Identification of the dichotomous role of age-related LCK in calorie restriction revealed by integrative analysis of cDNA microarray and interactome

• Published in: AGE 2013-08, Vol.35 (4), p.1045-1060
• Main Authors: Park, Daeui, Lee, Eun Kyeong, Jang, Eun Jee, Jeong, Hyoung Oh, Kim, Byoung-Chul, Ha, Young Mi, Hong, Seong Eui, Yu, Byung Pal, Chung, Hae Young
• Format: Article
• Language: English
• Subjects: Age; Aging; Aging - genetics; Aging - metabolism; Aging - pathology; Animals; Biomedical and Life Sciences; Body fat; Caloric Restriction - methods; Calories; Cell Biology; Cells, Cultured; Datasets; Disease Models, Animal; Energy Intake - genetics; Gene expression; Gene Expression Regulation; Geriatrics/Gerontology; Intervention; Investigations; Kidneys; Kinases; Life Sciences; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - biosynthesis; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics; Male; Mice; Mice, Inbred C57BL; Molecular Medicine; Musculoskeletal system; Oligonucleotide Array Sequence Analysis - methods; Oxidative Stress - genetics; Pharmacy; Proteins; Rats; Rats, Inbred F344; Real-Time Polymerase Chain Reaction; RNA - genetics
• ISSN: 0161-9152; 2509-2715; 1574-4647; 2509-2723
• DOI: 10.1007/s11357-012-9426-6

Among the many experimental paradigms used for the investigation of aging, the calorie restriction (CR) model has been proven to be the most useful in gerontological research. Exploration of the mechanisms underlying CR has produced a wealth of data. To identify key molecules controlled by aging and CR, we integrated data from 84 mouse and rat cDNA microarrays with a protein–protein interaction network. On the basis of this integrative analysis, we selected three genes that are upregulated in aging but downregulated by CR and two genes that are downregulated in aging but upregulated by CR. One of these key molecules is lymphocyte-specific protein tyrosine kinase (LCK). To further confirm this result on LCK, we performed a series of experiments in vitro and in vivo using kidneys obtained from aged ad libitum-fed and CR rats. Our major significant findings are as follows: (1) identification of LCK as a key molecule using integrative analysis; (2) confirmation that the age-related increase in LCK was modulated by CR and that protein tyrosine kinase activity was decreased using a LCK-specific inhibitor; and (3) upregulation of LCK leads to NF-κB activation in a ONOO − generation-dependent manner, which is modulated by CR. These results indicate that LCK could be considered a target attenuated by the anti-aging effects of CR. Integrative analysis of cDNA microarray and interactome data are powerful tools for identifying target molecules that are involved in the aging process and modulated by CR.