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Cambridge University Science Magazine
Ageing is an inevitable part of life - but what exactly makes us age? While researchers agree that there is no single cause of ageing – rather, it is a continuous multifactoral process – we are far from a complete understanding of the mechanisms at work. In particular, ageing of the brain remains a mystery. “Brain functions start to deteriorate from our early twenties; however, the impact on performance only appears after late middle age. This is because up until then we have ways to compensate”, explains Professor Michael Coleman, Chairman of the John van Geest Centre for Brain Repair at the University of Cambridge. He is convinced that there is no such thing as healthy ageing, reasoning that many processes slowly fail at every biological level.

“Since 1950, the number of people over 60 in the world has tripled. In 2050, the combined senior and geriatric population is expected to reach 2.1 billion”

Neurons, cells of the nervous system, undergo age-related changes at the cellular level. There are many types of neurons and together they form a huge network.  The typical structure of a neuron consists of a cell body with many dendrites and one axon.  The cell body is the core of the neuron and contains a nucleus with DNA. The dendrites are the receivers of signals from other neurons, while the long axon is the transmitter of signals. Both dendrites and the axon have specialised structures, called synapses, which are responsible for the communication between neurons. When we get older, there are several changes in the structure of neurons. Firstly, synapses are lost or become dysfunctional. Secondly, dendrites and the axon lose some of their branches that connect to other neurons, and thus the network begins to shrink. Finally, many of the neurons are lost due to cell death. All these contribute to phenomena like forgetfulness or slowness of movement, which are typical of old age.

Ageing also influences neurons at the molecular level. In fact, our DNA has a prominent role during ageing. Genetic material undergoes age-related changes in every cell. In the brain, only a small proportion of genes are modified when getting older. Most of these genes become less active when ageing, while the activity levels of others increases. For instance, the function of genes involved with memory and thinking are decreased and this could explain why we forget things when we get older, while the function of genes involved in the inflammatory and stress response are increased during ageing. Importantly, the changes in DNA are not equally distributed throughout the brain. The regions involved in memory and higher thinking processes appear to have more gene modifications. Thus, it is easy to understand why ageing is the major risk factor for brain diseases such as Alzheimer’s and Parkinson’s disease.

Another culprit involved in ageing is a small organelle located inside all our cells, the mitochondrion. Mitochondria are often referred to as the powerhouses of the cell: their primary function is to produce energy by metabolising nutrients and the oxygen we breathe. Our brain requires more energy than any other organ to function properly and therefore mitochondria are especially essential for neurons. But how are these organelles linked to ageing? Mitochondria contain a small amount of DNA, which has a mutation rate approximately fifteen times higher than nuclear DNA. This phenomenon partly occurs because energy production generates reactive oxygen by-products, called free radicals, which can damage DNA and introduce mutations. Given their proximity to the main site of free radical production, mitochondria are constantly exposed to oxidative stress. In other words, as we grow older, randomly occurring mutations begin to accumulate in the mitochondrial DNA, causing mitochondria to malfunction. This leads to energy depletion and ultimately neuronal cell death. Having said that, there are several contradictory studies and therefore the precise mechanisms of how mitochondria are involved in ageing remain a topic of debate.

However, it is not only toxic oxygen radicals that accumulate when we get older; other types of waste products can also hinder the normal function of cells. They are particularly detrimental for neurons because these cells do not have the capacity to replicate. From the beginning of our lives, waste products from metabolism such as damaged and misfolded proteins can accumulate inside neurons. Neurons can remove these unwanted molecules by different mechanisms; these processes start to decay and malfunction when we age. This can lead to the accumulation of pathological proteins, a major risk factor for neurological diseases common in older people. In these pathologies, the damaged proteins begin to stick to each other and form big aggregates. For example, Alzheimer’s disease, one of the most common neurological diseases of old age, is associated with the abnormal accumulation of two proteins, amyloid-beta and tau. The formation of those aggregates is a multi-step, dynamic process and can lead to neuronal degeneration. Yet, Coleman says, “Protein aggregation also occurs in individuals that never manifest pathological symptoms”.

In addition, a process termed demyelination contributes to ageing in the brain. What does this mean? One part of the neuron, the axon, is ensheathed by a white fatty layer called myelin. Neurons communicate with each other via electrical signals, and myelin acts as an essential insulation substance that improves the conduction of these electric pulses. When we age, neurons slowly start to lose this white matter. Coleman confirms that “MRI studies show massive loss of white matter in older brains and this could be due to the loss of the axons themselves or the loss of myelin”. Myelin gets shorter and thinner and this has consequences for the electric communication between neurons in the brain. Signals from one neuron to another are weakened, leading to characteristics associated with old age such as memory loss, weakness of limbs, and fatigue.

Is there any escape from our brain getting old? As Coleman remarks, “ The solution to slow down ageing is already partly out there: we know that following a healthy lifestyle, i.e. good diet, exercise, no smoking or excessive alcohol use, has a big impact on human lifespan”. He also mentioned that the future of ageing research looks promising since new fields are emerging, tackling the many processes by which the brain changes over our lifetime. Finally, “Ageing is the major risk factor for almost all neurodegenerative diseases. It is hence crucial to characterise the ongoing changes of normal ageing to better understand the underlying causes of disease.”

Image credit: Seth Capitulo