Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging

Males, who are bigger and stronger than females, live shorter in most species from flies to mammals including humans. Cellular mass growth is driven in part by mTOR (Target of Rapamycin). When developmental growth is completed, then, instead of growth, mTOR drives aging, manifested by increased cell...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Aging (Albany, NY.) NY.), 2012-12, Vol.4 (12), p.899-916
Hauptverfasser: Leontieva, Olga V, Paszkiewicz, Geraldine M, Blagosklonny, Mikhail V
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 916
container_issue 12
container_start_page 899
container_title Aging (Albany, NY.)
container_volume 4
creator Leontieva, Olga V
Paszkiewicz, Geraldine M
Blagosklonny, Mikhail V
description Males, who are bigger and stronger than females, live shorter in most species from flies to mammals including humans. Cellular mass growth is driven in part by mTOR (Target of Rapamycin). When developmental growth is completed, then, instead of growth, mTOR drives aging, manifested by increased cellular functions, such as hyper-secretion by fibroblasts, thus altering homeostasis, leading to age-related diseases and death. We hypothesize that MTOR activity is elevated in male mice compared with females. Noteworthy, 6 months old males were 28 % heavier than females. Also levels of phosphorylated S6 (pS6) and phospho-AKT (p-AKT, Ser 473), markers of the mTOR activity, were higher in male organs tested. Levels of pS6 were highly variable among mice and correlated with body weight and p-AKT. With age, the difference between levels of pS6 between sexes tended to minimize, albeit males still had hyperactive mTOR. Unlike fasting, the intraperitoneal (i.p.) administration of rapamycin eliminated pS6 in all organs of all females measured by immunoblotting and immunohistochemistry without affecting p-AKT and blood insulin. Although i.p. rapamycin dramatically decreased levels of pS6 in males too, it was still detectable by immunoblotting upon longer exposure. Our study demonstrated that both tissue p-AKT and pS6 were higher in young male mice and were associated with increased body weight and insulin. These data can explain bigger body size and faster aging in males. Our data suggest higher efficacy of rapamycin compared to fasting. Higher sensitivity of females to rapamycin may explain more pronounced life extension by rapamycin observed in females compared to males in several studies.
doi_str_mv 10.18632/aging.100528
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3615157</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1313420919</sourcerecordid><originalsourceid>FETCH-LOGICAL-c387t-7f3621426b09319a5cd53b1ac09beac8649d9d6304779648a94ee6034af64b123</originalsourceid><addsrcrecordid>eNpVkc1rFTEUxYMotlaXbiXLupiaTD5mshGk-AWVgtR1uJO5My8ySZ5JRng7_3SH92qpq3vh_jj3HA4hrzm74r0W7TuYfZyvOGOq7Z-Qc26kaqTqzdNH-xl5UcpPxrRSUj8nZ62QUigmzsmfb-h2EH2p3tGUaYAQYPEQaYU8Y6Vpohn2EA7OR3oZ7m6_v92gAx2xYg4-Is1pWEuNWArdkENa47wRC9LgHVKotO6QulSOWuAcLpih4kiPzl-SZxMsBV_dzwvy49PHu-svzc3t56_XH24aJ_quNt0kdMtlqwdmBDeg3KjEwMExMyC4XkszmlELJrvOaNmDkYiaCQmTlgNvxQV5f9Ldr0PA0WGsGRa7zz5APtgE3v5_iX5n5_TbCs0VV90mcHkvkNOvFUu1wZctzAIR01osF1zIlhluNrQ5oS6nUjJOD284s8fW7DG7PbW28W8ee3ug_9Uk_gLmlZWO</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1313420919</pqid></control><display><type>article</type><title>Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging</title><source>MEDLINE</source><source>PubMed Central Open Access</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Leontieva, Olga V ; Paszkiewicz, Geraldine M ; Blagosklonny, Mikhail V</creator><creatorcontrib>Leontieva, Olga V ; Paszkiewicz, Geraldine M ; Blagosklonny, Mikhail V</creatorcontrib><description>Males, who are bigger and stronger than females, live shorter in most species from flies to mammals including humans. Cellular mass growth is driven in part by mTOR (Target of Rapamycin). When developmental growth is completed, then, instead of growth, mTOR drives aging, manifested by increased cellular functions, such as hyper-secretion by fibroblasts, thus altering homeostasis, leading to age-related diseases and death. We hypothesize that MTOR activity is elevated in male mice compared with females. Noteworthy, 6 months old males were 28 % heavier than females. Also levels of phosphorylated S6 (pS6) and phospho-AKT (p-AKT, Ser 473), markers of the mTOR activity, were higher in male organs tested. Levels of pS6 were highly variable among mice and correlated with body weight and p-AKT. With age, the difference between levels of pS6 between sexes tended to minimize, albeit males still had hyperactive mTOR. Unlike fasting, the intraperitoneal (i.p.) administration of rapamycin eliminated pS6 in all organs of all females measured by immunoblotting and immunohistochemistry without affecting p-AKT and blood insulin. Although i.p. rapamycin dramatically decreased levels of pS6 in males too, it was still detectable by immunoblotting upon longer exposure. Our study demonstrated that both tissue p-AKT and pS6 were higher in young male mice and were associated with increased body weight and insulin. These data can explain bigger body size and faster aging in males. Our data suggest higher efficacy of rapamycin compared to fasting. Higher sensitivity of females to rapamycin may explain more pronounced life extension by rapamycin observed in females compared to males in several studies.</description><identifier>ISSN: 1945-4589</identifier><identifier>EISSN: 1945-4589</identifier><identifier>DOI: 10.18632/aging.100528</identifier><identifier>PMID: 23443503</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Age Factors ; Aging - metabolism ; Animals ; Blotting, Western ; Body Weight ; Enzyme Activation ; Fasting - blood ; Female ; Immunohistochemistry ; Injections, Intraperitoneal ; Insulin - blood ; Male ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Protein Kinase Inhibitors - administration &amp; dosage ; Proto-Oncogene Proteins c-akt - metabolism ; Research Paper ; Ribosomal Protein S6 Kinases - metabolism ; Sex Factors ; Signal Transduction - drug effects ; Sirolimus - administration &amp; dosage ; TOR Serine-Threonine Kinases - antagonists &amp; inhibitors ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Aging (Albany, NY.), 2012-12, Vol.4 (12), p.899-916</ispartof><rights>Copyright: © 2012 Leontieva et al. 2012</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-7f3621426b09319a5cd53b1ac09beac8649d9d6304779648a94ee6034af64b123</citedby><cites>FETCH-LOGICAL-c387t-7f3621426b09319a5cd53b1ac09beac8649d9d6304779648a94ee6034af64b123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615157/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615157/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23443503$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leontieva, Olga V</creatorcontrib><creatorcontrib>Paszkiewicz, Geraldine M</creatorcontrib><creatorcontrib>Blagosklonny, Mikhail V</creatorcontrib><title>Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging</title><title>Aging (Albany, NY.)</title><addtitle>Aging (Albany NY)</addtitle><description>Males, who are bigger and stronger than females, live shorter in most species from flies to mammals including humans. Cellular mass growth is driven in part by mTOR (Target of Rapamycin). When developmental growth is completed, then, instead of growth, mTOR drives aging, manifested by increased cellular functions, such as hyper-secretion by fibroblasts, thus altering homeostasis, leading to age-related diseases and death. We hypothesize that MTOR activity is elevated in male mice compared with females. Noteworthy, 6 months old males were 28 % heavier than females. Also levels of phosphorylated S6 (pS6) and phospho-AKT (p-AKT, Ser 473), markers of the mTOR activity, were higher in male organs tested. Levels of pS6 were highly variable among mice and correlated with body weight and p-AKT. With age, the difference between levels of pS6 between sexes tended to minimize, albeit males still had hyperactive mTOR. Unlike fasting, the intraperitoneal (i.p.) administration of rapamycin eliminated pS6 in all organs of all females measured by immunoblotting and immunohistochemistry without affecting p-AKT and blood insulin. Although i.p. rapamycin dramatically decreased levels of pS6 in males too, it was still detectable by immunoblotting upon longer exposure. Our study demonstrated that both tissue p-AKT and pS6 were higher in young male mice and were associated with increased body weight and insulin. These data can explain bigger body size and faster aging in males. Our data suggest higher efficacy of rapamycin compared to fasting. Higher sensitivity of females to rapamycin may explain more pronounced life extension by rapamycin observed in females compared to males in several studies.</description><subject>Age Factors</subject><subject>Aging - metabolism</subject><subject>Animals</subject><subject>Blotting, Western</subject><subject>Body Weight</subject><subject>Enzyme Activation</subject><subject>Fasting - blood</subject><subject>Female</subject><subject>Immunohistochemistry</subject><subject>Injections, Intraperitoneal</subject><subject>Insulin - blood</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Phosphorylation</subject><subject>Protein Kinase Inhibitors - administration &amp; dosage</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Research Paper</subject><subject>Ribosomal Protein S6 Kinases - metabolism</subject><subject>Sex Factors</subject><subject>Signal Transduction - drug effects</subject><subject>Sirolimus - administration &amp; dosage</subject><subject>TOR Serine-Threonine Kinases - antagonists &amp; inhibitors</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>1945-4589</issn><issn>1945-4589</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1rFTEUxYMotlaXbiXLupiaTD5mshGk-AWVgtR1uJO5My8ySZ5JRng7_3SH92qpq3vh_jj3HA4hrzm74r0W7TuYfZyvOGOq7Z-Qc26kaqTqzdNH-xl5UcpPxrRSUj8nZ62QUigmzsmfb-h2EH2p3tGUaYAQYPEQaYU8Y6Vpohn2EA7OR3oZ7m6_v92gAx2xYg4-Is1pWEuNWArdkENa47wRC9LgHVKotO6QulSOWuAcLpih4kiPzl-SZxMsBV_dzwvy49PHu-svzc3t56_XH24aJ_quNt0kdMtlqwdmBDeg3KjEwMExMyC4XkszmlELJrvOaNmDkYiaCQmTlgNvxQV5f9Ldr0PA0WGsGRa7zz5APtgE3v5_iX5n5_TbCs0VV90mcHkvkNOvFUu1wZctzAIR01osF1zIlhluNrQ5oS6nUjJOD284s8fW7DG7PbW28W8ee3ug_9Uk_gLmlZWO</recordid><startdate>20121201</startdate><enddate>20121201</enddate><creator>Leontieva, Olga V</creator><creator>Paszkiewicz, Geraldine M</creator><creator>Blagosklonny, Mikhail V</creator><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20121201</creationdate><title>Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging</title><author>Leontieva, Olga V ; Paszkiewicz, Geraldine M ; Blagosklonny, Mikhail V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-7f3621426b09319a5cd53b1ac09beac8649d9d6304779648a94ee6034af64b123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Age Factors</topic><topic>Aging - metabolism</topic><topic>Animals</topic><topic>Blotting, Western</topic><topic>Body Weight</topic><topic>Enzyme Activation</topic><topic>Fasting - blood</topic><topic>Female</topic><topic>Immunohistochemistry</topic><topic>Injections, Intraperitoneal</topic><topic>Insulin - blood</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Phosphorylation</topic><topic>Protein Kinase Inhibitors - administration &amp; dosage</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Research Paper</topic><topic>Ribosomal Protein S6 Kinases - metabolism</topic><topic>Sex Factors</topic><topic>Signal Transduction - drug effects</topic><topic>Sirolimus - administration &amp; dosage</topic><topic>TOR Serine-Threonine Kinases - antagonists &amp; inhibitors</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Leontieva, Olga V</creatorcontrib><creatorcontrib>Paszkiewicz, Geraldine M</creatorcontrib><creatorcontrib>Blagosklonny, Mikhail V</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Aging (Albany, NY.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leontieva, Olga V</au><au>Paszkiewicz, Geraldine M</au><au>Blagosklonny, Mikhail V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging</atitle><jtitle>Aging (Albany, NY.)</jtitle><addtitle>Aging (Albany NY)</addtitle><date>2012-12-01</date><risdate>2012</risdate><volume>4</volume><issue>12</issue><spage>899</spage><epage>916</epage><pages>899-916</pages><issn>1945-4589</issn><eissn>1945-4589</eissn><abstract>Males, who are bigger and stronger than females, live shorter in most species from flies to mammals including humans. Cellular mass growth is driven in part by mTOR (Target of Rapamycin). When developmental growth is completed, then, instead of growth, mTOR drives aging, manifested by increased cellular functions, such as hyper-secretion by fibroblasts, thus altering homeostasis, leading to age-related diseases and death. We hypothesize that MTOR activity is elevated in male mice compared with females. Noteworthy, 6 months old males were 28 % heavier than females. Also levels of phosphorylated S6 (pS6) and phospho-AKT (p-AKT, Ser 473), markers of the mTOR activity, were higher in male organs tested. Levels of pS6 were highly variable among mice and correlated with body weight and p-AKT. With age, the difference between levels of pS6 between sexes tended to minimize, albeit males still had hyperactive mTOR. Unlike fasting, the intraperitoneal (i.p.) administration of rapamycin eliminated pS6 in all organs of all females measured by immunoblotting and immunohistochemistry without affecting p-AKT and blood insulin. Although i.p. rapamycin dramatically decreased levels of pS6 in males too, it was still detectable by immunoblotting upon longer exposure. Our study demonstrated that both tissue p-AKT and pS6 were higher in young male mice and were associated with increased body weight and insulin. These data can explain bigger body size and faster aging in males. Our data suggest higher efficacy of rapamycin compared to fasting. Higher sensitivity of females to rapamycin may explain more pronounced life extension by rapamycin observed in females compared to males in several studies.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>23443503</pmid><doi>10.18632/aging.100528</doi><tpages>18</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1945-4589
ispartof Aging (Albany, NY.), 2012-12, Vol.4 (12), p.899-916
issn 1945-4589
1945-4589
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3615157
source MEDLINE; PubMed Central Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Age Factors
Aging - metabolism
Animals
Blotting, Western
Body Weight
Enzyme Activation
Fasting - blood
Female
Immunohistochemistry
Injections, Intraperitoneal
Insulin - blood
Male
Mice
Mice, Inbred C57BL
Phosphorylation
Protein Kinase Inhibitors - administration & dosage
Proto-Oncogene Proteins c-akt - metabolism
Research Paper
Ribosomal Protein S6 Kinases - metabolism
Sex Factors
Signal Transduction - drug effects
Sirolimus - administration & dosage
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
title Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T17%3A37%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mechanistic%20or%20mammalian%20target%20of%20rapamycin%20(mTOR)%20may%20determine%20robustness%20in%20young%20male%20mice%20at%20the%20cost%20of%20accelerated%20aging&rft.jtitle=Aging%20(Albany,%20NY.)&rft.au=Leontieva,%20Olga%20V&rft.date=2012-12-01&rft.volume=4&rft.issue=12&rft.spage=899&rft.epage=916&rft.pages=899-916&rft.issn=1945-4589&rft.eissn=1945-4589&rft_id=info:doi/10.18632/aging.100528&rft_dat=%3Cproquest_pubme%3E1313420919%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1313420919&rft_id=info:pmid/23443503&rfr_iscdi=true