Longevity

101 Facts About Ageing #26: DNA Accumulates Damage With Age

Posted on 11 August 2021

As Daniel Patrick Moynihan, an American sociologist, politician, and diplomat once said: “Everyone is entitled to his own opinion, but not his own facts”. And we wholeheartedly agree. A shared set of facts is the first step to building a better world with longevity for all. In that spirit, we are creating a series that covers 101 indisputable facts about ageing, health and longevity.

The DNA is the cell’s instruction manual, containing all of the information needed to synthesize the proteins essential for life. As we age, this instruction manual accumulates errors (mutations). This occurs when DNA is incorrectly copied during cell division, and when the DNA molecule is damaged. If the manual accumulates enough errors, some instructions might no longer be legible, which will impair the cell’s ability to function properly. These errors accumulate more rapidly with age, as our cells’ defences against DNA damage falter while exposure to damaging agents increases. This build-up of mutations is called genomic instability, and is one of the primary hallmarks of ageing.

Aside from simply reducing the cell’s ability to function correctly, genomic instability causes many other problems. As cancers are usually the result of not one but multiple genetic mutations in different genes, a higher level of genomic instability makes it more likely for a new mutation to result in the development of cancer. This is one of the reasons that age remains the most important risk factor for cancer (see fact #14).

Sufficient levels of genomic instability can cause a cell to ‘commit suicide’ (apoptosis) or become senescent (a state of arrested cell division) before it has the chance to become cancerous. While this does protect the organism against cancer in the short term, certain organs like muscle and the brain see their function impaired as more and more cells accumulate damage and undergo apoptosis or senescence.

DNA Damage Response: R&D Systems
DNA is constantly exposed to sources of damage (red), both from within the body and from outside. Cells have mechanisms to repair/limit this damage or alternatively to self-destruct if severe damage is sustained (blue).
Source

Studies in multiple organisms including humans have found that both the number and the rate of accumulation of genetic mutations is higher in older organisms. Defects in DNA repair mechanisms appear to accelerate ageing in both animals and humans, as does chemotherapy that damages the DNA. Genomic instability resulting from replication errors unsurprisingly occurs more commonly in cell types that divide more frequently. Measurements based on RNA sequencing puts the frequency of mutations in cells of the small intestine and the oesophagus (which have relatively high turnover rates) at around three times that of hippocampal cells and heart cells (which divide very slowly or not at all).

Graph showing the number of mutations across 36 human tissues. The x-axis shows the number of unique sequencing reads made for that tissue. The blue line shows the number of mutations that would be expected if mutations were evenly distributed amongst tissue cells. Points above and below the line represent tissues in which cells acquire mutations faster or more slowly than expected.
Source

Besides this, sources of DNA damage are varied. Some we have little control over, such as the ionising radiation originating from space and from the Earth, or certain molecules that are inevitable natural products of metabolic processes within our cells. Others we may have the ability to avoid, such as exposure to ultraviolet light and harmful chemicals, such as those found in cigarette smoke.


References

The somatic mutation landscape of the human body: https://doi.org/10.1186/s13059-019-1919-5

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