TY - JOUR
T1 - Klotho Deficiency Accelerates Stem Cells Aging by Impairing Telomerase Activity
AU - Ullah, Mujib
AU - Sun, Zhongjie
AU - Hare, Joshua M.
N1 - Funding Information:
The authors are grateful for the assistance of National Institute of Health (NIH) for funding and professors working at the department of physiology especially Dr. Shirley Wang and Dr. Yi Lin University of Oklahoma Health Science Center, and Sriya Jonnakuti for professional editing of the manuscript. This work could not be done without them. The authors also want to thank experts working at Biomedical Research Center, University of Oklahoma.
Funding Information:
This work was supported by the National Institute of Health (NIH), USA. The supported NIH grants number are R01 HL118558, DK093403, HL122166, HL116863, and AG049780.
Publisher Copyright:
© 2018 The Author(s). Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
PY - 2019/8/16
Y1 - 2019/8/16
N2 - Understanding the effect of molecular pathways involved in the age-dependent deterioration of stem cell function is critical for developing new therapies. The overexpression of Klotho (KL), an antiaging protein, causes treated animal models to enjoy extended life spans. Now, the question stands: Does KL deficiency accelerate stem cell aging and telomere shortening? If so, what are the specific mechanisms by which it does this, and is cycloastragenol (CAG) treatment enough to restore telomerase activity in aged stem cells? We found that KL deficiency diminished telomerase activity by altering the expression of TERF1 and TERT, causing impaired differentiation potential, pluripotency, cellular senescence, and apoptosis in stem cells. Telomerase activity decreased with KL-siRNA knockdown. This suggests that both KL and telomeres regulate the stem cell aging process through telomerase subunits TERF1, POT1, and TERT using the TGFβ, Insulin, and Wnt signaling. These pathways can rejuvenate stem cell populations in a CD90-dependent mechanism. Stem cell dysfunctions were largely provoked by KL deficiency and telomere shortening, owing to altered expression of TERF1, TGFβ1, CD90, POT1, TERT, and basic fibroblast growth factor (bFGF). The CAG treatment partially rescued telomerase deterioration, suggesting that KL plays a critical role in life-extension by regulating telomere length and telomerase activity.
AB - Understanding the effect of molecular pathways involved in the age-dependent deterioration of stem cell function is critical for developing new therapies. The overexpression of Klotho (KL), an antiaging protein, causes treated animal models to enjoy extended life spans. Now, the question stands: Does KL deficiency accelerate stem cell aging and telomere shortening? If so, what are the specific mechanisms by which it does this, and is cycloastragenol (CAG) treatment enough to restore telomerase activity in aged stem cells? We found that KL deficiency diminished telomerase activity by altering the expression of TERF1 and TERT, causing impaired differentiation potential, pluripotency, cellular senescence, and apoptosis in stem cells. Telomerase activity decreased with KL-siRNA knockdown. This suggests that both KL and telomeres regulate the stem cell aging process through telomerase subunits TERF1, POT1, and TERT using the TGFβ, Insulin, and Wnt signaling. These pathways can rejuvenate stem cell populations in a CD90-dependent mechanism. Stem cell dysfunctions were largely provoked by KL deficiency and telomere shortening, owing to altered expression of TERF1, TGFβ1, CD90, POT1, TERT, and basic fibroblast growth factor (bFGF). The CAG treatment partially rescued telomerase deterioration, suggesting that KL plays a critical role in life-extension by regulating telomere length and telomerase activity.
KW - Adipose stem cells
KW - Antiaging genes
KW - CD90
KW - Cycloastragenol
KW - Klotho
KW - Pluripotency
KW - Telomerase enzyme
KW - Telomere
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U2 - 10.1093/gerona/gly261
DO - 10.1093/gerona/gly261
M3 - Article
C2 - 30452555
AN - SCOPUS:85072058125
VL - 74
SP - 1396
EP - 1407
JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
SN - 1079-5006
IS - 9
ER -