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.
Highlights
Geroscience is an emerging, rapidly evolving field
Dermal fibroblasts are somatic cells obtained from a skin sample and reprogrammed to neuronal populations following two main strategies: fibroblasts can be directly converted to neurons [3, 71] or converted to induced pluripotent stem cells and subsequently differentiated to neurons [72, 73] (Figure 2)
IPSC-derived neurons require long culture periods that range from 30 to 100 days in vitro before they exhibit disease-associated phenotypes [80, 104]. These data underpin the pivotal role of the molecular context that might provide novel insights to complement our current knowledge about the aged human brain and neurodegeneration, even when associated with genetic mutations
Summary
Geroscience is an emerging, rapidly evolving field. Modern societies currently enjoy high life expectancies associated with improved healthcare systems and better living conditions. INs retain age-related signatures from the donor fibroblasts, including oxidative metabolism damage and mitochondrial dysfunction [3,4,5,6], DNA damage, epigenetic and transcriptional profiles, and nucleo-cytoplasm compartmentalization impairments [3,4,5]. Mitochondrial dysfunction contributes to impaired glucose metabolism and is vital to understanding neuronal aging and neurodegenerative diseases at a cellular level. We have recapitulated the existing evidence that shows that iNs retain age-associated features of the donor and evidence underpinning the relevance of maintaining certain age-related features to accurately model and neurodegeneration. We will discuss projections and potential uses of iNs to study brain aging and NDD to evaluate pharmacological and dietary interventions’ effects and their potential contribution to drug development and patientspecific therapeutic strategies
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