When do we start to age? Can the ageing process be stopped? How do we grow old in a healthy way? Here we answer the most important questions about ageing.
Even if some of these terms sound interchangeable, it is important to know the exact definition. Life expectancy describes the time a living being is expected to live, based on the year of birth, as well as on their current age and various demographic factors, including gender. It is always defined statistically as the average number of years of life remaining at a given age. Life expectancy is therefore basically the average lifespan of a population. In contrast, the maximum lifespan is the maximum time that one or more members of a population can survive between birth and death. The oldest woman in the world lived to be over 122 years old, which is why the maximum human lifespan is often given as 120 years . The term longevity describes the ability to live a long life beyond the species-specific average age of death . Longevity can be regarded as the average lifespan under ideal conditions. The term health span describes the period of time during which a person is healthy within his or her lifetime. The health span is therefore shorter or at most as long as the lifespan and a person can fall ill early in life but still live for several years .
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In general, one can say that ageing starts after development at a time point when the body is mature. In humans this can be set around the age of 20 years. This is the time the classic signs associated with ageing become visible, such as the appearance of wrinkles or the decrease in performance and stamina. The speed with which every person ages might be different, mainly as a result of different environmental factors and the contribution of the genetic predisposition. However, the general ageing processes responsible for ageing are probably the same between individuals.
If you are asked about your age you usually give your chronological age, i.e. the number of years you have lived. However, the chronological age does not say much about the current status of the body: while one person can still run a marathon without any problems at the age of 50, the other is already exhausted from climbing stairs to the first floor. In order to find out what state the body really is in the biological age can be determined. To do this, various indicators of the human body are analysed, so-called biomarkers. Biomarkers of ageing are features that allow a better prediction of the actual functioning of the organism at a higher age and are more reliable than chronological age . These include, for example, blood pressure, vision, hearing and joint mobility. In addition, the length of the telomeres and certain proteins in the bloodstream are among the measurable biomarkers. Probably the best-known biomarker measurable in the blood is cholesterol, but certain inflammation markers are also suitable for determining biological age . Another biomarker that enables the determination of biological age is the epigenetic clock . The values of these biomarkers together give an estimated biological age.
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Epigenetics deals with chemical and structural changes in the genetic material that do not affect the sequence of DNA building blocks. These changes can be caused by environmental influences, among other things, and are responsible, for example, for the differences between identical twins whose DNA sequence is the same. The pattern of DNA methylation, a specific epigenetic mark, changes in ageing cells . The ageing researcher Steve Horvath developed an algorithm to extract DNA methylation sites that can predict biological age. His epigenetic clock bases on a set of 353 DNA methylation sites sufficient to precisely predict biological age in different cells and tissues . The epigenetic clock, can be used to determine a person's biological age, which may soon help improve diagnoses and disease classification in medical research.
The genetic predisposition of each individual has an influence on the ageing process and thus on personal life expectancy. If the life span of identical twins in humans is compared the influence of genes can be estimated to be around 10-15 percent . In comparison to genes, individual lifestyle and external influences play a much more decisive role in ageing.
In some model organisms genes are known to have a direct influence on life expectancy. In both the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster the inactivation of certain genes even leads to a doubling of life span [2, 3]. However, the fact that such life-prolonging gene mutations have not become established in the wild suggests negative effects of the gene mutations that overshadow the benefits of long life.
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Everywhere in the world women live longer than men . And this is not only the case in humans, but also in many other mammalian species . The higher life expectancy of women is often attributed to the fact that women generally eat healthier food and pay more attention to their health. On average, women go to the doctor earlier and more often than men, they usually drink less alcohol, consume less tobacco and pay more attention to a healthy diet [3, 4]. In addition, statistics on life expectancy include suicide cases, which are significantly more common among men than among women [5, 6]. But there may also be a genetic component that makes women live longer. The advantage for women could be the double X chromosome . While women have two X chromosomes, men have one X chromosome and one Y chromosome. Important genetic information of the X chromosome is therefore duplicated in women and can compensate for possible gene mutations and defects of the other X chromosome. This is not the case in men and is responsible, for example, for the red-green vision deficiency that occurs much more frequently in men. The decisive factor for ageing may be that the X chromosome also contains gene segments that influence the body's immune system . If these gene sections are defective in men they cannot be compensated for by a second, faultless X chromosome. In addition to the different sex chromosomes, the influence of sex-specific hormones on the ageing process is also discussed. Thus, a possible connection between the hormone testosterone and risky behaviour as well as the increased rate of cardiovascular diseases in men is suspected [8, 9].
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Everyone knows the classic signs of ageing such as grey hair and wrinkles. However, some signs can be detected much earlier. Already from the age of 20 many classic signs of age become noticeable on the human body. Wrinkles become visible because the skin loses its elasticity due to the loss of collagen, elastin and hyaluronic acid. Endurance decreases because the production of the pulmonary alveoli decreases, resulting in a smaller breathing volume and less oxygen entering the blood. The number of hair cells in the cochlea decreases, which means that we hear high-pitched sounds increasingly poorly. At the age of 25 fertility decreases in women and testosterone levels decrease in men. A little later the sperm density also decreases in men. From the age of 30 the elasticity of the cartilage slowly decreases and certain movements become more difficult. From this time on the intervertebral discs also become thinner. From the age of 35 the first grey hairs become visible, because the production of melanin slows down and later even stops completely. At about 40 years of age thickening of the lens and loss of lens flexibility (presbyopia) takes place and reading becomes more difficult. From the age of 55 onwards muscle loss increases and the body changes its muscle/fat ratio towards fat. The ageing process is now noticeable because the blood vessels calcify and consequently blood pressure rises. The first organs such as kidney and liver begin to function less efficient, which means that the body's detoxification progresses more slowly. As we grow older, neurodegenerative diseases such as dementia (for instance Alzheimer’s disease), Parkinson's disease, cardiovascular diseases and cancer become more common, to name but a few of the most common age-associated diseases.
Although we cannot expect to stop the human ageing process completely, the molecular mechanisms underlying the ageing process, as outlined by the nine hallmarks of ageing, show that ageing is regulated by certain cellular processes. By affecting these processes, it could be possible to slow down ageing and improve our health in old age.
Eat less and get older: The influence of diet on ageing
In most animals, exercise and diet are the main influences on the speed of ageing. In various animals, a reduction in food intake (dietary restriction) leads to a healthier and often longer life . However, it seems that it is not so much the amount of food we eat that influences the body’s ageing process but rather what we eat. The particular nutrients in an animal’s diet directly impact its health and ageing . For example, the department of Linda Partridge found that fruit flies fed high levels of protein and amino acids die earlier than flies fed a balanced diet . Conversely, a study has shown that a reduced intake of certain amino acids has a positive effect on health - even in humans [4, 5]. These findings suggest that avoiding a protein-rich diet in particular might prolong life span and improve health in old age. However, most beneficial diets in model organisms are hard to adhere to for humans so that more research on this topic is needed.
Young intestinal bacteria
The food we eat, and the amount of it, therefore has a direct impact on our health and ageing. But the bacteria in our intestines that help digest the food we eat also seem to have a direct influence on our health and ageing process. Dario Riccardo Valenzano, research group leader at our institute, investigates the influence of intestinal bacteria on the ageing process. His research group is investigating ageing in the turquoise killifish and has been able to show that old fish remain active for longer and live up to 40 percent longer if they maintain the intestinal bacteria of young fish . The composition of the microorganisms in the fish's intestines, the so-called intestinal flora, thus seems to have a direct influence on the ageing process. Among other things, the microorganisms influence food intake, metabolism and immune defence. With age the composition of the bacterial community in the gut changes . The variety of bacteria that ensure a healthy intestine in youth decreases and among the bacteria still present there is a larger proportion of pathogens. How exactly the intestinal bacteria influence life span is the subject of current research in Dario Riccardo Valenzano's research group. Interestingly, the intestinal flora of the turquoise killifish shows great similarities with that of humans, which means that the results may also be important for human ageing.
The cell’s recycling program: Autophagy and the TOR pathway
The amount of nutrients we take in through food influences the availability of nutrients in the cells. When nutrients are scarce in the cells because a small amount of food has been taken in, our cells activate a recycling mechanism, called autophagy. The term "autophagy" comes from Latin and means "self-eating". This is because the process of autophagy breaks down components within our cells in order to recycle them and to reuse the single building blocks.
It is now known not only that the process of autophagy decreases with age, but also that activation of autophagy has positive effects on the health and lifespan of an organism . The role of autophagy in the ageing process is investigated in the research group of Martin Graef.
Activation of autophagy directly depends on the nutrient availability and the energy status of the cell. Thus, its regulation is linked to a network of molecular signalling pathways. The so-called “IIT network” is activated when there is only a small amount of amino acids in the cell and can be found in a wide range of organisms, from fruit flies to humans . The network controls development, cell division, growth, reproduction, and the response to stress. Similar to a very precise sensor, the IIT network measures the nutrient status in the body and adjusts metabolic processes accordingly, based on the demand for and availability of food . Reduced food consumption, as upon caloric restriction, evidently stops the activity of the network.
One of the signalling pathways of the IIT network is the TOR pathway. TOR links signals such as energy, nutritional and stress status to basic cellular activities. It can certainly be said that TOR is the master regulator of cellular metabolism . If the TOR signalling pathway is active, an increased number of cellular functions are activated, which are responsible for cell growth and division. Deactivation of the TOR signalling pathway, on the other hand, activates the process of autophagy, which has positive effects on our health. The exact regulation of TOR is therefore an extremely interesting study object for ageing research.
Mitochondria: More than just energy production sites
Most of the cell’s energy is produced by small components within our cells, the so-called mitochondria. Although mitochondria are most famous for their role in energy production, they are actually involved in over 1000 metabolic pathways of a cell making their correct function essential for the health of an organism.
Mitochondria have been particularly interesting for ageing research because they generate radical oxygen species (ROS) during energy production. ROS can damage all molecules of a cell and have therefore long been held to be the cause of the ageing process. However, recent findings show that both too high and too low ROS levels are unhealthy. This means that the radicals produced by mitochondria at just the right level are best for our health and the ageing process .
Since mitochondria provide the energy for the cell, their activity and functionality directly influence the energy status of a cell. The amount of energy produced by mitochondria is measured via a specific signalling pathway and influences the further behaviour of a cell. For example, if a lot of energy is available the TOR signalling pathway is activated, which among other things ensures cell growth and cell division. If the energy level in the cell is low, the TOR signalling pathway is inhibited and autophagy is switched on instead .
Since we obtain our energy primarily through the conversion of nutrients, it is not surprising that a reduced food intake also reduces the amount of energy available to the cell. As a result, the process of autophagy is increasingly switched on. On the other hand, the functions of mitochondria partly explains why exercise can be so beneficial for health and ageing. During physical activity, for example, slightly higher amounts of ROS are released, which in such quantities have been shown to have a positive effect on health. In addition, the body consumes a lot of energy during exercise, which in turn activates autophagy [13, 14].
Isn't there a pill for this? - Drugs that potentially stop ageing
There is currently no drug or treatment known that has been shown to extend lifespan of humans. However, in laboratory animals like worms, flies and mice it is already possible to increase survival and improve health via various interventions. Dietary restriction can extend the healthy lifespan in diverse animal species . Although a reduced food intake also improves certain aspects of human health, people have problems to adhere to such a diet. Therefore, several drugs are investigated that target the mechanisms mediating the health benefits of dietary restriction. People who are unable to prolong their lives even with optimal nutrition could still benefit from such drugs.
For example, the drug rapamycin is one of the most promising anti-ageing substances to date . Rapamycin is named after "Rapa Nui", the native translation for the Easter Islands, where the drug was discovered in a soil sample as a bacterial metabolite. Originally, these bacteria secreted rapamycin into the soil in order to stop the growth of competitive fungi, and to absorb as many nutrients as possible themselves. Initially, rapamycin was prescribed as an immunosuppressive drug following kidney transplantation . Interestingly, rapamycin has a very positive effect on health in old age and life expectancy in general. Rapamycin achieves this effect by switching off the TOR signalling pathway, thus activating the process of autophagy. For instance, if fruit flies are exposed to Rapamycin, their life expectancy increases considerably . The department of Linda Partridge, was able to increase the life expectancy of fruit flies by almost 50 percent, when exposing them to rapamycin and two additional compounds .
Another investigated potential anti-ageing drug is Metformin. Metformin is used to treat diabetes and, among other things, inhibits the formation of new glucose in the liver . Mice fed with metformin live longer and metformin is a safe drug without serious side effects. Therefore, it has been chosen for the first clinical trial of a drug directed against “ageing” in humans, termed the TAME trial, that is planned in the USA with three thousand participants.
Various so-called senolytics, which specifically induce cell death in senescent cells, i.e. cells that no longer divide , are also being studied in relation to their effect on ageing. One such compound is called tanespimycin and has proven to have an anti-ageing effect in the model organism Caenorhabditis elegans, a roundworm often used for basic research. Tanespimycin reduces the number of senescent cells and thus also the number of molecules secreted by them that cause chronic infection . Whether tanespimycin is really suitable as an anti-ageing drug in humans remains to be demonstrated. Its use is associated with serious side effects.
Thus, there are already some promising drugs that may slow down our ageing process in the future. More detailed research is required in order to show if they are suitable for use in humans and whether they keep their promise as anti-ageing cures.
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The positive influence of a healthy, balanced diet on the ageing process is not only a generally known assumption, but is supported by many scientific studies [1, 2]. In addition, sufficient sleep and exercise have a positive impact on age-related health parameters [3, 4]. On the other hand, chronic stress and the consumption of alcohol or cigarettes are among the factors that prevent healthy ageing [5, 6]. However, non-biological influences are also of decisive importance for the ageing process, such as the living situation, the level of education and the social and family environment. Anyone who wants to do something to grow old in a healthy way should make sure they maintain a healthy diet, stay physically fit, get enough sleep and avoid alcohol and cigarettes. If possible, avoid chronic stress and maintain social contacts.
The Mediterranean diet can be seen as a "recipe" for healthy eating: it is based on a low-meat diet, lots of fruit, vegetables and nuts, fish and olive oil. Studies show that such a Mediterranean diet has a direct influence on the composition of intestinal bacteria [7, 8]. This reduces the frequency of harmful bacterial species and at the same time increases the number of bacteria with health-promoting properties. In addition, volunteers on a Mediterranean diet showed longer and more intact telomeres and a lower level of inflammatory markers was found in the blood [8, 9]. The consumption of fresh fruit and vegetables also reduces the risk of chronic diseases such as diabetes or cardiovascular disorders.
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The term "blue zone" describes regions of the world where people live longer than average and in good health, and where particularly many centenarians live. Five regions are currently known as "Blue Zones": Okinawa (Japan), Sardinia (Italy), the Nicoya Peninsula (Costa Rica), Ikaria (Greece) and Loma Linda (California, USA) . All five regions have certain cultural similarities, which are used as an explanation for the long and healthy life. These include a predominantly plant-based diet and frequent consumption of vegetables, moderate calorie intake and low consumption of tobacco and alcohol. In addition, the inhabitants of "blue zones" hold family as particularly important, social commitment is very pronounced and sport activities are an integral part of life. Social cohesion, community and care thus seem to be decisive factors for healthy ageing, alongside a balanced diet and a healthy lifestyle .
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