What Makes Us Age? - The Nine Hallmarks of Ageing

The 9 Hallmarks of Ageing

Ageing is ‘just one of those things’….we accept it; we just have to, but what actually causes us to age, as we add on the years throughout our lives?

Since 1900, average life expectancy has risen from 47 to 79, with women living around 2-3 years more than men. Much of this has been due to lower infant mortality, where a century ago, one in ten babies died before they reached the age of one! Today this is 1 in 170. Better hygiene too, combined with better nutrition has also contributed somewhat to longer life. These factors combined with advances in medicine of course, have been the major drivers of life extension, though more recently, the rate of increased life expectancy has plateaued.

In essence, ageing takes place because our cells and their ability to be replaced, slowly declines over time, with many cells dying and not being replaced to the same extent. In other words, the equilibrium between dying cells and new replacement cells being created, becomes unbalanced with greater loss of overall cellular function.

Ageing is therefore characterised by a slow and progressive loss of physiological function and integrity, which in turn leads to chronic ailments, chronic diseases and ultimately passing away of course. But a huge amount of research is being carried out across the world in centres of excellence for ageing research, with the objective of understanding ageing in detail, slowing this process down and extending life, but more importantly, extending healthy life or ‘healthspan’.

Recently a small group of high calibre scientists studied this question and  agreed on a short list of nine separate mechanisms which have an effect on ageing and called these ‘The Nine Hallmarks of Ageing’.

This is quite a technical piece of science, but I have attempted to capture these hallmarks and mechanisms below, in order to give a basic overview of these, one by one :

Hallmark 1:  Gene Instability

Humans have around 20,000 genes of DNA, with each playing a fundamental role in producing proteins, which in turn, play the role of catalysts of many biochemical and physiological effects in our body. In effect, DNA is like a blueprint which provides all the basic plans on how every operation in our bodies should function. So, our DNA is incredibly important to our lives and notably our long term health too.

But every day, our DNA is prone to daily damage, which in turn causes DNA mutations, and it is this accumulation of such damage over time, that is a key hallmark of the ageing process. DNA can be easily damaged by a variety of internal and external insults, such as exogenous(coming from outside the body) chemicals, pollutants, toxins and even viruses. UV light from the sun is a classic source of skin damage for example. Also, the basic internal energy-making process within our bodies is also harmful in part, due to the production of highly reactive ‘free radicals’. Free radicals are very damaging, due to their high degree of reactivity and can therefore damage DNA itself.

According to the American Federation of Ageing Research, DNA is attacked and is damaged around a million times each day! However, DNA does have in turn, built-in protective mechanisms which constantly repair damaged DNA, but this is not one hundred percent effective all of the time. In addition to this DNA damage, the DNA itself can also be prone to errors during its replication when cells are dividing. This is what is meant by ‘genomic instability’. It is these deficiencies in DNA repair that can cause ageing and also in some cases , cancers of various types.

Hallmark 2:  Shortening of Telomeres (the ends of the DNA strands)

Like Hallmark 1, this is also a DNA related issue involved in ageing.

  All our DNA is tightly packed into discrete units       called chromosomes, of which there are twenty-   three separate entities. Telomeres are just   specialised parts of the very end of the DNA that   sits at the end of the chromosome, designed to   protect the main part of the chromosome from   damage or ‘fraying’. It can be likened to the ends   of shoelaces, which are designed to avoid similar   fraying of the laces. This end DNA protection is   very much needed because these chromosome ends are quite chemically reactive, possibly even capable of bonding with another chromosome, which would be disastrous for the cell.

Each time the cell divides, the chromosomes and therefore the end telomeres also divides, but at each division, the protectant telomere tends to shorten, little by little. Eventually there is no more telomere left and the cell then dies. The telomere is seen by some scientists as a kind of biological clock and there is a huge amount of research in this area studying how telomere length and its protection might be one way of extending cell life and overall life.

Furthermore, telomere shortening can lead to what some scientists call ‘zombie’ cells, where the cell is close to death, but tends to just cling on to life. This ‘sick’ cell then produces toxic proteins called cytokines, which can then in turn, cause damage to nearby healthy cells. People with shortened telomeres have a much higher chance of developing diseases including cancers too.

Hallmark 3:  Epigenetic Alterations

Let’s explain what epigenetic means first.

Anything concerning DNA, genes and chromosomes is referred to as genetic. Epigenetic simply refers to an additional change, which is literally ‘added on top of’ the genetic material itself. DNA is 100% fixed and can never change. It is also wrapped around specialised proteins called ‘histones’, which have a large influence as to how the DNA genes make certain key proteins, vital for life.

However, at the molecular level, it is possible to add small biochemicals to the DNA which play a huge role in how the DNA behaves and how it makes new proteins in our bodies. In essence, certain genes can be turned on or off, depending on whether they have been affected by the addition of these specialised biochemicals(usually methyl and acetyl groups for those of you who may have flouted with basic chemistry). If a gene is on or active, it will make and deliver a biologically active, key protein….if it is off, then no protein(no transcription to be scientific) is made at all.

Clearly epigenetics plays a very significant role in our biology and of course our overall health. But as this epigenome is affected by external factors such as diet, exercise , sleep and even stress, then the epigenome will affect how the DNA behaves. If the DNA is affected in a negative way, then this will speed up ageing factors. Perhaps if we can somehow understand and manipulate this epigenome, then life could be extended and health outcomes improved?

Hallmark 4:  Loss of Protein Equilibrium in Our Bodies (‘Proteostasis’)

Our metabolism and all the various biochemical reactions are controlled by a huge array of highly specialised proteins, together called the ‘proteome’. Proteins typically are large molecules whose function is critically important but can be affected by how these protein molecules are folded.  If some proteins lose their stability (eg incorrect folding), then certain functions are lost and this will cause a loss of overall biochemical performance and in turn will have a negative impact of our health. This is loss of proteostasis. An example of how these delicate proteins can lose their integrity, is via attack from highly reactive and damaging biochemicals call ‘reactive oxygen species (ROS), which exist naturally all over our bodies as part of our daily energy metabolism processes.

Age related pathologies such as Alzheimer’s, Parkinson’s and even cataracts are all the subject of unfolded, mis-folded or even aggregated proteins.

Hallmark 5:  Loss in Ability to Sense Nutrients

Our cells need nutrients for life and of course these nutrients come from our food, hence why diet is so very important to our health. Furthermore, our cells need to know when these food derived nutrients are available and they do this via a ‘sensing’ mechanism.

For example, growth hormone(GH) is released in pulses from the brain’s pituitary gland. This key hormone helps extend bone growth in children and many required growth areas. In adults though, GH maintains metabolism and normal body structure, including helping to keep blood sugar(glucose) constant. In essence GH is acting like a blood glucose sensor ie a nutrient sensor.

Another important hormone , made in the liver, called ‘Insulin-Like Growth Factor’ (IFG-1) also senses nutrients like glucose sugar in much the same way as insulin and is involved in promoting tissue growth. This means that if blood sugar increases, say after a meal, then IGF-1 is released together with insulin, thereby causing this sugar to be taken up by both the muscles (for energy) and also by the liver (for energy storage).

Both GH and IGF-1 are necessary for anabolic growth ,but as we age, levels of both GH and also IGF-1 fall, as growth is less important during our latter years. In fact, levels of these two hormones fall as we age, and some believe that this is a defensive mechanism to slow down growth and therefore protect us against cancers, where rapid and uncontrolled cell growth is a hallmark of such disease.

For the scientists amongst you, other important nutrient sensors include three other bio-actives, namely mTOR, AMPK and also the family of ‘Sirtuins’. Respectively these detect high amino acid concentrations(from protein intake), low energy states(from overly high AMP levels) and finally low energy from detecting NAD+ levels.

In summary, the ability to detect important nutrients can be useful when we are young, but in later years, this sensitive detection of glucose and amino acids from our food, can actually have a detrimental effect on longevity. This has been proven in many mouse models, but this is still a complex and controversial field in which there is no clear black and white answer to date.

Hallmark 6:  Poor Functioning of the Mitochondria (‘Dysfunction’)

Our bodies need energy to remain alive . This energy is used all over the body, not only in highly energetic muscles, but also in the brain and in every cell in the body. This energy is made from our food, and it is in these mitochondria, within each cell, that extract energy in a highly efficient manner.  

In essence, mitochondria are likened to the ‘powerhouses or batteries of the cell’ and any malfunctioning has a very serious downstream effect on our health.

Mitochondria also help decide which cells are put to death if they are malfunctioning or just old (apoptosis).

But this energy production comes at a cost in the form of damaging and highly reactive ‘free radicals’. In fact, one of the theories of ageing involves the chemistry within these mitochondria. During the ongoing energy production in each of the mitochondria, by-products are often formed called ‘free radicals’, otherwise know as ‘reactive oxygen species or ‘ROS’. These are undesirable, highly reactive molecules that cause damage to DNA, fats and also proteins, all of which have negative health effects.

 The scientific literature originally supported that ROS was the instigator of long-term serious damage to cells and chronic disease. However, as with most complex biochemistry, this theory has been modified to now suggest that a small amount of ROS is necessary, indeed healthy, though if ROS is raised too far, then serious inflammation can set in giving rise to a collection of chronic diseases.

In summary, poor mitochondrial function plus reducing numbers of mitochondria both have a profound effect on the ageing process and accelerates ageing in mammals. Lower energy levels in older adults is a classical sign of poorer mitochondrial function.

Hallmark 7:  Cellular Senescence

Cells do not live ad infinitum. Cells typically are programmed to die when they are old or damaged via the process called ‘apoptosis’, which basically clears out these failed cells. It can also be viewed as a kind of protective mechanism to ensure that these cells are extinguished before they produce problems.

However, as we age, this apoptosis mechanism of getting rid of these old or damaged cells starts to fail, which means that many of these ageing cells remain for extended periods. When this happens, these cells produce toxic chemicals called cytokines which end up causing nearby cells to produce toxic and inflammatory molecules and this can end up , rather like a mouldy piece of fruit in a bowl, to cause serious cell damage. These are ‘senescent’ cells.

The number of senescent cells in our body increases as we age, thereby tainting nearby healthy cells. In fact, according to some scientists, up to ten percent of all our cells are senescent in later years. This can inhibit the ability to withstand stress or illness, recuperate from injury and even cause cognitive failures too.

If we can somehow reduce the number of these senescent cell as we age, perhaps we can push back ageing and hopefully enhance quality of life too.In fact, there are some very interesting molecules that are being studied in labs across the world ,called senolytics, the most well known of which is Quercetin, which is a natural polyphenolic compound found in strawberries, red wine, grapes, and tomatoes. Research has already shown benefits across a raft of various disease states and this hallmark seems to be one of the priority areas for future ageing research.

Hallmark 8:  Stem Cell Exhaustion

Stem cells are incredibly interesting cells with the potential to develop into many different types of cells in the body. They also possibly offer new medical treatments for a variety of diseases in the near future.

Stem cells are quite different to all our other cells, in that they can divide and renew themselves over a long time. But they also have this extraordinary ability , that when they divide, to become specialised cells with a purpose, such as brain cells, liver cells, muscle cells, blood cells and so on. No other cell in the body has this ability. Once a stem cell becomes a decisive specialised cell (eg liver cell), then it cannot revert back to a stem cell, or indeed become another type of cell either.

These very special cells that originate from very young embryos, but also can be found in adults too, typically in bone marrow or even fat. Adult stem cells have a lower ability than those in embryos however, to decide which of these specialised cells they will become later on in the division process.

As we age, we lose this potential to easily regenerate our cells from stem cells, but if we could somehow achieve this, then this may be able to slow ageing. We know  cell damage is a key constituent of ageing, so if we could use stem cells to regenerate and repair this damage, perhaps life could be extended. This is early days in this biotechnology, but stem cell science could produce huge steps forward in ageing and health span.

Hallmark 9:  Inflammageing and Poor Cell to Cell Communication

Cells need to ‘talk’ or communicate to each other, using a kind of network of chemical signalling molecules, whether this be via hormonal signals, or other biological actives. Communication between cells is critical to health, but ageing unfortunately tends to reduce the efficiency of these communications, caused mainly by inflammatory chemicals that cause tissue damage. One example is the immune system, which can be diminished in its efficacy, thereby increasing susceptibility to various infections. This is titled ‘immuno-senescence’ and is simply the techie term for a less able immune system.

This inflammation is also associated with other chronic disease, such as type 2 diabetes and cardiovascular diseases, including atherosclerosis.

Further chronic issues also include bone density loss, age related loss of muscle mass and even skin atrophy too.

One of the main culprits is inflammation (as discussed above in Hallmarks 4 and 6) caused mainly by older senescent or ‘zombie’ cells, which produce these inflammatory biochemicals, causing damage to the old cell’s surrounding cells.

The Takeaway

Ageing research is still in its infancy and there is a great deal we simply do not know, though our knowledge has increased significantly in the last fifteen years or so.

The nine hallmarks of ageing is in reality, the very best and the most recent overview of the various mechanisms influencing the ageing process. In fact, these hallmarks are not clearly distinct mechanisms, as each has an effect on the other, making the hallmarks genuinely intertwined with each other.

There are now many scientists who are now saying that ageing is a disease and not simply a collection of separate illnesses. If we can somehow treat ageing as a whole ,then other more classical chronic diseases such as cardiovascular diseases or neurodegenerative illnesses would also be simultaneously be treated.

Typically, the medical profession operates in specialist silos, in which there are experts of each area, treating for example cardiovascular issues,  cancers or other orthopaedic problems like worn and sore joints. Of course, we all prefer to talk to a specialist, as they are experts in their field. But perhaps in the future, there will be more joined up thinking across the various areas and perhaps there will even be ageing specialists in the future. Who knows?