Ageing and the potential problems it can bring
Ageing is an inevitable process that every human being is subjected to. From the shortening of telomeres and mutations of the genetic code to hypertension and neurodegeneration, our bodies bear an increasing strain without a chance for all these to be reversed. However, hope still remains as current research in the field of senescence and age-dependent diseases is rapidly evolving.
By targeting the nine hallmarks of ageing, namely genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, it may become possible to successfully improve our health as we age, if not elongate lifespans, in the coming future.
Amongst all the homeostatic processes and organ systems that are influenced by ageing, one stands out - the processes that occur in our central nervous system (CNS).
Unlike our skeletal muscles or gut, both of which have regenerative potential, neurons often take on a post-mitotic, terminally differentiated state at a very early stage. This means that neurons would often remain in their mature state after cell division and rarely undergo mitosis after that. Therefore, the frequency of neuron regeneration and repair in the adult brain is considered to be significantly lower in comparison to the cells located within other regions of our body such as our gut, where cells are constantly renewed.
Given that our neurons function continuously throughout our lifetime, it comes with no surprise that ageing will pose an unavoidable strain on them, and possibly cause irreversible damage. With that in mind, scientific research on neurodegeneration and the development of potential treatments are crucial if we hope to maintain a healthy brain as we age.
The ruthless killers
As we grow older, neurodegenerative diseases have become an aspect of our health that we can no longer overlook.
Currently, the two most prominent neurodegenerative disorders that may emerge amongst elderlies are Alzheimer’s and Parkinson’s Disease. In particular, both of these conditions can lead to dementia, which is defined as “a syndrome (meaning a group of related symptoms) associated with an ongoing decline of brain functioning” by the British National Health Service (NHS).
The murderous power of dementia is unimaginable, accounting for 1 in 3 deaths amongst senior citizens.
To understand how these diseases impact our health, let’s first take a look at neuron structures and the fundamental processes in which they govern.
Figure 1: A schematic of a multipolar interneuron. The structures shown in this diagram represent the dendrites, cell body, axon, and axon terminals, respectively.
Neurons are the key to controlling every thought and motion performed by our bodies. The structure of neurons can differ greatly depending on the cell type. However, there are some common structural elements found in all nerve cells:
At the tip of neurons, we have dendrites reaching out to communicate with other neurons through electrical signals.
Microtubules are dynamic rod structures with their construction and deconstruction processes tightly regulated. They allow the transport of vesicles (containing packaged proteins) to the termini of neurons. Microtubules are also involved in diverse processes ranging from cellular motion to the segregation of chromosomes in mitosis and division.
The axon is localised below the soma and is the part of the neuron where action potentials travel along constantly.
The axon terminals
Healthy neuronal functioning underlies almost all our thoughts and actions, and it is critical for us to not take all of this for granted. Let’s figure why by exploring what happens when neurons fail to work.
As one of the most prevalent neurodegenerative disorders, Parkinsons’ Disease affects above 10 million individuals globally. A notable figure who lived with Parkinson’s Disease is the renowned actor Michael J. Fox. The progression of his condition began as early as the age of 29, falling into the class of young-onset Parkinson’s Disease. Nonetheless, he has also contributed remarkably to the field of Parkinson’s Research through founding The Michael J. Fox Foundation for Parkinson’s Research.
Parkinson’s Disease was initially referred to as “Shaking Palsy,” as one of the key symptoms include the shaking of our limbs. The common phenotypic characteristics during the onset of the disease include tremor and bradykinesia (meaning the slowness of movement). Its hallmarks can be attributed to neuronal death, especially within a region of the brain known as the substantia nigra, as well as the formation of α-synuclein deposits inside neurons.
The α-synuclein protein plays a critical role in the pathological definition of Parkinson’s Disease. Its assembly results in the formation of filamentous entities called Lewy Bodies, which can can act to hinder neural activity. Such structures look generally like a tangled ball of yarn, except with many loose ends of yarn lying around the core rather than a single one.
Ultimately, this causes a lack of dopamine supply as the dopamine neurons within the substantia nigra of our brain incur the damage. Dopamine is a type of neurotransmitters, which are chemical messengers that are released at synapses to communicate information across nerve fibres and other structures. As a matter of fact, dopamine influences a range of functions ranging from sleep to movement, and it is the mediation of physical movements that serves as the key for onset and progression of this disease.
Recent studies of patients with Parkinson’s Disease elucidate a range of factors which may play a role in disease onset and progression. Interestingly, pathological development may be closely tied to immune responses of the brain.
In earlier days, the brain was initially considered to be an immune-unresponsive site due to the presence of the blood-brain barrier. However, recent findings suggested that when neural functioning is disrupted, a type of cell known as microglia becomes activated and it consequently generates molecular factors as a form of feedback. These molecular factors produced by microglial populations, in turn, can contribute to a hyperactive and inflammatory microenvironment that is referred to as neuroinflammation (meaning the inflammation of the nervous tissue). In general, if the inflammatory condition goes out of control, intrinsic damages may surface.
Figure 2: A potential series of processes during neuroinflammation. The series of cause and effect for the progression of inflammatory responses is presented in a sequential manner: (1) ɑ-synuclein accumulation, (2) oligomer formation, (3) the activation of microglia, and (4) the cyclical amplification of Step 3. The figure presents events from left to right, whereby the sub-steps are detailed within each of the large processes.
At present, the most effective intervention for Parkinson’s Disease is by taking a drug called Levodopa. This drug, when consumed orally in the form of pills, enters the bloodstream through our digestive tract and eventually reaches our brain. As a precursor to dopamine, Levodopa is then transformed into dopamine in order to supplement its loss due to Parkinson’s Disease. Hence, we can classify Levodopa as a dopamine replacement agent.
Typically, Levodopa is administered along with another agent, Carbidopa, since the latter can relieve nausea, which is a side effect caused by taking levodopa. Moreover, Carbidopa delays the transformation of Levodopa into dopamine, thereby enhancing the amount of Levodopa that reaches the nervous system.
Moreover, the therapeutic potential of many anti-inflammatory agents was also discovered through meta-analytical investigations. In the case of neuroinflammation and degeneration, the risk of developing Parkinson’s Disease can be reduced by administering non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs). Not only does this demonstrates how inflammation is a driving factor for neuronal disorders, but it also suggests a direction to solve current questions in the field.
In comparison to Parkinson’s Disease, Alzheimer’s Disease is less well-understood in terms of its underlying biological cause and viable treatment options. However, similar to Parkinson’s Disease, the risk and development of Alzheimer’s Disease exacerbates with age. In fact, Alzheimer’s exceeds Parkinson’s Disease in terms of its global impact, with statistics showing that 1 in 10 elderly individuals above the age of 65 are affected! Patients diagnosed with Alzheimer’s Disease may experience memory impairment or even more detrimental symptoms such as difficulties in speaking, thinking clearly, or managing one's emotions.
Just like Parkinson’s Disease, there are many famous individuals who have experienced Alzheimer’s Disease such as Rosa Parks to President Ronald Reagan. Therefore, we have to always remain aware of the prevalence of this disease and its ruthless nature.
At the moment, Alzheimer’s Disease is thought to be linked to the accumulation of amyloid deposition and the formation of neurofibrillary tangles. In essence, the amyloid plaques are composed of amyloid-β proteins.
To understand how these proteins are synthesised, we need to first look at the amyloid precursor protein. The amyloid precursor protein initially exists as a transmembrane protein. This protein can undergo enzymatic cleavage by either the ɑ-secretase under normal conditions. However, when the person is in the diseased state, the protein can be cleaved by the β and ɣ-proteases (in that order) to produce the amyloid-β proteins. Do bear in mind that there is still much to be discovered regarding the processing of the amyloid precursor protein and biological mechanisms its cleavage.
On the other hand, the neurofibrillary tangles consist of the protein tau, which under healthy conditions, interact with microtubules within the neurons. These tau fibres undergo heavy phosphorylation (by a group of enzymes known as kinases) within Alzheimer's patients, ultimately causing the disassembly of microtubules. Now that free tau factors are generated, they can be used to build helical and filamentous neurofibrillary tangles.
Currently, drugs are available to treat certain symptoms of Alzheimer’s Disease, including memory-, behavioural-, and sleep-associated issues. cholinesterase inhibitors and memantine are both examples of such therapeutic agents that can be taken to amend cognitive deficits caused by neuronal death and thus the lack of interneuronal communication. Moreover, there were ideas related to creating drugs that interfere with the protein kinases responsible for the tau pathology. Neverthless, it is important for us to remember that these treatments can only ameliorate symptoms in a short-run, but it does not directly address the root cause of this disease.
What do we need to work on?
Altogether, Alzheimer’s and Parkinson’s Disease are neurodegenerative disorders which develop in the brain as we age, with proteins standing at the centre of their pathological characterisation. Along with Alzheimer’s and Parkinson’s Disease, many other neuronal disorders, such as multiple sclerosis and amyotrophic lateral sclerosis, can also manifest through a person's lifetime.
The overall dearth of effective therapeutic options in the field of neurodegenerative diseases still persists due to our lack of knowledge regarding the complexity of our brain. While research should continue to elucidate the molecular mechanisms underlying Alzheimer’s, Parkinson’s Diseases and many more, current treatments can also be further optimised. In the case of Levodopa for Parkinson’s Disease, it is important to recognise that consuming Levodopa can only replenish the scarcity of dopamine. Further research is still critical if we hope to eradicate neurodegenerative diseases entirely.
To end on a hopeful note, there are many aspects of our lives that we can take control of in order to lower the risk of developing neurodegenerative disorders. For instance, minimising the consumption of alcohol, smoking, as well as physical activities that may cause traumatic brain injury (e.g. boxing) could prevent harm to the brain. In short, let’s all take care of ourselves and help others if we can, so that we can all live our lives to the fullest!
Author: Lily Jiaqi Cao, BSc Biochemistry