Aging and Genome Maintenance: Lessons from the Mouse?
Abstract
Recent progress in the science of aging is driven largely by the use of model systems, ranging from yeast and nematodes to mice. These models have revealed conservation in genetic pathways that balance energy production and its damaging by-products with pathways that preserve somatic maintenance. Maintaining genome integrity has emerged as a major factor in longevity and cell viability. Here we discuss the use of mouse models with defects in genome maintenance for understanding the molecular basis of aging in humans.
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Genes that help maintain genomic integrity also prevent or retard the development of other aging phenotypes and age-related pathologies.
“In addition to preventing cancer, genes that help maintain genomic integrity also prevent or retard the development of other aging phenotypes and age-related pathologies (Hasty et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Hasty et al., 2003
Many kinds of oncogenic or stressful stimuli can induce a senescence response, foremost certain types of DNA damage including DNA breaks and oxidative lesions.
“It is now apparent that many kinds of oncogenic or stressful stimuli can induce a senescence response. Foremost among these are certain types of DNA damage, including DNA breaks and oxidative lesions caused by environmental insults, genetic defects, or endogenous processes (DiLeonardo et al., 1994; Hasty et al., 2003; Samper et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Hasty et al., 2003
Mutations in genes involved in BER do not produce aging manifestations: they are either lethal or confer no obvious phenotypes.
“mutations in genes involved in this pathway do not produce aging manifestations: they are either lethal or confer no obvious phenotypes (Hasty et al., 2003”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Hasty et al., 2003
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The candidate tumor suppressor ING1b can stabilize p53 by disrupting the regulation of p53 by MDM2.
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Antagonism of Myc functions by Arf
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Chemopreventive agents induce a senescence-like phenotype in rat mammary tumours
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pRb inactivation in senescent cells leads to an E2F-dependent apoptosis requiring p73.
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Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,359 · see citing works
“In addition to preventing cancer, genes that help maintain genomic integrity also prevent or retard the development of other aging phenotypes and agerelated pathologies (Hasty et al., 2003).”
BackgroundSelf-citationRejuvenation of aged progenitor cells by exposure to a young systemic environment
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BackgroundTrends in oxidative aging theories
Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A., & Van Remmen, H. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.03.034 · Cited by 1,053 · see citing works
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BackgroundDNA Repair, Genome Stability, and Aging
Lombard, D. B., Chua, K. F., Mostoslavsky, R., Franco, S., Gostissa, M., & Alt, F. W. (2005) · Cell · doi:10.1016/j.cell.2005.01.028 · Cited by 944 · see citing works
The Free Radical Theory of Aging
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Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks
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BackgroundBubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice
Baker, D. J., Jeganathan, K. B., Cameron, J. D., Thompson, M., Juneja, S., Kopecka, A., Kumar, R., Jenkins, R. B., de Groen, P. C., Roche, P., et al. (2004) · Nature Genetics · doi:10.1038/ng1382 · Cited by 731 · see citing works
“We next determined whether BubR1 deficiency triggers apoptosis or cellular senescence, two responses that have been linked to agin”
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A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis
Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., et al. (2006) · Nature · doi:10.1038/nature05456 · Cited by 669 · see citing works
“Gene ontology classification (Supplementary Table 4) revealed: (1) global attenuation of the somatotroph, lactotroph and thyrotroph hormonal axes and other growth-promoting mechanisms; (2) downregulation of oxidative and carbohydrate metabolism; (3) upregulation of genes associated with glycogen synthesis but downregu…”
BackgroundSelf-citationGenomic instability in laminopathy-based premature aging
Liu, B., Wang, J., Chan, K. M., Tjia, W. M., Deng, W., Guan, X., Huang, J.-D., Li, K. M., Chau, P. Y., Chen, D. J., et al. (2005) · Nature Medicine · doi:10.1038/nm1266 · Cited by 650 · see citing works
“Recent studies on premature aging syndromes suggest that defects in maintaining genomic integrity can accelerate the aging proces”
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“Moreover, DNA damage is probably an important contributor to the accumulation of senescent cells in vivo (Hasty et al., 2003).”
BackgroundSelf-citationVascular Cell Senescence: Contribution to Atherosclerosis
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Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression
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Cancer and ageing: rival demons?
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“Recent findings show that defects in certain DNA-repair pathways increase both the incidence of cancer and the rate at which specific ageing phenotypes develo”
BackgroundSelf-citationDNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy
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Inflamm‐ageing and lifelong antigenic load as major determinants of ageing rate and longevity
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“Genome instability, driven by oxidative damage, is a primary cause of normal aging [7].”
BackgroundDNA damage, cellular senescence and organismal ageing: causal or correlative?
Chen, J.-H., Hales, C. N., & Ozanne, S. E. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm681 · Cited by 481 · see citing works
NF-κB inhibition delays DNA damage–induced senescence and aging in mice
Tilstra, J. S., Robinson, A. R., Wang, J., Gregg, S. Q., Clauson, C. L., Reay, D. P., Nasto, L. A., St Croix, C. M., Usas, A., Vo, N., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci45785 · Cited by 462 · see citing works
“DNA damage is one type of damage implicated in aging based on the fact that mutations affecting a diverse array of DNA repair mechanisms lead to accelerated aging of one or more tissues (66).”
BackgroundCoppé, J.-P., Patil, C. K., Rodier, F., Krtolica, A., Beauséjour, C. M., Parrinello, S., Hodgson, J. G., Chin, K., Desprez, P.-Y., & Campisi, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009188 · Cited by 455 · see citing works
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Cellular senescence: a link between cancer and age-related degenerative disease?
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“However, the xenograft studies support the idea that -- as both senescent cells and (mutant) premalignant cells accumulate with age [74] -the SASP of senescent cells might stimulate nearby premalignant cells to progress to full blown malignancy (Fig.”
BackgroundSelf-citationChanges in DNA repair during aging
Gorbunova, V., Seluanov, A., Mao, Z., & Hine, C. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm756 · Cited by 405 · see citing works
Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis
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“Tissue decline due to genomic instability has been explained by cellular senescence or apoptosis (14, 19, 20).”
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Tissue-specific stem cells: Lessons from the skeletal muscle satellite cell
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BackgroundDNA damage checkpoints in stem cells, ageing and cancer
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Bystrykh, L. V., Weersing, E., Dontje, B., Sutton, S., Pletcher, M. T., Wiltshire, T., Su, A. I., Vellenga, E., Wang, J., Manly, K. F., et al. (2005) · Nature Genetics · doi:10.1038/ng1497 · Cited by 390 · see citing works
“Together with recent reports using similar approaches 14–16, 20 , our results document the power of genetical genomics to”
ResultSIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species
Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., Tan, R., Simon, M., Henderson, S., Steffan, J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.043 · Cited by 353 · see citing works
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Self-citationMolecular mechanisms of biological aging in intervertebral discs
Vo, N. V., Hartman, R. A., Patil, P. R., Risbud, M. V., Kletsas, D., Iatridis, J. C., Hoyland, J. A., Maitre, C. L. L., Sowa, G., & Kang, J. D. (2016) · Journal of Orthopaedic Research® · doi:10.1002/jor.23195 · Cited by 378 · see citing works
“Inherited defects in genome maintenance mechanisms invariably lead to a variety of diseases characterized by accelerated aging of one or more organ systems.(12) For example, deficiency in humans of certain genes involved in repair of DNA damage, such as ERCC1XPF, leads to dramatic progeroid, or accelerated aging syndr…”
BackgroundGenotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation
Inomata, K., Aoto, T., Binh, N. T., Okamoto, N., Tanimura, S., Wakayama, T., Iseki, S., Hara, E., Masunaga, T., Shimizu, H., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.037 · Cited by 368 · see citing works
DNA damage and ageing: new-age ideas for an age-old problem
Garinis, G. A., van der Horst, G. T. J., Vijg, J., & H.J. Hoeijmakers, J. (2008) · Nature Cell Biology · doi:10.1038/ncb1108-1241 · Cited by 366 · see citing works
“In some cases, a mouse model even paved the way for identifying the parallel human syndrom”
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“LOH is but one of the consequences of the accumulation of somatic mutations that is one of the proposed mechanisms of aging (Hasty et al. 2003).”
BackgroundDNA-Damage Response in Tissue-Specific and Cancer Stem Cells
Blanpain, C., Mohrin, M., Sotiropoulou, P. A., & Passegue, E. A. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.012 · Cited by 350 · see citing works
Cytomegalovirus infection enhances the immune response to influenza
Furman, D., Jojic, V., Sharma, S., Shen-Orr, S. S., L. Angel, C. J., Onengut-Gumuscu, S., Kidd, B. A., Maecker, H. T., Concannon, P., Dekker, C. L., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa2293 · Cited by 332 · see citing works
The mechanics of base excision repair, and its relationship to aging and disease
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Clinical aspects and molecular diagnostics of skin aging
Zouboulis, C. C., & Makrantonaki, E. (2011) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2010.07.001 · Cited by 341 · see citing works
A Transcriptional Profile of Aging in the Human Kidney
Rodwell, G. E. J., Sonu, R., Zahn, J. M., Lund, J., Wilhelmy, J., Wang, L., Xiao, W., Mindrinos, M., Crane, E., Segal, E., et al. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020427 · Cited by 338 · see citing works
“Telomere shortening may also play a role in aging by preventing DNA replication and cell division in later years (Hasty et al. 2003).”
BackgroundMelanocyte stem cells: a melanocyte reservoir in hair follicles for hair and skin pigmentation
Nishimura, E. K. (2011) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2011.00855.x · Cited by 316 · see citing works
“Why does the self-renewal of MelSCs become defective during the course of aging? Premature hair greying is commonly seen in a number of progeria syndromes, such as Werner syndrome and ataxia telangiectasia (AT) (Hasty et al., 2003; Martin, 2005) as well as after exposure to ionizing irradiation (Coolidge, 1925).”
BackgroundCisd2 deficiency drives premature aging and causes mitochondria-mediated defects in micePreprint
Chen, Y., Kao, C., Chen, Y.-T., Wang, C., Wu, C.-Y., Tsai, C., Liu, F.-C., Yang, C.-W., Wei, Y., Hsu, M., et al. (2009) · Genes & Development · doi:10.1101/gad.1779509 · Cited by 304 · see citing works
“Starting at 8 wk old, Cisd2 / mice begin to acquire a set of aged appearance phenomena remarkably similar to those of premature aging syndrome (Hasty et al. 2003; Kipling et al. 2004).”
Backgroundp63 deficiency activates a program of cellular senescence and leads to accelerated agingPreprint
Keyes, W. M., Wu, Y., Vogel, H. S., Guo, X., Lowe, S. W., & Mills, A. A. (2005) · Genes & Development · doi:10.1101/gad.342305 · Cited by 296 · see citing works
“…and atrophy, de- creased dermal and adipose thickness, and sebaceous gland hyperplasia (de Boer et al. 2002; Tyner et al. 2002; Cao et al. 2003; Hasty et al. 2003; Maier et al. 2004; Sun et al. 2004; Trifunovic et al. 2004)—many of which we have described herein in mice with compromised p63.”
BackgroundGoronzy, J. J., & Weyand, C. M. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-0970-0 · Cited by 292 · see citing works
Molecular Mechanisms of Skin Aging
Makrantonaki, E., & Zouboulis, C. C. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1404.027 · Cited by 288 · see citing works
DNA damage response and metabolic disease
Shimizu, I., Yoshida, Y., Suda, M., & Minamino, T. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.008 · Cited by 286 · see citing works
DNA Damage Response Genes and the Development of Cancer Metastasis
Broustas, C. G., & Lieberman, H. B. (2014) · Radiation Research · doi:10.1667/rr13515.1 · Cited by 276 · see citing works
“The connection between DNA repair defects and carcinogenesis is highlighted by the fact that inherited defects in DNA repair mechanisms that cause progeroid or accelerated aging syndromes (9), including Ataxia telangiectasia, Nijmegen syndrome, Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Xeroderma pigm…”
BackgroundFehrer, C., & Lepperdinger, G. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.07.006 · Cited by 269 · see citing works
Vascular Cell Senescence Contributes to Blood–Brain Barrier Breakdown
Yamazaki, Y., Baker, D. J., Tachibana, M., Liu, C.-C., van Deursen, J. M., Brott, T. G., Bu, G., & Kanekiyo, T. (2016) · Stroke · doi:10.1161/strokeaha.115.010835 · Cited by 263 · see citing works
“Impaired BBB Integrity and Reduced TJ Protein Coverage in BubR1H/H Mice Growing evidence suggests that lack of genomic integrity contributes to the aging process in both humans and mice.(23) Because BubR1 is an essential component of the spindle assembly checkpoint proteins during mitosis, BubR1 mice, in which BubR1 e…”
Laminopathies and the long strange trip from basic cell biology to therapy
Worman, H. J., Fong, L. G., Muchir, A., & Young, S. G. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37679 · Cited by 256 · see citing works
Aging and chronic DNA damage response activate a regulatory pathway involving miR‐29 and p53
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Do DNA Double-Strand Breaks Drive Aging?
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“Nevertheless, important new findings based on such models have provided new insights into possible causes of aging (Hasty et al., 2003).”
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TAp63 Prevents Premature Aging by Promoting Adult Stem Cell Maintenance
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“Also, regenerative failure of tissues and premature aging arise in mice lacking genes critical for genomic stability and maintenance (Hasty et al., 2003).”
BackgroundThe hallmarks of fibroblast ageing
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“It is well documented that mice defective in mechanisms involved in the repair of oxidative DNA damage age faster and live shorter (Hasty et al., 2003).”
BackgroundGenetic mouse models of brain ageing and Alzheimer's disease
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A Life‐History Perspective on Short‐ and Long‐Term Consequences of Compensatory Growth
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“…occurs as a consequence of oxidative damage (e.g., Minakami and Fridovich 1990; Chatgilialoglu and O’Neill 2001; Karanjawala and Lieber 2004; Lu et al. 2004), and the maintenance of genome integrity is increasingly recognized as a major factor in longevity and cell viability (Hasty et al. 2003).”
BackgroundA review and appraisal of the DNA damage theory of ageing
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“]. These observations, together with the notion that DNA lesions can provoke a permanent cell cycle arrest or apoptosis, led us to propose that ageing can result from (oxidative) DNA lesions that interfere with transcription and/or replication causing cell death or cellular senescence, ultimately leading to the loss o…”
Self-citationTranscription — guarding the genome by sensing DNA damage
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“Although a responsive apoptotic pathway would efficiently remove damaged cells and therefore suppress carcinogenesis, such increased cell loss is thought to promote accelerated agein”
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Relevance of the p53–MDM2 axis to aging
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Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms
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“invaluable for studying accelerated aging [1].”
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“A number of mouse lines that are deficient in DNA damage repair show an aging phenotype, and also exhibit increased rates of cancer (Hasty et al., 2003).”
BackgroundTelomere Shortening Exposes Functions for the Mouse Werner and Bloom Syndrome Genes
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Controlling the subcellular localization of DNA polymerases ι and η via interactions with ubiquitin
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“In human cells, nucleotide excision repair (NER) removes most UV-induced DNA damage before replication takes place (Hoeijmakers, 2001; Hasty et al, 2003).”
BackgroundMolecular bases of progeroid syndromes
Navarro, C. L., Cau, P., & Lévy, N. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl214 · Cited by 189 · see citing works
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“Genome instability in patients with Werner syndrome, due to mutations in the WRN DNA helicase, is associated with early onset of aging and cancer predisposition (Hasty et al. 2003).”
BackgroundInfluentialWhat Can Progeroid Syndromes Tell Us About Human Aging?
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“Cancer is a disease that generally affects most mammalian species and is usually believed to be an unavoidable accompaniment of aging (Campisi, 2003; Hasty et al., 2003; Lombard et al., 2005).”
BackgroundEarly aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice
Baker, D. J., Jeganathan, K. B., Malureanu, L., Perez-Terzic, C., Terzic, A., & van Deursen, J. M. A. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507081 · Cited by 175 · see citing works
Aging, tumor suppression and cancer: high wire-act!
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“These damaged cells may contribute to the age-related decline in tissue function because deficiencies in DNA repair can accelerate aging phenotypes (Hasty et al., 2003), the DNA damage that accumulates with age in hematopoietic stem cells greatly limits their function (Nijnik et al., 2007; Rossi et…”
BackgroundSelf-citationDNA Repair Defects in Stem Cell Function and Aging
Park, Y., & Gerson, S. L. (2004) · Annual Review of Medicine · doi:10.1146/annurev.med.56.082103.104546 · Cited by 166 · see citing works
Nuclear envelope defects cause stem cell dysfunction in premature-aging mice
Espada, J., Varela, I., Flores, I., Ugalde, A. P., Cadiñanos, J., Pendás, A. M., Stewart, C. L., Tryggvason, K., Blasco, M. A., Freije, J. M. P., et al. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200801096 · Cited by 163 · see citing works
The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk
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Systems biology of ageing and longevity
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Rodents for comparative aging studies: from mice to beavers
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“In gerontological research, the first mammalian mutants with altered lifespan were generated in mice (reviewed in Hasty et al. 2003; Bartke and Brown-Borg 2004; Hasty and Vijg 2004), and mice and rats were the first mammals to reveal the life-prolonging”
BackgroundFunctional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells
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Deletion of Ku70, Ku80, or Both Causes Early Aging without Substantially Increased Cancer
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“This is certainly true for many of the models of accelerated aging in humans like Werner’s syndrome and Hutchinson-Gilford syndrome ( 25 , 37).”
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SIRT6 in DNA repair, metabolism and ageing
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Genotype–phenotype correlations in Fanconi anemia
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“These data demonstrate that DNA damage and/or tumor suppressor gene mutation causes tumor formation and/or premature aging (Vijg and Dolle, 2002; Campisi, 2003; Hasty et al, 2003).”
BackgroundThe short-lived African turquoise killifish: an emerging experimental model for ageing
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Methusaleh's Zoo: How Nature provides us with Clues for Extending Human Health Span
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“These mice are invariably short-lived and exhibit some signs of accelerated ageing (Hasty et al., 2003).”
Premature aging in mice activates a systemic metabolic response involving autophagy induction
Mariño, G., Ugalde, A. P., Salvador-Montoliu, N., Varela, I., Quirós, P. M., Cadiñanos, J., van der Pluijm, I., Freije, J. M. P., & López-Otı́n, C. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn120 · Cited by 143 · see citing works
“Recently, several studies have demonstrated that the nuclear envelope abnormalities that lead to accelerated aging may also contribute to normal aging (23,24), supporting the idea that the laboratory-engineered progeroid models are useful tools for studying the mechanisms underlying normal aging (25).”
BackgroundThe oxidative DNA lesions 8,5′-cyclopurines accumulate with aging in a tissue-specific manner
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Genetics of Longevity and Aging
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- Authors
- Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H., & Vijg, J.
- Affiliations
- Department of Molecular Medicine,
- Buck Institute for Research on Aging (US)
- Erasmus University Rotterdam (NL)
- National Institute of Public Health and the Environment, Post Office Box 1, 3720 BA Bilthoven, Netherlands.
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Hasty, Paul
- Vijg, Jan
- Venue
- Science
- Published
- 2003-02-28
- Volume
- 299
- Issue
- 5611
- Pages
- 1355-1359
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2133469432
- Cited by
- 553
- References
- 124
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 7 · 2023: 12 · 2022: 12 · 2021: 10 · 2020: 14 · 2019: 15 · 2018: 13 · 2017: 8 · 2016: 25 · 2015: 18 · 2014: 27 · 2013: 29 · 2012: 32
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
- Funders
- National Institute on Aging (AG 17242, P01AG017242)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- aging, genome maintenance, genome stability, mouse model, longevity, somatic maintenance, energy metabolism, DNA damage, model organisms, human aging
- MeSH terms
- Werner Syndrome Helicase, Aging, Animals, DNA Damage, DNA Repair, DNA Helicases, Exodeoxyribonucleases, Humans, Longevity, Mutation, Syndrome, Transcription, Genetic, Genome, Human, Telomere, Genome, Cellular Senescence, Apoptosis, Reactive Oxygen Species, Aging, Premature, Mice, RecQ Helicases
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