Human iPSC-based modeling of late-onset disease via progerin-induced aging

Cell Stem Cell. 2013 Dec 5;13(6):691-705. doi: 10.1016/j.stem.2013.11.006.


Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Aging / pathology*
  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation
  • Cellular Reprogramming
  • Cellular Senescence
  • Child
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Dopaminergic Neurons / transplantation
  • Dopaminergic Neurons / ultrastructure
  • Fibroblasts / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Lamin Type A
  • Mesencephalon / pathology
  • Mice
  • Middle Aged
  • Models, Biological*
  • Nuclear Proteins / metabolism*
  • Parkinson Disease / pathology
  • Phenotype
  • Protein Precursors / metabolism*
  • Tissue Donors


  • Biomarkers
  • Lamin Type A
  • Nuclear Proteins
  • Protein Precursors
  • prelamin A