Age-dependent mitochondrial health decline in human induced neurons

In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. 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 leaving a crucial need for a better understanding of the effect of aging on neuronal health. 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. We show age-related mitochondrial impairment, as well as accumulation of mitochondria targeted for degradation in autophagosomes and unacidified autolysosomes following mitophagy induction in neurites of induced neurons (iNs) derived from older donors. These impairments culminate into incomplete elimination of damaged mitochondria. By showing age-dependant mitophagy impairment in human neurons, 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.