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Comparisons of Soluble Klotho Concentration Between Healthy and Patient Cohorts
Biomed Sci Letters 2023;29:1-10
Published online March 31, 2023;  https://doi.org/10.15616/BSL.2023.29.1.1
© 2023 The Korean Society For Biomedical Laboratory Sciences.

Myeong Kwan Kim1,3,* and Dongju Jung2,3,†,* *

1Department of Biotechnology, Hoseo University Graduate School, Hoseo University, Asan, Chungnam 31499, Korea
2Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea
3Klotho Sciences Corporation, Healthcare Innovation Park, Seoul National University Bundang Hospital Complex, Seongnam, Gyenggi 13605, Korea
Correspondence to: Dongju Jung. Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Chungnam 31499, Korea.
Tel: +82-41-540-9969, Fax: +82-41-540-9997, e-mail: djjungg@hoseo.edu
*Graduate Student, **Professor.
Received February 24, 2023; Accepted March 27, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Since its first identification in 1995, klotho (KL) has become the most promising gene to consider for suppressing aging and aging-related diseases. KL knockout mice exhibited similar phenotypes found in human with premature aging such as short lifespan, osteoporosis, arteriosclerosis and hearing loss. Genetically modified mice overexpressing KL prolonged lifespan more than 20%. Also, clinical reports have indicated decreased concentration of the circulating KL protein in blood, which is called soluble klotho (sKL), is closely related to development of senile diseases. The best way to discover significance of sKL on the development of the diseases might be comparison of sKL concentration between controls and patients. Here we analyzed published clinical reports identified sKL concentration in the cohorts. The sKL concentrations were displayed using heatmap for better comparison. In most of the senile diseases, disease progression was inversely related with sKL concentration. Hypertension was the only disease had no relationship, while schizophrenia was the only disease had direct proportion to the disease progression. Overall, sKL concentration in blood could be a marker to determine current severity of the senile diseases and even to estimate disease progression for the patients at the onset of their senile diseases.
Keywords : Klotho proteins, Aging, Cohort studies
꽌 濡

궗엺쓽 닔紐낆씠 利앷릺硫댁꽌 끂솕 諛 끂씤꽦 吏덊솚뿉 븳 愿떖씠 넂븘吏怨 엳떎. 끂씤꽦 吏덊솚 移섎즺媛 뼱젮썙 湲곗〈쓽 移섎즺 諛⑸쾿怨쇰뒗 떎瑜 떆룄媛 씠뼱吏怨 엳뒗뜲, 以꾧린꽭룷瑜 씠슜븯뿬 媛먯냼릺뒗 꽭룷瑜 蹂댁땐븯뒗 옱깮쓽븰(regenerative medicine) 諛⑸쾿怨, 끂솕愿젴 쑀쟾옄쓽 蹂씠瑜 李얠븘 씠瑜 移섎즺븯뒗 諛⑸쾿 벑씠 怨좊젮릺怨 엳떎. 듅엳 理쒓렐쓽 뿰援 寃곌낵瑜 넻빐 끂솕 쁽긽 媛蹂쟻씠뼱꽌 쑀쟾옄 諛쒗쁽 議곗젅쓣 넻빐 뿭끂솕瑜 씪쑝궗 寃쎌슦 끂솕맂 媛쒖껜媛 젇뼱 吏뒗 寃껊룄 媛뒫븯떎뒗 寃껋씠 븣젮吏寃 릺뿀떎(Yang et al., 2023). 끂솕 愿젴맂 쑀쟾옄瑜 李얘린 쐞븳 끂젰 袁몄엳 씠猷⑥뼱졇 솕떎. 泥섏쓬쑝濡 끂솕愿젴 쑀쟾옄濡 蹂닿퀬맂 寃껋 踰좊Ⅴ꼫利앺썑援(Werner's syndrome)씠씪 遺덈━뒗 議곌린 끂솕 吏덊솚쓽 썝씤 쑀쟾옄濡 諛쒓껄맂 Helicase 슚냼 吏묐떒씠떎(Epstein et al., 1966; Gray et al., 1997). 삉븳 留덉슦뒪 AKR/J 醫낆쓽 룞議깅쾲떇 怨쇱젙 以 슦뿰엳 諛쒓껄븳 SAM (Senescence-Accelerated Mouse)룄 湲됯꺽븳 끂솕 쁽긽쓣 諛쒖깮뻽뒗뜲, 씠 伊먯뿉꽌뒗 궛솕뒪듃젅뒪, 슦 諛 븘諛濡쒖씠뱶 떒諛깆쭏 異뺤쟻 蹂솕, 뇤떊寃 꽭룷 쑀吏 愿젴맂 떎닔쓽 쑀쟾옄쓽 諛쒗쁽 蹂솕媛 굹궃 寃껋씠 솗씤릺뿀떎(Liu et al., 2020). 씠뱾 끂솕愿젴 蹂씠뒗 떒씪 쑀쟾옄媛 븘땶 뿬윭 쑀쟾옄쓽 蹂듯빀쟻씤 蹂씠瑜 넻빐 씪뼱궃 寃껋쑝濡쒖꽌, 떒씪 쑀쟾옄 蹂씠뿉 쓽븳 끂솕쓽 利앷뒗 1997뀈뿉 끂솕뼲젣 湲곕뒫씠 諛앺吏 klotho 쑀쟾옄媛 쁽옱源뚯뒗 쑀씪븯떎(Kuro-o et al., 1997). Klotho 쑀쟾옄瑜 뾾븻 伊먯뿉꽌뒗 씤媛꾩쓽 끂솕 쁽긽怨 쑀궗븳 깮紐낆쓽 떒異, 怨⑤떎怨듭쬆, 룞留κ꼍솕, 泥젰 媛먯냼 벑씠 굹궗떎(Kuro-o et al., 1997). 諛섎濡 씤쐞쟻쑝濡 klotho 쑀쟾옄瑜 뜑 諛쒗쁽떆궓 留덉슦뒪쓽 寃쎌슦 닔紐낆씠 20% 씠긽 利앷븯뒗 寃곌낵媛 굹궗뒗뜲, 씠뒗 삁븸 궡濡 뼥뼱졇 굹삩 klotho 떒諛깆쭏 遺遺꾩씠 샇瑜대が泥섎읆 옉룞븯뿬 닔슜泥댁 寃고빀븿쑝濡 씤뒓由곌낵 씤뒓由 쑀궗 꽦옣씤옄 1 (insulin-like growth factor 1, IGF 1)뿉 쓽븳 떊샇쟾떖쓣 뼲젣븯湲 븣臾몄씤 寃껋쑝濡 蹂닿퀬릺뿀떎(Kurosu et al., 2005). 씠썑 klotho 끂씤꽦 吏덈퀝 궗씠쓽 愿怨꾩뿉 愿븳 留롮 닔쓽 뿰援 寃곌낵媛 諛쒗몴릺뿀怨, 씠 寃곌낵뱾 klotho 쑀쟾옄쓽 諛쒗쁽쓣 넻빐 議곗젅릺뒗 삁븸 궡 soluble klotho (sKL) 냽룄媛 吏덈퀝怨쇱쓽 뿰愿꽦씠 넂떎뒗 寃껋쓣 굹깉떎. 듅젙 씤援 吏묐떒쓽 쟾泥댁쟻씤 쑀쟾삎씠굹 몴쁽삎쓣 鍮꾧탳븯뒗 諛⑸쾿씤 肄뷀샇듃 뿰援(cohort study)뒗 sKL 吏덈퀝怨쇱쓽 뿰愿꽦쓣 뙆븙븯湲곗뿉 留ㅼ슦 쟻젅븳 諛⑸쾿씠씪怨 蹂 닔 엳떎. 씠 끉臾몄뿉꽌뒗 肄뷀샇듃瑜 씠슜븳 吏덈퀝援(patients cohort)怨 議곌뎔(control cohort) 媛꾩쓽 삁以 sKL 냽룄瑜 蹂닿퀬븳 끉臾몄쓣 씠슜븯뿬 sKL 냽룄 뿰愿꽦씠 넂 吏덊솚쓣 젙由ы븯怨좎옄 븯떎. 鍮꾧탳瑜 돺寃 븯湲 쐞빐꽌 엳듃留(heat map)쓣 씠슜븯뿬 諛쒗몴맂 寃곌낵瑜 넻씪꽦 엳寃 떎떆 몴떆뻽뒗뜲, 씠瑜 쐞빐 씠슜븳 肄뷀샇듃 遺꾩꽍 끉臾몄 븣젮吏 紐⑤뱺 sKL 愿젴 肄뷀샇듃 뿰援 寃곌낵 以 吏덈퀝援곌낵 議곌뎔씠 紐낇솗엳 援щ텇릺뼱 엳怨, 肄뷀샇듃 닽옄媛 넻怨꾩쟻쑝濡 異⑸텇븳 뿰援 寃곌낵留뚯쓣 꽑蹂꾪븯뿬 씠슜븯떎.

蹂 濡

뒪럹씤 肄뷀샇듃瑜 씠슜븳 끂솕 젙룄뿉 뵲瑜 삁以 sKL 냽룄 蹂솕 솗씤

sKL뒗 끂솕긽깭瑜 꽕紐낇븯뒗 以묒슂븳 씤옄 以 븯굹濡쒖꽌 以묒슂븯떎怨 븣젮議뚯留, 궗엺쓽 嫄닿컯긽깭, 굹씠, 洹몃━怨 꽦蹂꾧낵 愿젴븯뿬 李멸퀬븷 닔 엳뒗 湲곗移섏뿉 븳 蹂닿퀬뒗 뾾뿀떎. Espuch-Oliver 벑 sKL 삁以 냽룄뿉 븳 李멸퀬 湲곗移섎 꽕젙븯湲 쐞븯뿬 嫄닿컯븳 꽦씤쓽 sKL 냽룄瑜 뿰援ы븯떎. 뒪럹씤 궓遺쓽 Andalusian Public Health System쑝濡쒕꽣 18꽭 씠긽쓽 吏덈퀝씠 뾾뒗 嫄닿컯븳 諛깆씤 씤醫낆뿉 븳 삁븸 깦뵆쓣 젣怨듬컺븯怨, 삁以 sKL 냽룄뒗 Enzyme-Linked Immunosorbent Assay (ELISA; kit reference number: JP27998; IBL International GmbH laboratories, Hamburg, Germany)濡 遺꾩꽍릺뿀떎. sKL쓽 룊洹 삁以 냽룄뒗 167紐낆쓽 泥뀈 洹몃9(18~34.9꽭)뿉꽌뒗 932.6 pg/mL, 88紐낆쓽 以묐뀈 洹몃9(35~54.9꽭)뿉꽌뒗 796.7 pg/mL, 洹몃━怨 끂씤 洹몃9(55~ 85꽭)뿉꽌뒗 612.1 pg/mL濡 솗씤릺뿀떎. 以묐뀈 洹몃9 泥뀈 洹몃9뿉 鍮꾪빐 sKL쓽 냽룄媛 14.6%媛 궙븯怨(P<0.05), 끂씤 洹몃9 泥뀈 洹몃9뿉 鍮꾪빐 34.4% 궙븯떎(P<0.001) (Espuch-Oliver et al., 2022). 蹂닿퀬맂 끉臾몄쓣 넻빐 굹씠媛 넂븘吏덉닔濡 삁以 sKL쓽 냽룄媛 넻怨꾩쟻쑝濡 쑀쓽븯寃 媛먯냼맂 寃껋쓣 솗씤븷 닔 엳뿀떎(Fig. 1). 씠 끉臾몄뿉꽌뒗 젙긽씤쓽 삁以 sKL쓽 냽룄媛 굹씠媛 利앷븿뿉 뵲씪 鍮꾨쟻쑝濡 媛먯냼븯뒗 寃껋쓣 굹깉쑝誘濡, 떎쓬쓽 吏덈퀝뿰愿 肄뷀샇듃 遺꾩꽍 寃곌낵 鍮꾧탳 떆 엳듃留 궡뿉 李멸퀬옄猷뚮줈 씠슜븯떎.

Fig. 1. Heatmap of a Spaniard cohort study. A total of 346 (59% women) healthy Spaniards from southern Spain were included for the study. Subjects were divided by sex and age as young group (18~34.9 years), middle-aged group (35~54.9 years), and senior group (55~85 years). Average sKL concentrations in blood for the aged groups are displayed. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants. Statistical significance is indicated using asterisks: *indicates significant (P<0.05), ***indicates highly significant (P<0.001).

삁以 sKL쓽 냽룄 끂솕 吏덊솚怨쇱쓽 뿰愿꽦

1. 怨좏삁븬(Hypertension)

겢濡쒖냼 떒諛깆쭏씠 怨좏삁븬 吏덈퀝怨 愿怨꾧 엳떎怨 븣젮議뚭퀬, 씠瑜 엯利앺븷 肄뷀샇듃 遺꾩꽍 떎뿕씠 蹂닿퀬릺뿀떎. 以묎뎅씤 肄뷀샇듃 以 怨좏삁븬 솚옄 洹몃9怨 젙긽씤 洹몃9 媛꾩쓽 삁以 sKL 냽룄, 삁븬 諛 룞留κ꼍솕 諛쒖깮쓣 痢≪젙븯뿬 sKL 怨좏삁븬怨쇱쓽 뿰愿꽦쓣 議곗궗븯떎. 肄뷀샇듃쓽 援ъ꽦 以묎뎅쓽 쐢궃꽦 떖由ъ뿉 嫄곗<븯뒗 18꽭 씠긽쓽 716紐낆씠뿀떎. sKL 냽룄瑜 쐞븳 삁븸 깦뵆 ELISA (DY5334-05, R&D Systems, Inc., Minneapolis, MN, USA) 諛⑸쾿뿉 쓽빐 遺꾩꽍릺뿀떎. 227紐낆쓽 怨좏삁븬 솚옄 洹몃9(58.3짹10.4꽭)쓽 sKL 룊洹 냽룄뒗 382 pg/mL怨, 489紐낆쓽 젙긽씤 洹몃9(48.9짹12.4꽭)쓽 sKL 룊洹 냽룄뒗 382 pg/mL濡 痢≪젙릺뿀떎(Fig. 2). 몢 吏묐떒 媛꾩쓽 넻怨꾩쟻 李⑥씠뒗 뾾뒗 寃껋쑝濡 솗씤릺뿀떎(P= 0.52) (Liang et al., 2021). 怨좏삁븬 끂씤꽦 吏덈퀝씠吏留 以묎뎅씤 肄뷀샇듃瑜 씠슜븳 鍮꾧탳뿉꽌뒗 sKL쓽 뼇怨쇰뒗 愿怨꾧 뾾뒗 寃껋쑝濡 굹궗떎. 븯吏留 誘멸뎅 Tuft medical center뿉꽌 吏꾪뻾븳 肄뷀샇듃 뿰援ъ뿉꽌뒗 삁以 sKL 냽룄媛 닔異뺢린 삁븬(systolic blood pressure)怨쇰뒗 愿怨꾧 뾾吏留, 씠셿湲 삁븬(diastolic blood pressure)怨쇰뒗 愿怨꾧 엳쓬씠 蹂닿퀬릺뿀떎 (Drew et al., 2021). 洹몃윭誘濡 뼢썑 떎瑜 肄뷀샇듃瑜 씠슜븳 寃곌낵뿉꽌뒗 뼱뼡 뿰愿꽦씠 굹궇吏 솗씤씠 븘슂븷 寃껋쑝濡 삁긽맂떎.

Fig. 2. Heatmap of a Chinese cohort study displaying sKL concentration in blood from the control (healthy) group and case (hypertensive) group. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants.

2. 議고쁽蹂 (Schizophrenia)

以묒쬆 젙떊 옣븷 吏덊솚씤 議고쁽蹂묒 끂씤꽦 吏덈퀝 븘땲吏留, 理쒓렐 뿰援ъ뿉 뵲瑜대㈃ 겢濡쒖냼 떒諛깆쭏씠 뇤뿉꽌 씤吏 湲곕뒫뿉 以묒슂븳 뿭븷쓣 븯뒗 寃껋씠 諛앺졇꽌(Chen and Sun, 2018) sKL 냽룄瑜 議곗궗븿쑝濡 議고쁽蹂묎낵쓽 뿰愿꽦쓣 솗씤빐蹂닿퀬옄 떆룄릺뿀떎. 以묎뎅쓽 肄뷀샇듃뒗 Jiangxi Mental Hospital뿉 엯썝븳 솚옄 40紐낃낵 吏뿭 궗쉶쓽 嫄닿컯븳 媛쒖씤 40紐낆쓣 紐⑥쭛븯뿬 吏꾪뻾릺뿀떎. 젙긽씤 洹몃9쓽(33.23짹8.57꽭) 삁以 sKL 룊洹 냽룄뒗 844 pg/mL濡 痢≪젙릺뿀怨, 議고쁽蹂 솚옄 洹몃9(30.36짹7.97꽭) 룊洹 1,233 pg/mL濡 痢≪젙릺뿀떎(Fig. 3). 몢 洹몃9 媛꾩쓽 sKL 냽룄 李⑥씠뒗 넻怨꾩쟻쑝濡 넂 쑀쓽꽦씠 엳뿀떎(P<0.001) (Xiong et al., 2020). 利 삁以 sKL쓽 냽룄媛 넂 寃껋 議고쁽蹂 諛쒖깮怨 뿰愿맂떎뒗 寃곌낵떎.

Fig. 3. Heatmap of Chinese and Turkist cohort studies displaying sKL concentration in blood from the control (healthy) group and case (schizophrenia) group. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants. Statistical significance is indicated using asterisks: *indicates significant (P<0.05), ***indicates highly significant (P<0.001).

젙긽씤怨 議고쁽蹂 솚옄 궗씠쓽 삁以 sKL 냽룄瑜 鍮꾧탳븳 議곗궗뒗 꽣궎 肄뷀샇듃瑜 씠슜븯뿬꽌룄 뿰援щ릺뿀떎. Elazi휓 Fethi Sekin City Hospital뿉 엯썝븳 40紐낆쓽 議고쁽蹂 솚옄뱾怨 젙떊 吏덊솚쓽 蹂묐젰씠 뾾뒗 젙긽씤 40紐낆쓣 긽쑝濡 吏꾪뻾릺뿀떎. 젙긽씤 洹몃9쓽(37.4짹11.9꽭) 삁以 sKL 룊洹 냽룄뒗 480 pg/mL濡 痢≪젙릺뿀怨, 議고쁽蹂 솚옄 洹몃9쓽(37.2짹11.1꽭) 삁以 sKL 룊洹 냽룄뒗 585 pg/mL濡 痢≪젙릺뿀떎(Fig. 3). 몢 洹몃9 媛꾩쓽 sKL 냽룄 李⑥씠뒗 넻怨꾩쟻쑝濡 쑀쓽꽦씠 엳뿀떎(P<0.05) (Kilicaslan et al., 2022). 꽣궎씤 肄뷀샇듃 以묎뎅씤 肄뷀샇듃 寃곌낵 紐⑤몢 議고쁽蹂 솚옄쓽 寃쎌슦 sKL쓽 삁以 냽룄媛 젙긽씤蹂대떎 넂 寃껋쑝濡 굹궗떎. 븯吏留 븘吏곴퉴吏 sKL媛 議고쁽蹂 諛쒖깮쓽 썝씤쑝濡 옉룞븯뒗吏뒗 諛앺吏吏 븡븯떎.

3. 떦눊蹂묒꽦 留앸쭑吏덊솚(Diabetic Retinopathy)

떦눊蹂묒꽦 留앸쭑吏덊솚 떦눊蹂 솚옄뿉寃뚯꽌 쓷엳 굹굹뒗 빀蹂묒쬆 以 븯굹씠硫, 뿰援ъ뿉 뵲瑜대㈃ klotho 쑀쟾옄 諛쒗쁽씠 利앷븯뒗 KS-VS 蹂씠泥대 媛吏怨 엳뒗 젣1삎 떦눊蹂 솚옄쓽 寃쎌슦 留앸쭑吏덊솚쓽 諛쒕퀝씠 뼲젣릺뒗 寃껋쑝濡 蹂닿퀬릺뿀떎(Slominski et al., 2018). Corcillo A 벑 klotho 諛쒗쁽怨 떦눊蹂묒꽦 留앸쭑吏덊솚 諛쒖깮怨쇱쓽 뿰愿꽦쓣 쁺援씤 肄뷀샇듃瑜 씠슜븯뿬 遺꾩꽍븯떎. 씠뱾 젣2삎 떦눊蹂묒쓣 媛吏 솚옄 81紐(궓꽦 62%)쓣 룊洹 44媛쒖썡 룞븞 愿李고븯硫댁꽌 삁以 sKL 냽룄瑜 痢≪젙븯怨, 留앸쭑吏덊솚 吏꾪뻾 젙룄뒗 룞怨듭쓣 넻빐 븞遺쓽 궗吏꾩쓣 李띿뼱꽌 솗씤븯떎. 씠뱾 以 留앸쭑吏덊솚씠 吏꾪뻾맂 洹몃9怨 吏꾪뻾릺吏 븡 洹몃9 媛꾩뿉 삁以 sKL 냽룄瑜 痢≪젙븯뿬 鍮꾧탳븿쑝濡쒖뜥 吏덈퀝怨쇱쓽 뿰愿꽦쓣 넻怨꾩쟻쑝濡 遺꾩꽍븯떎. 洹 寃곌낵 35紐낆쓽 留앸쭑吏덊솚 鍮꾩쭊뻾 洹몃9(60.7짹9.3꽭)쓽 삁以 sKL 룊洹 냽룄뒗 484.5 pg/mL濡 痢≪젙릺뿀怨, 留앸쭑吏덊솚 吏꾪뻾 洹몃9(61.2짹8.8꽭)쓽 삁以 sKL 룊洹 냽룄뒗 226.9 pg/mL濡 痢≪젙릺뿀떎(Fig. 4). 몢 吏묐떒 媛꾩쓽 떦눊蹂묒꽦 留앸쭑吏덊솚 吏꾪뻾怨 삁以 sKL 냽룄 궗씠뿉뒗 넻怨꾩쟻씤 뿰愿꽦씠 留ㅼ슦 넂(P<0.001) 寃껋쑝濡 굹궗떎(Corcillo et al., 2020). 利 떦눊蹂 솚옄 以 留앸쭑吏덊솚씠 뜑 븙솕릺뒗 궗엺쓽 寃쎌슦뒗 洹몃젃吏 븡 궗엺뿉 鍮꾪빐 삁以 sKL쓽 뼇씠 쟻떎뒗 寃껋쓣 굹깉떎.

Fig. 4. Heatmap of Briton cohort study displaying sKL concentration in blood from the control (healthy) group and case (retinopathy) group. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants. Statistical significance is indicated using asterisks: ***indicates highly significant (P<0.001).

4. 留뚯꽦떊옣吏덊솚(Chronic Kidney Disease, CKD)

CKD뒗 몴쟻씤 끂솕꽦 吏덈퀝쑝濡, sKL쓽 뿰愿꽦씠 옒 븣젮졇 엳떎(Hu et al., 2013; Hu et al., 2011; Giachelli, 2009; Lindberg et al., 2014). CKD 솚옄 洹몃9쓽 삁以 sKL 냽룄瑜 痢≪젙븯뿬 吏덈퀝怨쇱쓽 뿰愿꽦쓣 議곗궗븳 寃곌낵媛 Sven-Jean Tan 벑뿉 쓽빐 蹂닿퀬릺뿀떎. 샇二쇱쓽 Royal Melbourne Hospital (RMH)뿉꽌 CKD 吏꾨떒쓣 諛쏆 솚옄 77紐낃낵 젙긽씤 39紐낆쓣 긽쑝濡 吏꾪뻾릺뿀떎. 77紐낆쓽 CKD 솚옄 洹몃9(룊洹 57꽭)쓽 삁以 sKL 룊洹 냽룄뒗 408 pg/mL씠뿀怨, 39紐낆쓽 젙긽씤 洹몃9(룊洹 17꽭)쓽 삁以 sKL 룊洹 냽룄뒗 542 pg/mL떎(Fig. 5). 몢 吏묐떒 媛 sKL 냽룄뒗 넻怨꾩쟻쑝濡 留ㅼ슦 넂(P<0.001) 젙룄濡 李⑥씠媛 엳쓬쓣 솗씤븷 닔 엳뿀떎(Tan et al., 2017). 洹몃윭굹 씠 끉臾몄뿉꽌 씠슜븳 솚옄 洹몃9怨 젙긽씤 洹몃9 궗씠쓽 겙 룊洹 뿰졊 李⑥씠濡 씤빐 sKL CKD 뿰愿꽦쓣 꽕紐낇븯湲곗뿉뒗 遺議깊븳 젏씠 엳떎怨 뙋떒맂떎. 鍮꾩듂븳 굹씠 吏묐떒 媛 鍮꾧탳쑝硫 뜑 젙솗븳 寃곌낵濡 씤떇맆 닔 엳쓣 寃껋씠떎.

Fig. 5. Heatmap of Australian cohort study displaying sKL concentration in blood from the control (healthy) group and case (chronic kidney disease, CKD) group. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants. Statistical significance is indicated using asterisks: ***indicates highly significant (P<0.001).

CKD쓽 뿰愿꽦 븳援씤 肄뷀샇듃瑜 씠슜븳 蹂닿퀬瑜 넻빐꽌룄 븣젮議뚮뒗뜲, CKD 솚옄 洹몃9뿉꽌 sKL쓽 냽룄媛 궙쓣닔濡 궗利앺썑援(metabolic syndrome) 諛쒖깮 鍮꾩쑉씠 넂븯떎(Kim et al., 2019). 삉븳 CKD瑜 솚옄 洹몃9뿉꽌 吏덈퀝쓽 吏꾪뻾씠 뜑 굹鍮좎뒗 寃곌낵瑜 굹궦 솚옄뱾쓽 寃쎌슦 궙 sKL 냽룄瑜 媛吏怨 엳뒗 寃껋씠 솗씤릺뿀떎(Fig. 6) (Kim et al., 2013). 씠 寃곌낵뱾쓣 醫낇빀븯硫 샇二쇱씤 肄뷀샇듃 븳援씤 肄뷀샇듃瑜 씠슜븳 議곗궗뿉꽌 CKD 吏덊솚怨 sKL 삁以 냽룄뒗 넂 뿰愿꽦씠 엳뼱꽌 엫긽뿉꽌 CKD 吏덊솚뿉 븳 諛붿씠삤 留덉빱濡쒖꽌 sKL瑜 씠슜븯뒗 寃껋씠 쟻젅븳 寃껋엫쓣 솗씤떆耳쒖<뿀떎.

Fig. 6. Heatmap of Korean cohort study displaying sKL concentration in blood from the CKD patients. sKL concentrations were measured from the chronic kidney disease (CKD) patients at different stages. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants.

5. 떖삁愿吏덊솚(Cardiovascular Disease, CVD)

CVD뒗 몴쟻씤 끂솕꽦 吏덈퀝쑝濡, klotho 떒諛깆쭏怨쇱쓽 뿰愿꽦씠 븣젮졇 엳떎(Donate-Correa et al., 2015). CVD 吏덊솚 洹몃9怨 젙긽씤 洹몃9 궗씠쓽 삁以 sKL 냽룄 李⑥씠뿉 븳 遺꾩꽍씠 뒪럹씤 肄뷀샇듃瑜 씠슜븯뿬 뿰援щ릺뿀떎. Hospital Universitario Nuestra Se챰ora de Candelaria (UHNSC)쓽 CVD 솚옄 76紐낃낵 CVD 뿰愿 뾾뒗 16紐낆쓽 옣湲 湲곗쬆옄瑜 젙긽씤쑝濡 븯뿬 鍮꾧탳 떎뿕씠 吏꾪뻾릺뿀떎. CVD 솚옄 洹몃9쓽(65.3짹7.4꽭) 삁以 sKL 룊洹 냽룄뒗 507.7 pg/mL濡 痢≪젙릺뿀怨, 젙긽씤 洹몃9쓽(63.2짹9.3꽭) 삁以 sKL 룊洹 냽룄뒗 1,007 pg/mL濡 愿李곕릺뿀떎(Fig. 7) (Martin-Nunez et al., 2022). 씠 寃곌낵뒗 떖삁愿 吏덈퀝쓽 諛쒖깮怨 삁以 sKL쓽 냽룄 궗씠뿉 넻怨꾩쟻쑝濡 넂(P<0.01) 뿰愿꽦씠 엳쓬쓣 굹궦떎.

Fig. 7. Heatmap of Spaniard cohort study displaying sKL concentration in blood from the control (healthy) group and case (cardiovascular disease, CVD) group. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants. Statistical significance is indicated using asterisks: **indicates very significant (P<0.01).

6. 궗꽦吏덊솚 (Metabolic Disease)

궗꽦吏덊솚 굹씠媛 뱾닔濡 諛쒖깮씠 利앷븯뒗뜲, 끂솕愿젴 쑀쟾옄씤 klotho쓽 寃쎌슦 궗꽦吏덊솚怨 愿젴씠 엳뒗 寃껋쑝濡 嫄닿컯寃吏 寃곌낵瑜 湲곗큹濡 蹂닿퀬릺뿀떎(Cheng et al., 2022). 궗꽦吏덊솚 솚옄 젙긽씤 궗씠쓽 뿰愿꽦뿉 븳 肄뷀샇듃 뿰援щ뒗 븳援씤뿉꽌 議곗궗릺뿀떎. 븳援 궡 二쇱슂 븰 遺냽 蹂묒썝쓽 20媛 엫긽꽱꽣뿉꽌 뵾뿕옄瑜 紐⑥쭛븯뿬 궗꽦吏덊솚쓣 媛吏 솚옄 1,118紐낃낵 젙긽씤 議곌뎔 636紐낆쑝濡 援ъ꽦맂 肄뷀샇듃瑜 씠슜븯뿬 궗꽦吏덊솚怨 삁以 sKL 냽룄 媛 愿젴꽦뿉 빐 떎뿕쓣 吏꾪뻾븯떎. 궗꽦吏덊솚 洹몃9쓽(56.3짹11.4꽭) 삁以 sKL 룊洹 냽룄뒗 541 pg/mL濡 痢≪젙릺뿀怨, 젙긽씤 洹몃9쓽(52.3짹12.8꽭) 삁以 sKL 룊洹 냽룄뒗 521 pg/mL濡 痢≪젙릺뿀떎(Fig. 8) (Kim et al., 2019). 몢 吏묐떒 媛꾩쓽 sKL 냽룄뒗 넻怨꾩쟻쑝濡 쓽誘몄엳뒗(P<0.05) 李⑥씠瑜 굹궡뒗 寃껋쑝濡 蹂댁븘 sKL쓽 삁以 냽룄뒗 궗꽦吏덊솚쓽 諛쒖깮怨쇰룄 뿰愿꽦씠 엳쓬쓣 솗씤븷 닔 엳떎.

Fig. 8. Heatmap of Korean cohort study displaying sKL concentration in blood from the control (healthy) group and case (metabolic syndrome) group. Numbers indicate concentration of sKL (pg/mL). M & F indicates male and female. n means number of participants. Statistical significance is indicated using asterisks: *indicates significant (P<0.05).

7. 븣痢좏븯씠癒몃퀝(Alzheimer's Disease, AD)

눜뻾꽦 뇤吏덊솚쓽 諛쒖깮뿉 klotho 떒諛깆쭏씠 愿젴릺뼱 엳쓬 뿬윭 뿰援щ낫怨좊 넻빐 븣젮議뚮떎(Torbus-Paluszczak et al., 2018). 듅엳 븣痢좏븯씠癒몃퀝 紐⑤뜽 留덉슦뒪뿉 諛붿씠윭뒪瑜 넻빐 뇤議곗쭅뿉 klotho쓽 怨쇰컻쁽씠 쑀룄맂 寃쎌슦 移섎즺 슚怨쇨 굹굹뒗 寃껋씠 솗씤릺뿀떎(Zeng et al., 2019). 몴쟻씤 끂씤꽦 吏덈퀝 以 븯굹씤 AD쓽 寃쎌슦 klotho쓽 뿰愿꽦씠 룞臾 紐⑤뜽쓣 넻빐 留롮씠 뿰援щ릺뿀쑝굹, 궗엺쓽 寃쎌슦 뇤泥숈닔븸(cerebrospinal fluid, CSF) 梨꾩랬쓽 뼱젮쑝濡 留롮 궗엺쑝濡쒕꽣 CSF 궡 sKL쓽 뼇쓣 痢≪젙빐 鍮꾧탳빐빞 븯뒗 洹몃9 뿰援ъ뿉뒗 뼱젮씠 엳뿀떎. 誘멸뎅쓽 議댁뒪 솄궓뒪 쓽怨쇰븰뿉꽌 移섎즺 以묒씤 AD 吏덊솚옄뱾濡쒕꽣 젙湲곗쟻씤 寃궗 以 뼸 CSF, 洹몃━怨 泥숈닔 泥쒖옄 寃궗瑜 諛쏆 젙긽씤쑝濡쒕꽣 뼸 CSF瑜 씠슜븯뿬 몢 吏묐떒媛 sKL쓽 냽룄瑜 鍮꾧탳븳 寃곌낵媛 蹂닿퀬릺뿀떎. AD 吏덊솚쓣 븪怨 엳뒗 끂씤 20紐, 젙긽 끂씤 20紐, 洹몃━怨 젙긽쟻씤 젇 꽦씤 20紐낆쓣 긽쑝濡 寃궗媛 吏꾪뻾릺뿀쑝硫, 삁븸 寃궗 留덉갔媛吏濡 CSF 궡쓽 sKL쓽 뼇쓣 ELISA 諛⑸쾿쑝濡 遺꾩꽍븯떎. 젙긽 끂씤 洹몃9쓽 CSF 궡 sKL 룊洹 냽룄뒗 776 pg/mL濡 痢≪젙릺뿀쑝硫, AD 솚옄 洹몃9뿉꽌쓽 CSF 궡 sKL 룊洹 냽룄뒗 664 pg/mL濡 몢 吏묐떒 媛꾩뿉 넻怨꾩쟻쑝濡 쑀쓽븳(P< 0.05) 李⑥씠媛 엳쓬씠 굹궗떎. 젇 젙긽 洹몃9쓽 CSF 궡 sKL 룊洹 냽룄뒗 922 pg/mL濡 痢≪젙릺뼱 AD 솚옄 洹몃9怨 넻怨꾩쟻쑝濡 留ㅼ슦 넂(P<0.01) 젙룄濡 李⑥씠媛 엳쓬씠 굹궗떎(Fig. 9) (Semba et al., 2014). 利 뿰졊씠 李⑥씠媛 굹뒗 AD 吏덊솚 洹몃9怨 젙긽 洹몃9 궗씠肉먮쭔 븘땲씪, 굹씠媛 꽌濡 鍮꾩듂븳 AD 吏덊솚 洹몃9怨 젙긽 洹몃9 媛꾩뿉룄 넻怨꾩쟻쑝濡 CSF 궡쓽 sKL 냽룄 李⑥씠媛 엳쓬씠 솗씤맂 寃껋씠떎. 理쒓렐 諛쒗몴맂 끉臾몄뿉 뵲瑜대㈃ 삁以 sKL 냽룄 CSF 궡 sKL 냽룄뒗 꽌濡 鍮꾨븯뿬 利앷컧븳떎뒗 寃곌낵媛 蹂닿퀬릺뿀떎(Belloy et al., 2020). 洹몃윭誘濡 梨꾩랬媛 뼱젮슫 CSF 떊 삁以 sKL 냽룄瑜 痢≪젙븿쑝濡쒖뜥 AD 吏덊솚쓽 긽깭瑜 紐⑤땲꽣留 븷 닔 엳떎怨 뙋떒맂떎. 씠뒗 留ㅻ뀈 뒛뼱굹뒗 AD 솚옄뱾뿉 븳 吏덈퀝 吏꾪뻾쓽 젙룄瑜 紐⑤땲꽣留 븯뒗 醫뗭 諛붿씠삤 留덉빱濡쒖꽌 삁以 sKL 냽룄媛 쑀슜븯寃 벐씪 닔 엳쓬쓣 젣떆븳떎.

Fig. 9. Heatmap of American cohort study displaying sKL concentration in cerebrospinal fluid (CSF) from the control (healthy) group and case (Alzheimer's disease) group. Numbers indicate concen-tration of sKL (pg/mL). M & F indicates male and female. n means number of participants. Statistical significance is indicated using asterisks: *indicates significant (P<0.05), **indicates very significant (P<0.001).

寃 濡

엫긽 떎뿕쓣 넻빐 떎닔쓽 궗엺뱾濡쒕꽣 뼸 삁븸씠굹 뇤泥숈닔븸뿉꽌 痢≪젙맂 sKL쓽 냽룄뒗 遺遺꾩쓽 끂씤꽦 吏덈퀝쓽 諛쒖깮 洹몃━怨 蹂묒쓽 吏꾪뻾怨 諛젒븳 뿰愿꽦씠 엳쓬씠 솗씤릺뿀떎. 젇씠뿉寃뚯꽌 二쇰줈 諛쒖깮븯뒗 議고쁽蹂묒쓽 寃쎌슦 삁以 sKL쓽 냽룄媛 吏덈퀝 洹몃9뿉꽌 넂븯쑝硫, 遺遺꾩쓽 끂씤꽦 吏덈퀝쓽 寃쎌슦 삁以 삉뒗 뇤泥숈닔븸 궡쓽 sKL쓽 냽룄뒗 吏덈퀝쓽 諛쒖깮 삉뒗 吏꾪뻾怨 諛섎퉬濡 愿怨꾩엫씠 諛앺議뚮떎. 怨좏삁븬쓽 寃쎌슦 쓽쇅濡 삁以 sKL 냽룄 넻怨꾩쟻쑝濡 쓽誘멸 뾾뒗 寃껋쑝濡 굹궗쑝굹 뼢썑 떎瑜 肄뷀샇듃 遺꾩꽍 寃곌낵뒗 뼱뼥吏 湲곕떎젮蹂대뒗 寃껋씠 醫뗭쓣 寃껋쑝濡 뙋떒맂떎. 議고쁽蹂묒쓽 寃쎌슦 젇 떆湲곗뿉 諛쒖깮븯뒗 寃껋쑝濡 븣젮졇 엳뼱꽌 끂씤꽦 吏덈퀝 븘땲吏留 sKL 삁以 냽룄 뿰愿꽦 엳뒗 寃껋쑝濡 굹궗떎. 씠뒗 뼢썑 klotho 쑀쟾옄瑜 寃잛쑝濡 媛쒕컻릺뒗 쓽빟뭹 끂씤꽦 吏덈퀝쓽 移섎즺젣濡쒖꽌 媛쒕컻릺뼱빞 븯뒗 씠쑀媛 맆 寃껋쑝濡 삁긽맂떎. 끂솕媛 吏꾪뻾릺硫댁꽌 鍮꾨쟻쑝濡 媛먯냼븯뒗 삁以 sKL 냽룄뒗 끂솕쓽 留덉빱濡 궗슜맆 닔 엳쓬怨 룞떆뿉 끂씤꽦 吏덈퀝쓽 留덉빱濡쒕룄 궗슜븷 닔 엳쓬쓣 젣떆빐以떎.

ACKNOWLEDGEMENT

None.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

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