Ageing is inevitable and always leads to death. Such a statement, although one we like to avoid, is something we all seem to accept as reality. In the modern-day, war and famine no longer threaten us, it is ageing, the slow weakening of our body that leaves us vulnerable to hosts of diseases. Thus, it is essential to discover the meaning and causes of ageing, and what research is occurring today. A good way to consider ageing is as the ‘escalating loss of molecular fidelity’ which ‘ultimately exceeds repair and turnover capacity’ This ‘breakdown of self-organising systems results in a reduced ability to adapt to the environment’ and ‘increases vulnerability to pathology or age-associated diseases’ However, both the average person and some scientists have misconceptions, primarily the failure to distinguish between ageing (senescence) and age-related diseases. Ageing should not be considered a disease due to the following observations, shared by no known disease:
(1) ageing occurs in every multicellular animal that reaches a fixed size at reproductive maturity
(2) ageing crosses virtually all species barriers
(3) ageing occurs in all members of a species only after the age of reproductive maturation
(4) ageing occurs in all animals removed from the wild and protected by humans even when that species probably has not experienced ageing for thousands or even millions of years
(5) ageing occurs in virtually all animate and inanimate matter
(6) ageing has the same universal molecular aetiology, that is, thermodynamic instability.
Ageing is effectively the universal weakening and damaging of the body over time. Age-related diseases take advantage of this significantly increased vulnerability, causing further ‘damage’ and for most of human history, resulting in death. Without ageing, age-related diseases would be inconsequential due to the countermeasures that we as a society have effectuated against premature-death.
It is also necessary to discuss the determinants of an individual’s lifespan; their rate of ageing, the longevity of their body and their resistance to age-related diseases. It is still contested today whether ageing is genetically pre-programmed or a consequence of random decay, but the various factors can be attributed to one or the other. The rate of ageing refers to how quickly an organism loses its molecular fidelity; the faster that an individual ages, the quicker that entropy is acting and complex molecules are being deformed and broken down. It is important to note that this rate is an exponential curve, owing to the build-up of errors in an organism, especially in the mechanisms of repair and maintenance. The next determinant is the longevity of their body, which, to put it simply, refers to ‘how much life you have left in you’ by the time you pass reproductive maturity. Longevity includes a vast range of different factors which are mostly genetic. Examples are the rate of repair and maintenance, the structural integrity of the system and the length of telomeres. The final determinant is the individual’s resistance to age-related diseases; certain people will be genetically predisposed to be less likely to get Alzheimer’s disease when they become older. These factors, affected by both nature and nurture all contribute to how long an individual will live.
Types of damage and how to fix them
There are many different types of ageing, but they can be grouped into seven main categories, according to Aubrey de Grey and the SENS Research Foundation. Some of these topics are main-stream and have been well-developed while others are still primarily theoretical. The types of damage and their potential solutions are as follows:
Cell loss and tissue atrophy: Over time, and due to various environmental factors such as trauma, toxins and multiple forms of stress, the cells in our body become damaged, destroying themselves via apoptosis. Thus, to reverse this atrophy, new cells must be made and inserted back into the body. Stem Cell research is far and away the most promising field in fulfilling the aforementioned criteria. Recent discoveries in the use of hematopoietic stem cells, cells that are abundant in the body and can self-replicate has allowed useful quantities to be produced that when inserted into mice, completely regenerated their cardio-vascular systems.
Cancerous cells: Cells can become cancerous as a result of two possible routes; mutation and epimutation. A mutation is effectively a change in the sequence of DNA and can occur when a base pair is changed, added or removed. Mutations occur as a result of mutagens and radiation, but most often in the process of replication. An epimutation is a change to DNA without an actual change to the sequence of bases. Both forms of mutation cause the cells to malfunction, more often than not, resulting in cancerous cells with uncontrolled growth. Huge amounts of funding have been funnelled into cancer research, whether it is information about the nature of cancer, treatments for cancer, such as chemotherapy and radiotherapy, or lifestyles that best resist cancer. Although it is contested that cancer can ever be truly ‘cured’, advances can limit both the rate of incidence and damage of cancer.
Mitochondrial mutations: When mitochondria produce ATP by respiration, they also produce dangerous by-products which are called radicals. Radicals are highly reactive and can cause significant damage throughout the cell; however, more often than not, they produce mutations in the mitochondrial DNA which is not stored in the nucleus but the cell cytoplasm. These damaged mitochondria produce even more waste products and very little ATP and are not destroyed by the cell. This results in cells producing vast amounts of harmful waste products, placing stress on the entire organism. A simple solution to this issue would be to move the mitochondrial DNA from the cytoplasm to the nucleus. MitoSENS, a sub-research group of SENS has succeeded in transferring 8 out of 13 mitochondrial genes to the nucleus. As such, significant progress is being made but it is still nowhere near clinical applications.
Death-resistant cells: Often, when cells are damaged or just no longer useful, their ability to divide and reproduce can be stopped by the body making cells senescent. This would not present a problem in younger individuals where the number of senescent cells is relatively low, but as an individual becomes older, there is a build-up of these cells. Moreover, these cells secrete a large number of proteins that cause inflammation and begin to damage surrounding cells. This creates clusters of senescent cells that are at higher risk of cancer and don’t function properly. Senolytics refer to a group of medication that attempts to cause senescent cells to die and are often based on anti-cancer medication. There are many private companies that are already undergoing human trials and evidence has shown that their treatments help reverse or slow certain characteristics of ageing.
Extracellular matrix stiffening: The connective and structural issues that exist throughout the entirety of an individual’s body consist of proteins. These tissues are replaced incredibly slowly, and so any damage that occurs to them often builds up. These proteins, which are elastic to allow movement and such, can be joined together or cross-linked. They become cross-linked when they are exposed to substances such as blood sugar. When these proteins are connected, they can no longer stretch and move around so freely, nor are they as effective at absorbing shock. When this occurs on a large enough scale, serious problems result that creates a large amount of stress on the body. As a result of recent advances at Yale University, a method has been found to produce artificial glucosepane, a common and long-lasting crosslink which has and will rapidly increase the pace of research and testing on reversing the effects of extracellular matrix stiffening. Antibodies have already been developed and bacterial solutions are also being considered by the wider community.
Extracellular aggregates: Proteins in an individual’s body can be damaged, with their shape-changing and so misfolding. These changes mean that these proteins begin to clump together into amyloids, which can be very harmful, as they are toxic and resistant to most forms of decomposition available to the individual. These amyloid clumps gather in organs and tissues negatively affecting the function of their structures. Damage most often presents itself in the kidneys, lungs and heart. Most solutions so far have been attempting to reshape the cross-linked proteins into their original structures, including the GAIM platform funded by Michael J Fox and various other private companies. Another idea proposed by a research team at Dundee University is to destroy the harmful proteins.
Intracellular aggregates: Over time, as the components of our cells become damaged, they can fuse into clumps of unwanted material that are very difficult to dispose of by the cell. Lysosomes are structures that deal with waste products in cells, yet even they are unable to remove these intracellular aggregates. After a sufficient build-up of these un-removable waste materials in the lysosomes, they begin to fail. In heart and brain tissue, where cells aren’t replaced, this poses a severe threat and as such, this aggregation is often associated with heart diseases and neurodegenerative diseases. The LysoSENS team have recently succeeded in developing a family of small molecules that can selectively remove the built-up junk from the inside of cells. Although this specific treatment has not yet reached animal testing, significant progress is being made.
Ageing is inevitable and always leads to death, or so we thought. The first step in tackling the ageing problem is understanding what it is. Two main theories explain how ageing works; program theory and error theory. Scientists have also discovered and categorised the main types of damage that can occur in our bodies as a result of ageing. The process of learning why this happens is more complicated, but multiple theories, such as genomic instability and oxidative damage, have been put forth. In medical history, however, the focus has been very much on tackling age-related diseases, something that potentially provides significantly less benefit than research into ageing. For example, if Alzheimer’s disease were to be eliminated, only 19 days would be added on to average human life expectancy (this has likely increased in recent years). However, a large portion of the medical community doubts the feasibility of the aforementioned solutions and I admit that a few are mostly theoretical and will likely not see clinical applications for some decades to come, but they present a framework by which the ageing problem can be tackled. Yet, society as a whole must consider the quality of life for the elderly, for those whom this research will be too late. This imbalance of funding and research is beginning to shift, proven by examples such as the SENS Research Foundation which is making significant progress to rectifying all seven identified types of damage. It is conceivable that humanity may soon reach the “longevity escape velocity”, a phrase coined by de Grey to describe the point at which advancements in longevity extension begin to outweigh ageing. New research and therapies would always be introduced before an individual managed to age enough such that they would die. However, we as a society must consider all the ethical aspects involved in gaining the ability to prolong life indefinitely and whether ageing is a problem we want to solve.