What causes ageing?

Ageing is caused by a complex interplay between genes and environment. Both external environment, things like diet, exercise, stress and infection, and the environment of each cell, things like oxidative stress and epigenetic changes (changes in marks on DNA) affect how our cells, and therefore how our whole body ages. Ageing is an accumulation of cellular damage and a loss of cellular fitness over time. The question is what causes the cellular damage and what is an attempt to compensate? And do the compensatory mechanisms make things better or worse?

Hallmarks of Ageing

After 1000s of studies looking at the changes in cells that occur with ageing, scientists have come up with 10 hallmarks of ageing. These hallmarks can be divided into: things that always accelerate ageing – DNA damage, mitochondrial DNA mutations, telomere shortening, epigenetic changes, and defective protein handling; things that are sometimes good for the cell and sometimes bad – nutrient sensing, oxidative stress and senesence; and things that happen outside of the cell that cause ageing within the cell – stem cell malfunction and intercellular communication. I’ll briefly outline what all of these mean in this post, then go through them in more details over the next few weeks.

DNA Damage

DNA inside our cells is constantly being damaged. This is normally repaired by ‘in house’ DNA repair mechanisms. But these mechanisms become less effective as we age. So DNA damage accumulates in older tissues. DNA mutations and chromosomal abnormalities are more common in cells from old animals and humans than in young cells. Also mutations in DNA repair genes can accelerate ageing. People born with these mutations suffer from progeria, and age very quickly.

mitochondrial dysfunction with age
Upper left image shows a cell. The nucleus is in the centre and mitochondria are shown in red. The lower picture shows an electron micrograph of a mitochondrion. Image by Countincr from Wikimedia Commons

Mitochondrial DNA mutations

Mitochondria are organelles inside each cell that generate the energy needed for the cell to survive. When mitochondria don’t work properly, the cell ages more quickly. And mitochondria are less efficient in older cells – they make less ATP (which the cell uses for energy). Older cells also have more byproducts of energy synthesis called reactive oxygen species. However, it isn’t yet clear whether more ROS causes ageing or is just a consequence of ageing.

Telomere shortening

Telomeres are the regions at the end of chromosomes. They comprise repeated DNA sequences that protect the important DNA from being chopped off each time DNA is copied so the cell can divide and reproduce. Every time the cell divides, some of the telomeres are lost, so older cells, which have divided more times than younger cells, have shorter telomeres than younger cells. Telomeres can’t be repaired by normal DNA repair mechanisms – they are protected against the DNA repair proteins and enzymes by the shelterin complex of proteins. If telomeres were repaired how DNA breaks are repaired, chromosomes would fuse together. So telomeres are repaired by an enzyme called telomerase, but this enzyme is not in most cells in the adult human body. Since telomeres can’t be repaired like other DNA, they are more susceptible to age-related damage. DNA damage in telomeres can cause the cell to die. Once there are no more telomores, the cell can no longer divide. Humans born with telomerase deficiency have tissues that can’t regenerate properly and can suffer from diseases like pulmonary fibrosis, aplastic anaemia, and dyskeratosis congenita.

Epigenetic changes

Epigenetic alterations are reversible marks on DNA that do not change the DNA sequence. These include DNA methylation, post-translation histone modification, and chromatin remodelling. Epigenetic marks change as we age. These changes may cause problems with DNA repair and genome stability, or change how certain genes are regulated. This could alter metabolism and energy production in the cell. Epigenetic changes are easier to alter than DNA mutations. So epigenetic causes of ageing are good targets for anti-ageing treatments.

Defective Protein Handling

Proteins in our cells are constantly being recycled. Old damaged proteins are removed, and new proteins are made to replace them. If this system doesn’t work, there is an accumulation of damaged proteins in cell. Damaged proteins can aggregate together becoming toxic to the cell. Protein aggregrates are a major cause of diseases like Alzheimer’s and Huntington’s.

Nutrient Sensing

Each cell has an intricate nutrient sensing system that balances how energy is produced, stored and used inside the cell. The nutrient sensing system can be manipulated to slow down or speed up ageing in animal models, from worms to mice. cells age more quickly. Overall, a decrease in nutrients, from either calorie restriction, or from changing key nutrient sensing genes, can increase life span. This effect only happens if each cell still has the minimal energy required to live. If not, the animal will die.

Oxidative Stress

Oxidative stress is caused by reactive oxygen species (ROS) which are produced as a byproduct of energy production. For a long time, scientists have thought that ROS cause ageing. Now we think that ROS can work as a stress signal that turns on compensatory pathways to offset the stress. However, if the ROS levels go up over a certain threshold, they can cause cellular damage.

Cellular Senescence

Cellular senescence occurs when the cell can no longer divide. This can be caused by telomere shortening or DNA damage.

Stem Cell Exhaustion

Stem cells are immature cells that can divide to generate different adult cells. One stem cell can create many adult cells. So stem cells are an important mechanisms for regenerating aged and damaged tissues. Our stem cell numbers decline as we age, so we are less able to regenerate tissues.

Altered Intracellular Communication

There are many different ways that cells and organs can communicate to each other. A number of organs in the body secrete hormones that can affect other organs or the whole body. This is called endocrine signalling. Endocrine signalling and signalling both between neurons and from the brain to the rest of the body is all affected by ageing.

The Scientific Review (it’s free and open access – woohoo!):
Lopez-Otin et al. The hallmarks of aging. Cell. 2014.

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