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 cannot be repaired by the body is the cause of the loss of function associated with ageing. What is less clear is what causes this damage at the molecular level and why it can be repaired in young organisms but not in old ones.

To better characterise the ageing process, researchers have begun to identify and categorise the cellular and molecular hallmarks of ageing [López-Otín et al. 2013 & 2023, Kennedy et al. 2014]. It is generally accepted that different 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, whereas 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. This is why DNA damage accumulates as we age, which can have several adverse effects. DNA mutations increase the risk of tumour growth, so our risk of cancer increases with age [Roos et al. 2016, Nicolai et al. 2015]. DNA damage can also lead to a reduction in cell function or even drive cells into senescence, which can contribute to the loss of organ function in old age.

The Max Planck Research Group Panier and the Max Planck Research Group Jachimowicz at our institute are investigating this topic.

2. Telomere degradation

Telomeres are the protective caps at the ends of the chromosomes in the human genome. They are like the closed end of a shoelace and keep our chromosomes intact. Each time a cell divides, a piece of telomere is lost, so the more cells divide and the older we get, the shorter the chromosome ends become. When a certain length is reached, cells enter a resting phase and stop dividing. These cells can then die or even cause inflammation, which accelerates the ageing process and triggers disease [Aubert et al. 2008]. A special enzyme called telomerase prevents telomere shortening and can even restore telomere length. However, with the exception of our germ line, most cells in our body do not express telomerase. This is a precaution against the development of cancer cells, which are characterised by high telomerase activity, helping them to become immortal [Jaskelioff et al. 2011, Djojosubroto et al. 2003].

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, 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 modifications to these letters and to the histone proteins that package our DNA. The sum of these chemical modifications is known as 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, allowing the cell to adapt to environmental changes. The epigenome also changes with age [Booth et al. 2016, Zhang et al. 2020]. A particular modification called DNA methylation is important in this context. Our DNA carries millions of small methyl groups, and this pattern changes with age in a tissue-specific way.

Surprisingly, the DNA methylation pattern of only 350 methylation sites is sufficient to predict a person’s biological age [Horvath 2013]. 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 may not only serve as a biomarker but also play a causal role in the ageing process.

The former Max Planck Research Group Tessarz and the Max Planck Research Group Jachimowicz investigate epigenetic changes in ageing.

4. Loss of proteostasis

Proteins are the most important molecules in our cells, catalysing most biochemical reactions and being important for cell signalling and stability. 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 mainly degraded by the proteasome or by a recycling process called autophagy [Hartl et al. 2011].

The ageing process is characterised by a loss of proteostasis leading to an accumulation of damaged and non-functional proteins [Hipp et al. 2019]. Misfolded proteins can clump together to form aggregates, a characteristic feature of many age-related neurodegenerative diseases such as Alzheimer's and Parkinson's [Hartl et al. 2017]. 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 Departments Antebi and Langer at our institute are working on this topic.

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 wide range of organisms, from worms and flies to mice and rhesus monkeys [Ke et al. 2020, Sohal et al. 1994, Piper et al. 2011]. DR has also been shown to have positive health effects in humans [Rizza et al. 2014, Heilbronn et al. 2003, Fontana et al. 2015]. It was originally thought that the health benefits of DR were due to reduced calorie intake. However, more recent studies suggest that the reduction in certain dietary components, particularly protein, and the fasting periods associated with DR are more important [Soultoukis et al. 2016].

Cells need to link their growth and metabolism to the availability of nutrients. They therefore have nutrient-sensing pathways that sense 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 [Hartl 2016, Swovick et al. 2018, Denzel et al. 2014]. Interestingly, genetic or pharmacological inhibition of the pathways extends lifespan in a variety of animals, making them a good target for anti-ageing drug development [Castillo-Quan et al. 2019, Harrison et al. 2009, Fontana et al. 2010].

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 the ‘cellular power plants’ but also form a central hub for metabolic processes in the cell. They use oxygen to produce energy in a process called mitochondrial respiration. An important feature of mitochondria is that they contain their own DNA, called mtDNA, which codes for the proteins needed for respiration. An important finding involving mitochondria in the ageing process was that mice with a high mutation rate in their mtDNA, known as mtDNA mutator mice, have a short lifespan and show signs of premature ageing [Vermulst et al. 2008].

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 thought 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 that are important for mitochondrial respiration, are often long-lived [Dunn et al. 2015, Sies et al. 2020, Nunnari & Suomalainen 2012].

The Department Langer, the Larsson Adjunct Group and the Max Planck Research Group Pernas are investigating 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 has been the discovery that removing senescent cells from aged mice by genetic or pharmacological treatment improves the health and extends the lifespan of these animals [Faragher et al. 2017]. Drugs that kill or silence these cells are called senolytics and are now being tested for their potential beneficial effects on ageing in humans [Childs et al. 2017, Ming et al. 2018].

8. Exhaustion of stem cells

Most cells in our body lose the ability to divide when they reach their final identity, such as a nerve cell or skin cell. Therefore, most organs rely on stem cells to repair tissue damage or to promote tissue renewal. Stem cells have the ability to divide and differentiate into different cell types. They play a vital 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 where cells renew frequently. Stem cells can be lost during ageing, leading to stem cell depletion and a reduced ability to repair organ damage [Goodell & Rando 2015].

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 was long thought to be 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 [Villeda et al. 2014]. Rejuvenating old stem cells could therefore be an approach to enable healthy ageing.

The former Max Planck Research Group Tessarz and the Max Planck Research Group Huppertz are investigating 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 has been shown 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 [Villeda et al. 2014]. It has also been shown that targeted life-prolonging interventions in one tissue can delay ageing in other tissues, thereby extending lifespan [Rando & Jones 2021, Fafian-Labora & O’Loghlen 2020].

10. Deteriorated autophagy

Autophagy is a kind of recycling system in human cells. It is the body’s way of breaking down unwanted and diseased cell components and recycling them elsewhere. There is strong evidence that autophagy is involved in the ageing process. Studies show that the activity of autophagy-related genes decreases with age in humans [Lipinski et al. 2010]. In addition, genetic inhibition of autophagy accelerates ageing in model organisms [Cassidy et al. 2020]. This could be due to an increased accumulation of proteins and cellular components, but also to a reduced ability to degrade pathogens. There is also ample evidence that stimulating autophagy increases lifespan and longevity in model organisms, highlighting the importance of autophagy in the ageing process [Lu et al. 2021, Pyo et al. 2013].

In a recent publication on fruit flies rapamycin stimulated autophagy. However only in female fruit flies:

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11. Chronic inflammation

Ageing is characterised by an increase in inflammation, also known as ‘inflammaging’. In young people, inflammation is usually a direct response to injury and is switched off once the injury has healed. However, chronic low-level inflammation often occurs in ageing tissues, causing tissue damage and being implicated in the development of age-related diseases such as obesity and type 2 diabetes [Carrasco et al. 2022]. Directly targeting inflammatory pathways in mice has been shown to rejuvenate tissue and improve survival [Desdin-Mico et al. 2020].

The Departments Antebi and Schaefer are investigating the connection between the immune system and ageing.

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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 bodies.

Microorganisms live on our skin and in our body fluids, but the majority are found in our digestive tract and are therefore referred to as the gut microbiome. The gut microbiome has important functions for our bodies: 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 depends on environmental factors such as diet and stress. It also changes with age.

While young, healthy people have a complex microbiome with many different species of bacteria, diversity decreases with age, and the microbiome of older people is less complex and characterised by the presence of more pathogenic bacteria [Ghosh et al. 2022]. Interestingly, extremely long-lived people, known as supercentenarians, contain microbes normally found only in younger people, suggesting that they have a healthier microbiome [Wilmanski et al. 2021]. 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 using the killifish Nothobranchius furzeri suggest that the gut microbiome may indeed play a causal role in ageing. In their experiment, the researchers showed that transferring the gut microbiome from young to middle-aged fish was sufficient to increase their lifespan [Smith et al. 2017].

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