What happens in our body when we age? What are the molecular and cellular mechanisms that regulate ageing and can we delay ageing by targeting these processes? These are some of the questions we want to answer at the Max Planck Institute for Biology of Ageing. We are all aware of the external features that appear at old age, such as wrinkles and grey hair but why do we age and what exactly happens inside our body when we age is much less understood.
There is much discussion among researchers about the mechanisms that contribute to the ageing process. However, it is widely accepted that damage to genetic material, cells and tissues that accumulate with age and cannot be repaired by the body are causal factors for the functional decline associated with old age. But what causes this damage on the molecular level and why it can be repaired in young but not old organisms is much less clear.
To better characterize the ageing process, scientists have started to identify and categorize the cellular and molecular hallmarks of ageing [1, 2]. Nine candidate hallmarks are generally considered to contribute to the ageing process and together determine the observable characteristics of ageing. A corresponding process is considered a hallmark of ageing, if its deterioration causes premature ageing, while its improvement ameliorates health during ageing and extends lifespan.
The nine hallmarks of ageing are briefly outlined below:
1) Genomic instability
With the exception of the red blood cells, each of our body cells contains the instructions for all the cellular processes required. This blueprint is our DNA and consists of over 3 billion so-called nucleotides, the individual DNA building blocks that together make up our individual genome.
Since the genome contains the instructions for all functions in a cell, its correct operation is essential for our body to work properly. However, our genome is permanently under attack by internal and external influences. Harmful influences from outside the body include UV radiation and air pollution. Inside the body, oxygen radicals produced during our respiration can damage the genome. It has been estimated that the DNA in every single cell of our body is damaged up to one million times a day .
Fortunately, our DNA also contains the information for several processes that can detect and repair such damage. Therefore, our cells have a self-repairing capacity of the genome.
The problem is that these repair processes are not perfect. Although our cells can repair most DNA damage events, a subset of DNA lesions are not properly repaired and are instead fixed as mutations in our genome. These mutations, which can impair all aspects of a cell’s function, accumulate over time, particularly as we get older. People who have impaired repair processes of the genome often show signs of accelerated ageing. DNA damage also contributes to the development of cancer . The research groups of Ron Jachimowicz and Stephanie Panier both investigate different aspects of these DNA repair mechanisms. You can find more information on their respective pages.
Interestingly, it has been shown that caloric restriction, i.e. reduced food intake, slows down the increase in DNA damage that occurs over time [5, 6]. In addition, the obvious health advice such as avoiding sunburn, eating less grilled/fried foods, and not smoking also help. This shows that there are ways of reducing damage to our DNA or improving the repair mechanisms of our cells to delay the ageing process.
2) Telomere attrition
One particular type of genome instability is the shortening of our telomeres. Telomeres are the ends of the chromosomes of the human genome. They are comparable to the sealed end of a shoelace and keep our chromosomes stable. With each cell division, a piece of the telomeres is lost, so that the chromosome ends shorten more and more the older we get . When a certain minimum length is reached, the cell becomes inactive and no longer divides. Such cells can then die or even cause inflammation, speeding up the ageing process and triggering diseases. A specific enzyme called telomerase prevents telomere shortening and even restores the length of telomeres. In mice that do not have this enzyme, symptoms of premature ageing have been observed . In accordance, higher levels of telomerase in mice result in long-lived animals. In most adult cells, telomerase is only little or not at all active. However, activation of telomerase to increase the lifespan is a dangerous solution, as telomerase activity is associated with many types of cancer .
3) Epigenetic alterations
Our genome consists of more than 3 billion nucleotides of four types: A, T, C and G. To fit into the cell’s nucleus, which is only a few micrometres in size, the genetic material is well packed and rolled up. If the DNA thread were to be unwound and spread out, we would be dealing with a molecule 2 metres long. The individual DNA strands are wrapped around proteins called histones in the cell nucleus. Both DNA and histones can contain small chemical changes that can be used to switch individual genes on or off. The sum of these chemical changes is called the epigenome. In their laboratories, research group leaders Peter Tessarz and Ivan Matic analyse the role of such epigenomic changes on the ageing process.
The epigenome changes with age. Some of the chemical changes are misplaced, added in the wrong place or lost. As a result, the control over gene activity also changes, i.e. the precise switching on and off of some genes .
Our epigenome is influenced by our diet and lifestyle, but chronic stress or certain drugs can also change it. Studies in yeast, worms and flies have shown that alterations in the epigenome directly influence the lifespan of these organisms .
4) Loss of proteostasis
The DNA of our cells contains the instructions for all cellular functions. But it is not the DNA itself that carries out these functions. Instead, our DNA contains the information for the production of proteins and enzymes that take over tasks and control processes within the cell. Proteins and enzymes control all chemical reactions in the cells and also give the cell its structure. In order to carry out such functions, proteins must be folded precisely into a very specific structure, similar to origami. The term protein homeostasis, or proteostasis for short, describes the maintenance of the form and abundance of all proteins .
With age, proteins are increasingly damaged due to normal cellular processes, which also influences their shape and folding. Not only can misfolded proteins no longer perform their normal work, but they also tend to clump together, which can have a toxic effect on the cell . Alzheimer's disease, for example, is an age-related disease caused by misfolded proteins . In our institute, the research group of Martin Denzel investigates novel pathways that ensure protein quality control.
Because the maintenance of proteostasis is so important, the cell has several mechanisms to control the folding and quality of proteins. Not only are there mechanisms to repair and refold disturbed proteins, but there are also ways to degrade such proteins and then replace them with new ones . Misfolded and damaged proteins, for example, can be degraded by a recycling process known as autophagy. The research group of Martin Graef is conducting research on this process.
Many study results suggest an important role of proteostasis in ageing: misfolded proteins increase with age; several age-related diseases such as Alzheimer's are associated with misfolded proteins; improving protein quality control increases the lifespan of mice and other model organisms [15-17].
5) Deregulated nutrient sensing
When sufficient nutrients are available, cells and tissues store energy and grow, whereas when nutrients are deficient, mechanisms for homeostasis and repair are activated. This behaviour has become established in the course of evolution and may be associated with slowing down the ageing process. When cells are constantly exposed to excess nutrients, as is the case with diabetes and obesity, the cellular mechanisms that recognize nutrients become desensitized. This process also occurs during ageing and causes cells to fail to respond properly to the signals that normally regulate energy production, cell growth and other important cellular functions.
Therefore, many studies have investigated the effect of food intake or the perception of food on the ageing process. For example, when the overall food intake is reduced (caloric restriction), or the body is tricked to “believe” to have less food, for example through the use of certain drugs, the insulin signalling pathway is switched off and the lifespan increases in fruit flies. Similar effects have also been observed in mice. [18, 19]. The result of all these studies is that reduced food intake improves health and increases the lifespan of a wide range of animals.
Two nutrient sensing pathway are especially in focus of ageing research: The insulin/insulin growth factor (IGF) and the Target of Rapamycin (TOR) pathway together constitute a key nutrient sensing network within the cell, that has also been implicated in the beneficial effects of dietary restriction. Interestingly, genetical or pharmacological inhibition of the insulin/TOR network extends lifespan in a wide range of animals, making it a prime target for the development of anti-ageing drugs.
The departments of Linda Partridge and Adam Antebi as well as the research groups of Costas Demetriades, Martin Denzel and Joris Deelen address this hallmark of ageing.
6) Mitochondrial dysfunction
To maintain all the cellular processes and chemical reactions, the cell needs energy. The cellular energy production takes place in the mitochondria, whose influence on the ageing process is investigated in the department of Thomas Langer, the research group of Lena Pernas as well as in the research group of external member Nils-Göran Larsson.
Mitochondria are small components within the cell, also known as the "power houses of the cell". They are essential for the production of energy by utilising the oxygen we breathe in.
However, this process sometimes produces free radicals, so-called Reactive Oxygen Species or ROS .
ROS can damage just about every molecule in the cell, from DNA to proteins to fatty acids. For a long time, it was thought that ROS were the main drivers behind the ageing process. It has been believed that a reduction in the amount of ROS would automatically lead to a healthier and longer life.
However, it has been known for some years now that reducing ROS levels sometimes has no effect on health at all. In some cases, it is even the other way around and a slight increase in the amount of ROS in the cells actually has beneficial effects. For this reason, it has been concluded that ROS in general have an important function in signalling cellular stress .
Cells, organs and tissues that perceive stress increase their maintenance and repair processes in response to it. For healthy ageing, the amount of ROS must therefore be just right: not too much and not too little.
Mitochondrial dysfunction can generally affect important cellular signalling pathways and processes. Eventually, the cell becomes less efficient at producing energy, and at the same time, the level of oxidative stress increases, leading to damage to other cellular components. As a result, mitochondrial dysfunction contributes to several age-related diseases, such as myopathies and neuropathies .
7) Cellular senescence
Cells divide to make an organism grow or to replace old cells in a particular tissue or organ. But at some point, this capacity is lost; the vast majority of cells cannot divide infinitely. Cells that have entered a permanent, non-dividing state are called senescent cells. However, these cells do not die. Instead, some of them release harmful molecules into their environment, which can negatively influence other cells [23, 24].
One reason for cellular senescence is the shortening of the telomeres. However, there are a whole range of other influences that can trigger a senescent state in a cell, including damage to DNA, for example.
For a long time, it was unclear whether senescent cells contribute to the ageing process or are an effective protection against the development of cancer. A recent study has shown that senescent cells decreased survival even in young mice . Drugs that kill or silence senescence cells are called senolytics, and are now being tested for their potential beneficial effect in humans in the context of ageing and cancer therapy.
8) Stem cell exhaustion
It is essential for the health of our body that tissues and organs can renew old cells and repair damage. The ability of our body to renew parts of tissues and organs is based on stem cells, which are present in almost every tissue. Stem cells are the ultimate source of new cells, as they can theoretically divide indefinitely and thus produce new cells.
Healthy stem cells must be able to divide when the body or a specific tissue needs new cells, but only then and not without control. The ability of stem cells to divide, and the ability to divide only when new cells are needed, decreases with age. In the worst case, the unstopped division of cells can lead to cancer .
Several studies have shown that certain molecules, for example the drug rapamycin, can maintain the functions of stem cells and thus not only improve the health of stem cells but also have a positive effect on the body's ageing process [27, 28].
9) Altered intercellular communication
The cells of our body communicate with each other. A maintained cell-to-cell communication is crucial for our health and also influences our ageing process.
Cells can use different types of communication. If they are directly next to each other, they communicate via their physical connection. By releasing certain molecules, however, it is also possible to reach cells that are not in the immediate vicinity. By secreting hormones into the bloodstream, it is even possible to reach recipients located in completely different regions of the body and different organs can communicate with each other in this way .
Ageing not only changes the signals sent by cells, but also the ability of recipient cells to respond to these signals. This impaired communication leads to problems such as chronic tissue inflammation as well as the failure of the immune system to recognize and eliminate pathogens or defective cells, increasing susceptibility to infections and cancer .
The nine characteristics of ageing clearly show how complex the ageing process is at the molecular level and how it can be influenced in many different ways . Although the knowledge of ageing research is constantly evolving, the nine hallmarks of ageing provide an excellent basis for our knowledge of the fundamental biology of ageing.
The nine hallmarks of ageing provide a good overview of the mechanisms that answer the question of "how do we age?". But why do we age at all? If there are processes in our cells that can extend our lifespan, why have organisms not developed mechanisms to do so?
Lifespan varies greatly between animals ranging from only a few hours in mayflies up to fivehundred years in Iceland clams. Some more primitive animals like sea anemones and the fresh-water polyp hydra do not seem to age at all, while the longest-living vertebrate species is the Greenland shark, that can live up to 400 years and only reaches sexual maturity at the age of 150. However, ageing is not the only strategy developed during evolution, as some animals like the giant pacific octopus, male ants or males of the small marsupial Antechinus agilis die immediately after reproduction. Thus, although most organisms age the questions “Why do we age?” and “What determines the difference in longevity between species?” are much less understood.
From an evolutionary perspective ageing is a paradox. Ageing makes us less healthy and why would such a deleterious process evolve? The answer is, ageing evolves not because it is useful but as a side-effect of something else . This conclusion is derived from two popular ageing theories proposed by evolutionary biologists Peter Medawar and George Williams already in the 1950s and 1960s.
The “mutation accumulation” theory by Peter Medawar states that the force of natural selection stays high until first reproduction . Afterwards, it declines with age. Therefore, deleterious mutations, whose effects only occur late in life, can accumulate because they are not selected against. This consideration is also termed the “selection shadow”. This means that the most important goal of an organism is its reproduction and until that point natural selection ensures the maintenance of the cellular processes essential for survival. After reproduction, there is no evolutionary pressure to ensure the continued survival of the organism. Cellular processes decline, the organism ages and ultimately dies.
The “antagonistic pleiotropy” theory by George Williams states that natural selection can favour gene variants with beneficial effects early in life, even if the same variants have detrimental effects later on . As the harmful effects of these genes only occur in old age after the reproductive phase, they have little evolutionary impact. Nature cannot directly select against a gene or its mutation that causes the death of an individual in old age, if its harmful effects do not occur before the end of the reproductive phase.
Another conclusion derived from these theories is that the intrinsic rate of ageing of an organism is expected to evolve in accordance with the level of extrinsic hazard encountered. This means, the more likely an animal is to die due to predation or lack of food, the shorter-lived it usually is. Animals that developed strategies to avoid hazard are usually longer-lived. For example, birds and bats, which can escape hazardous situation by flying are often long-lived, other strategies include social organization, or protection via poison or armour.
In summary, ageing only evolves as a side effect and therefore is not a programmed process like development, i.e. no genes evolved to cause damage and death. This may also explain why it is such a variable process within and between different individuals.
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