New Theory Suggests Autism Is a Treatable Metabolic Signaling Disorder

When a child is diagnosed with autism, the first question parents often ask is simply, “Why?” It is a question that has proven incredibly difficult to answer, offering us a confusing mix of genetic clues and environmental factors that never quite seem to fit into a single picture. But a new framework proposed by researchers at the University of California San Diego might finally connect these scattered dots.

Finding a Unified Cause for Autism

For over a century, scientists have worked to identify the root causes of autism, yet a singular explanation has remained elusive. The complexity arises from the sheer variety of contributing factors. Researchers have pinpointed hundreds of genetic markers linked to the condition, alongside environmental variables like pollution, maternal infections, and metabolic irregularities.

The difficulty lies in connecting these disparate dots. While genetics play a significant role, specific genes do not produce the same outcome in every child. Similarly, environmental factors increase risk primarily during specific windows of brain development, such as pregnancy and early infancy. Furthermore, many autistic children experience co-occurring medical issues involving the immune system or metabolism, suggesting the condition impacts the body more broadly than previously understood.

Without a unifying framework, findings regarding stress chemistry, gut health, and mitochondrial function have often felt disconnected. Dr. Robert Naviaux, a professor at UC San Diego School of Medicine, notes that what has been missing is a model capable of weaving these diverse biological and environmental threads together. This fragmentation has made it challenging to explain how such distinct triggers can lead to the same developmental outcome, leaving researchers searching for a coherent narrative to guide future strategies.

The “Three-Hit” Metabolic Model

Dr. Naviaux proposes that autism is not the result of a single error but rather a chain reaction involving three distinct stages. This new framework, known as the “Three-Hit” model, helps explain how biological traits and environmental events collide to alter development.

Hit One: Genetic Sensitivity
The process begins with genetics, but not in the way many people assume. Rather than inheriting a specific “autism gene,” some children are born with a sensitive genetic makeup. This makes their cells highly reactive to their surroundings. Specifically, their mitochondria, which are responsible for creating energy, are primed to react strongly to stress. On its own, this sensitivity does not cause autism, but it sets the stage for a stronger biological reaction to the environment.

Hit Two: The Early Trigger
The second step occurs when something in the environment activates this genetic sensitivity. This happens during a critical window of development, ranging from early pregnancy through the first three years of life. Triggers can include things like maternal inflammation, exposure to pollution, or metabolic stressors. In a child with sensitive genetics, these common triggers push their cells into a defensive state at a specific, vulnerable moment.

Hit Three: The “Stuck” Switch
The final hit is the persistence of this stress. Normally, cells react to a threat and then return to a healing and growth mode. In this model, the cells get stuck in a “danger” mode, known as the Cell Danger Response. Because the body thinks it is still under threat, it diverts energy away from normal brain development and focuses entirely on cellular defense. This chronic stress signal eventually alters how the brain connects and functions.

How Extended Stress Blocks Neural Development

At the center of this “Three-Hit” model is a biological mechanism that explains why the body stays in a stress state. The key player is a molecule called extracellular ATP. Under normal conditions, ATP acts as fuel inside the cells. However, when it escapes outside the cell, it takes on a completely different role. It acts as a siren, signaling danger to the rest of the body.

Dr. Naviaux argues that when these danger signals remain high, cells get locked in a defensive mode known as the Cell Danger Response (CDR). Instead of returning to normal function after a threat has passed, the cells continue to behave as if they are under attack.

This state creates a critical resource problem. The body has a limited amount of energy. When cells focus entirely on defense, they steal resources away from normal growth and complex tasks like social development or speech.

“Behavior has a chemical basis. The CDR regulates that chemistry,” Dr. Naviaux explained. “When it remains activated too long, it diverts the body’s resources from normal growth and development toward cellular defense, leaving fewer resources for the developing brain.”

The review describes this as a “stalled healing” cycle. In a typical scenario, the body enters a healing phase called salugenesis to recover from stress. In this model, that cycle gets blocked. The prolonged stress prevents the brain from shifting gears, leading to the over-excitation and sensory sensitivities often seen in autistic children.

A New Approach to Prevention and Care

This metabolic model offers a fresh perspective on why autism often comes with physical challenges, not just behavioral ones. Many parents observe that their autistic children struggle with sleep disturbances, digestion problems, or immune sensitivities. According to Dr. Naviaux, these are not random coincidences. They are visible signs that the body’s cells are stuck in a chronic stress response.

Because the Cell Danger Response affects the entire body, the symptoms appear system-wide. The gut, the immune system, and the brain are all communicating using the same chemical signals. When those signals are jammed in “defense mode,” every system feels the impact.

To show that this type of problem can be solved, the researchers point to a condition called Phenylketonuria (PKU). PKU is a purely genetic disorder. Decades ago, it guaranteed severe intellectual disability. However, scientists discovered that by altering the child’s metabolism, specifically through a specialized diet, they could bypass the genetic defect entirely. Today, children with PKU live typical, healthy lives.

Dr. Naviaux suggests this serves as a powerful “proof of concept” for autism. It demonstrates that even if a condition has a strong genetic root, managing the metabolic environment can change the outcome. If autism is indeed a metabolic signaling disorder similar to PKU, it implies that finding the right metabolic key could unlock new treatments that were previously thought impossible.

Piecing the Puzzle Together

While this model is still a theory that needs rigorous testing, it offers something that has been missing for a long time. For decades, families have navigated a maze of disconnected symptoms and isolated therapies. This research suggests that the confusion might actually be pieces of a single puzzle. It changes the conversation from what is broken to what is blocked, offering a kinder and more coherent way to look at the body’s struggle to heal itself.

The most profound shift here is moving away from the idea that autism is a fixed destiny written entirely in DNA. Instead, it paints a picture of a body trying to protect itself. This perspective honors the biological reality of these children. It suggests that their bodies are not malfunctioning out of error, but reacting out of defense. If science can find a way to signal safety to those cells, it might unlock potential that has simply been waiting for the right resources to flourish.

We are likely years away from a clinical treatment that can reset this cellular stress, but the path is now visible. As Dr. Naviaux stated, understanding the condition through this lens changes what we can do about it. For now, this research stands as a beacon of possibility. It reminds us that science is still moving forward, working tirelessly to translate complex biology into better, healthier lives for future generations.

Source:

1. Robert K. Naviaux, A 3-hit metabolic signaling model for the core symptoms of autism spectrum disorder, Mitochondrion, Volume 87, 2026, 102096, ISSN 1567-7249, https://doi.org/10.1016/j.mito.2025.102096