Could autophagy enhancement slow aging and combat Alzheimer's?

By Dr. Chinta SidharthanReviewed by Susha Cheriyedath, M.Sc.Jan 9 2025

Researchers uncover how aging disrupts autophagy, driving neurodegeneration, and explore therapeutic pathways to restore brain health.

Review: Autophagy, aging, and age-related neurodegeneration. Image Credit: Kateryna Kon / Shutterstock

In a recent study published in the journal Neuron, researchers at the University of Cambridge and Newcastle University, UK, examined the relationship between autophagy, aging, and neurodegeneration. The research explored how these processes influence the progression of Alzheimer's and Parkinson's diseases, Huntington’s disease, and other conditions, providing insights for potential therapeutic strategies targeting autophagy-related pathways.

Background

Aging involves gradual functional decline across various biological systems, including impaired cellular mechanisms such as autophagy. Autophagy is responsible for degrading and clearing damaged proteins and organelles from cells. It ensures cellular homeostasis and prevents the accumulation of toxic components, which is vital for neuronal health, given neurons' inability to divide.

With age, autophagy efficiency diminishes due to molecular changes such as altered signaling pathways, reduced protein expression, and impaired lysosomal function. These changes interact with other proteostasis systems, like the ubiquitin-proteasome pathway, amplifying vulnerabilities to neurodegenerative diseases. These changes are characterized by protein aggregation and mitochondrial dysfunction, increasing vulnerability to neurodegenerative diseases.

However, although aging is known to be a major risk factor, the molecular underpinnings linking autophagy impairment to neurodegeneration remain unclear. Studies have shown that restoring autophagy may alleviate age-related neurodegenerative symptoms, but therapeutic applications require a deeper understanding of how autophagy alterations contribute to disease onset and progression.

The Current Study

In the present study, the researchers comprehensively reviewed the autophagy process and its regulation in the context of aging and neurodegeneration. Using advanced molecular biology and genetic tools, they analyzed the major autophagy-related pathways in neuronal and glial cells.

The study also investigated the key signaling networks, including the mechanistic targets of rapamycin complex 1 (mTORC1) and adenosine monophosphate-activated protein kinase (AMPK), which regulate autophagy initiation and progression, and examined lysosomal activity, which is the final stage of autophagy. Age-associated changes in these pathways were also assessed through cellular and animal models.

Additionally, the interplay between autophagy and other proteostasis systems was analyzed, revealing how disruptions in autophagy exacerbate protein aggregation through feedback loops. Selective processes related to autophagy, such as mitophagy, were studied to evaluate the impact of damaged mitochondrial clearance on aging neurons.

The roles of key proteins such as the microtubule-associated protein 1 light chain 3 (LC3), beclin 1, and p62 in autophagy initiation and substrate recognition were also explored. Further, genetic mutations in neurodegenerative disease-related proteins, such as tau, alpha-synuclein, and huntingtin, were examined to understand their impacts on autophagy.

The researchers also conducted cellular experiments to investigate autophagy flux using fluorescence-based assays, autophagosome formation markers, and lysosomal activity measurements. Additionally, animal models of neurodegenerative diseases were used to understand the pathological consequences of impaired autophagy in vivo.

The study highlighted the role of glial autophagy, particularly in microglia, showing how its impairment amplifies neuroinflammation and neuronal stress. Potential therapeutic approaches were also explored by analyzing the effects of genetic or pharmacological modulation of autophagy.

Results

The study found that the various changes associated with aging significantly impair autophagy and contribute to the progression of neurodegenerative diseases. An important finding was that autophagy dysfunction leads to the accumulation of toxic proteins and damaged organelles, which exacerbate cellular stress and inflammation.

These findings were linked to impaired mitochondrial clearance (mitophagy), which further increases cellular dysfunction. The researchers also identified a decline in autophagy-regulating pathways, such as mTORC1 hyperactivation and reduced AMPK activity, with age.

In Alzheimer's disease, autophagy impairment was linked to the accumulation of beta-amyloid and tau proteins, further disrupting autophagic processes and creating a feedback loop.

Similarly, the study found that in Parkinson's disease, mutations in autophagy-associated genes such as synuclein alpha (SNCA) and leucine-rich repeat kinase 2 (LRRK2) impaired the clearance of alpha-synuclein, leading to its toxic aggregation. Huntington's disease models showed that the mutant huntingtin protein hindered autophagosome formation and cargo recognition, exacerbating protein aggregation and neuronal damage.

The study also highlighted the role of glial autophagy in neurodegeneration, showing that microglial autophagy defects amplify neuroinflammation and neuronal stress. Impaired mitophagy was also observed across models, which indicated that defective mitochondrial clearance contributes to age-related cellular dysfunction. These findings emphasize the interconnectedness of autophagy with other cellular clearance mechanisms and its broad impact on proteostasis.

However, the study also demonstrated that pharmacological and genetic enhancement of autophagy successfully alleviated disease symptoms in experimental models. These interventions reduced protein aggregates, restored mitochondrial function, and improved neuronal survival, suggesting potential therapeutic benefits. Challenges remain, such as avoiding “traffic jams” caused by upstream autophagy enhancement in diseases with downstream defects.

Furthermore, by uncovering the intricate links between aging, autophagy, and neurodegeneration, the research highlighted the importance of targeting autophagy pathways to mitigate age-related cognitive decline and neurodegenerative disease progression.

Conclusions

To summarize, the study confirmed that autophagy plays a pivotal role in maintaining neuronal health, and its impairment is a significant factor in driving age-related neurodegenerative diseases. The findings also highlighted the potential of autophagy enhancement as a therapeutic strategy to combat protein aggregation and mitochondrial dysfunction. The research underscored the importance of glial cell contributions to neurodegeneration and called for therapies tailored to specific genetic and molecular contexts.

The researchers believe that future studies should focus on understanding the precise mechanisms of autophagy regulation and its therapeutic application in diverse disease contexts with the goal of developing effective interventions against neurodegeneration and age-related cognitive decline.