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Induced neurons (iNs) from aged donors show age-specific gene expression and impaired nucleocytoplasmic compartmentalization (NCC). This study demonstrates iNs as a viable model for studying human aging in vitro.

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Area of Science:

  • Neuroscience
  • Gerontology
  • Cell Biology

Background:

  • Aging is a primary risk factor for numerous human diseases, particularly neurodegenerative disorders.
  • Modeling age-related brain conditions in vitro is crucial but challenging with differentiated human neurons.

Purpose of the Study:

  • To investigate the potential of induced neurons (iNs) to model human aging in vitro.
  • To identify age-associated molecular and functional changes in neurons derived from human donors of varying ages.

Main Methods:

  • Generation of neurons via induced pluripotent stem cells (iPSCs) and direct conversion into iNs from human fibroblasts across a wide age range.
  • Analysis of age-specific transcriptional profiles in iNs.
  • Assessment of nucleocytoplasmic compartmentalization (NCC) and the role of RanBP17.

Main Results:

  • While iPSCs and their differentiated neurons lost aging signatures, iNs retained age-specific transcriptional profiles.
  • An age-dependent decrease in RanBP17 and impaired NCC were observed in fibroblasts and iNs.
  • Reduced RanBP17 function impaired NCC in young cells, and iPSC rejuvenation restored NCC in aged cells.

Conclusions:

  • Induced neurons (iNs) successfully model key aspects of human aging in vitro, including age-specific gene signatures and functional deficits.
  • Impaired nucleocytoplasmic compartmentalization (NCC) is identified as a significant factor in cellular aging.
  • This work provides a valuable platform for studying aging-related neurological diseases.