How Metabolism and Ageing May Shape Alzheimer's Disease

Ageing is a biological process from which nobody is exempt. In an ideal world, later life would offer an opportunity to unwind and enjoy the rewards of your labour. Yet ageing has a less positive aspect too, as it is frequently associated with illness.

Each second, cells carry out billions of biochemical reactions that power functions vital to life and create an intricately connected metabolic network. This network allows cells to grow, multiply and repair themselves; when it is disrupted, it may contribute to ageing.

So, does ageing lead to metabolic decline, does metabolic disruption hasten ageing, or are both processes at work?

Answering this chicken-or-egg question first requires an understanding of how metabolic systems deteriorate in ageing and disease.

I am a scientist and researcher whose laboratory examines the complicated relationship between metabolism, stress and ageing. In the long term, we hope this research will help identify ways to support healthier ageing and more energetic lives.

The link between metabolism and ageing

Ageing is the greatest risk factor for many of the most prevalent diseases in society, including diabetes, cancer, cardiovascular disease and neurodegenerative disorders.

One major driver of these conditions is a breakdown in cellular and metabolic homeostasis - the balance that keeps internal processes stable.

When homeostasis is disturbed, the body’s internal environment becomes unstable. The resulting imbalances can set off a chain of problems, including metabolic disorders, chronic disease and impaired cellular activity that contributes to ageing and other serious conditions.

Altered metabolism is associated with several hallmarks of ageing cells, including telomere shortening - damage to the protective chromosome ends - and genomic instability, or a greater tendency to develop genetic mutations.

Metabolic dysfunction is also connected with poorly functioning mitochondria, cellular senescence - in which cells cease dividing - disruptions to gut microbes, and a reduced cellular capacity to sense and respond to nutrients.

Neurological conditions including Alzheimer's disease provide striking examples of age-related disorders in which dysregulated metabolism is closely tied to declining function.

For instance, my team previously found that, in ageing mice, bone marrow cells have a diminished ability to generate, store and use energy because of heightened activity of a protein that regulates inflammation.

This lack of energy increases inflammation, an effect compounded by the ageing cells’ dependence on glucose as their principal fuel.

However, experimentally blocking this protein in bone marrow cells from ageing mice restores their capacity for energy production, lowers inflammation and enhances the plasticity of a brain region involved in memory.

The result indicates that certain aspects of cognitive ageing may be reversible by reprogramming glucose metabolism in bone marrow cells to reinstate immune function.

Repurposing drugs to treat Alzheimer's

In recently published research, my colleagues and I identified another connection between impaired glucose metabolism and neurodegenerative disease. This discovery led us to a drug first developed for cancer that might also be used in Alzheimer's treatment.

Our work centred on an enzyme known as IDO1, which is essential to the initial stage of breaking down the amino acid tryptophan.

This route generates an important compound, kynurenine, that supports further energy pathways and inflammatory responses. Too much kynurenine, however, can be harmful, including by raising the risk of Alzheimer's.

We discovered that inhibiting IDO1 can restore memory and brain function across several preclinical models, including cell cultures and mice. To establish the reason for this effect, we examined brain-cell metabolism.

The brain is among the body’s tissues most dependent on glucose. Failing to use glucose effectively to power crucial brain functions can result in metabolic and cognitive decline.

Elevated IDO1 levels suppress glucose metabolism through the production of excess kynurenine. IDO1 inhibitors - initially created to treat cancers including melanoma, leukaemia and breast cancer - could therefore be repurposed to lower kynurenine and enhance brain function.

Across a variety of laboratory models, including mice and cells obtained from Alzheimer's patients, we also found that IDO1 inhibitors can reinstate glucose metabolism in brain cells.

In addition, by blocking IDO1, we restored glucose metabolism in mice with accumulations of both amyloid and tau - abnormal proteins implicated in many neurodegenerative disorders. We think repurposing these inhibitors may prove useful for a range of neurodegenerative disorders.

Supporting healthier cognitive ageing

Neurological disorders and metabolic decline impose a considerable burden on people, families and the economy.

Although many researchers have concentrated on downstream consequences of these diseases, such as controlling symptoms and slowing their progression, earlier treatment could improve cognition as people age.

Our results indicate that targeting metabolism could not only slow neurological decline, but potentially reverse the course of neurodegenerative diseases including Alzheimer's, Parkinson's and dementia.

New understanding at the intersection of stress, metabolism and ageing could open routes to healthier ageing. Further research may clarify how metabolism influences stress responses and cellular balance across the lifespan.

Melanie R. McReynolds, Assistant Professor of Biochemistry, Penn State

This article is republished from The Conversation under a Creative Commons licence. Read the original article.