How do we age? The hallmarks of ageing

When we have fully deciphered the mechanisms that contribute to the aging process, we will be able to influence and even reverse the aging process in a more targeted way. In aging research, this field is the subject of intensive research and much discussion. According to the current state of science, it is the damage to genetic material, cells and tissues that accumulates with age and can no longer be repaired by the body that causes the loss of function associated with aging. 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.
 
We now know that there are twelve hallmarks of aging.

1. Genomic instability

Our genetic material, DNA, is constantly 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 one million times per 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. For this reason, DNA damage accumulates with age, which can have several negative effects. DNA mutations increase the risk of tumor growth, so our risk of cancer increases with age. 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.

2. Degradation of the telomeres

Telomeres are the protective caps at the ends of 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 aging 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 is a precaution against the development of cancer cells, which are characterized by high telomerase activity, helping them to become immortal.

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 DNA is not only stored in the base pairs, but also in chemical changes in these letters and in the histone proteins that package our DNA. The sum of these chemical changes is called the epigenome. Unlike 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. One particular modification, DNA methylation, is important in this context. Our DNA carries millions of small methyl groups, and this pattern changes with age in tissue-specific ways.

Surprisingly, the DNA methylation pattern of just 350 methylation sites is sufficient to predict a person's biological age. This so-called "epigenetic clock" has now become an important tool as a biomarker to assess whether a particular intervention will have a positive impact on human health and survival without waiting years or even decades. Whether changes in DNA methylation during aging play a causal role is still unclear. However, changes in histone protein modification have been shown to affect lifespan in yeast, worms, and flies, suggesting that the epigenome may not only serve as a biomarker but also play a causal role in aging.

4. Loss of proteostasis

Proteins are the most important molecules in our cells. They catalyze most biochemical reactions and are important for cell signaling 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 by a recycling process called autophagy.

The aging process is characterized by a loss of proteostasis that leads to an accumulation of damaged and nonfunctional proteins. Misfolded proteins can clump together to form aggregates, a characteristic feature of many age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease. 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 aging.

5. Reduction of nutrient intake

 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. 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 caloric 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 must couple their growth and metabolism to the availability of nutrients. Therefore, they have nutrient-sensing signaling pathways that detect the nutrient status of the environment either through hormones or specific nutrient components and adjust cell metabolism accordingly. Together, the insulin and mTOR signaling pathways form a central nutrient sensing network in the cell, which is also associated with the beneficial effects of DR. Genetic or pharmacological inhibition of the signaling pathways extends lifespan in a variety of animals, making them a good target for anti-aging drug development.

6. Mitochondrial dysfunction

Mitochondria are small organelles in the cell that are not only the "powerhouses of the cell" 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, known as mtDNA, which codes for the proteins needed for respiration. An important finding involving mitochondria in the aging process was that mice with a high mutation rate in their mtDNA, called mtDNA mutator mice, have a short lifespan and show signs of premature aging.

Mitochondria are also the major source of reactive oxygen species (ROS), which are generated as a byproduct 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 culprit in the aging process, as suggested by the free radical theory. However, recent studies have challenged this view and suggest that ROS may instead act as signaling molecules within the cell. In some ways, elevated levels of ROS may even be beneficial by activating cellular defense and repair mechanisms. Animals with mutations in mitochondrial complexes important for mitochondrial respiration are often very long lived.

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 releasing 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. In humans and mice, senescent cells also accumulate during the normal aging process. A recent major breakthrough was the discovery that removing senescent cells from aged mice by genetic or pharmacological treatment improves the health of these animals and extends their lifespan. Drugs that kill or silence these cells are called senolytics and are now being tested for their potential beneficial effects on aging in humans.

8. Exhaustion of stem cells

Most cells in our bodies lose the ability to divide when they reach their final identity, such as a nerve cell or a skin cell. Therefore, most organs rely on stem cells to repair tissue damage or promote tissue renewal. Stem cells have the ability to divide and differentiate into different cell types. They play an important role in keeping our organs and body healthy. Aging negatively affects stem cells in many ways, and stem cell aging itself is thought to contribute to tissue aging, especially in tissues where cells renew frequently. Stem cells may be lost during aging, leading to stem cell depletion and a diminished ability to repair organ damage.

9. Modified intercellular communication

The cells and organs in our bodies do not age in isolation, but communicate with each other via hormones, cytokines and metabolites. That this intercellular communication plays an important role in the aging 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 aging, suggesting that there are factors in the blood that contribute to whole organism aging. It has also been shown that targeted life-prolonging interventions in one tissue can delay aging in other tissues, thereby extending lifespan.

10. Disrupted autophagy

Autophagy is a type 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 aging process. Studies show that the activity of genes related to autophagy decreases with age in humans. Furthermore, genetic inhibition of autophagy accelerates aging in model organisms. This phenomenon could be due to increased accumulation of autophagy genes. There is also considerable evidence that stimulation of autophagy increases lifespan and longevity in model organisms, highlighting the importance of autophagy in the aging process.

11. Chronic inflammation

The aging process is characterized by an increase in inflammation, also known as “inflammaging.” In young people, inflammation is usually a direct response to an injury and shuts down once the injury has healed. However, chronic, low-level inflammation often occurs in aging tissues, causing tissue damage and being linked to the development of age-related diseases such as obesity and type 2 diabetes. Directly interfering with the inflammatory pathways in mice has been shown to rejuvenate tissue and improve survival rates.

12. Imbalance of intestinal flora (dysbiosis)

The human body is colonized by a large number of microorganisms, including bacteria, fungi, protists and viruses, collectively referred to 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 our body fluids, but most of them are found in our digestive tract and are therefore called the gut microbiome.The intestinal microbiome has important functions for our body: microorganisms help digest food, produce vital vitamins, shape our immune system and help fight pathogens.The composition of gut microbiome is dynamic and depends on environmental factors such as diet and stress. 

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 characterized by the presence of more pathogenic bacteria. Interestingly, extremely long-lived people, called supercentenarians, contain microbes normally only found in younger people, suggesting they have a healthier microbiome. Whether the observed changes in the intestinal microbiome are just a sign of aging or whether they causally contribute to human aging is an open question. In a study, researchers were able to show that transferring the intestinal microbiome from young to middle-aged fish is sufficient to increase their lifespan.