Ageing: Why? How? And if we could stop it, should we?

Ageing is a natural part of life. Forever, it has been viewed as an inevitable process; we are born, we age and we die. That is the supposed order of things. However, what happens if we could stop ageing, would we or, possibly more importantly, should we? The answer for most would be yes as the fear of ageing, or senility grows more prominent as we grow older ironically. Though this fear is pretty much non-existent in late life.
Scientists have forever been trying to combat this phenomenon. The purpose of medicine is to cure ill patients of their afflictions, which is just another way of saying life extension. Although it is important to note here there is a difference between lifespan and healthspan. Lifespan is the time for which we are alive and health span is the time in our lives for which we are considered ‘healthy’. Healthspan relates to the time we are fit and can be altered throughout our lives e.g. by smoking. The current goal of most medicines is to increase healthspan. There is no point in trying to increase lifespan if we spend all those years in a hospital, it is not economically efficient. Though it might be time to slightly modify our aims and attack the root cause of all illnesses, ageing, instead of focusing on one disease at a time. Humans are living for the longest they ever have now and are healthy for most of their life, on average. In the last 100 years alone the average life expectancy has gone up by 25 years. So, what if we could increase our lifespan and our healthspan? To make an informed decision on whether we should stop ageing it may be useful to understand why we age (the biological purpose) and how we age.

Ageing has been at the forefront of scientific minds since Greek philosophers first pondered its usage in the Golden Age of Philosophy. Up until the mid-20th century, it was mainly believed that ageing was the result of a purposeful, beneficial, biological adaptation in humans (i.e. ageing is advantageous to the species). We aged and died to make way for a much younger, healthier and more fertile generation. This, however, does not make sense; if ageing were not a thing then humans, presumably, would forever remain just as healthy and fertile as they were in the peak period of their lives so there would be no need to clear out older generations. Although this is taken on the basis that natural selection is no longer a crutch for humanity (in other words there is no environmental factor (abiotic or biotic) forcing humans to adapt and evolve in a certain way to avoid extinction). If this were the case, the purpose of ageing and death would be to evolve as fast as possible. Assuming natural selection has slowed drastically (or even stopped) for humanity (probably as we lack predators and can build shelters to survive harsh conditions), ageing cannot be an adaptation or the result of a beneficial allele(s). Afterall for a species that does not need to evolve as it has found its niche and has no competitors, death is more advantageous to an individual than itself, which wants to be as big as it can be.

So then, why do we age? It’s nice to think that everything has a purpose, all the little intricacies within our bodies and the universe were perfectly placed. Sadly, that is not the case. Mistakes happen and mistakes, in biological terms, normally mean mutations. Random changes to the genetic code which can result in a negative outcome, for example, the wrong protein being coded for. As aforementioned, ageing is not a positive result of natural selection but could it be the opposite.

Natural selection is our friend, since we came into existence it has been weeding out the weak and passing on the most beneficial alleles. It does this through reproduction, the individual with the most desirable characteristics is most likely to breed (due to the increased chances of survival) and therefore pass on its traits which, over generations, leads to evolution. On the counter, the organism with the least desirable characteristics is least likely to reproduce. But these characteristics only relate to survival as the more likely the organism is to survive the more likely it is to reproduce. This means that natural selection has very little effect in later life (the time after which reproduction has taken place). Any alleles that have negative effects but don’t affect reproductive success or appear later in life can be passed onto future generations without the barrier of natural selection stopping them. This means that over the thousands of years humans were evolving we could have been stacking up or accumulating disadvantageous mutations to genes that we can not get rid of. Therefore, ageing is a maladaptive by-product of evolution, not a purge-of-sorts. This theory was proposed by Peter Medawar in 1952 and was appropriately named the mutation accumulation theory. The diagram below demonstrates this theory with the ‘selection shadow’ representing the time period over which natural selection has a reduced effect.

This theory was taken further a few years later by George Williams who proposed ‘antagonistic pleiotropy’. He thought that even though some genes may have positive effects in early life (thus are advantageous and natural selection will make sure they make up a larger percentage of the gene pool) they could have negative effects in later life. These detrimental effects could cause ageing. An example of this is p53. This gene helps prevent cancer in younger people by stopping damaged cells from reproducing but this could cause ageing as, obviously, more cells get damaged as we get older. The diagram below compares mutation accumulation and antagonistic pleiotropy.

 

Together, these two theories make up the currently accepted theory as to why we age: ‘The evolutionary senescence theory of ageing’ (There is actually another theory within it as well. The ‘disposable soma theory’. This, very briefly, states that organisms have to put energy into maintaining body cells (soma cells) as well as reproducing. This needs to be balanced depending on the organism. Mutations gather in the body over time, but organisms cannot fix them as they have put resources into reproducing. This, quite nicely, explains why some organisms die immediately after reproducing, they have pushed all their energy into that so there is none left for repair).

This then begs the question: if we have been collecting these deleterious alleles for so long, why has our lifespan not decreased? The simple answer to this is hygiene and medical advancements. Doctors used to use leeches to cure people of their ‘bad blood’ and then contaminate these leeches with another’s blood, the seasons used to change more often than some bathed and, more recently, smoking indoors was not considered a health hazard. None of these were done to be purposefully unhygienic or lazy but, rather, because people were ignorant of the effects of these things. Fixing these has increased our lifespan as we have better diets and are more conscious of our health. Just being able to go to a doctor, get checked or search online for advice (although not always advisable) on certain symptoms has raised our lifespan through awareness. On the other hand, there are medical advancements. Vaccines directly increase our lifespan by removing or diminishing the possibility of certain lethal diseases. Medicine in its self has helped push the maximum life expectancy to 120 years as humans are healthier for longer.

Though it is not strictly necessary to understand why we age it is useful to know that there is evidence for these theories. If we did accumulate mutations over thousands of years due to not being able to stop it as natural selection loses its influence, if we started to reproduce later in life then the time over which natural selection has an effect would increase. This would lead to a longer lifespan as more disadvantageous genes can be erased from the gene pool. Experiments on fruit flies, an ideal candidate, showed that this was true. However, the age of maturity also increased as their fertility in youth decreased. That does not mean the same would happen with humans but would it be worth the longer life if we remained pre-pubescent for longer or have we got it just right. It is hard to know as the average age of mothers continually increases (due to the longer lives), there hasn’t been a great change to human fertility or development but women are fertile for longer – the average age of menopause was 45 in 1900 but it in 2012 it was 49 (these statistics were taken in the US).

Now we have established that there is a reason, albeit a side effect, for ageing we can look at how that happens. Looking at it, ageing is more physical than it is biological. Its all about friction and the build-up of broken-down parts. Although not mine, a nice analogy is that of a car which after years will no longer function how it did in the start due to the way the parts have ground against one another over the years. This is known as the wear and tear theory of ageing that was proposed by Dr August Weismann in 1882. But let’s look at it in more depth. The following are *six possible hypotheses as to why we age summed up briefly:

1) The cross-linking hypothesis: The longer the time we are alive the more mutations there will be in our body due to the nature of DNA replication. These mutations cause links to form between proteins and DNA with our cells (this is known as glycation). These links decrease the elasticity of the newly bonded (or linked) proteins and change the tertiary structure of the protein. The active site of proteases (the enzymes that break down proteins) are no longer complementary to these proteins due to the new bonds. That means these proteins stay in the body and cause altercations.

2) The free-radical hypothesis: Oxygen free radicals are produced by metabolic reactions (reactions that are vital to life) within our cells. Radicals are very reactive which means dangerous in the human body. If these free radicals get through the antioxidants which normally neutralise them, they can seriously damage organelles and proteins (oxidative damage) as well as causing cross-linking between proteins. It seems that as well as destroying the ozone layer (mainly chlorine radicals) they are also destroying us from the inside out.

3) The genome maintenance hypothesis: This is a more general overview and relates to the build-up of DNA mutations with age. DNA mutations occur either through damage or spontaneously. The body can not keep up with them all and thus changes to our genome are made within each cell. This can have various effects for example if genome maintenance genes are not activated or are changed, humans may start to show an older appearance at a younger age. This is due to other mutations being allowed to build up. As mitochondria have their own DNA, a build-up of mutations in them explains why we become more lethargic as we age. Less aerobic respiration means less energy (ATP) released.

4) The replicative senescence hypothesis: At the end of our chromosomes we have structures called telomeres, they are made up of lots of repeat base sequences. They do not code for any proteins but act as a protective barrier to the cell, one could think of them as aglets on shoelaces. Every time a cell replicates its DNA the telomere shortens just ever so slightly, it’s worn down. When there is no telomere left the cell stops dividing and is known as ‘senescent’. The number of times a cell can divide before reaching this stage is known as the Hayflick limit, interestingly the majority of cells don’t reach this limit. Most cells have a little self-destruct button (a protein) in them that causes them to die once they have reached this stage. However, there are those that survive this process and in turn, stay in the body. This causes problems.

5) The neuroendocrine hypothesis: Hormones are vital to development in the human body, this is especially true throughout puberty. This theory questions whether hormones play a role in ageing. It was initially thought that hormones cause ageing as we have fewer in our bodies as we get older. Though it is now thought to be the other way around and could explain why women live longer than men; there are fewer hormones (notably estrogen) in the female body after menopause.

6) The Ageing by Program hypothesis: According to twin studies about 20%-30% of our longevity is decided upon before we are born (in our genes) but increases as we get older. However, there is still the belief that everything about humans is preprogrammed whether it is biological or not. This theory specifically relates to the biological aspect. All cells have a cell cycle, they go through synthesis (organelles, DNA) and replication and eventually death. As we are just collections of cells maybe we have our cycle too. It could be controlled by hormones for example.
Having looked at why we age and how we age, we can now look at what it would mean to stop ageing. If we could stop ageing that would not mean the end of death. Death and ageing are separate issues as there is no such thing as dying of old age. Rather, people die due to old age-related illnesses e.g. a weakened immune system (a parallel with HIV). We would still die as accidents will always happen (as well as diseases) and there will be a time in which our bodies can no longer cope, we were not designed to live forever.

So not immortality but biological immortality. Some types of jellyfish are biologically immortal as they replenish their cells after sexual reproduction almost reverting to a youthful state. These jellyfish still die due to predation and competition. This means that death will always be an inevitability, we cannot live forever.
But assuming we could extend our lives by another 50 years for say, would it be worth it? Ending ageing would not mean that we are senile for a longer time, our bodies would not age as well. So if we did live for longer would we take better care of the planet knowing that we are the ones who would have to face the consequences of our actions, or would we put more effort into reconciling with those we have wronged knowing that we had more time to waste? What would happen with overpopulation? Obviously, these questions cannot be answered now but as trials are soon to start taking place in humans, to extend our lifespan, maybe they will be answered one day.

Jack Pacey, Year 13

*the first five hypotheses are taken from https://www.afar.org/pdfs/AFAR-Guide-to-Theories-of-Agingsm.pdf along with some other information in this blog – this is quick and definitely worth the read!
1) Ageing is the British/ Australian spelling whereas aging is the American spelling