Why do we age? Simply put, we age for the same reason a car ages: because the components from which we are made accumulate damage. While some of this damage can be repaired, a lot of it can’t, and this wear and tear eventually causes our biological machinery to fail.
Where does this damage come from, and what forms does it take? Answering these questions thoroughly is important if we are to devise ways of slowing or reversing the ageing process. What follows are 7 fundamental changes that could lie at the heart of the ageing process.
The DNA that resides in the nuclei of our cells is a biological instruction book, a vast molecule that contains all the information necessary to produce a human. Well, almost all of it – there’s mitochondrial DNA as well, but we’ll talk about that later.
Most people are familiar with what DNA is and why it’s important, but you may not be aware that your DNA is constantly under attack. Indeed, nuclear DNA is being continually damaged by naturally occurring radiation and chemicals produced within the cell. Since we have evolved alongside these sources of damage, cells have become extremely good at repairing DNA – but they aren’t perfect, and once in a while, a mutation slips through the net.
The most commonly thought of consequence of a genetic mutation is cancer, however, cancer is a rare consequence of a single incidence of genetic damage. It is more likely that the gene in which the mutation occurred will simply become non-functional. This isn’t really a problem if it occurs once in a single cell, but DNA damage accelerates over the course of life, and it is hypothesised that genomic instability (the presence of a large number of mutations within the DNA) contributes to age-related degeneration.
Each of your cells contain many mitochondria, the biological power plants that convert chemicals from food into the cellular energy source called ATP. In their ancient evolutionary past, mitochondria were separate organisms that were incorporated into more complex cells. As such, they have their own DNA which is also continually damaged, primarily due to the reactive chemicals that are produced as a by-product of making ATP.
If you want to read a more detailed explanation of how this damage occurs and what the consequences are, this article provides an excellent summary. The take home message is that mitochondrial DNA damage makes the production of ATP significantly less efficient. As more and more mitochondria within the cell become dysfunctional, they start to deplete a vital molecule used in many cellular processes (including ATP production) called NAD. Running out of NAD would be fatal for the cell, so it is forced to generate more NAD in a process that involves exporting electrons.
These electrons go on to react with oxygen molecules to produce reactive oxygen species (ROS). ROS are chemicals that attack and modify other molecules, and are heavily implicated in diseases of ageing. They can damage DNA, RNA and proteins, and they generate oxidised LDL, which drives the formation of atherosclerotic plaques. They also induce inflammation which, as we’ll get to, is also an important driver of age related disease.
So in summary, mitochondrial DNA damage causes mitochondria to become dysfunctional, making cells less energy efficient, depleting NAD and resulting in further damage through the production of ROS.
Cells have a defence mechanism against irreparable damage called senescence. In response to internal damage and various signals, a cell can permanently cease dividing. Cells also have a limit to the number of times they can divide due to telomere shortening. Telomeres are protective sections of DNA at the ends of each chromosome. The molecule that copies DNA misses the very end of the telomere at each replication, and once telomeres become too short, the chromosome can’t be copied without losing genetic information.
Senescence itself is a good thing because it protects against cancer by ‘shutting down’ heavily damaged cells, which are more likely to mutate into cancer cells. Even if a cell does acquire a cancer-causing mutation, telomere shortening limits the number of times it can divide unless it can also develop a mutation to escape senescence.
Unfortunately, senescent cells have their downsides. They don’t really contribute to the tissue that they are a part of and act as a ‘dead weight’. They also secrete a variety of harmful signalling molecules that cause inflammation and damage surrounding cells. Ironically, this means that senescent cells can produce a favourable environment for the formation and growth of tumours.
Senescent cells can self-destruct, and the immune system can also remove them. However, these processes falter with age, and the accumulation of senescent cells has been linked to every major chronic disease of ageing. We now have drugs (called senolytics) that can remove senescent cells in a targeted way. Whether this is effective in the treatment of age-related diseases in humans is a question that remains to be fully answered, though some promising results are beginning to emerge.
The immune system is a complex and powerful defensive system against infectious diseases. Unfortunately, the ageing immune system ceases to function correctly. How and why this happens is complicated, but all you really need to know is that the ageing immune system tends to activate when it shouldn’t, and fails to activate when it should.
The adaptive immune system – the part of the immune system that remembers specific specific pathogens – essentially runs out of free memory, and also becomes more prone to mistaking your own cells for pathogens. On the other hand, the innate immune system – the part of the immune system responsible for inflammation – starts to become chronically more active. This results in the background inflammation that drives many age-related diseases (inflammageing).
You may be familiar with amyloid in connection with its role in Alzheimer’s disease, but there are many other forms of amyloid. Amyloid simply refers to unwanted ‘junk’ proteins that aggregate and build up between our cells. These proteins should ideally be cleared from the body, but are resistant to destruction in their aggregated form.
Amyloid deposits are found not only in the brain, but also in the liver, joints, and many other organs. Amyloid deposition is closely linked to the development of type II diabetes and neurodegenerative disease. However, we still don’t fully understand the relationship between amyloid deposits and age-related disease, especially neurodegeneration.
Inflammation seems to be one key mechanism of damage, as immune cells that attack amyloid deposits are unable to remove them and become chronically active. However, some people found to have significant amyloid deposition in their brains post-mortem showed no signs of dementia. Furthermore, our efforts to treat neurodegenerative disease by clearing amyloid deposits from the brain have so far failed. Some argue this suggests that amyloid is not the main cause of disease, but rather the consequence of other underlying processes.
Perhaps the most superficially obvious aspect of ageing results from cross-linking of extracellular matrix proteins. The extracellular matrix is a network of protein fibres in between our cells and determines the mechanical properties of our tissues. These proteins are what allows skin to be both strong and elastic, for example.
Protein cross linking is what it sounds like – some molecules such as glucose are able to react with two proteins to link them together. When components of the extracellular matrix are joined together, this reduces the elasticity of the tissue overall, and also makes it more prone to damage. This is most clearly visible in ageing skin, but also affects other tissues such as blood vessels and the joint connective tissue, both of which become stiff and more prone to damage.
Autophagy, meaning ‘self-eating’ is the process in which cells destroy and recycle their damaged components (such as mitochondria). Cells do this using lysosomes: packages that contain digestive enzymes capable of fusing with cell components to destroy them. Unfortunately, there are some molecules that lysosomes can’t break down. This junk builds up, resulting in bloated, inefficient lysosomes that can’t properly do their job.
This results in a vicious circle, because damaged components like mitochondria that aren’t rapidly removed will cause even more damage. Defective autophagy seems to play an important role in the ageing process, at least in certain tissues. For example, genetically engineering mice to raise their lysosome activity makes their livers behave like those of young mice.
How Age-Damaged Mitochondria Cause Your Cells To Age-Damage You: https://www.fightaging.org/archives/2006/10/how-age-damaged-mitochondria-cause-your-cells-to-damage-you/
Self-Destructive Behavior in Cells May Hold Key to a Longer Life: https://www.nytimes.com/2009/10/06/science/06cell.html?pagewanted=print