Specific premature epigenetic aging of cartilage in osteoarthritis
Identifieur interne : 000918 ( Pmc/Corpus ); précédent : 000917; suivant : 000919Specific premature epigenetic aging of cartilage in osteoarthritis
Auteurs : Laura Vidal-Bralo ; Yolanda Lopez-Golan ; Antonio Mera-Varela ; Ignacio Rego-Perez ; Steve Horvath ; Yuhua Zhang ; Álvaro Del Real ; Guangju Zhai ; Francisco J. Blanco ; Jose A. Riancho ; Juan J. Gomez-Reino ; Antonio GonzalezSource :
- Aging (Albany NY) [ 1945-4589 ] ; 2016.
Abstract
Osteoarthritis (OA) is a disease affecting multiple tissues of the joints in the elderly, but most notably articular cartilage. Premature biological aging has been described in this tissue and in blood cells, suggesting a systemic component of premature aging in the pathogenesis of OA. Here, we have explored epigenetic aging in OA at the local (cartilage and bone) and systemic (blood) levels. Two DNA methylation age-measures (DmAM) were used: the multi-tissue age estimator for cartilage and bone; and a blood-specific biomarker for blood. Differences in DmAM between OA patients and controls showed an accelerated aging of 3.7 years in articular cartilage (95 % CI = 1.1 to 6.3,
Url:
DOI: 10.18632/aging.101053
PubMed: 27689435
PubMed Central: 5076459
Links to Exploration step
PMC:5076459Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Specific premature epigenetic aging of cartilage in osteoarthritis</title><author><name sortKey="Vidal Bralo, Laura" sort="Vidal Bralo, Laura" uniqKey="Vidal Bralo L" first="Laura" last="Vidal-Bralo">Laura Vidal-Bralo</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Lopez Golan, Yolanda" sort="Lopez Golan, Yolanda" uniqKey="Lopez Golan Y" first="Yolanda" last="Lopez-Golan">Yolanda Lopez-Golan</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Mera Varela, Antonio" sort="Mera Varela, Antonio" uniqKey="Mera Varela A" first="Antonio" last="Mera-Varela">Antonio Mera-Varela</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Rego Perez, Ignacio" sort="Rego Perez, Ignacio" uniqKey="Rego Perez I" first="Ignacio" last="Rego-Perez">Ignacio Rego-Perez</name><affiliation><nlm:aff id="A2"> Grupo de Reumatología, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Universidade da Coruña. As Xubias, sn. 15006- A Coruña, Spain</nlm:aff></affiliation></author><author><name sortKey="Horvath, Steve" sort="Horvath, Steve" uniqKey="Horvath S" first="Steve" last="Horvath">Steve Horvath</name><affiliation><nlm:aff id="A3"> Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA</nlm:aff></affiliation></author><author><name sortKey="Zhang, Yuhua" sort="Zhang, Yuhua" uniqKey="Zhang Y" first="Yuhua" last="Zhang">Yuhua Zhang</name><affiliation><nlm:aff id="A4"> Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, A1B- St. John's, NL, Canada</nlm:aff></affiliation></author><author><name sortKey="Del Real, Alvaro" sort="Del Real, Alvaro" uniqKey="Del Real A" first="Álvaro" last="Del Real">Álvaro Del Real</name><affiliation><nlm:aff id="A5"> Department of Internal Medicine, Hospital U. M. Valdecilla-IDIVAL, University of Cantabria, Cardenal Herrera Oria, 39011, Santander, Spain</nlm:aff></affiliation></author><author><name sortKey="Zhai, Guangju" sort="Zhai, Guangju" uniqKey="Zhai G" first="Guangju" last="Zhai">Guangju Zhai</name><affiliation><nlm:aff id="A4"> Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, A1B- St. John's, NL, Canada</nlm:aff></affiliation></author><author><name sortKey="Blanco, Francisco J" sort="Blanco, Francisco J" uniqKey="Blanco F" first="Francisco J" last="Blanco">Francisco J. Blanco</name><affiliation><nlm:aff id="A2"> Grupo de Reumatología, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Universidade da Coruña. As Xubias, sn. 15006- A Coruña, Spain</nlm:aff></affiliation></author><author><name sortKey="Riancho, Jose A" sort="Riancho, Jose A" uniqKey="Riancho J" first="Jose A." last="Riancho">Jose A. Riancho</name><affiliation><nlm:aff id="A5"> Department of Internal Medicine, Hospital U. M. Valdecilla-IDIVAL, University of Cantabria, Cardenal Herrera Oria, 39011, Santander, Spain</nlm:aff></affiliation></author><author><name sortKey="Gomez Reino, Juan J" sort="Gomez Reino, Juan J" uniqKey="Gomez Reino J" first="Juan J" last="Gomez-Reino">Juan J. Gomez-Reino</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Gonzalez, Antonio" sort="Gonzalez, Antonio" uniqKey="Gonzalez A" first="Antonio" last="Gonzalez">Antonio Gonzalez</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27689435</idno><idno type="pmc">5076459</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076459</idno><idno type="RBID">PMC:5076459</idno><idno type="doi">10.18632/aging.101053</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000918</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000918</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Specific premature epigenetic aging of cartilage in osteoarthritis</title><author><name sortKey="Vidal Bralo, Laura" sort="Vidal Bralo, Laura" uniqKey="Vidal Bralo L" first="Laura" last="Vidal-Bralo">Laura Vidal-Bralo</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Lopez Golan, Yolanda" sort="Lopez Golan, Yolanda" uniqKey="Lopez Golan Y" first="Yolanda" last="Lopez-Golan">Yolanda Lopez-Golan</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Mera Varela, Antonio" sort="Mera Varela, Antonio" uniqKey="Mera Varela A" first="Antonio" last="Mera-Varela">Antonio Mera-Varela</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Rego Perez, Ignacio" sort="Rego Perez, Ignacio" uniqKey="Rego Perez I" first="Ignacio" last="Rego-Perez">Ignacio Rego-Perez</name><affiliation><nlm:aff id="A2"> Grupo de Reumatología, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Universidade da Coruña. As Xubias, sn. 15006- A Coruña, Spain</nlm:aff></affiliation></author><author><name sortKey="Horvath, Steve" sort="Horvath, Steve" uniqKey="Horvath S" first="Steve" last="Horvath">Steve Horvath</name><affiliation><nlm:aff id="A3"> Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA</nlm:aff></affiliation></author><author><name sortKey="Zhang, Yuhua" sort="Zhang, Yuhua" uniqKey="Zhang Y" first="Yuhua" last="Zhang">Yuhua Zhang</name><affiliation><nlm:aff id="A4"> Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, A1B- St. John's, NL, Canada</nlm:aff></affiliation></author><author><name sortKey="Del Real, Alvaro" sort="Del Real, Alvaro" uniqKey="Del Real A" first="Álvaro" last="Del Real">Álvaro Del Real</name><affiliation><nlm:aff id="A5"> Department of Internal Medicine, Hospital U. M. Valdecilla-IDIVAL, University of Cantabria, Cardenal Herrera Oria, 39011, Santander, Spain</nlm:aff></affiliation></author><author><name sortKey="Zhai, Guangju" sort="Zhai, Guangju" uniqKey="Zhai G" first="Guangju" last="Zhai">Guangju Zhai</name><affiliation><nlm:aff id="A4"> Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, A1B- St. John's, NL, Canada</nlm:aff></affiliation></author><author><name sortKey="Blanco, Francisco J" sort="Blanco, Francisco J" uniqKey="Blanco F" first="Francisco J" last="Blanco">Francisco J. Blanco</name><affiliation><nlm:aff id="A2"> Grupo de Reumatología, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Universidade da Coruña. As Xubias, sn. 15006- A Coruña, Spain</nlm:aff></affiliation></author><author><name sortKey="Riancho, Jose A" sort="Riancho, Jose A" uniqKey="Riancho J" first="Jose A." last="Riancho">Jose A. Riancho</name><affiliation><nlm:aff id="A5"> Department of Internal Medicine, Hospital U. M. Valdecilla-IDIVAL, University of Cantabria, Cardenal Herrera Oria, 39011, Santander, Spain</nlm:aff></affiliation></author><author><name sortKey="Gomez Reino, Juan J" sort="Gomez Reino, Juan J" uniqKey="Gomez Reino J" first="Juan J" last="Gomez-Reino">Juan J. Gomez-Reino</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author><author><name sortKey="Gonzalez, Antonio" sort="Gonzalez, Antonio" uniqKey="Gonzalez A" first="Antonio" last="Gonzalez">Antonio Gonzalez</name><affiliation><nlm:aff id="A1"> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</nlm:aff></affiliation></author></analytic><series><title level="j">Aging (Albany NY)</title><idno type="eISSN">1945-4589</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Osteoarthritis (OA) is a disease affecting multiple tissues of the joints in the elderly, but most notably articular cartilage. Premature biological aging has been described in this tissue and in blood cells, suggesting a systemic component of premature aging in the pathogenesis of OA. Here, we have explored epigenetic aging in OA at the local (cartilage and bone) and systemic (blood) levels. Two DNA methylation age-measures (DmAM) were used: the multi-tissue age estimator for cartilage and bone; and a blood-specific biomarker for blood. Differences in DmAM between OA patients and controls showed an accelerated aging of 3.7 years in articular cartilage (95 % CI = 1.1 to 6.3, <italic>P</italic> = 0.008) of OA patients. By contrast, no difference in epigenetic aging was observed in bone (0.04 years; 95 % CI = −1.8 to 1.9, <italic>P</italic> = 0.3) and in blood (−0.6 years; 95 % CI = −1.5 to 0.3, <italic>P</italic> = 0.2) between OA patients and controls. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Aging (Albany NY)</journal-id><journal-id journal-id-type="iso-abbrev">Aging (Albany NY)</journal-id><journal-id journal-id-type="publisher-id">Aging</journal-id><journal-id journal-id-type="publisher-id">ImpactJ</journal-id><journal-title-group><journal-title>Aging (Albany NY)</journal-title></journal-title-group><issn pub-type="epub">1945-4589</issn><publisher><publisher-name>Impact Journals LLC</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27689435</article-id><article-id pub-id-type="pmc">5076459</article-id><article-id pub-id-type="publisher-id">101053</article-id><article-id pub-id-type="doi">10.18632/aging.101053</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject></subj-group></article-categories><title-group><article-title>Specific premature epigenetic aging of cartilage in osteoarthritis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Vidal-Bralo</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lopez-Golan</surname><given-names>Yolanda</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mera-Varela</surname><given-names>Antonio</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rego-Perez</surname><given-names>Ignacio</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Horvath</surname><given-names>Steve</given-names></name><xref ref-type="aff" rid="A3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Yuhua</given-names></name><xref ref-type="aff" rid="A4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>del Real</surname><given-names>Álvaro</given-names></name><xref ref-type="aff" rid="A5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhai</surname><given-names>Guangju</given-names></name><xref ref-type="aff" rid="A4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Blanco</surname><given-names>Francisco J</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Riancho</surname><given-names>Jose A.</given-names></name><xref ref-type="aff" rid="A5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gomez-Reino</surname><given-names>Juan J</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gonzalez</surname><given-names>Antonio</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib></contrib-group><aff id="A1"><sup>1</sup> Laboratorio Investigacion 10 and Rheumatology Unit, Instituto Investigacion Sanitaria, Hospital Clinico Universitario de Santiago, Travesia Choupana, sn. 15706- Santiago de Compostela, Spain</aff><aff id="A2"><sup>2</sup> Grupo de Reumatología, Instituto de Investigación Biomédica de A Coruña, Complexo Hospitalario Universitario de A Coruña, Universidade da Coruña. As Xubias, sn. 15006- A Coruña, Spain</aff><aff id="A3"><sup>3</sup> Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA</aff><aff id="A4"><sup>4</sup> Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, A1B- St. John's, NL, Canada</aff><aff id="A5"><sup>5</sup> Department of Internal Medicine, Hospital U. M. Valdecilla-IDIVAL, University of Cantabria, Cardenal Herrera Oria, 39011, Santander, Spain</aff><author-notes><corresp id="cor1"><bold>Correspondence to:</bold> Antonio Gonzalez; <email>agmartinezp@ser.es</email></corresp></author-notes><pub-date pub-type="collection"><month>9</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>28</day><month>9</month><year>2016</year></pub-date><volume>8</volume><issue>9</issue><fpage>2222</fpage><lpage>2230</lpage><history><date date-type="received"><day>14</day><month>6</month><year>2016</year></date><date date-type="accepted"><day>14</day><month>9</month><year>2016</year></date></history><permissions><copyright-statement>Copyright: © 2016 Vidal-Bralo et al.</copyright-statement><copyright-year>2016</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Osteoarthritis (OA) is a disease affecting multiple tissues of the joints in the elderly, but most notably articular cartilage. Premature biological aging has been described in this tissue and in blood cells, suggesting a systemic component of premature aging in the pathogenesis of OA. Here, we have explored epigenetic aging in OA at the local (cartilage and bone) and systemic (blood) levels. Two DNA methylation age-measures (DmAM) were used: the multi-tissue age estimator for cartilage and bone; and a blood-specific biomarker for blood. Differences in DmAM between OA patients and controls showed an accelerated aging of 3.7 years in articular cartilage (95 % CI = 1.1 to 6.3, <italic>P</italic> = 0.008) of OA patients. By contrast, no difference in epigenetic aging was observed in bone (0.04 years; 95 % CI = −1.8 to 1.9, <italic>P</italic> = 0.3) and in blood (−0.6 years; 95 % CI = −1.5 to 0.3, <italic>P</italic> = 0.2) between OA patients and controls. Therefore, premature epigenetic aging according to DNA methylation changes was specific of OA cartilage, adding further evidence and insight on premature aging of cartilage as a component of OA pathogenesis that reflects damage and vulnerability.</p></abstract><kwd-group><kwd>osteoarthritis</kwd><kwd>biological age</kwd><kwd>epigenetics</kwd><kwd>DNA methylation</kwd><kwd>telomere length shortening</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>INTRODUCTION</title><p>OA is the most common chronic disease affecting the joints with about a 45 % lifetime risk of developing OA of the knee [<xref rid="R1" ref-type="bibr">1</xref>, <xref rid="R2" ref-type="bibr">2</xref>]. It can affect any joint, but it occurs most often in knees, hips, spine, or hands. Symptoms include pain and stiffness, bony enlargement, crepitus with movement and decreased function of the joint. OA pathogenesis is complex and includes multiple risk factors that are still incompletely known, but old age is a critical contributor [<xref rid="R3" ref-type="bibr">3</xref>, <xref rid="R4" ref-type="bibr">4</xref>]. The relationship between old age and OA is not fully understood. Classically, it was suspected that the association was related to the “wear and tear” of articular cartilage by continuous mechanical stress. Today, we know that this model of OA is insufficient because OA involves an active response to injury comprising remodeling of articular cartilage and neighboring bone, in addition of synovial inflammation and damage to ligaments and menisci [<xref rid="R2" ref-type="bibr">2</xref>]. In addition, the other component of the association with old age, biological aging, has shown unsuspected complexity, including its multidimensionality, variable progression, possibility of modulation and the pivotal role played by senescent cells [<xref rid="R5" ref-type="bibr">5</xref>].</p><p>The many facets of biological aging have been typified in nine cellular and molecular hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mito-chondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication [<xref rid="R6" ref-type="bibr">6</xref>]. Variable progression of biological aging with dissociation between biological and chronological age is observed in progeroid syndromes. Less dramatically, it is also observed as a reflection of lifestyle with smoking, heavy drinking, obesity, stress and depression as accelerators, and exercise and caloric restriction as rejuvenators. The pivotal role of cellular senescence and of the senescence-associated secretory phenotype has been established in multiple studies, but most strikingly with the reversal of age-associated changes obtained with their removal [<xref rid="R7" ref-type="bibr">7</xref>]. This rejuvenation has been obtained either through genetic manipulation or with senolytic drugs in mice in spite of the eliminated senescent cells were only a minor fraction in mouse tissues [<xref rid="R5" ref-type="bibr">5</xref>]. All these aspects could be of relevance for OA as exemplified by the secretory phenotype that includes secretion of metalloproteases and pro-inflammatory mediators, which could be involved in OA cartilage damage [<xref rid="R2" ref-type="bibr">2</xref>-<xref rid="R4" ref-type="bibr">4</xref>]. There is already persuasive evidence of accelerated biological aging at the affected cartilage [<xref rid="R3" ref-type="bibr">3</xref>, <xref rid="R4" ref-type="bibr">4</xref>]. Many of the aging hallmarks have been described as exacerbated in OA chondrocytes and articular cartilage, including telomere length shortening, mitochondrial dysfunction, cellular senescence and genome instability [<xref rid="R3" ref-type="bibr">3</xref>, <xref rid="R4" ref-type="bibr">4</xref>]. In contrast, biological age has not been studied in any other joint tissue although a systemic component of premature aging has been suggested by accelerated telomere length shortening in blood cells of 160 hand OA subjects compared with 926 controls [<xref rid="R8" ref-type="bibr">8</xref>]. Telomere shortening correlated with radiographic severity of OA in the hands in this study. These findings have not yet been independently confirmed, with a small subsequent study showing no telomere attrition in blood of knee OA patients [<xref rid="R9" ref-type="bibr">9</xref>], and a second small study reporting telomere shortening only in knee OA patients experiencing high stress and chronic pain [<xref rid="R10" ref-type="bibr">10</xref>]. A systemic premature aging component in OA is an attractive hypothesis because it is congruent with some epidemiological studies that have found increased prevalence of old-age comorbidities [<xref rid="R11" ref-type="bibr">11</xref>-<xref rid="R14" ref-type="bibr">14</xref>], frailty [<xref rid="R15" ref-type="bibr">15</xref>], and mortality in OA patients [<xref rid="R16" ref-type="bibr">16</xref>-<xref rid="R18" ref-type="bibr">18</xref>]. The two aspects, local and systemic, of premature aging could contribute to OA by further impairing cartilage and joint function, decreasing mobility and increasing joint vulnerability.</p><p>An opportunity to explore a different aging hallmark in OA cartilage, bone and blood has become possible thanks to the recent development of biomarkers of epigenetic aging [<xref rid="R19" ref-type="bibr">19</xref>-<xref rid="R24" ref-type="bibr">24</xref>]. The available biomarkers, called DNA methylation age-measures (DmAM), combine methylation levels at CpG sites that experience methylation changes with aging. The mechanism seems to include slowly accumulating failures of methylation maintenance (epigenetic drift) that could be accelerated by somatic mutations, cell divisions and environmental stress [<xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R21" ref-type="bibr">21</xref>, <xref rid="R25" ref-type="bibr">25</xref>, <xref rid="R26" ref-type="bibr">26</xref>]. Some of the changes are tissue-specific; others are shared by several tissues. This motivates a distinction between DmAM that are tissue-specific and include as few as 3 CpG sites showing strong correlation with age in blood, [<xref rid="R20" ref-type="bibr">20</xref>, <xref rid="R24" ref-type="bibr">24</xref>] or in saliva [<xref rid="R23" ref-type="bibr">23</xref>], and biomarkers applicable to many tissues that require investigating more CpG sites [<xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R21" ref-type="bibr">21</xref>]. The most comprehensive is the “epigenetic clock” method by Horvath, which includes 353 CpG and is valid for multiple tissues including bone and cartilage [<xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R27" ref-type="bibr">27</xref>, <xref rid="R28" ref-type="bibr">28</xref>]. The DmAM are useful biomarkers of biological age that show accelerated aging in several diseases of old age [<xref rid="R19" ref-type="bibr">19</xref>-<xref rid="R21" ref-type="bibr">21</xref>, <xref rid="R29" ref-type="bibr">29</xref>, <xref rid="R30" ref-type="bibr">30</xref>] and in subjects under elevated lifetime stress [<xref rid="R26" ref-type="bibr">26</xref>], and that correlate with cognitive and physical fitness in the elderly and with all-cause and cause-specific mortality [<xref rid="R30" ref-type="bibr">30</xref>-<xref rid="R35" ref-type="bibr">35</xref>].</p></sec><sec id="s2"><title>RESULTS</title><p>The cartilage samples from OA patients showed premature aging in comparison with cartilage from controls (Figure <xref ref-type="fig" rid="F1">1A</xref>). The difference in the estimated mean age obtained with Horwath's DmAM was of 3.7 years (Table <xref ref-type="table" rid="T1">1</xref>). This result was obtained with the whole set of samples that included cartilage from the tibial plateau and from the femoral head. A significant premature aging was also observed with the subgroup of tibial plateau samples, with a mean difference of 5.3 years (95 % CI = 2.4 to 8.2). Cartilages from the femoral heads were too few for meaningful analysis. All the comparisons were adjusted for age and sex as covariates.</p><table-wrap id="T1" orientation="portrait" position="float"><label>Table 1</label><caption><title>Specific premature epigenetic aging in OA cartilage compared with control cartilage</title><p>ΔDmAM = (age- and sex-adjusted mean DmAM in OA patients) – (age- and sex-adjusted mean DmAM in controls); CI = confidence interval.</p></caption><table frame="box" rules="all"><thead><tr><th align="left" valign="bottom" rowspan="1" colspan="1">Tissue</th><th align="left" valign="bottom" rowspan="1" colspan="1">OA set</th><th align="center" valign="bottom" rowspan="1" colspan="1">ΔDmAM<sup>a</sup> (95% CI)</th><th align="center" valign="bottom" rowspan="1" colspan="1"><italic>P</italic>-value</th></tr></thead><tbody><tr><td align="left" valign="bottom" rowspan="1" colspan="1">Cartilage</td><td align="left" valign="bottom" rowspan="1" colspan="1">Knee/hip</td><td align="center" valign="bottom" rowspan="1" colspan="1">3.7 (1.1 to 6.3)</td><td align="center" valign="bottom" rowspan="1" colspan="1">0.008</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Bone</td><td align="left" valign="top" rowspan="1" colspan="1">Hip</td><td align="center" valign="top" rowspan="1" colspan="1">0.04 (−1.8 to 1.9)</td><td align="center" valign="top" rowspan="1" colspan="1">0.3</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td rowspan="3" align="left" valign="top" colspan="1">Blood</td><td align="left" valign="top" rowspan="1" colspan="1">Hand</td><td align="center" valign="top" rowspan="1" colspan="1">0.01 (−1.1 to 1.1)</td><td align="center" valign="top" rowspan="1" colspan="1">0.98</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Knee</td><td align="center" valign="top" rowspan="1" colspan="1">0.04 (−0.9 to 1.0)</td><td align="center" valign="top" rowspan="1" colspan="1">0.9</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Hip</td><td align="center" valign="top" rowspan="1" colspan="1">−0.7 (−1.7 to 0.3)</td><td align="center" valign="top" rowspan="1" colspan="1">0.11</td></tr></tbody></table></table-wrap><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Comparison of epigenetic age in joint tissues from controls and patients with OA</title><p>(<bold>A</bold>) Accelerated aging in OA cartilage samples (n = 31) in comparison with control cartilage (n = 36) with ΔDmAM = 3.7 years (P = 0.008); and (<bold>B</bold>) no difference (ΔDmAM = 0.04 years, P = 0.3) in bone samples between OA patients (n = 33) and controls (n = 45). Epigenetic ages are represented as age- and sex-adjusted values with horizontal lines for the mean of each group.</p></caption><graphic xlink:href="aging-08-2222-g001"></graphic></fig><p>In contrast with the cartilage results, there were no differences in epigenetic aging of bone (Figure <xref ref-type="fig" rid="F1">1B</xref>). The mean estimated age obtained from DNA methylation data was very similar in patients with hip OA and in controls (Table <xref ref-type="table" rid="T1">1</xref>). The lack of difference was validated in a sub-analysis including only the fracture controls (ΔDmAM = 0.5 years, 95 % CI = −1.50 to 2.54, <italic>P</italic> = 0.6). Bone samples from cadaver controls were too few for meaningful analysis. All the comparisons were adjusted for age and sex as covariates.</p><p>The study of epigenetic aging in blood required de novo analyzes of methylation levels at the 8 CpG sites. The MS-SNuPE assays showed a 93.0 % call rate, and between-plate CV of 3.2 %. Age of the 182 controls without OA was accurately predicted with the 8CpG DmAM (Figure <xref ref-type="fig" rid="F2">2</xref>), as shown by the good fit of the mean age estimate (mean difference age – DmAM = −0.1 years, SD = 8.7 years). Comparison of the epigenetic ages obtained in this way did not show differences between OA patients and controls (Figure <xref ref-type="fig" rid="F2">2</xref>). The epigenetic ages for each of the joint-specific OA subgroups were very similar to the epigenetic age for the control subjects, as shown for the hand OA patients (Figure <xref ref-type="fig" rid="F2">2A</xref>), knee OA patients (Figure <xref ref-type="fig" rid="F2">2B</xref>) and hip OA patients (Figure <xref ref-type="fig" rid="F2">2C</xref>). This similarity in blood cells was clearly shown by the near zero year ΔDmAM (Table <xref ref-type="table" rid="T1">1</xref>). The largest difference in blood was observed between patients with hip OA and controls, but it was not significant and with direction opposed to premature aging in the OA subjects. All the comparisons were adjusted for age and sex as covariates.</p><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Lack of accelerated epigenetic aging in blood cells of OA patients</title><p>The scatterplots represent age in the horizontal axis against epigenetic age in the vertical axis from the controls without OA (empty circles, n =182) together with (<bold>A</bold>) the hand OA (n = 206), (<bold>B</bold>) the knee OA (n = 229), and (<bold>C</bold>) the hip OA (n = 273) patients (filled circles). Straight lines represent least squares regression fit to the data.</p></caption><graphic xlink:href="aging-08-2222-g002"></graphic></fig></sec><sec id="s3"><title>DISCUSSION</title><p>Our results showed for the first time premature epigenetic aging as detected with DmAM in cartilage of the OA affected joint, but not in bone nearby the OA affected joint, or in blood cells of OA patients irrespective of the joint affected. These results add epigenetic aging to the list of hallmarks of aging showing accelerated changes in OA cartilage. Each of these hallmarks provide complementary and non-redundant evidence of the different facets of the premature biological aging taking place in chondrocytes and the extracellular matrix of the OA affected cartilage. In addition, our results could be interpreted as questioning systemic premature aging in OA, or even a local component of premature aging in nearby bone, but exploration of other aging hallmarks would be required to exclude them.</p><p>Previously, several hallmarks of biological aging have been found exacerbated in chondrocytes and cartilage from OA patients [<xref rid="R3" ref-type="bibr">3</xref>, <xref rid="R4" ref-type="bibr">4</xref>]. Our work adds epigenetic aging to the list of hallmarks that show premature biological aging in this tissue. This is a significant addition because the different aging hallmarks, although extensively interconnected, show tissue and disease specificity and the involvement of each of them cannot be assumed from the presence of other hallmarks [<xref rid="R5" ref-type="bibr">5</xref>, <xref rid="R6" ref-type="bibr">6</xref>, <xref rid="R35" ref-type="bibr">35</xref>]. They need to be tested in the specific tissue or situation under study. This necessity is exemplified by the lack of correlation between epigenetic age and telomere length observed in the elderly population [<xref rid="R35" ref-type="bibr">35</xref>]. In addition, diseases of abnormal telomere attrition are different from diseases in which the dominant mechanism is genomic instability and both are different from normal aging. The first group includes pulmonary fibrosis, dyskeratosis congenita and aplastic anemia, whereas genome instability is the dominant aging hallmark in progeroid syndromes such as Hutchinson-Gilford progeria syndrome and Werner's syndrome [<xref rid="R5" ref-type="bibr">5</xref>, <xref rid="R6" ref-type="bibr">6</xref>]. In addition, the DNA methylation changes that are included in the Horvath DmAM have been shown to be independent from cellular senescence and mitotic age [<xref rid="R19" ref-type="bibr">19</xref>]. Similar lack of redundancy is observed between the other aging hallmarks, making it necessary to study each of them to know their involvement in OA.</p><p>Epigenetic changes with age are not restricted to DNA methylation. They encompass also histone modifica-tions regulated by sirtuins and chromatin remodeling [<xref rid="R6" ref-type="bibr">6</xref>]. None of the other age-associated epigenetic changes has yet been analyzed in the context of OA, but they are of interest given their potential reversibility as with histone deacetylase inhibitors or inhibitors of histone acetyltransferases as anti-aging drugs [<xref rid="R6" ref-type="bibr">6</xref>]. The meaning of these epigenetic changes is still poorly understood. They likely contribute to the loss of transcriptional regulation and increase of transcriptional noise observed with aging [<xref rid="R5" ref-type="bibr">5</xref>, <xref rid="R6" ref-type="bibr">6</xref>]. Changes in DNA methylation are concentrated in genes with some functional categories including cell growth and survival, organismal development and cancer [<xref rid="R19" ref-type="bibr">19</xref>], and in sites within glucocorticoid response elements [<xref rid="R26" ref-type="bibr">26</xref>], but the pattern of hypermethylation and hypomethylation has not yet being linked to specific molecular or cellular processes [<xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R20" ref-type="bibr">20</xref>]. Interpretation of the changes should also include the magnitude of the change: the increase in 3.7 years in ΔDmAM observed in the OA cartilage samples of our study is a modest acceleration compared with changes observed in tumoral tissue, but similar to the reported in a recent abstract in hip OA cartilage, which provides independent confirmation of our findings [<xref rid="R36" ref-type="bibr">36</xref>], and in blood of HIV infected patients [<xref rid="R37" ref-type="bibr">37</xref>], or in blood of Down syndrome patients [<xref rid="R29" ref-type="bibr">29</xref>], but larger than the observed in blood from patients with Parkinson disease [<xref rid="R38" ref-type="bibr">38</xref>], or in blood of women after menopause [<xref rid="R39" ref-type="bibr">39</xref>].</p><p>Some of the previously described aging hallmarks are strongest in the damaged cartilage and less clear in cartilage of preserved areas. Hallmarks showing this pattern are mean telomere length shortening [<xref rid="R40" ref-type="bibr">40</xref>-<xref rid="R42" ref-type="bibr">42</xref>] senescence-associated heterochromatin foci [<xref rid="R41" ref-type="bibr">41</xref>, <xref rid="R42" ref-type="bibr">42</xref>], and senescence-associated β-galactosidase (SA-β-gal). These results have been interpreted as representing, at least in part, consequences of cellular stress and the senescence status of the chondrocytes in OA. However, it is possible that epigenetic aging is a biomarker of cellular vulnerability more than of damage and, therefore, a potential target for treatment. Experiments aimed to differentiate between the two mechanisms are necessary but there are already preliminary results showing similar epigenetic aging in damaged and in preserved cartilage from the same OA patient [<xref rid="R36" ref-type="bibr">36</xref>]. Potential treatments could include specific senolytic drugs [<xref rid="R5" ref-type="bibr">5</xref>] that have not yet been assayed in chondro-cytes, and other approaches with capacity to delay aging in OA chondrocytes as already shown for statins [<xref rid="R38" ref-type="bibr">38</xref>] and sirtuin activation [<xref rid="R37" ref-type="bibr">37</xref>, <xref rid="R39" ref-type="bibr">39</xref>].</p><p>Our results are contrary to widespread premature epigenetic aging given the lack of increased ΔDmAM at the blood and bone levels. However, the only previous direct evidence of a systemic component of accelerate aging in OA was obtained with telomere length in blood cells of OA patients [<xref rid="R8" ref-type="bibr">8</xref>, <xref rid="R10" ref-type="bibr">10</xref>], and it is likely that telomere length and DmAM capture different aspects of biological aging [<xref rid="R6" ref-type="bibr">6</xref>, <xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R21" ref-type="bibr">21</xref>, <xref rid="R25" ref-type="bibr">25</xref>, <xref rid="R27" ref-type="bibr">27</xref>]. Telomere attrition results from cell divisions, in the absence of the enzyme telomerase, and from DNA damage induced by extrinsic stress, as oxidative or inflammatory stress. The authors that found accelerated telomere length attrition in blood of OA patient interpreted it as reflecting oxidative stress and low-level chronic inflammation [<xref rid="R8" ref-type="bibr">8</xref>], or associated with chronic pain and high stress [<xref rid="R10" ref-type="bibr">10</xref>]. In contrast, epigenetic aging as measured with DmAM seems to be due to perturbations of the DNA methylation mainte-nance system [<xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R21" ref-type="bibr">21</xref>, <xref rid="R25" ref-type="bibr">25</xref>]. Therefore, our results do not question systemic accelerated aging as detected with telomere shortening, but exclude the epigenetic aspect of aging.</p><p>The lack of accelerated aging in blood and in bone was not attributable to insufficient power. In effect, blood samples were enough to exclude ΔDmAM half as fast as the observed in cartilage (1-β > 0.95 to exclude a difference of 1.83 years for each of the three joints). Bone samples, in turn, were enough to detect ΔDmAM as large as the observed in cartilage (1-β = 0.90). In addition, the use of different DmAM for cartilage and bone, in one side, and for blood, in the other, does not interfere with our results because no analysis compared results across different DmAM. We also avoided biases due to differences in age or sex between the OA patients and the controls by adjusting for these two variables, as recommended [<xref rid="R19" ref-type="bibr">19</xref>-<xref rid="R21" ref-type="bibr">21</xref>]. However, limitations of our study are that the different tissues were not from the same subjects, the lack of other joint tissues, and the absence of a larger number of cartilage samples from femoral heads allowing specific analysis of epigenetic aging at this site. The meaning of these limitations seems modest because bone and cartilage are arguably the most relevant tissues in OA [<xref rid="R2" ref-type="bibr">2</xref>], and because epigenetic aging in hip cartilage from OA patients has been independently found [<xref rid="R36" ref-type="bibr">36</xref>], as already mentioned. In any case, we cannot completely exclude that other tissues or joints show a different behavior than the reporter here, or that additional insight could be gained from analyzing several tissues from the same subjects, as epigenetic age correlation between tissues.</p><p>In summary, we have found specific accelerated aging as measured with DNA methylation in cartilage from OA affected joints. Knowledge of the mechanisms of this type of premature aging will help to understand OA pathology, but already it is apparent that these particular mechanisms are not widespread. This was indicated by the results obtained with the same DNA methylation methodology in bone near the affected joint and in blood cells. They showed absence of a systemic component of premature aging. These results cannot exclude that other hallmarks of aging could be more widespread than the DNA methylation changes analyzed here.</p></sec><sec sec-type="methods" id="s4"><title>METHODS</title><sec id="s4_1"><title>Cartilage and bone epigenetic age</title><p>Epigenetic age was estimated with the 353 age-related CpG probes according with Horvath [<xref rid="R19" ref-type="bibr">19</xref>]. Methylation information of these sites has been obtained in previous studies addressing cartilage and bone samples (Table <xref ref-type="table" rid="T1">2</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>) [<xref rid="R43" ref-type="bibr">43</xref>-<xref rid="R46" ref-type="bibr">46</xref>]. Cartilage samples were from 31 controls and 36 OA patients (Table <xref ref-type="table" rid="T2">2</xref>).</p><table-wrap id="T2" orientation="portrait" position="float"><label>Table 2</label><caption><title>Main characteristics of the sample collections used in this study</title><p>N = number of samples, SD = standard deviation.</p></caption><table frame="box" rules="all"><thead><tr><th align="left" valign="bottom" rowspan="1" colspan="1">Tissue</th><th align="center" valign="bottom" rowspan="1" colspan="1">Set</th><th align="center" valign="bottom" rowspan="1" colspan="1">N</th><th align="center" valign="bottom" rowspan="1" colspan="1">Age<break></break>Mean ± SD (Range)</th><th align="center" valign="bottom" rowspan="1" colspan="1">Woman %</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">Cartilage</td><td align="left" valign="bottom" rowspan="1" colspan="1">Control knee/hip<xref ref-type="table-fn" rid="tfn_001"><sup>a</sup></xref></td><td align="center" valign="bottom" rowspan="1" colspan="1">31</td><td align="center" valign="bottom" rowspan="1" colspan="1">64.8 ± 15.0 (40-95)</td><td align="center" valign="bottom" rowspan="1" colspan="1">48.4</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="bottom" rowspan="1" colspan="1">Knee/hip OA</td><td align="center" valign="bottom" rowspan="1" colspan="1">36</td><td align="center" valign="bottom" rowspan="1" colspan="1">67.1 ± 9.3 (41-80)</td><td align="center" valign="bottom" rowspan="1" colspan="1">75.0</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Bone</td><td align="left" valign="bottom" rowspan="1" colspan="1">Control hip<xref ref-type="table-fn" rid="tfn_001"><sup>a</sup></xref></td><td align="center" valign="bottom" rowspan="1" colspan="1">45</td><td align="center" valign="bottom" rowspan="1" colspan="1">78.0 ± 11.0 (40-104)</td><td align="center" valign="bottom" rowspan="1" colspan="1">93.3</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="bottom" rowspan="1" colspan="1">Hip OA</td><td align="center" valign="bottom" rowspan="1" colspan="1">33</td><td align="center" valign="bottom" rowspan="1" colspan="1">75.4 ± 6.7 (58-89)</td><td align="center" valign="bottom" rowspan="1" colspan="1">100.0</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td rowspan="4" align="left" valign="top" colspan="1">Blood</td><td align="left" valign="bottom" rowspan="1" colspan="1">Control</td><td align="center" valign="bottom" rowspan="1" colspan="1">182</td><td align="center" valign="bottom" rowspan="1" colspan="1">60.7 ± 11.5 (45-88)</td><td align="center" valign="bottom" rowspan="1" colspan="1">46.7</td></tr><tr><td align="left" valign="bottom" rowspan="1" colspan="1">Hand OA</td><td align="center" valign="bottom" rowspan="1" colspan="1">206</td><td align="center" valign="bottom" rowspan="1" colspan="1">60.6 ± 10.1 (32-88)</td><td align="center" valign="bottom" rowspan="1" colspan="1">88.4</td></tr><tr><td align="left" valign="bottom" rowspan="1" colspan="1">Knee OA</td><td align="center" valign="bottom" rowspan="1" colspan="1">229</td><td align="center" valign="bottom" rowspan="1" colspan="1">67.7 ± 5.6 (55-78)</td><td align="center" valign="bottom" rowspan="1" colspan="1">82.1</td></tr><tr><td align="left" valign="bottom" rowspan="1" colspan="1">Hip OA</td><td align="center" valign="bottom" rowspan="1" colspan="1">273</td><td align="center" valign="bottom" rowspan="1" colspan="1">68.4 ± 5.5 (55-84)</td><td align="center" valign="bottom" rowspan="1" colspan="1">59.7</td></tr></tbody></table><table-wrap-foot><fn id="tfn_001"><label>a</label><p>3 cartilage and 4 bone control samples were from undefined localization</p></fn></table-wrap-foot></table-wrap><p>The controls were from tibial plateau of 18 cadavers with no macroscopic signs of OA [<xref rid="R43" ref-type="bibr">43</xref>], and the femoral head of 10 subjects with hip fracture and without macroscopic or microscopic evidence of OA [<xref rid="R46" ref-type="bibr">46</xref>]. In addition, 3 cartilage samples from cadavers without information of status and location were included [<xref rid="R45" ref-type="bibr">45</xref>]. The OA samples included 29 from the tibial plateau of severe knee OA patients [<xref rid="R43" ref-type="bibr">43</xref>, <xref rid="R46" ref-type="bibr">46</xref>], and 7 from the femoral head of severe hip OA patients [<xref rid="R46" ref-type="bibr">46</xref>], obtained at the time of joint replacement. Bone samples were from 45 controls and 33 hip OA patients (Table <xref ref-type="table" rid="T2">2</xref>). The controls included femoral heads of 34 subjects with osteoporotic hip fracture (OP) and 7 cadavers [<xref rid="R44" ref-type="bibr">44</xref>]. They lacked OA lesions on macroscopic examination of the hip joints and the bone pieces excluded subchondral and fractured regions. Patients with fractures due to high-energy trauma or with disorders causing secondary OP or OA were not included. In addition, 4 control bone samples from cadavers that lacked detailed information of status and place of retrieval were included.[<xref rid="R45" ref-type="bibr">45</xref>] The bone samples of the 33 hip OA patients were obtained from femoral heads at the time of total joint replacement for primary hip OA [<xref rid="R44" ref-type="bibr">44</xref>]. Methylation data were obtained either with the Human Methylation 27 BeadChip (Illumina), [<xref rid="R43" ref-type="bibr">43</xref>, <xref rid="R44" ref-type="bibr">44</xref>] or with the HumanMethylation 450 Bead-Chip microarray (Illumina, San Diego, California, USA) [<xref rid="R45" ref-type="bibr">45</xref>, <xref rid="R46" ref-type="bibr">46</xref>]. These samples were obtained with informed consent of the donors and approval of the relevant ethics committees as reported in the primary publications [<xref rid="R43" ref-type="bibr">43</xref>-<xref rid="R46" ref-type="bibr">46</xref>].</p></sec><sec id="s4_2"><title>Analysis of epigenetic aging in blood</title><p>Epigenetic aging in blood was assessed with a 8 CpG DmAM specific for whole blood and amenable to assay in large number of samples [<xref rid="R24" ref-type="bibr">24</xref>]. Methylation data were obtained for this study with methylation-sensitive single-nucleotide primer extension (MS-SNuPE) following the reported procedure [<xref rid="R47" ref-type="bibr">47</xref>]. Genomic DNA from 890 subjects of Spanish ancestry was assayed (Table <xref ref-type="table" rid="T1">2</xref> and <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 1</xref>). This collection of samples included 182 controls recruited at the time of intravenous urography. They had not OA signs at exploration including both hands or in the radiographs either at the hip or column joints, and they did not complain of OA symptoms in a systematic question-naire. The remaining 708 subjects were suffering from primary OA as assessed by a rheumatologist. The subjects affected by knee OA, 229, or hip OA, 273, were selected from consecutive patients aged 55–75 years at the time of surgery that were undergoing total joint replacement. The patients with hand OA, 206, were selected among those attending the Rheumatology Unit fulfilling the American College of Rheumatology classification criteria for hand OA [<xref rid="R48" ref-type="bibr">48</xref>]. Exclusion criteria were inflammatory, infectious, traumatic or congenic joint pathology, as well as, lesions due to crystal deposition or osteonecrosis. Morbid obesity and occupational strain were not exclusion causes. All donors provided blood DNA samples for genetic studies with written informed consent according to the Declaration of Helsinki (most recently at the General Assembly on October 2008) and the approval of the Ethics Committee for Clinical Research of Galicia, as described [<xref rid="R49" ref-type="bibr">49</xref>].</p></sec><sec id="s4_3"><title>Statistical analysis</title><p>We estimated the epigenetic age of the cartilage and bone samples with Horvath's DmAM [<xref rid="R19" ref-type="bibr">19</xref>], and of the blood samples with the 8 CpG DmAM [<xref rid="R24" ref-type="bibr">24</xref>]. Comparisons between samples from OA patients and controls were done with analysis of variance (ANOVA) including age and sex as covariates. Mean differences in DmAM estimates (ΔDmAM) were calculated as:</p><p>ΔDmAM = (age- and sex-adjusted mean DmAM in OA patients) – (age- and sex-adjusted mean DmAM in controls)</p><p>Age- and sex-adjustment was done with the residuals from multiple linear regression of estimated age <italic>versus</italic> age and sex. All these analyses were done with Statistica 7.0 (Stat Soft, Inc.). Post-hoc power analysis was done with G*Power 3 for α = 0.05 [<xref rid="R50" ref-type="bibr">50</xref>].</p></sec></sec><sec sec-type="supplementary-material" id="s5"><title>SUPPLEMENTARY MATERIAL TABLE</title><supplementary-material content-type="local-data" id="SD1"><media mimetype="application" mime-subtype="pdf" xlink:href="aging-08-2222-s001.pdf" orientation="portrait" xlink:type="simple" id="d36e954" position="anchor"></media></supplementary-material></sec></body><back><ack><p>The authors are indebted to the patients that generously have contributed the samples and time to this work. They also thank Carmen Pena for her excellent technical support.</p></ack><fn-group><fn fn-type="supported-by"><p><bold>FUNDING</bold></p><p>This work was supported by the Instituto de Salud Carlos III (Spain) [grants PI14/01651, PI12/01909, RD12/009/008, and P12/615] with participation of the European Regional Development Fund of the EU (FEDER).</p></fn><fn fn-type="COI-statement"><p><bold>CONFLICTS OF INTEREST</bold></p><p>The authors declare they have no conflict of interest.</p></fn></fn-group><ref-list><title>REFERENCES</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group 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