WHAT IS AGEING?
In Biology we can define ageing as the accumulation of random structural and functional molecular damages that occur at a cellular level among all the cells from an organism. This cellular defect ends up in tissue disfunction leading to a decrease in physical and mental capacity as we get older. (3,38,39). In this case we are going to talk about the human body in specific.
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One of the main problems of ageing is the dysregulation of the cellular and all the other processes that are carried on an organism (1). This can lead to the appearance of some diseases that can become chronic over the time or lethal e.g.: some types of cancers. Cancers are not always related with age, but the malfunction of the mechanisms involved with ageing can be one of the causes of cancer (1,3).
In terms of biological ageing this is known as senescence (40). This process of ageing ends up with the death of the organism’s life cycle. Once we know how this process work, we can alter it so that we can slow it down. However, ageing does not consist in just one molecular process but in multiple processes, functions and it is also conditioned by some other factors that can affect how fast and how healthy and individual ages, increasing or decreasing the risks of having any type of disease (38,40).
FACTORS THAT AFFECT AGEING
Ageing can be affected by hereditable traits in genetics, the type of diet you maintain and pharmacological factors such as drugs (1). The cell and all its molecular components can be damaged by intrinsic factors (reactive oxygen species and reactive nitrogen species) or extrinsic factors (UV light, irradiation or the exposure of an organism to toxins) (3). Our cells possess some control systems that prevent cell division or antioxidant systems and repairing mechanisms systems that recognise, repair and remove the damaged component. These systems are not always efficient and accurate and as we get older their efficiency declines (4). Stress can also be determinant in the process of ageing.
As we mentioned earlier, ageing does not consist just on a single process but different molecular mechanisms interacting together. This is known as the Network Theory that states that all the different mechanisms are relates and interact with each other having many different types of interactions (4). In order to understand this better we use computational modelling, based on many different types of tests leading to the models of ageing. We are just going to talk about 2 of them.
Telomeres are repetitive DNA sequences found at the end of the chromosomes. Its main function is to protect the genetic material from been damaged or shortened by external factors (15). This end of the chromosome is known as the cap. Occasionally, telomeres are misread by the DNA-repairing systems as damaged DNA because they have single stranded overhangs, so they attack them and make them shorter. This overhangs function is to bind to complementary repeats un order to form a protective loop.
As the cell replicates, the length of the telomere gets shorter progressively (14). When there is no telomere left, the cell can suffer from senescence, apoptosis or an oncogenic transformation in some of the stomatic cells. This can lead to the tissue malfunction or to the complete loose of its function (3,17). They impose the number of cell divisions that a cell can perform efficiently before the cell suffers from any of the consequences mentioned above (17).
The length of the telomeres might not be the same in individuals from the same specie due to differences in genetics and the type of lifestyle that they have had. This can change their lifespan according to the events they have gone through like stressful situations or how healthy was their diet and the amount of exercise they tent to do (13).
Telomere shortening is related with cancer, degenerative and age-related diseases (14). The speed at which telomeres shorten it has to be related with oxidative stress systems, usually increasing the speed (3). This has been proved by some studies on mice and culturized cells. Not only increases the speed at which telomeres shorten but also oxidative stress systems are associated with numerous diseases because the sensitivity of telomeres to oxidative DNA damage it is significantly high, being this the type of damage that suffer the telomeres more frequently (17,19). Non-control in the balance of the production of antioxidants and reactive oxygen species can contribute to all of this (17).
Telomere shortening can be dragged by an inflammatory response, intrinsic cell factors and environmental exposures (18). As a consequence, we have oxidative lesions and a DNA damage response creating an arrest in the replication fork as a quality control process, where the DNA it is stopped from being replicated any further than the replication fork (19,20)
Telomerase is a ribonucleoprotein with enzymatic functions that is found in cancer cells but not in the somatic ones (17). This ribonucleoprotein adds consecutive 5’-TTAGGG_3’ sequence repeats to the end of the chromosome avoiding them from been shortened and sometimes it makes the telomeres longer than what they used to be. These types of cells are known as “immortal cells”. Telomerase can be used to expand the lifespan (3,14,17).
PROTEIN DEGRADATION PATHWAYS
When it comes to eliminating damaged proteins, we can find two different pathways to do it. The proteasomal system (also known as ubiquitin-proteasome) and the autophagic system (also known as lysosomal-proteolysis (3). Proteins are also determined by two different types of rate, synthesis or degradation. Usually we can tell how long its going to take to degrade a protein according to it type of function. Ageing can cause that the proteasome that is working on elimination the damaged proteins becomes less efficient and consequently an impairment self-amplified cycle is started (21).
Ubiquitin-proteasome pathway (UPP)
Being able to keep a constant equilibrium of cellular homeostasis it is very important in every aspect of living. But when it comes to ageing this equilibrium can play quite an important role.
UPP is the major pathway to degrade those unwanted proteins (3,22). In general, the proteins that are being degraded in this pathway are rapidly degraded. This type of proteins includes, those with an enzymatic activity, regulatory molecules (like transcription factors) and short-lived proteins or abnormal proteins (mutants) (21). This prevents the accumulation and aggregation of ubiquitinated proteins found in neurodegenerative disorder.
The rapid degradation of this proteins avoids us the consequences form having errors during replication and protein synthesis. Damaged abnormal proteins are usually accumulated in the cytosol which impairs cellular function leading to an impaired protein degradation (24).
UPP decreases its efficiency with ageing but the levels of Ub and of ubiquitinating enzymes remain the same so that the pathway does not stop working completely (21,24). Ub is required to target those proteins that need to degrade so that they can be detected (3).
We can relate UPP to some pathogenesis of neurodegenerative diseases. The development of this diseases is enhanced by the presence of immunoproteasomes. Proteasome impairment can be detected if there are high levels of oxidised proteins in the brains or muscles of long-lived organisms (25). These proteins are present in inflammatory response as a defence of an anti-stress mechanism, associated with this, the UPP plays a role in signalling transduction. In some cases, nuclear proteins are used for rapid proteolysis (3,23,24). FoXO can increase lifespan when it is used. It is activated when we are facing a decrease in the signalling factor insulin/IGF1 which role is to regulate ageing in some other life forms like worms, flies or mammals (23).
This pathway is the most affected one by age. Its main role is related with cell metabolism, essential for the post-transcriptional process (3,21,31). Lysosomes act like a waste disposal system. They are type of membrane-bound organelle found in animal eukaryotic cells that contains a series of enzymes produced at the rough endoplasmic reticulum and imported from the Golgi apparatus. These enzymes and some proteases hydrolyse the proteins and the biomolecules we want to get rid of and they will disintegrate the cell after its death as well . The lysosomes digest the obsolete and the un-used materials in the cytoplasm. If the material is founded in the extracellular matrix, e.g. a protein, this protein will be engulfed by endocytosis (26,27). The proteases prevent uncontrolled degradation (21).
The lysosomes are highly selective with what they are going to engulf and degrade but sometimes this selection can be random. We can see this when we subject the cell to be under starvation conditions. The suppression of some nutrients can make the cell work in an inefficient way. This is used to synchronize different cultures (30). If there is a situation of starvation, proteins will be degraded in order to obtain some amino acids and energy that is released from breaking the bonds of the molecule. In this way the cell will be able to continue its normal metabolic cycle and it will not suffer any damage (21).
Whatever we want to be degraded will need to be engulfed by the lysosomes first as a security process. This is carried on by macroautophagy. Autophagy is a catabolic process that consist on the degradation and removal of dysfunctional molecules (28). This involves the formation of autophagosomes (a type of vesicle which membrane is derived from the endoplasmic reticulum; this one is a double membrane) (29,32). These vesicles transport the materials that need to be degraded to the lysosomes and fusion with them so that they can perform their work (21).
Chaperone-mediated autophagy (CMA) is another process of protein degradation as the one mentioned before. This one in particular is regulated by oxidative stress and can be inhibited by mutant proteins (3). The proteins related to CMA are selectively targeted to the lysosomes and all of this process is regulated by chaperones. Chaperones can be found in either side of the lysosome membrane (34). They are a functional type of protein that recognise and bind to non-nature structures to prevent the formation of unspecific unfolded and aggregated molecular structures under specific conditions (36,37).
CMA plays an important role in the enzymatic metabolic process as well as in the process of transcription. This forms part of the cell’s quality control systems but it has a more important role in the maintenance of homeostasis as in the cellular starvation response (34). Once the proteins are degraded, their residues are directly expelled from the lysosomes through the membrane without the formation of another vesicle for this process (33).
Any minor failure in the functioning of cellular processes can lead to premature cell death. The older we get, the more susceptible we are to this type of error. This may be because we have already had more cell divisions than a young person, thus increasing the possibility of suffering some genetic mutation in our genetic material. In addition, we have to take into account that a middle-aged person, having lived longer, may also have been exposed to more toxic agents and radiation or stress situations than a young person as a rule. Therefore, these possible small faults have been able to gradually accumulate in our DNA and those harmful elements have been deposited in our cells. as a consequence, the cells are unable to carry out the cellular processes safely and in the way they should. in this way they end up losing their function as such and become defective, making the tissues in which they are involved also defective.
Libro: the solution of the telomeres
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