How do we age? The hallmarks of ageing
There is much debate 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 accumulates with age and can no longer be repaired by the body is the cause of the loss of function associated with age. But what causes this damage at the molecular level and why it can be repaired in young but not in old organisms is far less clear.
To better characterise the ageing process, researchers have begun to identify and categorise the cellular and molecular hallmarks of ageing. It is generally assumed that various hallmarks contribute to the ageing process and together determine the observable features of ageing. A relevant process is considered a hallmark of ageing if its deterioration causes premature ageing, while its improvement promotes health during ageing and extends lifespan.
The hallmarks of ageing:
1. Genomic instability
Our genetic material, DNA, is constantly being damaged by external and internal factors. These damaging factors include UV radiation from sunlight or reactive oxygen species produced in our mitochondria. It is estimated that our DNA is damaged up to a million times a day. Most of this damage is repaired immediately because cells have efficient detection and repair mechanisms. However, these repair processes are not perfect and a small percentage of damage remains unrepaired. Therefore, as we age, DNA damage accumulates, which can have several adverse effects. DNA mutations increase the risk of tumour growth, so our risk of cancer increases with age. DNA damage can also lead to reduced cell function or even drive cells into senescence, contributing to reduced organ function in old age.
The Max Planck Research Group Panier and the Max Planck Research Group Jachimowicz at our institute conduct research on this topic.
2. Telomere degradation
Telomeres are the protective caps at the ends of chromosomes in the human genome. They are comparable to the closed end of a shoelace and keep our chromosomes intact. Each time a cell divides, a piece of the telomeres is lost, so the chromosome ends shorten the more cells divide and the older we get. When a certain length is reached, the cells go into a resting phase and stop dividing. These cells can then die or even cause inflammation, which accelerates the ageing process and triggers disease. A special enzyme called telomerase prevents the shortening of telomeres and can even restore telomere length. However, with the exception of our germ line, most cells in our body do not express telomerase. This serves as a precaution against the development of cancer cells, which are characterised by high activity of telomerase, helping them to become immortal.
The Max Planck Research Group Panier at our institute conducts research on the importance of telomere function and ageing.
3. Epigenetic changes
Our genome consists of more than 3 billion letters, the so-called nucleotide base pairs, which encode the blueprint of our body. However, the information in the DNA is not only stored in the base pairs, but also in chemical changes to these letters and to the histone proteins that package our DNA. The sum of these chemical changes is called the epigenome. Unlike the genetically encoded information, which is very stable, the epigenome is very dynamic and changes in response to diet, drugs or stress so that the cell can adapt to environmental changes. The epigenome also changes with age. In this context, a particular modification called DNA methylation is important. Our DNA carries millions of small methyl groups, and this pattern changes with age in a tissue-specific way.
Surprisingly, however, the DNA methylation pattern of only 350 methylation sites is sufficient to predict the biological age of humans. This so-called epigenetic clock has now become an important tool as a biomarker to assess whether a particular intervention will have a positive effect on human health and survival without having to wait years or even decades. Whether changes in DNA methylation during ageing play a causal role is still unclear. However, changes in the modification of histone proteins have been shown to affect the lifespan of yeast, worms and flies, suggesting that the epigenome not only serves as a biomarker but may also play a causal role in the ageing process.
The Max Planck Research Group Tessarz and the Max Planck Research Group Jachimowicz and the Research Group Matic investigate epigenetic changes in ageing.
4. Loss of proteostasis
Proteins are the most important molecules in our cells, catalysing most biochemical reactions and important for cellular signalling and stability. In order for cells to function properly, proteins must be kept in good condition, a process known as protein homeostasis, or proteostasis for short. To maintain proteostasis, cells have several systems that regulate protein synthesis, folding and degradation. Misfolded and damaged proteins are degraded mainly by the proteasome or via a recycling process called autophagy.
The ageing process is characterised by a loss of proteostasis leading to an accumulation of damaged and non-functional proteins. Misfolded proteins can clump together and form aggregates, a characteristic feature of many age-related neurodegenerative diseases such as Alzheimer's and Parkinson's. Importantly, improved protein turnover through activation of the proteasome or autophagy is sufficient to extend lifespan in model organisms, demonstrating the importance of proteostasis in the ageing process.
The Department Langer conducts research on mitochondrial proteostasis.
5. Impaired perception of nutrients
The effects of what and how much animals eat on healthy ageing are well studied. Reduced food intake without malnutrition, known as dietary restriction (DR), extends lifespan and improves health in a variety of organisms, from worms and flies to mice and rhesus monkeys. In addition, DR has also been shown to have positive health effects in humans. Originally, it was thought that the health benefits of DR were due to reduced calorie intake. However, recent studies suggest that the reduction of certain dietary components, especially protein, and the fasting periods associated with DR are more important.
Cells need to link their growth and metabolism to the availability of nutrients. Therefore, they have so-called nutrient sensing pathways that detect the nutrient status of the environment either through hormones or specific nutrient components and adjust cell metabolism accordingly. The insulin and mTOR pathways together form a central nutrient sensing network within the cell, which has also been linked to the beneficial effects of DR. Interestingly, genetic or pharmacological inhibition of the pathways extends lifespan in a variety of animals, making it a good target for anti-ageing drug development.
The Department Partridge, the Department Antebi, the Max Planck Research Group Demetriades conduct research on nutrient-sensing pathways.
6. Mitochondrial dysfunction
Mitochondria are small organelles in the cell that are not only "cellular power plants" but also form a central hub for metabolic processes in the cell. They raise energy with the help of oxygen, a process called mitochondrial respiration. An important feature of mitochondria is that they contain their own DNA, called mtDNA, which codes for proteins needed for the respiration process. An important finding involving mitochondria in the ageing process was that mice with a high mutation rate in their mtDNA, so-called mtDNA mutator mice, are short-lived and show signs of premature ageing.
Mitochondria are also the main source of reactive oxygen species (ROS), which are produced as a by-product of mitochondrial respiration. These free radicals can damage other macromolecules such as DNA, lipids and proteins and are therefore potentially harmful to the cell. For a long time, ROS were considered to be the main culprits in the ageing process, as suggested by the free radical theory. However, recent studies challenge this view and suggest that ROS may instead act as signalling molecules within the cell. In some ways, increased levels of ROS may even be beneficial, activating cellular defence and repair mechanisms. Animals with mutations in mitochondrial complexes, which are important for mitochondrial respiration, are often long-lived.
The Department Langer, the Larsson Adjunct Group and the Max Planck Research Group Pernas investigate mitochondrial function in ageing.
7. Cellular senescence
Stress or the accumulation of damage over time can cause cells to enter a state called cellular senescence. Senescent cells stop dividing, lose their original function and begin to release harmful molecules, including inflammatory cytokines, growth factors and other molecules. Importantly, senescent cells also negatively affect surrounding cells, contributing to impaired organ function.
There are several triggers for cellular senescence, including telomere shortening, DNA damage or mitochondrial dysfunction. Senescent cells also accumulate during the normal ageing process in both humans and mice. A major recent breakthrough was the finding that removing senescent cells from aged mice through genetic or pharmacological treatment improves health and extends the lifespan of these animals. Drugs that kill or silence these cells are called senolytics and are now being tested for their potential beneficial effects in humans in the context of ageing.
8. Exhaustion of stem cells
Most cells in our body lose the ability to divide when they reach their final identity, e.g. as a nerve cell or skin cell. Therefore, most organs rely on so-called stem cells to repair tissue damage or to drive tissue renewal. Stem cells have the ability to divide themselves and differentiate into different cell types. They play an essential role in keeping our organs and body healthy. Ageing negatively affects stem cells in many ways, and stem cell ageing itself is thought to contribute to tissue ageing, especially in tissues whose cells renew frequently. Stem cells can be lost during ageing, leading to stem cell depletion and a reduced ability to repair organ damage.
In addition, stem cells have been shown to change their differentiation potential with age. This means that they give rise to a different spectrum of differentiated cells in old organisms than in young ones. Interestingly, the ageing of stem cells has long been considered irreversible, but recent research suggests that it may be possible to rejuvenate old stem cells. For example, it has been shown that injecting blood plasma from young mice into old mice improves stem cell function in the old animals. So rejuvenating old stem cells could be one approach to enabling healthy ageing.
The Max Planck Research Group Tessarz and the Max Planck Research Group Huppertz investigate ageing stem cells.
9. Altered intercellular communication
The cells and organs in our body do not age in isolation, but communicate with each other via hormones, cytokines and metabolic products. That this intercellular communication plays an important role in the ageing process was demonstrated in experiments in which the blood circulation of young and old mice was connected, an approach known as parabiosis. Old mice were partially rejuvenated by this procedure, while young mice showed signs of premature ageing, suggesting that there are factors in the blood that contribute to the ageing of the whole organism. In addition, it has been shown that targeted life-prolonging interventions in one tissue can delay ageing in other tissues and thus prolong lifespan.
10. Deteriorated autophagy
Autophagy is a kind of recycling system of the human cell. In this process, the body breaks down unneeded and diseased cellular components and recycles them elsewhere. There is clear evidence that autophagy is relevant to the ageing process. Studies show that in humans, the activity of genes related to autophagy decreases with age. Moreover, genetic inhibition of autophagy accelerates the ageing process in model organisms. The reason for this could be an increased accumulation of proteins and cell components, but also the fact that pathogens can no longer be broken down as well. There is also ample evidence that the stimulation of autophagy increases life expectancy and lifespan in model organisms, which underlines the importance of autophagy in the ageing process.
In a recent publication on fruit flies rapamycin stimulated autophagy. However only in female fruit flies:
11. Chronic inflammation
Ageing is characterised by an increase in inflammation, also known as "inflammaging". When young, inflammation is usually a direct response to injury and is switched off once the injury has healed. However, in aged tissues, chronic low-level inflammation often occurs, causing tissue damage and is implicated in the development of age-related diseases such as obesity and type 2 diabetes. Directly targeting inflammatory pathways in mice has been shown to rejuvenate tissues and positively impact survival.
The Department Schaefer investigates neuronal "inflammaging", or immune-neuron interaction during brain ageing.
12. Imbalance of the intestinal flora (dysbiosis)
The human body is colonised by a large number of microorganisms, including bacteria, fungi, protists and viruses, collectively known as the microbiome. It is estimated that for every human cell there is at least one non-human cell in our body.
Microorganisms live on our skin and in bodily fluids, but the majority are found in our digestive tract and are therefore referred to as the gut microbiome. The gut microbiome has an important function for our body: microorganisms help digest food, produce essential vitamins, shape our immune system and help fight off pathogens. The composition of the gut microbiome is dynamic and dependent on environmental factors such as diet or stress. In addition, the composition changes with age.
While young, healthy people have a complex microbiome with many different bacterial species, the diversity decreases with age and the microbiome of old people is less complex and characterised by the presence of more pathogenic bacteria. Interestingly, extremely long-lived people, known as supercentenarians, contain microbes normally found only in younger people, suggesting that they have a healthier microbiome. Whether the observed changes in the gut microbiome are just a sign of ageing or whether they causally contribute to human ageing is still an open question. Recent results from our institute with the killifish Nothobranchius furzeri suggest that the gut microbiome may indeed play a causal role in ageing. In their experiment, the researchers were able to show that the transfer of the gut microbiome from young to middle-aged fish is sufficient to increase their lifespan.
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