Our brains are built to last for decades, but they require ongoing biological maintenance. Over time, normal aging can lead to a buildup of damaged cells and leftover cellular material that the brain needs to clear away to stay healthy. In a healthy brain, that clearing function is handled by microglia, specialized immune cells that monitor the brain, remove debris, and help keep neural circuits working smoothly. As we age, however, microglia can become less effective. Instead of protecting the brain, they can drift into a stressed, dysfunctional state that fuels inflammation, disrupts synapses (the communication points between neurons), and contributes to cognitive decline. This shift is increasingly recognized as a shared feature of brain aging and Alzheimer’s disease.
A key insight comes from people who stay mentally sharp into very advanced age. Human genetics suggests that some individuals carry naturally occurring “resilience” signals that help the brain’s immune system stay protective over time. This opens a major opportunity: if we can understand what makes those brains resilient, we may be able to design prevention-first strategies that keep more people cognitively well for longer. The challenge is that resilience is still poorly defined at the mechanistic level. What keeps microglia functional? What prevents them from tipping into a harmful state? And why do some brain regions remain more protected than others?
That’s why the Longevity Science Foundation is supporting Dr. Andy Tsai’s project to decode microglial resilience, specifically how the brain’s cleanup system remains functional under the pressure of aging and Alzheimer’s-like stress. His work focuses on a key failure mode observed in older and Alzheimer’s-affected brains: microglia that become overloaded by lipid-rich debris (fats) and develop stressed internal recycling systems (lysosomes). When microglia struggle to manage this cellular stress, waste accumulates, inflammation rises, and the surrounding brain tissue becomes more vulnerable, setting the stage for faster functional decline.
Instead of only studying what goes wrong late in disease, Dr. Tsai’s team is reverse-engineering what goes right in natural resilience. Starting from human evidence of reduced Alzheimer’s risk and preserved cognition in extreme old age, the project will build detailed maps of microglial health across different brain regions and across the lifespan. This matters because brain aging does not affect every area equally: some circuits are more vulnerable, and microglia appear to adapt differently depending on the local brain environment they are in. By comparing resilient vs. vulnerable microglial states in a controlled way, the team aims to reveal the protective programs that keep microglia functioning during aging-related stress.
The work is designed to answer three relevant questions:
1. What does a “resilient” microglia look like in the aging brain?
The team will identify the biological signatures that distinguish microglia that remain protective from those that become dysfunctional and connect those signatures to indicators of cognitive performance.
2. Which stress-management systems prevent microglia from failing?
Aging brains accumulate large amounts of lipid-rich debris, including breakdown products from myelin (the insulation around nerve fibers). Processing that material is a heavy metabolic load. The project will examine the cellular programs that enable microglia to manage this load without progressing into chronic dysfunction.
3. How much of microglial dysfunction is driven by the aging environment and can resilience persist under pressure?
Even a healthy cell can struggle in a hostile environment. The team will test how aging- and disease-like conditions reshape microglial behavior, and whether resilient microglia can remain functional under those pressures.
If successful, this research will deliver something the aging field urgently needs: a clearer definition of microglial resilience that can be measured, tracked, and ultimately supported. Rather than chasing symptoms late, it aims to preserve one of the brain’s most fundamental defenses earlier: its ability to clean up damage and maintain healthy neural circuits over time.
This is exactly the Longevity Science Foundation’s approach: prevention-first, biology-first, and built to translate. Donor support helps accelerate the path from discovery to impact by strengthening the scientific foundation for future therapies and diagnostics that keep brains healthier, longer, and help push cognitive decline from “expected” toward “avoidable.”
A key insight comes from people who stay mentally sharp into very advanced age. Human genetics suggests that some individuals carry naturally occurring “resilience” signals that help the brain’s immune system stay protective over time. This opens a major opportunity: if we can understand what makes those brains resilient, we may be able to design prevention-first strategies that keep more people cognitively well for longer. The challenge is that resilience is still poorly defined at the mechanistic level. What keeps microglia functional? What prevents them from tipping into a harmful state? And why do some brain regions remain more protected than others?
That’s why the Longevity Science Foundation is supporting Dr. Andy Tsai’s project to decode microglial resilience, specifically how the brain’s cleanup system remains functional under the pressure of aging and Alzheimer’s-like stress. His work focuses on a key failure mode observed in older and Alzheimer’s-affected brains: microglia that become overloaded by lipid-rich debris (fats) and develop stressed internal recycling systems (lysosomes). When microglia struggle to manage this cellular stress, waste accumulates, inflammation rises, and the surrounding brain tissue becomes more vulnerable, setting the stage for faster functional decline.
Instead of only studying what goes wrong late in disease, Dr. Tsai’s team is reverse-engineering what goes right in natural resilience. Starting from human evidence of reduced Alzheimer’s risk and preserved cognition in extreme old age, the project will build detailed maps of microglial health across different brain regions and across the lifespan. This matters because brain aging does not affect every area equally: some circuits are more vulnerable, and microglia appear to adapt differently depending on the local brain environment they are in. By comparing resilient vs. vulnerable microglial states in a controlled way, the team aims to reveal the protective programs that keep microglia functioning during aging-related stress.
The work is designed to answer three relevant questions:
1. What does a “resilient” microglia look like in the aging brain?
The team will identify the biological signatures that distinguish microglia that remain protective from those that become dysfunctional and connect those signatures to indicators of cognitive performance.
2. Which stress-management systems prevent microglia from failing?
Aging brains accumulate large amounts of lipid-rich debris, including breakdown products from myelin (the insulation around nerve fibers). Processing that material is a heavy metabolic load. The project will examine the cellular programs that enable microglia to manage this load without progressing into chronic dysfunction.
3. How much of microglial dysfunction is driven by the aging environment and can resilience persist under pressure?
Even a healthy cell can struggle in a hostile environment. The team will test how aging- and disease-like conditions reshape microglial behavior, and whether resilient microglia can remain functional under those pressures.
If successful, this research will deliver something the aging field urgently needs: a clearer definition of microglial resilience that can be measured, tracked, and ultimately supported. Rather than chasing symptoms late, it aims to preserve one of the brain’s most fundamental defenses earlier: its ability to clean up damage and maintain healthy neural circuits over time.
This is exactly the Longevity Science Foundation’s approach: prevention-first, biology-first, and built to translate. Donor support helps accelerate the path from discovery to impact by strengthening the scientific foundation for future therapies and diagnostics that keep brains healthier, longer, and help push cognitive decline from “expected” toward “avoidable.”
Grant Awarded:
Building Brain Resilience for Lifespan Extension and Cognitive Health
Sign up for our mailing list
Contact Us
Make a Donation
If you are interested please leave your information below and we will contact you
Volunteer
Help us make longevity accessible for all and educate the public about aging research
This website uses cookies to ensure you get the best experience