Ink4a/Arf expression is a biomarker of aging
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly...
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| Veröffentlicht in: | The Journal of clinical investigation 2004-11, Vol.114 (9), p.1299-1307 |
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| creator | Krishnamurthy, Janakiraman Torrice, Chad Ramsey, Matthew R Kovalev, Grigoriy I Al-Regaiey, Khalid Su, Lishan Sharpless, Norman E |
| description | The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging. |
| doi_str_mv | 10.1172/jci200422475 |
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To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/jci200422475</identifier><identifier>PMID: 15520862</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>ADP-Ribosylation Factor 1 - biosynthesis ; ADP-Ribosylation Factor 1 - genetics ; Aging ; Animals ; beta-Galactosidase - metabolism ; Biomarkers ; Biomedical research ; Caloric Restriction ; Cell Cycle ; Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Cyclin-dependent kinases ; Disease Models, Animal ; Fibroblasts ; Homeostasis ; Humans ; Immunohistochemistry ; Kinases ; Mice ; Models, Biological ; Ovaries ; Polymerase Chain Reaction ; Ratios ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Rodents ; Senescence ; Stem cells ; Time Factors ; Tissue Distribution ; Uterus</subject><ispartof>The Journal of clinical investigation, 2004-11, Vol.114 (9), p.1299-1307</ispartof><rights>Copyright American Society for Clinical Investigation Nov 2004</rights><rights>Copyright © 2004, American Society for Clinical Investigation 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c437t-4b6cdd2311381270d255fff595e9a2571cb9b1f0a94d01d8846a743cf880ea463</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC524230/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC524230/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15520862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Krishnamurthy, Janakiraman</creatorcontrib><creatorcontrib>Torrice, Chad</creatorcontrib><creatorcontrib>Ramsey, Matthew R</creatorcontrib><creatorcontrib>Kovalev, Grigoriy I</creatorcontrib><creatorcontrib>Al-Regaiey, Khalid</creatorcontrib><creatorcontrib>Su, Lishan</creatorcontrib><creatorcontrib>Sharpless, Norman E</creatorcontrib><title>Ink4a/Arf expression is a biomarker of aging</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.</description><subject>ADP-Ribosylation Factor 1 - biosynthesis</subject><subject>ADP-Ribosylation Factor 1 - genetics</subject><subject>Aging</subject><subject>Animals</subject><subject>beta-Galactosidase - metabolism</subject><subject>Biomarkers</subject><subject>Biomedical research</subject><subject>Caloric Restriction</subject><subject>Cell Cycle</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - genetics</subject><subject>Cyclin-dependent kinases</subject><subject>Disease Models, Animal</subject><subject>Fibroblasts</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Kinases</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Ovaries</subject><subject>Polymerase Chain Reaction</subject><subject>Ratios</subject><subject>Rats</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Rodents</subject><subject>Senescence</subject><subject>Stem cells</subject><subject>Time Factors</subject><subject>Tissue Distribution</subject><subject>Uterus</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkD1PwzAQhi0EoqWwMaOIgYnQ81fsDAxVxUelSiwwW05iF7epXewGwb8niIKA6YZ73tNzL0KnGK4wFmS8rB0BYIQwwffQEHMuc0mo3EdDAILzUlA5QEcpLQEwY5wdokEPEZAFGaLLmV8xPZ5Em5m3TTQpueAzlzKdVS6sdVyZmAWb6YXzi2N0YHWbzMlujtDT7c3j9D6fP9zNppN5XjMqtjmrirppCMWYSkwENIRzay0vuSk14QLXVVlhC7pkDeBGSlZowWhtpQSjWUFH6Prr7qar1qapjd9G3apNdL3Quwraqb8b757VIrwqThih0OcvdvkYXjqTtmrtUm3aVnsTuqQKAZSy8hM8_wcuQxd9_5vqO-WCYiF76Oy3zY_Gd4n0A9I3cdc</recordid><startdate>200411</startdate><enddate>200411</enddate><creator>Krishnamurthy, Janakiraman</creator><creator>Torrice, Chad</creator><creator>Ramsey, Matthew R</creator><creator>Kovalev, Grigoriy I</creator><creator>Al-Regaiey, Khalid</creator><creator>Su, Lishan</creator><creator>Sharpless, Norman E</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200411</creationdate><title>Ink4a/Arf expression is a biomarker of aging</title><author>Krishnamurthy, Janakiraman ; Torrice, Chad ; Ramsey, Matthew R ; Kovalev, Grigoriy I ; Al-Regaiey, Khalid ; Su, Lishan ; Sharpless, Norman E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c437t-4b6cdd2311381270d255fff595e9a2571cb9b1f0a94d01d8846a743cf880ea463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>ADP-Ribosylation Factor 1 - biosynthesis</topic><topic>ADP-Ribosylation Factor 1 - genetics</topic><topic>Aging</topic><topic>Animals</topic><topic>beta-Galactosidase - metabolism</topic><topic>Biomarkers</topic><topic>Biomedical research</topic><topic>Caloric Restriction</topic><topic>Cell Cycle</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - genetics</topic><topic>Cyclin-dependent kinases</topic><topic>Disease Models, Animal</topic><topic>Fibroblasts</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Kinases</topic><topic>Mice</topic><topic>Models, Biological</topic><topic>Ovaries</topic><topic>Polymerase Chain Reaction</topic><topic>Ratios</topic><topic>Rats</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Rodents</topic><topic>Senescence</topic><topic>Stem cells</topic><topic>Time Factors</topic><topic>Tissue Distribution</topic><topic>Uterus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Krishnamurthy, Janakiraman</creatorcontrib><creatorcontrib>Torrice, Chad</creatorcontrib><creatorcontrib>Ramsey, Matthew R</creatorcontrib><creatorcontrib>Kovalev, Grigoriy I</creatorcontrib><creatorcontrib>Al-Regaiey, Khalid</creatorcontrib><creatorcontrib>Su, Lishan</creatorcontrib><creatorcontrib>Sharpless, Norman E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krishnamurthy, Janakiraman</au><au>Torrice, Chad</au><au>Ramsey, Matthew R</au><au>Kovalev, Grigoriy I</au><au>Al-Regaiey, Khalid</au><au>Su, Lishan</au><au>Sharpless, Norman E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ink4a/Arf expression is a biomarker of aging</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2004-11</date><risdate>2004</risdate><volume>114</volume><issue>9</issue><spage>1299</spage><epage>1307</epage><pages>1299-1307</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>15520862</pmid><doi>10.1172/jci200422475</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | ADP-Ribosylation Factor 1 - biosynthesis ADP-Ribosylation Factor 1 - genetics Aging Animals beta-Galactosidase - metabolism Biomarkers Biomedical research Caloric Restriction Cell Cycle Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis Cyclin-Dependent Kinase Inhibitor p16 - genetics Cyclin-dependent kinases Disease Models, Animal Fibroblasts Homeostasis Humans Immunohistochemistry Kinases Mice Models, Biological Ovaries Polymerase Chain Reaction Ratios Rats Reverse Transcriptase Polymerase Chain Reaction Rodents Senescence Stem cells Time Factors Tissue Distribution Uterus |
| title | Ink4a/Arf expression is a biomarker of aging |
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