title: Influence of donor age on induced pluripotent stem cells.
abstract: Induced pluripotent stem cells (iPSCs) are being pursued as a source of cells for autologous therapies, many of which will be aimed at aged patients. To explore the impact of age on iPSC quality, we produced iPSCs from blood cells of 16 donors aged 21-100. We find that iPSCs from older donors retain an epigenetic signature of age, which can be reduced through passaging. Clonal expansion via reprogramming also enables the discovery of somatic mutations present in individual donor cells, which are missed by bulk sequencing methods. We show that exomic mutations in iPSCs increase linearly with age, and all iPSC lines analyzed carry at least one gene-disrupting mutation, several of which have been associated with cancer or dysfunction. Unexpectedly, elderly donors (>90 yrs) harbor fewer mutations than predicted, likely due to a contracted blood progenitor pool. These studies establish that donor age is associated with an increased risk of abnormalities in iPSCs and will inform clinical development of reprogramming technology.
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lo Sardo
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: William
authors.identifier: http://orcid.org/0000-0001-5848-0340
authors.initials: W
authors.lastname: Ferguson
authors.affiliation: The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Galina A
authors.initials: GA
authors.lastname: Erikson
authors.affiliation: The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Baldwin
authors.affiliation: The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Torkamani
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation; D014019:Tissue Donors; D055815:Young Adult