Aging is a biological process that no one can avoid. Ideally, growing older should be a time to relax and enjoy the fruits of your labor. However, aging also has a dark side, which is often associated with disease.
Every second, your cells perform billions of biochemical reactions that fuel essential life functions, forming a highly interconnected metabolic network. This network allows cells to grow, proliferate, and repair themselves, and disruption can accelerate the aging process.
But does aging lead to a decrease in metabolism, or does a disruption of metabolism accelerate aging? Or both?
To answer this chicken-and-egg question, you first need to understand how metabolic processes break down during aging and disease. I am a scientist and researcher, and my lab focuses on investigating the complex relationships between metabolism, stress, and aging. Ultimately, we hope that this work will yield strategies to promote healthier aging and more vital lives.
Relationship between metabolism and aging
Aging is the leading risk factor for many of society’s most prevalent diseases, including diabetes, cancer, cardiovascular disease, and neurodegenerative disorders. A major factor in the development of these health conditions is the disruption of cellular and metabolic homeostasis, or balance. Disruption of homeostasis destabilizes the body’s internal environment, leading to imbalances that can trigger a cascade of health problems, including metabolic disorders, chronic diseases, and impaired cellular function that contribute to aging and other serious conditions.
Disrupted metabolism is associated with many hallmarks of cellular aging, such as telomere shortening (damage to the protective ends of chromosomes) and genomic instability (the tendency for genetic mutations).
Disrupted metabolism is also associated with poorly functioning mitochondria, cellular aging (when cells stop dividing), imbalances in the gut flora, and the reduced ability of cells to detect and respond to different nutrients.
Neurological disorders, such as Alzheimer’s disease, are good examples of age-related conditions with a strong link between dysregulated metabolism and functional decline. For example, my research team previously found that in aging mice, the ability of bone marrow cells to produce, store, and use energy is suppressed by increased activity of a protein that modulates inflammation. This energy-deficient state leads to increased inflammation that is exacerbated by the reliance of these aging cells on glucose as their primary fuel source.
Experimentally inhibiting this protein in the bone marrow cells of aging mice, however, revitalizes the cells’ ability to produce energy, reduces inflammation, and improves the plasticity of a region of the brain involved in memory. This finding suggests that some cognitive aging might be reversed by reprogramming the glucose metabolism of bone marrow cells to restore immune functions.
Repurposing drugs for the treatment of Alzheimer’s
In our recently published study, my team and I discovered a novel link between impaired glucose metabolism and neurodegenerative disease, leading 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, which plays a crucial role in the first step of breaking down the amino acid tryptophan. This pathway produces an important compound called kynurenine, which fuels additional energy pathways and inflammatory responses. However, excessive kynurenine can have harmful effects, including an increased risk of developing Alzheimer’s.
We found that inhibiting IDO1 can restore 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. The brain is one of the most glucose-dependent tissues in the body. An inability to properly use glucose to fuel critical brain processes can lead to metabolic and cognitive decline.
High levels of IDO1 impair glucose metabolism by producing excess kynurenine. So 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 laboratory models, including mice and cells from Alzheimer’s patients, we also found that IDO1 inhibitors can restore glucose metabolism in brain cells. In addition, we were able to restore glucose metabolism in mice with both amyloid and tau accumulation – abnormal proteins involved in many neurodegenerative diseases – by blocking IDO1. We believe that repurposing these inhibitors could be beneficial for a variety of neurodegenerative diseases.
Promoting healthier cognitive aging
The consequences of neurological disorders and metabolic decline have major implications for individuals, families and the economy.
While many scientists have focused on addressing the downstream effects of these diseases, such as controlling symptoms and slowing progression, treating these diseases earlier may improve cognition as we age. Our findings suggest that targeting metabolism may not only slow neurological decline, but also 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 could pave the way for healthier aging. More research can improve our understanding of how metabolism influences stress responses and cellular balance throughout life.
This article is republished from The Conversation, a nonprofit, independent news organization that brings you facts and reliable analysis to help you understand our complex world. It was written by: Melanie R. McReynolds, Penn State
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Melanie R. McReynolds receives funding from the Howard Hughes Medical Institute Hanna H. Gray Fellows Program Faculty Phase and the Burroughs Welcome Fund PDEP Transition to Faculty.