This Overlooked Enzyme is the Reason You are Feeling Older

Why missing these early metabolic warning signs could mean losing decades of vitality

Author

My Longevity Experiment
April 28, 2025

How Metabolism Affects Aging and Brain Health

Aging is a biological process that you cannot avoid. Ideally, growing older should be a time for you to relax and enjoy the rewards of your hard work. However, aging often brings a darker side closely linked to disease.

Every second, your cells carry out billions of biochemical reactions that drive essential life functions, forming a highly interconnected metabolic network. This network allows your cells to grow, proliferate and repair themselves. When this network becomes disrupted, it can drive the aging process.

You may wonder whether aging causes metabolic decline or if metabolic disruption accelerates aging, or both. To answer this, you first need to understand how your metabolic processes break down during aging and disease.

I am a scientist and researcher, and my lab focuses on exploring the complex relationship between metabolism, stress and aging. Ultimately, we hope this work will provide strategies to promote healthier aging and more vibrant lives.

The Link Between Metabolism and Aging

Aging is the most significant risk factor for many of the most common diseases in society, including diabetes, cancer, cardiovascular disease and neurodegenerative disorders.

A major factor behind these health issues is the disruption of cellular and metabolic homeostasis, or balance.

When you disrupt homeostasis, you destabilize your body's internal environment. This leads to imbalances that can trigger a cascade of health issues, including metabolic disorders, chronic diseases and impaired cellular functions that contribute to aging and other serious conditions.

Disrupted metabolism is linked to many hallmarks of aging cells, including telomere shortening, which refers to damage at the protective ends of chromosomes, and genomic instability, the tendency to form genetic mutations.

A dysfunctional metabolism is also tied to poorly functioning mitochondria, cellular senescence when your cells stop dividing, imbalances in gut microbes and your cells' reduced ability to detect and respond to different nutrients.

Neurological disorders such as Alzheimer's disease are prime examples of age-related conditions with a strong connection between dysregulated metabolism and functional decline.

For example, my research team discovered that in aging mice, the ability of bone marrow cells to produce, store and use energy becomes suppressed due to increased activity from a protein that modulates inflammation.

This energy-deficient state leads to increased inflammation, worsened by aging cells relying on glucose as their main fuel source.

However, when we experimentally inhibited this protein in the bone marrow cells of aging mice, we revitalized the cells' ability to produce energy, reduced inflammation and improved the plasticity of an area of the brain involved in memory.

This finding suggests that some aspects of cognitive aging could be reversed by reprogramming the glucose metabolism of bone marrow cells to restore immune functions.

Repurposing Drugs to Treat Alzheimer's

In our newly published research, my team and I discovered a new connection between disrupted glucose metabolism and neurodegenerative disease. This discovery led us to identify a drug originally designed for cancer that could potentially be used to treat Alzheimer's.

We focused on an enzyme called IDO1 that plays a critical role in the first step of breaking down the amino acid tryptophan.

This pathway produces a key compound called kynurenine, which fuels additional energy pathways and inflammatory responses. However, excessive kynurenine can have detrimental effects, including increasing the risk of developing Alzheimer's.

IDO1 is a key player in brain cell metabolism. (Goultard59/Wikimedia Commons/CC BY-SA)

We found that inhibiting IDO1 can recover memory and brain function in a range of preclinical models, including cell cultures and mice. To understand why, we looked at the metabolism of brain cells.

Your brain is one of the most glucose-dependent tissues in your body. An inability to properly use glucose to fuel critical brain processes can lead to metabolic and cognitive decline.

High levels of IDO1 reduce glucose metabolism by producing excess kynurenine. Therefore, IDO1 inhibitors, originally designed to treat cancers such as melanoma, leukemia and breast cancer, could be repurposed to reduce kynurenine and improve brain function.

Using a range of lab models, including mice and cells from Alzheimer's patients, we found that IDO1 inhibitors can restore glucose metabolism in brain cells.

Furthermore, we restored glucose metabolism in mice with both amyloid and tau accumulation, abnormal proteins involved in many neurodegenerative disorders, by blocking IDO1. We believe that repurposing these inhibitors could be beneficial across various neurodegenerative disorders.

Promoting Healthier Cognitive Aging

The effects of neurological disorders and metabolic decline weigh heavily on individuals, families and the economy.

While many scientists have focused on targeting the downstream effects of these diseases, such as managing symptoms and slowing progression, treating these diseases earlier can improve cognition with aging.

Our findings suggest that targeting metabolism has the potential to not only slow neurological decline but also to reverse the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's and dementia.

Discovering new insights at the intersection of stress, metabolism and aging can pave the way for healthier aging. More research can improve your understanding of how metabolism affects stress responses and cellular balance throughout your life.

Your Call to Action for How Metabolism Affects Aging and Brain Health

You have the opportunity to influence how your body and brain age by focusing on your metabolic health. Support your metabolism through a balanced diet, regular exercise, and proactive stress management. Stay informed about new research linking metabolism to brain health and discuss preventative strategies with your healthcare provider. By making metabolic health a priority today, you can help protect your memory, cognitive function and overall vitality as you age.

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