0892-0362(99)00069-0
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).
Estrada, S. et al. FatSegNet: A fully automated deep learning pipeline for adipose tissue segmentation on abdominal dixon MRI. Magn. Reson Med 83, 1471–1483 (2020).
doi: 10.1002/mrm.28022
Ehninger, D. Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice. Zenodo https://doi.org/10.5281/zenodo.7142629 (2022).