Human iPSC-based Modeling of Late-Onset Disease using Progerin-induced Aging

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features.