title: Restoration of Mitochondrial NAD+Levels Delays Stem Cell Senescence and Facilitates Reprogramming of Aged Somatic Cells.
abstract: The fundamental tenet that aging is irreversible has been challenged by the development of reprogramming technology that can restore molecular and cellular age by reversing the progression of aging. The use of cells from aged individuals as sources for reprogramming or transplantation creates a major barrier in stem cell therapy with respect to cell quality and quantity. Here, we investigated the molecular features underlying senescence and rejuvenation during aged cell reprogramming and identified novel factors that can overcome age-associated barriers. Enzymes, such as nicotinamide nucleotide transhydrogenase (NNT) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), that control mitochondrial NAD+levels appear to be susceptible to aging. In aged cells, mitochondrial NAD+levels decrease, accompanied by reduced SIRT3 activity; these changes severely impede cell fate transition. However, in cells collected from aged p16 knockout mice, which exhibit delayed cellular senescence, no changes in NNT or NMNAT3 expression were found. Importantly, restoring mitochondrial NAD+levels by overexpressing NNT and NMNAT3 enhanced reprogramming efficiency of aged somatic cells and extended the lifespan of human mesenchymal stem cells by delaying replicative senescence. These results demonstrate that maintenance of mitochondrial NAD+levels is critical for reversing the mechanisms of aging and ensuring that cells collected from aged individuals are of high quality. Stem Cells 2016;34:2840-2851.
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-Gu, Daejeon, Republic of Korea.|Department of Functional Genomics, University of Science & Technology (UST), Yuseong-Gu, Daejeon, Republic of Korea.
authors.forename: Myung Jin
authors.initials: MJ
authors.lastname: Son
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-Gu, Daejeon, Republic of Korea.|Department of Functional Genomics, University of Science & Technology (UST), Yuseong-Gu, Daejeon, Republic of Korea.
authors.forename: Youjeong
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
authors.forename: Taekwon
authors.initials: T
authors.lastname: Son
authors.affiliation: Department of Functional Genomics, University of Science & Technology (UST), Yuseong-Gu, Daejeon, Republic of Korea.|Stem Cell Research Laboratory, Immunotherapy Convergence Research Center, KRIBB, Yuseong-Gu, Daejeon, Republic of Korea.
authors.forename: Yee Sook
authors.initials: YS
authors.lastname: Cho
mesh_terms: D000375:Aging; D000818:Animals; D019070:Cell Lineage; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D009250:NADP Transhydrogenases; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D009243:NAD; D009250:NADP Transhydrogenases; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D056566:Sirtuin 3
keywords: Aging; Mitochondria; NAD; Nicotinamide mononucleotide adenylyltransferase 3; Nicotinamide nucleotide transhydrogenase