Figure 3.

Patients’ fibroblast can be converted into neurons via induced pluripotent stem cell (iPSC)-based reprogramming (left) or direct reprogramming (right). Both the approaches allow to obtain human neuronal models of neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). However, neurons and neuronal subtypes derived from iPSCs do not retain the main aging hallmarks of donor fibroblasts which are required for a reliable model of late-onset neurodegeneration. The induction of pluripotency reverts the cell age to an embryonic-like state, resetting epigenetic age, mitochondrial function, telomeres length, and proteostasis. Instead, direct reprogramming of induced neurons (iNs) bypasses the pluripotent intermediate state and retains the age of patients’ fibroblasts.