Autophagy Brain Benefits: Fasting’s Cellular Cleanup Crew

Autophagy, the body’s natural cellular cleanup process, plays a crucial role in the cognitive benefits often associated with Intermittent Fasting (IF). By clearing out damaged proteins and worn-out components, especially in energy-demanding brain cells, autophagy helps maintain neural health and may reduce the risk of cognitive decline. IF triggers this process by reducing nutrient intake and suppressing growth pathways like mTOR, giving brain cells regular opportunities to repair, recycle, and boost efficiency. This can lead to improved focus, sharper memory, and mental clarity. While autophagy works best alongside good nutrition, sleep, and exercise, its activation through IF adds powerful support for long-term brain health and peak cognitive performance.

Imagine your body, right down to the cellular level, has its own sophisticated recycling and cleanup program. A microscopic crew diligently working behind the scenes to identify old, damaged, or malfunctioning parts, break them down, and reuse the valuable materials. Sounds pretty neat, right? This natural, vital process is called autophagy, literally meaning “self-eating.” While it might sound a bit cannibalistic, it’s actually one of the most crucial housekeeping functions your cells perform to stay healthy, efficient, and resilient. We briefly touched upon this “cellular spring cleaning” in our main guide, Unlock Peak Focus: Intermittent Fasting Brain Hacks, as one of the fascinating mechanisms potentially linking Intermittent Fasting (IF) to enhanced cognitive function.

But what exactly is autophagy, and why should you even care about it if your goal is sharper focus and better brain health? You might be practicing IF, perhaps experiencing improved energy or noticing shifts in your mental clarity, and wondering about the deeper biological processes at play. While shifts in fuel sources like ketones are key, autophagy represents another powerful pathway through which IF impacts your cells – particularly your highly active and sensitive brain cells. Ignoring this cleanup process means missing a significant piece of the puzzle explaining IF’s potential benefits.

Think about it: just like a cluttered house makes it hard to find things and function efficiently, cells cluttered with damaged components struggle to perform optimally. This is especially true for neurons, which need to communicate rapidly and reliably to support everything from memory recall to sustained concentration. Over time, the accumulation of cellular “junk” – like misfolded proteins or worn-out mitochondria (the cell’s power plants) – is increasingly linked to age-related cognitive decline and neurodegenerative diseases. Anything that helps clear this debris could be profoundly beneficial for maintaining brainpower.

This article is your simple guide to understanding autophagy and its specific relevance to your brain. We’ll demystify the process, explain how Intermittent Fasting acts as a powerful trigger, and explore the significant autophagy brain benefits – from clearing potentially toxic proteins to maintaining energy production and reducing inflammation. We’ll delve into how this cellular cleanup might translate directly into improved cognitive function, sharper thinking, and enhanced focus. Ready to meet your internal cleanup crew and learn how fasting helps them get the job done?

What is This “Autophagy” Thing Anyway? Your Cell’s Recycling Program

Before we connect autophagy to brainpower and fasting, let’s get clear on what this process actually involves. The term “autophagy” might sound intimidatingly scientific, but the core concept is elegant and essential for life. It’s your body’s ultimate quality control system operating at the cellular level.

Beyond Fancy Words: Defining “Self-Eating”

Autophagy comes from the Greek words “auto” (self) and “phagein” (to eat). So, it literally means “self-eating.” But don’t picture cells randomly munching on themselves! It’s a highly regulated, orderly process where a cell identifies components within itself that are damaged, unnecessary, or potentially harmful, and targets them for degradation and recycling [4]. It’s less about destruction and more about renovation and resource management – breaking down the old to build the new or provide energy during stress.

Meet the Cleanup Crew: How the Process Works

Think of autophagy like a multi-step household cleanup:

1. Identifying the Junk (Damaged Proteins, Organelles): Specialized cellular sensors detect problems – maybe a protein has misfolded into a useless or even toxic shape, or a mitochondrion (the cell’s power plant) isn’t producing energy efficiently anymore and is generating excessive damaging byproducts.
2. Bagging and Tagging (Autophagosome Formation): Once the junk is identified, the cell begins to form a double-membraned sac, called an autophagosome, around the targeted material. It’s like putting the trash in a specific, designated bag.
3. The Recycling Center (Lysosomal Degradation): This ‘trash bag’ (autophagosome) then travels through the cell and fuses with another organelle called a lysosome. Lysosomes are like the cell’s recycling center, filled with powerful enzymes that can break down complex molecules. Inside the fused structure (now called an autolysosome), the enzymes dismantle the contents – proteins are broken back down into amino acids, lipids into fatty acids, etc.
4. Reuse and Renew: These basic building blocks are then released back into the cell’s interior, ready to be used to build new components or be burned for energy.

This constant cycle of breakdown and renewal is fundamental for cellular health.

Why Bother Cleaning? The Importance of Cellular Maintenance

Why is this cellular housekeeping so vital?

• Quality Control: It removes damaged or potentially toxic components that could otherwise accumulate and impair cell function or even trigger cell death.
• Energy Regulation: During periods of stress or nutrient scarcity (like fasting!), autophagy can break down less essential components to provide fuel and building blocks for survival.
• Defense Mechanism: Autophagy can help clear intracellular pathogens like viruses and bacteria.
• Preventing Disease: Dysfunctional autophagy is implicated in a wide range of diseases, including cancer, metabolic disorders, infectious diseases, and neurodegenerative conditions like Alzheimer’s and Parkinson’s [7].

Essentially, autophagy is critical for keeping cells running smoothly, adapting to stress, and preventing the buildup of problematic cellular waste. Without efficient autophagy, cells become cluttered, dysfunctional, and more vulnerable – not exactly a recipe for sharp thinking.

Fasting Flips the Switch: Triggering Autophagy for Brain Health

So, autophagy is crucial cellular maintenance. But how does Intermittent Fasting fit into the picture? It turns out that IF is one of the most potent known natural activators of this cleanup process. Understanding why fasting flips the autophagy switch is key to appreciating its potential autophagy brain benefits.

Why Nutrient Scarcity Signals Cleanup Time

Autophagy isn’t typically running at full blast all the time. Its activity level is finely tuned based on the cell’s environment, particularly nutrient availability.

• Growth vs. Cleanup Mode: When nutrients (especially amino acids and glucose) are plentiful, cellular pathways promoting growth and proliferation (like the mTOR pathway – mechanistic Target of Rapamycin) are active. High mTOR activity tends to suppress autophagy. The cell senses abundance and prioritizes building and growing.
• The Fasting Signal: When you fast, nutrient levels drop. Glucose falls, leading to lower insulin. Amino acid levels may also decrease. This signals to the cell that resources are scarce. The mTOR pathway activity decreases, lifting the brakes off autophagy [1, 4]. Simultaneously, other pathways sensitive to energy stress (like AMPK activation) become active and further promote autophagy.
• Survival Strategy: From a cellular perspective, activating autophagy during fasting makes perfect sense. It allows the cell to:
  • Conserve energy by recycling existing components.
  • Generate internal fuel by breaking down non-essential parts.
  • Clear out potentially damaged components that might become problematic under stress.

How Intermittent Fasting Becomes an Autophagy Power-Up

By creating regular periods of nutrient scarcity, Intermittent Fasting essentially gives your cells a scheduled opportunity to switch from “growth mode” to “cleanup and repair mode.”

• Lowered Insulin and mTOR Inhibition: The drop in insulin and subsequent decrease in mTOR activity during the fasting window are primary triggers kicking autophagy into gear.
• How Long Does it Take? Autophagy Activation Timeframes: Pinpointing the exact moment autophagy ramps up significantly during a fast in humans is tricky and varies. However, research suggests it likely begins to increase after 12-16 hours of fasting and becomes more robust with longer durations [4]. Schedules involving longer fasts induce deeper or more prolonged autophagy than shorter daily fasts like 16/8, though even 16/8 likely provides a regular, beneficial stimulus.

Linking IF, Autophagy, and Potential Cognitive Gains

This connection is central to the brain benefits. By activating autophagy, IF helps maintain the health and efficiency of brain cells. Clean, well-functioning neurons are better able to:

• Transmit signals effectively.
• Maintain energy homeostasis (especially important given the brain’s high energy demands).
• Resist stress and damage.

This improved cellular function, driven by IF-induced autophagy, provides a strong biological basis for the potential improvements in focus, mental clarity, and overall cognitive function reported by many practitioners. It’s not just about changing fuel; it’s about maintaining the machinery.

Clearing the Cobwebs: How Autophagy Directly Benefits Your Brain

We know IF triggers autophagy, and autophagy cleans up cells. But how does this cellular tidiness translate specifically into autophagy brain benefits and potentially sharper thinking? The impact is multifaceted, targeting several key aspects of neuron health and function.

Taking Out the Trash: Removing Toxic Protein Aggregates

One of the most critical roles of autophagy in the brain is clearing out misfolded or aggregated proteins. Over time, certain proteins can clump together, forming aggregates that disrupt cellular function and are hallmarks of various neurodegenerative diseases.

• The Protein Problem: Imagine proteins are like origami – they need to be folded into precise shapes to work correctly. Misfolded proteins lose their function and can become “sticky,” clumping together. In the brain, examples include amyloid-beta plaques and tau tangles associated with Alzheimer’s disease, and alpha-synuclein aggregates found in Parkinson’s disease [7].
• Autophagy to the Rescue: Autophagy is a primary mechanism for identifying and removing these potentially toxic protein aggregates before they build up to dangerous levels. By efficiently clearing this cellular debris, autophagy helps maintain neuronal health and prevent the disruptions in communication and function caused by protein clumps.
• Implications for Cognitive Resilience: Boosting autophagy through strategies like intermittent fasting might therefore help protect the brain against the accumulation of these harmful proteins, potentially contributing to long-term cognitive resilience and reducing the risk or slowing the progression of neurodegenerative conditions.

Power Plant Maintenance: Recycling Damaged Mitochondria

Mitochondria are the powerhouses of our cells, generating the ATP energy needed for virtually all cellular processes. Brain cells are incredibly energy-hungry, making mitochondrial health absolutely paramount for cognitive function.

• Mitochondrial Wear and Tear: Like any power plant, mitochondria can become damaged or inefficient over time, especially under conditions of high energy demand or oxidative stress. Dysfunctional mitochondria produce less energy and generate more harmful reactive oxygen species (ROS), contributing to cellular damage and brain fog.
• Mitophagy: Specialized Cleanup: Autophagy has a specialized branch called “mitophagy,” specifically dedicated to identifying and removing damaged mitochondria [4]. This ensures that only healthy, efficient power plants remain online.
• Brain Energy and Focus: By promoting mitophagy, IF helps maintain a pool of healthy mitochondria in brain cells. This supports optimal brain energy production – crucial for sustaining attention, processing information quickly, and maintaining focus. It ties into the energy aspect discussed in our article on ketones (Brain Fuel Upgrade), ensuring the machinery to use fuel efficiently is also maintained.

Reducing Inflammation and Oxidative Stress Indirectly

While autophagy’s primary role is cleanup, its effects ripple outwards. By removing damaged components (like dysfunctional mitochondria that spew ROS) and potentially toxic protein aggregates (which can trigger inflammatory responses), efficient autophagy helps lower the overall burden of oxidative stress and neuroinflammation in the brain [1]. This creates a healthier, calmer cellular environment, further supporting optimal neuron function and clearer thinking.

Sharper Signals, Clearer Thoughts? Autophagy and Cognitive Function

We’ve established that autophagy cleans house within brain cells, removing junk proteins and faulty power plants. That’s great for long-term health, but how might this cellular tidiness translate into the sharper focus you might be seeking now through Intermittent Fasting? The link lies in how clean cells communicate and function more effectively.

How Clean Cells Communicate Better

Think of neuronal communication as a complex, high-speed data network. For optimal performance, the lines need to be clear, and the signals strong. Cellular clutter acts like static or interference.

• Reducing Interference: The accumulation of misfolded proteins or damaged organelles can physically obstruct cellular pathways or trigger stress responses that interfere with normal synaptic transmission (the communication points between neurons). By clearing this debris, autophagy helps reduce this “noise,” allowing for smoother, more efficient signaling.
• Maintaining Synaptic Health: Autophagy also plays a role in maintaining the health and function of synapses themselves, ensuring the connections between neurons remain robust and responsive. Efficient signaling is fundamental for learning, memory, and rapid information processing – all components of sharp cognitive function.

Potential Links to Improved Memory, Learning, and Focus

While direct human studies isolating autophagy’s effect on specific cognitive tasks during IF are challenging, the biological plausibility is strong:

• Memory Formation: Learning and memory rely heavily on synaptic plasticity – the ability of synapses to strengthen or weaken. Autophagy supports the underlying cellular health needed for efficient plasticity. Clearing out old or damaged synaptic components might even be necessary for forming new, stable memories.
• Sustained Attention (Focus): Maintaining focus requires sustained, coordinated neuronal activity without excessive “noise” or energy dips. By ensuring efficient energy production (via healthy mitochondria) and clear signaling pathways (by removing debris), autophagy contributes to the cellular stability needed for prolonged concentration.
• Information Processing Speed: When neurons are functioning optimally, free from clutter and powered efficiently, they can fire and communicate more rapidly. This could translate to quicker thinking and faster processing of information.

Can Autophagy Boost Mental Clarity? The Plausibility

That feeling of mental clarity – the absence of brain fog and the sensation of thinking quickly and effortlessly – is likely a result of multiple factors aligning: stable energy supply (perhaps via ketones), reduced inflammation, and optimal neuronal function. Autophagy contributes significantly to that last piece. By ensuring brain cells are well-maintained, free of performance-hindering junk, and communicating effectively, IF-induced autophagy provides a strong foundation for experiencing enhanced mental clarity. While it’s just one part of the IF puzzle, it’s a crucial one for explaining the potential cognitive uplift. It’s the deep clean that helps the whole system run better.

Beyond Fasting: Other Ways to Gently Support Autophagy

While Intermittent Fasting is undoubtedly a powerful trigger for autophagy, it’s helpful to know that other lifestyle factors can also influence this crucial cellular cleanup process, potentially working synergistically with your fasting efforts.

The Role of Exercise

Physical activity, particularly endurance exercise, is another known activator of autophagy in various tissues, including potentially the brain [3].

• Metabolic Stress Signal: Exercise creates a temporary metabolic stress (increased energy demand, mild oxidative stress) that, similar to fasting, can signal cells to initiate cleanup and repair processes like autophagy.
• Synergy with IF: Combining regular exercise with your IF schedule might offer additive benefits for promoting autophagy and overall brain health.

Certain Foods and Compounds?

While no food directly triggers autophagy in the way fasting does (as autophagy is generally inhibited by nutrient intake), some compounds found in certain foods are being researched for their potential to support or enhance autophagy pathways, often through antioxidant or anti-inflammatory effects that reduce the cellular ‘junk’ needing removal in the first place.

• Polyphenols: Compounds found in colorful plants, berries, green tea (EGCG), coffee, dark chocolate, and olive oil have antioxidant and anti-inflammatory properties that support cellular health and are being investigated for links to autophagy regulation [4]. Eating a diet rich in these during your eating window complements IF.
• Spermidine: A polyamine found in foods like aged cheese, mushrooms, soy products, and whole grains, spermidine has been shown to induce autophagy in various models and is linked to longevity, though human brain effects need more study.

It’s crucial to remember that eating generally suppresses autophagy; these compounds likely work indirectly or support the process once initiated by fasting or exercise.

Quality Sleep’s Contribution

Sleep is prime time for brain maintenance. While the direct link between specific sleep stages and autophagy activation is still being fully mapped out, it’s clear that restorative sleep is essential for overall cellular repair processes in the brain [5].

• Waste Clearance: During sleep, the brain’s glymphatic system actively clears metabolic waste products. Efficient waste removal likely reduces the burden on the autophagy system.
• Cellular Repair: Sleep allows cells time to repair damage incurred during waking hours, potentially working in concert with autophagy.

Prioritizing good sleep hygiene supports the brain’s natural maintenance cycles, likely including autophagy, reinforcing the cognitive benefits you seek from IF.

While IF is the star player for activating autophagy, incorporating regular exercise, a nutrient-dense diet rich in polyphenols, and prioritizing quality sleep creates a holistic lifestyle that supports this vital cellular cleanup process from multiple angles.

Practical Considerations: Autophagy Isn’t Everything

We’ve sung the praises of autophagy, highlighting its crucial role in cellular maintenance and its potential contribution to the autophagy brain benefits associated with Intermittent Fasting. However, it’s important to maintain a balanced perspective. Autophagy is one piece of a complex biological puzzle, and more isn’t always better.

Balancing Autophagy with Growth and Repair

While cleanup (autophagy) is vital, so are periods of building and repair (which often involve processes inhibited when autophagy is high, like mTOR activation). Cells need both cycles. Chronic, excessive activation of autophagy without adequate periods for rebuilding could theoretically be detrimental, though this is generally more of a concern in extreme, prolonged starvation scenarios rather than typical IF protocols. The cycling between fasting (promoting autophagy) and feeding (allowing for growth, repair, and nutrient replenishment) inherent in IF is likely key to its benefits – providing the best of both worlds.

Why Consistency Matters More Than Extreme Measures

Trying to induce maximum autophagy through overly aggressive or prolonged fasting might backfire. Extreme fasts can be difficult to sustain, lead to nutrient deficiencies if eating windows aren’t managed well, and cause significant stress that negates the benefits. Finding a consistent, sustainable IF schedule (like 16/8 for many) that provides a regular autophagy stimulus is likely more beneficial for long-term brain health and focus than sporadic, extreme fasts. The goal is regular maintenance, not constant demolition.

Focusing on Overall Healthy Habits

Autophagy is fascinating, but it’s not a magic bullet operating in isolation. Achieving optimal cognitive function and brain clarity relies on a foundation of overall health. Don’t become so focused on maximizing autophagy that you neglect other critical factors:

• Nutrient-Dense Diet: Providing the building blocks your brain needs during your eating window is crucial.
• Quality Sleep: Essential for memory consolidation and overall brain restoration.
• Regular Exercise: Boosts blood flow, BDNF, and complements autophagy.
• Stress Management: Chronic stress actively harms brain function.
• Hydration: Fundamental for optimal cognitive processing.

Autophagy is only one important tool in your brain health toolkit, activated effectively by IF. But use it wisely, in balance with other healthy habits, to achieve the best results for your focus and long-term well-being.

Quick Takeaways: Autophagy & Brain Health

• Autophagy = Cellular Cleanup: It’s the body’s natural process for removing damaged cell parts and recycling materials, crucial for cell health.
• IF is a Potent Trigger: Intermittent fasting, by creating nutrient scarcity, lowers mTOR activity and strongly stimulates autophagy.
• Key Autophagy Brain Benefits:
  • Clears potentially toxic misfolded protein aggregates (linked to Alzheimer’s, Parkinson’s).
  • Recycles damaged mitochondria (mitophagy), ensuring efficient brain energy production.
  • Helps reduce inflammation and oxidative stress indirectly.
• Supports Cognitive Function: By maintaining clean, efficient neurons and clear communication pathways, autophagy likely contributes to better focus, memory, learning, and mental clarity.
• Longer Fasts, Stronger Stimulus (Potentially): Schedules like ADF may induce more autophagy than 16/8, but consistency and sustainability are vital.
• Other Supporters: Exercise, quality sleep, and potentially polyphenol-rich foods can also gently support autophagy processes.
• Balance is Key: Autophagy needs to be balanced with periods of building and repair; extreme measures aren’t necessary or always better. Focus on consistent IF and overall healthy habits.

Conclusion

Autophagy, the sophisticated “self-eating” process, might just be one of the unsung heroes behind the cognitive benefits reported by many Intermittent Fasting practitioners. Moving beyond a simple definition, we’ve seen how this intricate cellular cleanup mechanism is vital for maintaining the health and efficiency of all our cells, particularly the energy-hungry and sensitive neurons in our brain. By diligently removing damaged proteins and worn-out organelles like mitochondria, autophagy acts as essential maintenance, preventing the buildup of cellular “junk” linked to cognitive decline and neurodegenerative diseases [7].

We’ve explored how Intermittent Fasting serves as a powerful natural switch, leveraging periods of nutrient scarcity to dial down growth pathways (like mTOR) and ramp up this critical cleanup process [1, 4]. This regular activation, whether through daily schedules like 16/8 or more intermittent patterns, gives our brain cells a scheduled opportunity to tidy up, repair, and recycle. The result? Potentially clearer signaling pathways, more efficient energy production, reduced inflammation, and enhanced resilience – all contributing factors to the sought-after autophagy brain benefits like improved focus, sharper memory, and enhanced mental clarity.

Understanding autophagy adds another layer of appreciation for the “why” behind IF’s effects, complementing the roles of ketone metabolism and BDNF enhancement. It highlights that IF isn’t just about when you eat, but about the profound cellular renewal processes that timing allows. While autophagy isn’t the whole story – needing balance with growth phases and support from overall healthy habits like good nutrition, sleep, and exercise – recognizing its importance underscores the potential of IF as a strategy not just for managing weight, but for actively supporting long-term brain health and optimizing cognitive function. Harnessing your body’s own cleanup crew through mindful fasting might be one of the smartest moves you can make for your mind.

Cellular Cleanup Crew: Your Thoughts on Autophagy?

Did this explanation of autophagy shed new light on the potential benefits of Intermittent Fasting for you?

• Were you aware of this cellular cleanup process before?
• Does understanding autophagy change how you think about your fasting schedule or goals?
• Have you noticed any long-term benefits from IF (like improved clarity or resilience) that might be linked to processes like autophagy?

Share your thoughts or questions about autophagy and its connection to brain health in the comments below!

Found this deep dive into cellular cleanup interesting? Share it with others curious about the science behind IF!

Autophagy FAQs: Your Cellular Cleanup Questions Answered

1. How long do I need to fast for autophagy to start in the brain?
   • The exact timing varies, but studies suggest autophagy begins to increase significantly after about 12-16 hours of fasting and becomes more robust with longer durations (e.g., 24 hours or more) [4]. Even shorter daily fasts like 16/8 likely provide a beneficial, regular stimulus for autophagy activation time fasting.
2. Can I measure my autophagy levels at home?
   • Currently, there are no reliable or practical ways for individuals to measure their autophagy levels at home. Research methods involve complex lab techniques (like analyzing specific protein markers in tissue samples). Focus on consistent adherence to autophagy-promoting habits like IF rather than trying to measure the process directly.
3. Do supplements that claim to boost autophagy actually work for brain benefits?
   • Some compounds (like resveratrol, spermidine, EGCG from green tea) show potential to influence autophagy pathways in lab studies [4]. However, robust human evidence, especially for direct autophagy brain benefits from supplements, is often lacking. Relying on proven methods like Intermittent Fasting and exercise is generally more effective than relying solely on supplements. Consult a healthcare provider before taking supplements.
4. Is more autophagy always better for cognitive function?
   • Not necessarily. Autophagy needs to be balanced with cellular growth and repair. Excessive or chronic autophagy without adequate recovery periods could theoretically be harmful. The cyclical nature of Intermittent Fasting (fasting followed by feeding) naturally provides this balance. Consistency with a sustainable IF schedule is likely more beneficial than extreme, prolonged fasting aiming for maximum autophagy.
5. Besides clearing protein aggregates, how else does autophagy improve focus?
   • By removing damaged mitochondria (mitophagy), autophagy ensures efficient brain energy production, reducing fatigue and supporting sustained concentration. It also helps clear general cellular debris that can interfere with neuronal signaling, leading to potentially faster processing speed and enhanced mental clarity. Reducing underlying inflammation and oxidative stress further contributes to an optimal environment for focus.

References

1. Mattson, M. P., Longo, V. D., & Harvie, M. (2017). Impact of intermittent fasting on health and disease processes. Ageing Research Reviews, 39.
2. Gasior, M., Rogawski, M. A., & Hartman, A. L. (2006). Neuroprotective and disease-modifying effects of the ketogenic diet. Behavioural Pharmacology, 17(5-6).
3. He, C., Sumpter Jr, R., & Levine, B. (2012). Exercise induces autophagy in peripheral tissues and in the brain. Autophagy, 8(10).
4. Alirezaei, M., Kemball, C. C., Flynn, C. T., Wood, M. R., Whitton, J. L., & Kiosses, W. B. (2010). Short-term fasting induces profound neuronal autophagy. Autophagy, 6(6).
5. Mizushima, N., & Komatsu, M. (2011). Autophagy: renovation of cells and tissues. Cell, 147(4).
6. Anton, S. D., Moehl, K., Donahoo, W. T., Marosi, K., Lee, S. A., Mainous III, A. G., … & Mattson, M. P. (2018). Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting. Obesity, 26(2).
7. Menzies, F. M., Fleming, A., Caricasole, A., Pasco, M., Jaber-Hijazi, F., & Rubinsztein, D. C. (2017). Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. Neuron, 93(5).