The 9 signs of ageing
The human body is made up of billions of cells that work together and are driven by a metabolism consisting of thousands of processes. In such a complex system, ageing seems unfathomable. In recent years, however, scientists have discovered a number of causes that explain the ageing process. These are known as the 9 hallmarks of ageing.
A common denominator of ageing is the accumulation of genetic damage over the course of a lifetime. Mutations can affect essential genes and transcriptional pathways, leading to dysfunctional cells. DNA damage not only impairs the function of mature cells, but also that of stem cells, leading to additional problems with tissue renewal. Evidence for the link between lifelong increase in genome damage and ageing comes from studies in both mice and humans. These studies showed that deficiencies in DNA repair mechanisms in genetically altered mice lead to accelerated aging; in humans, several genetic diseases are known to have defective DNA repair mechanisms, which also lead to premature aging. However, genomic instability is not only due to DNA damage, but also to damage to the proteins of the so-called nuclear lamina (a structure in the cell nucleus that helps to keep the genome stable). Furthermore, genomic instability affects both the nuclear and mitochondrial DNA of a cell (you can learn more about mitochondria in section 6).
Fortunately, evidence suggests that by supporting the mechanisms that keep our chromosomes healthy, we can improve our longevity.
A telomere is the region of DNA at the end of a chromosome that protects the chromosome from both decay and fusion with neighboring chromosomes. Telomeres are essential for the correct functioning of chromosomes and their length is an important indicator of cell ageing. Metaphorically, they can be compared to the ends of shoelaces, whereby with each cell division a piece of the shoelace is cut off, shortening the telomere. If the telomeres fall below a certain length, the cell can no longer divide. Telomeres therefore limit the number of times a cell can divide. In order to understand the effects of telomere length on ageing, genetically modified mice were examined. Mice with shortened telomeres live shorter, mice with longer telomeres live longer. In humans, short telomeres have been associated with an increased risk of death, especially at a younger age.
There is evidence that part of the ageing process can be reversed by activating telomerase (an enzyme that lengthens telomeres).
The epigenome determines which genes are switched on or off. Epigenetic changes can be caused by the environment, lifestyle and age. These are often characterized by changes in so-called methylation patterns (methylation means that a molecule is chemically modified by adding a methyl group as a marker). Methylation takes place both on the so-called histones (proteins that contribute to the packaging of DNA) and on the DNA. Put simply, epigenetic changes can be accompanied by a deviation in the production and maturation of many mRNAs (mRNA or messenger RNA are molecules that transport the blueprint of a protein from the DNA from the cell nucleus into the cell body, where protein synthesis then takes place). This can lead to an imbalance in the translation of the genetic code. These changes affect not only protein-coding RNAs, but also so-called microRNAs, which influence the function of metabolic networks (more on this in section 5).
Epigenetic changes are theoretically reversible, i.e. they could be used to treat ageing. This distinguishes them from DNA mutations, which usually cannot be reversed.
The proteome is the complete set of proteins produced by a cell or organism. Proteins are the most important functional molecules in cells and fulfill a variety of tasks. The proteome is constantly changing in response to the needs of the cell and the organism. Ageing and some age-related diseases are associated with a disturbed balance of the proteome (called protein homeostasis or proteostasis). This means that with increasing age, cells find it difficult to maintain the stability and functionality of their proteomes. Unfolded, misfolded or clumped proteins are increasingly formed, which can lead to the development of age-related diseases such as Alzheimer's, Parkinson's and cataracts.
Approaches to maintain or improve proteostasis aim to activate protein folding and stability mediated by so-called chaperones and/or to promote autophagy (more on this under "Deep Dive").
There are various metabolic pathways in the cell that signal either a lack or an excess of nutrients via nutrient sensors. To put it simply, intensive anabolic signals tend to accelerate ageing, while signals of nutrient scarcity and catabolism promote healthy ageing. With increasing age, the nutrient sensors become more and more susceptible to disruption.
Mitochondria are organelles in the cells of plants and animals that are responsible for energy production. These organelles are often referred to as the "power plants" of the cell. Mitochondria are unique in that they have their own DNA, separate from the DNA of the cell nucleus. This DNA is needed to produce proteins that are essential for mitochondria to function. The mitochondrion contains several important enzymes that are responsible for the production of ATP, the energy currency of the cell. It has long been suspected that mitochondrial dysfunction and ageing are linked. However, it is only in recent years that science has begun to decipher and understand the details of these relationships.
Senescent cells are cells that have stopped dividing and are in a state of permanent cell cycle arrest. This was originally described by Hayflick in human connective tissue cells that were serially propagated in culture. Today we know that the senescence observed by Hayflick was caused by telomere shortening, but there are other age-related stimuli that trigger senescence independently of this telomeric process. Senescent cells accumulate with age and are thought to contribute to the age-related decline in tissue function. Although senescent cells do not divide, they remain metabolically active, and some of them secrete a number of pro-inflammatory messengers that can promote age-related chronic inflammation and cell death. These cells are referred to as senescence-associated secretory phenotypes (SASP).
Understanding the role of cell senescence in aging is challenging. While SASP cells appear to have profound deleterious effects on tissue and accelerate aging, cellular senescence may conversely also be a beneficial response to cell damage and help prevent further damage.
Stem cells are cells in our body that can transform into other cell types. They serve as a cell reserve, but also help us to repair damage and keep our bodies healthy. The decline in stem cells and thus the regenerative potential of tissues is one of the most obvious features of ageing. As we age, our tissues no longer have the same ability to regenerate and heal as they did when we were younger. For example, hematopoiesis (the production of blood cells) declines with age, leading to reduced production of immune cells - a process known as immunosenescence. The depletion of stem cells correlates with the accumulation of DNA damage and the overexpression of proteins that inhibit the cell cycle. The shortening of telomeres is also an important cause of the age-related decline of stem cells. These are just a few examples that illustrate how different types of damage can lead to stem cell decline. Some studies suggest that we may be able to reverse some of the aging process by rejuvenating and preserving our stem cells.
A common denominator of ageing is the accumulation of genetic damage over the course of a lifetime. Mutations can affect essential genes and transcriptional pathways, leading to dysfunctional cells. DNA damage not only impairs the function of mature cells, but also that of stem cells, leading to additional problems with tissue renewal. Evidence for the link between lifelong increase in genome damage and ageing comes from studies in both mice and humans. These studies showed that deficiencies in DNA repair mechanisms in genetically altered mice lead to accelerated aging; in humans, several genetic diseases are known to have defective DNA repair mechanisms, which also lead to premature aging. However, genomic instability is not only due to DNA damage, but also to damage to the proteins of the so-called nuclear lamina (a structure in the cell nucleus that helps to keep the genome stable). Furthermore, genomic instability affects both the nuclear and mitochondrial DNA of a cell (you can learn more about mitochondria in section 6).
Fortunately, evidence suggests that by supporting the mechanisms that keep our chromosomes healthy, we can improve our longevity.
A telomere is the region of DNA at the end of a chromosome that protects the chromosome from both decay and fusion with neighboring chromosomes. Telomeres are essential for the correct functioning of chromosomes and their length is an important indicator of cell ageing. Metaphorically, they can be compared to the ends of shoelaces, whereby with each cell division a piece of the shoelace is cut off, shortening the telomere. If the telomeres fall below a certain length, the cell can no longer divide. Telomeres therefore limit the number of times a cell can divide. In order to understand the effects of telomere length on ageing, genetically modified mice were examined. Mice with shortened telomeres live shorter, mice with longer telomeres live longer. In humans, short telomeres have been associated with an increased risk of death, especially at a younger age.
There is evidence that part of the ageing process can be reversed by activating telomerase (an enzyme that lengthens telomeres).
The epigenome determines which genes are switched on or off. Epigenetic changes can be caused by the environment, lifestyle and age. These are often characterized by changes in so-called methylation patterns (methylation means that a molecule is chemically modified by adding a methyl group as a marker). Methylation takes place both on the so-called histones (proteins that contribute to the packaging of DNA) and on the DNA. Put simply, epigenetic changes can be accompanied by a deviation in the production and maturation of many mRNAs (mRNA or messenger RNA are molecules that transport the blueprint of a protein from the DNA from the cell nucleus into the cell body, where protein synthesis then takes place). This can lead to an imbalance in the translation of the genetic code. These changes affect not only protein-coding RNAs, but also so-called microRNAs, which influence the function of metabolic networks (more on this in section 5).
Epigenetic changes are theoretically reversible, i.e. they could be used to treat ageing. This distinguishes them from DNA mutations, which usually cannot be reversed.
The proteome is the complete set of proteins produced by a cell or organism. Proteins are the most important functional molecules in cells and fulfill a variety of tasks. The proteome is constantly changing in response to the needs of the cell and the organism. Ageing and some age-related diseases are associated with a disturbed balance of the proteome (called protein homeostasis or proteostasis). This means that with increasing age, cells find it difficult to maintain the stability and functionality of their proteomes. Unfolded, misfolded or clumped proteins are increasingly formed, which can lead to the development of age-related diseases such as Alzheimer's, Parkinson's and cataracts.
Approaches to maintain or improve proteostasis aim to activate protein folding and stability mediated by so-called chaperones and/or to promote autophagy (more on this under "Deep Dive").
There are various metabolic pathways in the cell that signal either a lack or an excess of nutrients via nutrient sensors. To put it simply, intensive anabolic signals tend to accelerate ageing, while signals of nutrient scarcity and catabolism promote healthy ageing. With increasing age, the nutrient sensors become more and more susceptible to disruption.
Mitochondria are organelles in the cells of plants and animals that are responsible for energy production. These organelles are often referred to as the "power plants" of the cell. Mitochondria are unique in that they have their own DNA, separate from the DNA of the cell nucleus. This DNA is needed to produce proteins that are essential for mitochondria to function. The mitochondrion contains several important enzymes that are responsible for the production of ATP, the energy currency of the cell. It has long been suspected that mitochondrial dysfunction and ageing are linked. However, it is only in recent years that science has begun to decipher and understand the details of these relationships.
Senescent cells are cells that have stopped dividing and are in a state of permanent cell cycle arrest. This was originally described by Hayflick in human connective tissue cells that were serially propagated in culture. Today we know that the senescence observed by Hayflick was caused by telomere shortening, but there are other age-related stimuli that trigger senescence independently of this telomeric process. Senescent cells accumulate with age and are thought to contribute to the age-related decline in tissue function. Although senescent cells do not divide, they remain metabolically active, and some of them secrete a number of pro-inflammatory messengers that can promote age-related chronic inflammation and cell death. These cells are referred to as senescence-associated secretory phenotypes (SASP).
Understanding the role of cell senescence in aging is challenging. While SASP cells appear to have profound deleterious effects on tissue and accelerate aging, cellular senescence may conversely also be a beneficial response to cell damage and help prevent further damage.
Stem cells are cells in our body that can transform into other cell types. They serve as a cell reserve, but also help us to repair damage and keep our bodies healthy. The decline in stem cells and thus the regenerative potential of tissues is one of the most obvious features of ageing. As we age, our tissues no longer have the same ability to regenerate and heal as they did when we were younger. For example, hematopoiesis (the production of blood cells) declines with age, leading to reduced production of immune cells - a process known as immunosenescence. The depletion of stem cells correlates with the accumulation of DNA damage and the overexpression of proteins that inhibit the cell cycle. The shortening of telomeres is also an important cause of the age-related decline of stem cells. These are just a few examples that illustrate how different types of damage can lead to stem cell decline. Some studies suggest that we may be able to reverse some of the aging process by rejuvenating and preserving our stem cells.
SCIENCE BEHIND BEYOND AGE
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