by Aging is a biological process that no one can avoid. Ideally, getting old should be the time to relax and enjoy the fruits of your labor. Aging also has a darker side, however, often associated with disease.
Every second, your cells carry out billions of biochemical reactions that trigger functions essential to life, creating a highly interconnected metabolic network. This network enables cells to grow, multiply and repair themselves, and this disruption can drive the aging process.
But does aging lead to metabolic decline, or does metabolic disruption accelerate aging? Or both?
To address this chicken or egg question, you must first understand how metabolic processes break down during aging and disease. I am a scientist and researcher, and my laboratory focuses on exploring the complex relationship between metabolism, stress and aging. Ultimately, we hope this work will provide strategies to promote healthier aging and livelier lives.
Link between metabolism and ageing
Aging is the most significant risk factor for many of society’s most common diseases, including diabetes, cancer, cardiovascular disease and neurodegenerative disorders. A key factor behind the onset of these health issues is the disruption of cellular and metabolic homeostasis, or balance. Disrupting homeostasis destabilizes the body’s internal environment, leading 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.
Disturbed metabolism is linked to many hallmarks of aging cells, such as telomere shortening, which is damage to the protective ends of chromosomes, and genomic instability, the tendency to form genetic mutations.
Dysfunctional metabolism is also linked to poorly functioning mitochondria; cellular senescence, or when cells stop dividing; imbalances in gut microbes; and the reduced ability of cells to sense and respond to various nutrients.
Neurological disorders, such as Alzheimer’s disease, are prime examples of age-related conditions with a strong link between dysregulated metabolism and functional decline. For example, my research team previously found that bone marrow’s ability to produce, store and use energy is suppressed in aging mice due to increased activity from a protein that modulates inflammation. This energy-starved state leads to increased inflammation that is exacerbated by the dependence of these aging cells on glucose as a primary fuel source.
However, by experimentally inhibiting this protein in the bone marrow cells of aging mice, it revives the cells’ ability to produce energy, reduces inflammation and improves plasticity in an area of the brain associated with memory. This finding suggests that some cognitive aging could be reversed by reprogramming the glucose metabolism of bone marrow cells to restore immune functions.
Reusing drugs to treat Alzheimer’s
In our newly published research, my team and I discovered a new link between disturbed glucose metabolism and neurodegenerative disease. This led us to identify a drug originally designed for cancer that could be used to treat Alzheimer’s.
We focused on an enzyme called IDO1 which plays a crucial role in the first step of the amino acid tryptophan breakdown. This pathway produces an important compound called kynurenine, which promotes additional energy pathways and inflammatory responses. However, excess kynurenine can have adverse effects, including increasing the risk of developing Alzheimer’s.
We found that inhibition of 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 use glucose properly to fuel vital brain processes can lead to metabolic and cognitive decline.
High levels of IDO1 reduce glucose metabolism by producing excess kynurenine. So IDO1 inhibitors – originally designed to treat cancers such as melanoma, leukemia and breast cancer – could be revamped to reduce cinurine and improve brain function.
Using a range of laboratory models, including mice and cells from Alzheimer’s patients, we also discovered that IDO1 inhibitors can restore glucose metabolism in brain cells. Furthermore, we were able to restore 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 across different neurodegenerative disorders may be beneficial.
Promoting healthier cognitive ageing
Neurological disorders and metabolic decline have a significant impact on individuals, families and the economy.
Although many scientists have focused on the downstream effects of these diseases, such as managing symptoms and slowing progression, it is possible to improve cognition in aging by treating these diseases earlier. Our findings suggest that targeting metabolism has the potential to not only slow neurological decline but also reverse the progression of neurodegenerative diseases such as Alzheimer’s, Parkinson’s and dementia.
Finding new insights at the intersection of stress, metabolism and aging can pave the way for healthier ageing. More research can improve our understanding of how metabolism affects stress responses and cellular balance throughout life.
This article is republished from The Conversation, a non-profit, independent news organization that brings you reliable facts and analysis to help you make sense of our complex world. Written by: Melanie R. McReynolds, Penn State
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Melanie R. McReynolds receives funding from the Faculty Phase of the Howard Hughes Medical Institute’s Hanna H. Gray Hanna Fellows Program and from the PDEP Burroughs Transition to Faculty Welcome Fund.
