How can we explain ageing? Some theories trace the source of the process back to the very essence of the living cell.
According to these theories, the essence of a cell features mechanisms programmed to bring about the death of that very same cell. This approach has a sense of purpose about it. Other concepts point to wear and tear as the reason for ageing. All biomolecules whose activity comprises the phenomenon known as life have to be produced as and when needed, because, having carried out their function several times, these molecules begin to go into decline and need to be replaced. This approach emphasizes the accumulation of damage. Today, there are more than 300 theories grappling with the mystery of ageing. The important thing, however, is to try not to perceive the hypotheses put forward as mutually exclusive; nor should we see the symptoms of ageing as discrete, given that each of them has its roots in all the others and influences them in turn. A living cell is an immensely complicated system of various interactions – dysfunction in but one of them will have an impact on all the others. Rather than a specific ailment, ageing is the sum of various symptoms.
1. Lack of genome stability. This amounts to an increased mutation rate in a cell’s genetic material. To simplify things: if we regard genetic material as a set of instructions from which we obtain information about how the body works, any change to the text of the manual can clearly have dangerous implications. Mutations of all kinds occur in the genome all the time – for example, when we expose ourselves to UV light or when we come into contact with viruses and bacteria from our environment. When we do sport, we expose our body to oxidative stress. Yet oxidative stress also occurs when we are still, rest, and do nothing. Not a moment goes by without something going awry in the genetic material. However, we are equipped with error detection and correction systems – this ensures our ‘inner manual’ is consistent. As we age, these mechanisms begin to fail and undetected mutations accumulate. Proteins with a slightly altered structure emerge on the matrix of the mutated DNA. Obviously, such a mutation could make a positive impact – as a rule, however, it leads to a decline in protein activity. Gene-reading regulation systems are similarly vulnerable to instability, leading the cell to produce too much (or too little) of the protein coded by the gene in question. The mutations drive one another and, if you add to that the (by now imperfect) error rectification system, chaos is inevitable. Cancers are keen to emerge out of such chaos. In a younger body, these cancers can be quickly detected and neutralized, but when they encounter fatigued protection mechanisms, they have a greater opportunity of developing into a serious illness.
2. Shortening of telomeres. This phenomenon can be observed in most human cells. Because genetic material is exceptionally precious, evolution has come up with a plethora of ways to protect it from damage. The function of telomeres is to shield chromosome endings. This is essential because DNA rectification mechanisms can mistake a chromosome ending for a crack and attempt to glue this ending to another nearby ending. For a cell, that would be disastrous. This is why chromosome endings include repetitive sequences protecting them from degeneration. However, telomeres shorten with each division of the cell, one stage of which is DNA duplication. At a certain point, the telomeres will run out and the genetic material will thus lose essential protection. The number of divisions a cell is able to carry out before its telomeres degenerate is known as the Hayflick Limit. In human cells, this number is between 50 and 70. Fascinatingly, the DNA of every human cell contains a telomerase-coding gene. The task of these enzymes is to lengthen telomeres, so in theory, they need not shorten as time goes by. Unfortunately, the other side of the coin here is that most human cells are unable to read that gene, and hence telomerase does not appear in these cells. It is mostly produced in stem cells, but also in cancer cells, which have the opportunity to proliferate without constraint as a result of this process.
3. Epigenetic changes. If a genome is a cell’s set of instructions, then the epigenome corresponds to how these instructions are interpreted. Although the genome itself carries a wealth of information, when it comes to a complicated entity, such as a cell, what is needed are refined methods of regulating the processes occurring within this entity. This is where the epigenome comes in: a set of reversible genetic modifications that influence how the genes in question are read. Despite being buttressed by years of research, epigenetics remains a somewhat obscure field. I think of it as the equivalent of the unconscious in psychoanalysis: though deeply hidden, it has significant bearing on an individual’s actions in the world. Epigenetic modifications are not permanent – they change depending on the experiences a cell is subject to. Deregulation of the machinery in charge of epigenetic modifications has been linked to ageing and the process of canceration.
4. Loss of proteostasis. A living cell can be envisaged as a biological factory whose purpose is to produce itself. The factory’s employees – and its machinery – are proteins. They include: enzymes responsible for chemical reactions in metabolism; receptors on the surface of the cell whose job is to spot hormones and other signal recognition particles (SRPs). They also include SRPs themselves and structural proteins that are part of muscle fibres, among others. This entire protein jumble remains coherent because it is based on interactions. It is thus essential for a cell to have just the right amount of every protein – and to have it in the right place. Unfortunately, as wear and tear sets in, proteins become frail. Enzymatic reactions tend to slow down, the number of receptors falls, and SRPs are lost in the organic labyrinth. The fine protein balance is disrupted, and its capacity for self-regulation is more limited than it used to be. This can lead directly to chaos and random glitches, which have an impact on the quality of all cell processes.
5. Mitochondrial dysfunction. We have all heard that the mitochondrion is a cellular power plant, but it is also responsible for a number of other processes. It is the driving force behind haem synthesis (a compound necessary for the transportation of oxygen and carbon dioxide); it coordinates numerous pathways of communication whose job is to maintain (relative) order within a cell; it regulates cell metabolism, etc. However, mitochondrion-related issues are to do primarily with its best-known function: the production of energy. The process generates a variety of side products, reactive oxygen species being among the most dangerous of these. These species have a tendency to enter a chemical reaction with any biomolecule they encounter – as a result, the biomolecule faces the threat of annihilation. The intensity with which reactive oxygen species develop increases as we age. This causes damage to the mitochondria themselves and leads to even more intense production of reactive oxygen species – it can be difficult to distinguish between cause and effect when thinking about the process. Still, one thing is clear: mitochondrial dysfunctions translate into how the entire cell operates, and it is in the secrets of the mitochondrion that many search for an answer to the question of eternal youth.
6. Stem cell atrophy. Every human being was once a single cell from which billions of biological machines emerged in the process of division and specialization (i.e. focus on a specific function). Taken together, these biological machines comprise the human body. All cells have the potential to breed initially, but, with time, the number of cells capable of multiplying falls. Obviously, we do still have stem cells in parts of our body – the role of these cells is to regenerate worn out tissue. After all, a person loses a lot of skin cells every day. Liver cells age and need to be replaced, and bone marrow constantly produces blood components. All of this is possible thanks to stem cells, which do not seem to care about the principle of organic divisions. In a lab environment, taking natural mechanisms as our model, we are able to produce any cell we like from a single stem cell. In theory, the transformation of any living cell into a stem cell is probable, but this process does not occur in a mature body. Hence the decline in stem cell numbers and, consequently, the slackening pace of cell regeneration.
Translated from the Polish by Joanna Błachnio
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