Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging
- 1Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada
- 2Center for Interdisciplinary Research on Brain and Learning (CIRCA), Montreal, QC, Canada
Abstract
Introduction: In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). In neurons, the effect of aging on intrinsic molecular processes, and how they tie to age-related neurodegeneration remains unclear. Animal studies have shown that mitochondrial function decline, autophagy impairment and defective elimination of damaged mitochondria by mitophagy are all central features of neuronal aging. However, very few studies have investigated such events in human neurons, due to a lack of models showing aging features. Therefore, there is a crucial need for a better understanding of the effect of aging on neuronal health.
Methods: Here, we use direct neuronal reprogramming, which maintains signatures of cellular aging, to study the effect of aging on mitochondrial health and mitophagy in human neurons derived from healthy donors ranging from 11 to 91 years old. We use confocal imaging to assess colocalization of mitochondria with autophagic structures following mitophagy induction.
Results: We show age-related mitochondrial impairment in neurites of induced neurons (iNs) derived from older donors. Additionally, in these neurites, we show an accumulation of mitochondria targeted for degradation in autophagosomes and LAMP1-positive lysosomal vesicles following mitophagy induction. These impairments culminate into incomplete elimination of damaged mitochondria, despite preserved activity of the lysosomal enzymes assessed.
Conclusion: This study shows for the first time age-related mitophagy impairment in human neurons, and confirms findings of age-related mitochondrial impairments in human neurons. By doing so, this study paves the way for more in-depth mechanistic studies that would allow for the identification of therapeutic targets for anti-aging treatment and in the context of age-associated neurodegenerative diseases.
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BibTeX
@article{legault2026decline,
title = {{Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging}},
author = {Emilie M. Legault and Juan-Pablo Izabal Gamez and Janelle Drouin-Ouellet},
journal = {Frontiers in Aging Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnagi.2026.1903701},
url = {https://doi.org/10.3389/fnagi.2026.1903701},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging
AU - Emilie M. Legault
AU - Juan-Pablo Izabal Gamez
AU - Janelle Drouin-Ouellet
PY - 2026
DA - 2026/10/20
JO - Frontiers in Aging Neuroscience
DO - 10.3389/fnagi.2026.1903701
UR - https://doi.org/10.3389/fnagi.2026.1903701
AB - Introduction: In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). In neurons, the effect of aging on intrinsic molecular processes, and how they tie to age-related neurodegeneration remains unclear. Animal studies have shown that mitochondrial function decline, autophagy impairment and defective elimination of damaged mitochondria by mitophagy are all central features of neuronal aging. However, very few studies have investigated such events in human neurons, due to a lack of models showing aging features. Therefore, there is a crucial need for a better understanding of the effect of aging on neuronal health. Methods: Here, we use direct neuronal reprogramming, which maintains signatures of cellular aging, to study the effect of aging on mitochondrial health and mitophagy in human neurons derived from healthy donors ranging from 11 to 91 years old. We use confocal imaging to assess colocalization of mitochondria with autophagic structures following mitophagy induction. Results: We show age-related mitochondrial impairment in neurites of induced neurons (iNs) derived from older donors. Additionally, in these neurites, we show an accumulation of mitochondria targeted for degradation in autophagosomes and LAMP1-positive lysosomal vesicles following mitophagy induction. These impairments culminate into incomplete elimination of damaged mitochondria, despite preserved activity of the lysosomal enzymes assessed. Conclusion: This study shows for the first time age-related mitophagy impairment in human neurons, and confirms findings of age-related mitochondrial impairments in human neurons. By doing so, this study paves the way for more in-depth mechanistic studies that would allow for the identification of therapeutic targets for anti-aging treatment and in the context of age-associated neurodegenerative diseases.
SN - 1663-4365
ER -