Directly reprogrammed human neurons to understand age-related energy metabolism impairment and mitochondrial dysfunction in healthy aging and neurodegeneration
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Gudenschwager Ruiz, Camila Andrea
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Directly reprogrammed human neurons to understand age-related energy metabolism impairment and mitochondrial dysfunction in healthy aging and neurodegeneration
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Abstract
Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including
organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately
and collectively, these features degrade the most critical neuronal function: transmission of information in the brain. It is
widely accepted that aging is the leading risk factor contributing to the onset of the most prevalent pathological conditions that
affect brain functions, such as Alzheimer’s, Parkinson’s, and Huntington’s disease. One of the limitations in understanding the
molecular mechanisms involved in those diseases is the lack of an appropriate cellular model that recapitulates the “aged”
context in human neurons. The advent of the cellular reprogramming of somatic cells, i.e., dermal fibroblasts, to obtain directly
induced neurons (iNs) and induced pluripotent stem cell- (iPSC-) derived neurons is technical sound advances that could
open the avenues to understand better the contribution of aging toward neurodegeneration. In this review, we will summarize
the commonalities and singularities of these two approaches for the study of brain aging, with an emphasis on the role of
mitochondrial dysfunction and redox biology. We will address the evidence showing that iNs retain age-related features in
contrast to iPSC-derived neurons that lose the aging signatures during the reprogramming to pluripotency, rendering iNs a
powerful strategy to deepen our knowledge of the processes driving normal cellular function decline and neurodegeneration in
a human adult model. We will finally discuss the potential utilization of these novel technologies to understand the differential
contribution of genetic and epigenetic factors toward neuronal aging, to identify and develop new drugs and therapeutic strategies.
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Oxidative Medicine and Cellular Longevity Volume 2021, Article ID 5586052, 14 pages
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