Not All Diseases Come From Germs

Have you ever wondered why you can catch a cold or the measles from someone sitting next to you, but you cannot develop diabetes just by being around someone who has it? Diseases that spread from person to person, called infectious diseases, are caused by germs such as viruses or bacteria. In contrast, non-communicable chronic diseases (NCDs) do not involve germs and cannot spread between people (“non-communicable”). Instead, they develop inside the body over time (“chronic”). You may have heard of some of the major NCDs: cancer, diabetes, heart disease, and Alzheimer’s disease.

Today, NCDs are a much bigger health problem than infectious diseases in many countries. In fact, they are responsible for about 3 out of 4 deaths worldwide [1]. In the United States, 6 of 10 people have at least one NCD, and 4 out of 10 have two or more! Because NCDs often develop gradually and last for many years, they are causing a growing strain on people, families, and health systems.

NCDs become more common as people get older, but aging alone does not explain why so many people develop these diseases. Everyday habits can raise the risks of NCDs—such as not getting enough physical activity, eating poorly, smoking, feeling stressed for long periods, and not getting enough sleep. This means that many NCDs are not just the result of “bad luck” or bad genes but are also shaped by how people live.

Different Diseases, Same Cause?

At first glance, NCDs look very different from one another. Cancer, one of the deadliest NCDs, can begin in almost any part of the body and involves cells that grow out of control. Diabetes affects the pancreas and how the body manages sugar in the blood. Heart disease involves damage to the heart and the blood vessels that carry oxygen and nutrients throughout the body. Alzheimer’s disease affects the brain, slowly disrupting memory, thinking, and behavior.

Because these diseases affect different organs and cause different symptoms, they are usually studied as separate problems. However, researchers are noticing an important pattern. In many NCDs, cells seem to struggle with the same thing: energy metabolism. Energy metabolism is the process of making and managing the energy cells need to function. Interestingly, increasing energy problems also seem to be common in normal aging. When energy metabolism is not working properly, it can affect how cells grow and respond to stress, and it can even cause cells to die. Over time, these energy problems can build up and lead to illness. You could think about this like a car that starts to break down because the engine is struggling to burn fuel efficiently—eventually, the whole vehicle stops working correctly.

Mitochondria: Powering Cells and Shaping Health

Every cell in the body needs a constant supply of energy to grow, repair damage, communicate with other cells, and respond to changes in its environment. In healthy cells, most energy is produced inside small structures called mitochondria. Mitochondria act a bit like the “engines” of the cell, turning nutrients from food into energy cells can use (Figure 1). Well-functioning mitochondria can help cells adjust their energy production to meet the body’s changing energy needs, such as during physical activity, stress, or growth. When mitochondria are working well, cells, tissues, and organs can stay stable and healthy over time.

Problems arise when mitochondria become damaged or less efficient—a condition known as mitochondrial dysfunction. Mitochondrial dysfunction can involve reduced numbers of mitochondria or problems with their structure and function. Like NCDs, mitochondrial dysfunction has been linked to poor diet, lack of exercise, and exposure to certain toxic substances in the environment. When mitochondria cannot produce energy properly, cells struggle to keep up with their basic needs and eventually become sicker.

Inefficient energy production also leads to another problem. When mitochondria are under stress, they can make higher amounts of harmful byproducts called reactive oxygen species (ROS) [2]. Going back to our “engine” analogy, you can think of ROS as “toxic exhaust” coming out of a malfunctioning engine. Small amounts of ROS are normal and can even help cells respond to short-term challenges. However, when too much “toxic exhaust” builds up, it can damage important parts of the cell, including proteins and DNA. ROS damage can also trigger inflammation, the body’s response to injury, which can add to cell stress if it continues for a long time.

Interestingly, researchers have observed signs of mitochondrial dysfunction in all major cancers and NCDs, including diabetes, heart disease, obesity, and some mental health disorders [3–5]. This tells us that long-term problems with energy metabolism may play an important role in NCDs. In fact, cells may start struggling with energy metabolism long before a person shows obvious signs of NCDs.

Measuring Cellular Fuel Use

If these energy problems start out quietly, deep inside a person’s cells before they even feel sick, how can researchers find them? They need a biomarker—something easily measurable (like checking the level of sugar in the blood), that lets them predict which fuels the mitochondrial engines are using to produce energy.

Human cells can get the energy they need from several types of fuels, but we will focus on two: glucose and ketones. Glucose is a type of sugar that comes mainly from carbohydrates in foods. Ketones are small energy-rich molecules that the body can make from dietary or body fat. Most of the time, cells use glucose as fuel because it is more readily available. However, healthy mitochondria help cells switch between glucose and ketones when energy demands change, like during exercise or fasting. Evidence suggests that ketones are a cellular “superfuel” because they make the mitochondrial engines run much cleaner and generate energy more efficiently, producing less ROS and other “toxic exhaust” substances.

When mitochondria are not working well, cells may rely more heavily on inefficient use of glucose while making little use of ketones. Eventually, this can stress cells, causing ROS to build up and contributing to the development of NCDs.

The glucose-ketone index (GKI) is a relatively new tool researchers can use to study these important cellular fuel patterns [6, 7]. The GKI is a simple ratio between amounts of glucose and ketones present in the blood. Both fuels can be measured with simple blood tests, so the GKI is an easy way to track fuel balance. A high GKI means glucose levels are higher and ketone levels are lower, suggesting that cells are relying mainly on glucose for energy. A low GKI means glucose levels are lower and ketone levels are higher, giving mitochondria more access to the “superfuel” that may place less stress on cells (Figure 2).

GKI as a Biomarker of Disease

Researchers are currently studying how the GKI relates to disease. They first developed the GKI as a biomarker to check whether brain cancer patients were sticking to a diet designed to increase their ketone levels [6, 8]. When researchers looked at GKIs in people with brain cancer, they noticed that many patients had high GKI values. A high GKI was a clear signal that the patients had high blood glucose levels, meaning brain cancer cells had easy access to the fuel that helps them grow quickly. In contrast, a low GKI meant less glucose was available to cancer cells, while healthy cells could rely more on the ketone “superfuel”.

As research continued, scientists saw similar GKI patterns in other NCDs, like heart disease and Alzheimer’s [9]. Even though these diseases affect different organs, they show the same “broken engine” pattern in patients: high glucose use and low ketone use. This suggests that the GKI could be a “universal” biomarker for energy metabolism, helping researchers track energy use across a variety of health conditions.

It is important to keep in mind that a high GKI cannot diagnose a disease on its own—a high GKI reading does not tell doctors what disease someone has or even if they have a disease at all. Instead, a consistently high GKI could mean that a person’s energy metabolism is out of balance because of everyday factors, such as eating a high-carbohydrate diet, being less active, or constantly feeling stressed. To return to our analogy once again, the GKI is kind of like a “check engine” warning light in a car: it tells researchers there may be a problem with the energy metabolism “under the hood”, but other tests are still needed to find the exact cause.

Can GKI be Used to Help Treat or Prevent Diseases?

If the GKI acts as a “check engine” light for the body’s energy system, the next logical question is whether it can be used to help a struggling cellular engine run smoothly again... and thus whether changing a person’s GKI could protect them against NCDs.

To explore this idea, researchers are focusing on diet and lifestyle choices that can naturally produce a low GKI, shifting cells toward using more ketones. One way to do this is through nutritional ketosis. Nutritional ketosis occurs when a person consistently eats far fewer carbohydrates and more fat than usual. With less sugar entering the body, blood glucose levels drop and the body begins breaking down fat for energy instead, producing ketones. In this state, blood ketone levels increase, resulting in a low GKI and therefore giving mitochondria greater access to ketone “superfuels” and essentially reducing the cellular stress that leads to NCDs.

When researchers looked at GKIs to see if patients were sticking to their treatment diets, they found that patients who kept a low GKI (meaning their cells were fueled mainly by ketones rather than glucose) often stayed healthier for longer periods of time [10]. This suggests that the GKI is more than just a warning signal—it is also a tool that researchers can use to monitor how well a person’s cellular “engines” are responding to a medical therapy or healthy lifestyle changes, such as specialized exercise routines or stress-management techniques.

Rethinking Chronic Disease

In summary, GKI research is helping scientists and doctors think about NCDs in a new way. Instead of treating each disease as a completely unique condition, they are asking whether long-lasting energy problems inside cells could raise the risk of many different diseases as people get older. As you have learned, NCDs that affect very different parts of the body, such as cancer, heart disease, diabetes, and brain disorders, often show similar signs of strained cellular engines that are relying on the wrong fuel and producing too much “exhaust”.

By studying energy metabolism with the GKI, researchers can see how lifestyle habits, like nutrition and exercise, work together to improve mitochondrial health across the whole body. While this research is still in its early stages, these findings may point to a potential new strategy for restoring the body’s natural balance, regardless of a person’s age or even their genes (Figure 3).

Ultimately, this new way of thinking about NCDs may be an important step toward keeping our cellular engines healthy over many years. The goal is not just to help people live longer, but to extend their healthspan—the number of “good” years they spend feeling strong, active, and healthy enough to keep doing the things they love.

Glossary

Non-Communicable Chronic Diseases (NCDs): ↑ Diseases that do not spread between people and develop slowly over time, such as cancer, diabetes, heart disease, and Alzheimer’s disease.

Energy Metabolism: ↑ The process cells use to turn food into energy needed for growth, repair, communication, and everyday functions.

Mitochondrial Dysfunction: ↑ When mitochondria do not work properly, making it harder for cells to produce enough energy to stay healthy.

Reactive Oxygen Species (ROS): ↑ Harmful byproducts made when cells produce energy. Small amounts are normal, but too much can damage cells and cause long-term stress.

Biomarker: ↑ Something measurable, like a substance in the blood, that gives clues about what is happening inside the body.

Glucose-Ketone Index (GKI): ↑ A measurement that compares levels of glucose and ketones in the blood to show which fuels the body is using for energy.

Nutritional Ketosis: ↑ A state in which the body makes and uses ketones for energy because it is getting much less sugar from food.

Healthspan: ↑ The number of years a person stays healthy, active, and able to do everyday activities, not just how long they live.

Conflict of Interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We wish to thank Dr. Susan Debad for providing us with a first draft and for her continued collaborative input as co-author. We would also like to thank the coauthors of the original manuscript: Isabella D. Cooper, Joseph C. Maroon, Kris Smith, Wafaa Abdel-Hadi, Egiroh Omene, and Athanasios E. Evangeliou. The authors thank the Foundation for Metabolic Cancer Therapies, the Nelson and Claudia Peltz Foundation, Dr. Edward Miller, Ezzio Partesano, Iren Vitanova, The Broken Science Initiative, Children with Cancer UK, The Corkin Family Foundation, The Elizabeth Ann Weathers Breast Cancer Research Fund, and the Boston College Research Expense Fund for their support. The funders were not involved in the writing, editing, or conceptualization of this manuscript or the decision to submit it for publication.

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