Longevity, Magazine

1. genomic instability


The genome is a term that, in simplified terms, describes the totality of hereditary information of an individual. This is information for the production of proteins, which can help determine and change the appearance of the body in many ways. The DNA as the storage location for this information is thus similar to a blueprint for the body. For this reason, it is imperative for each individual cell that the DNA is preserved as flawlessly as possible. Because: If certain parts are missing, the whole plan sometimes makes no sense. In healthy people, such changes can be better repaired by the body at a young age than in later phases of life. This circumstance also explains the fact that genetic disorders become more frequent in old age. Genomic instability, however, is an issue throughout life.

The fact is that the integrity and stability of DNA is continuously being challenged. The attacks come from external (exogenous) and endogenous threats.

External threats

Threats of external origin include chemical or biological agents and thus, for example, drugs. In addition, physics via UV light, specifically UV-C light, can also damage DNA.


Image: By Mrmw - This file was derived from: DNA UV mutation.svg:, CC0, https://commons.wikimedia.org/w/index.php?curid=90042281

Internal threats

Let's move on to the threats of endogenous origin. In the course of cell division, two daughter cells develop from one cell. Both daughter cells must naturally receive the same genetic information so that they can develop according to their purpose. For this purpose, the DNA doubles in the course of cell division (replication) and then divides evenly between the two new cells that arise. This sometimes results in so-called DNA replication errors, for example incorrect pairings between the two strands. This is suboptimal, but the body is prepared for it.

Cell division is organized as a cycle and control stations are built into this cycle. When a defect is detected, cell division stops and the defect is repaired in the best case. In the case that the repair system cannot repair the damage, the cell is put into the state of senescence. Senescence is the seventh hallmark of aging in our chronology and will be highlighted in a separate article.

Furthermore, metabolic processes in the body may produce free radicals. These are particularly reactive molecules that can disturb the reaction equilibrium and thus hinder useful reactions in the body. If it is an oxygen molecule, these molecules are referred to in technical jargon as reactive oxygen species. The body has an answer to this too, because antioxidants (article: Antioxidants and the relationship police) can neutralise these troublemakers to a certain extent.

Genomic instability & nuclear envelope defects

The aforementioned damages, whether of external or internal origin, are among the direct lesions of our blueprint, the DNA. In addition to this, defects in the cell nuclear architecture can also cause genome instability.
This works as follows.

The nucleus is a separate space surrounded by an envelope and is the place in the cell where DNA resides. The envelope of the cell nucleus is made up of many different proteins, including proteins from the lamin family. "lamina" is Latin and stands for plate, disc or layer. These "layer proteins" must be formed correctly for the envelope to function properly. This is similar to a house roof, which must be neither too rigid nor too soft in order to distribute the loads in the best possible way. If a problem occurs in connection with these "layer proteins" of the nuclear envelope, the genome becomes unstable. The reason for this is the fact that the DNA is connected to the nuclear envelope via molecules.

Let's look at a real-life example. There are people who can only form a shortened form of a special lamine. The shortened protein is called progerin. Accordingly, the disease is called progeria (=accelerated ageing). In these people, the nuclear envelope is not sufficiently stable (see picture). The result is a five- to tenfold increase in the speed of ageing. Affected people often die in childhood or adolescence.


Image: Scaffidi P, Gordon L, Misteli T (2005) The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. PLoS Biol 3(11): e395. https://doi.org/10.1371/journal.pbio.0030395

Genomic instability in the future

Even though progeria is an extraordinarily rare disease with a frequency of 1:1 million, the underlying defect is also relevant for each and every one of us. Scientists have shown that progerin, which disrupts the nuclear architecture, is also produced in people with a normal ageing process.

The genome is therefore practically constantly unstable due to the influences mentioned. No human being is exempt from this. The body as a man or woman just in case is prepared for many of these challenges. However, the efforts to keep instability in check or to repair it function only suboptimally with increasing age. For example, initially small micro-cracks develop into whole craters - our skin becomes wrinkled.

The good news is that the extent varies from individual to individual and, if anti-ageing research is anything to go by, is not definitive.

The next article in this series is about the second hallmark of ageing: telomere attrition.

From the series: Hallmarks of Aging
What invisible changes happen in the body as we get older? What are the reasons for wrinkles, cataracts or high blood pressure? We take a look at the hallmarks of aging in the series "Hallmarks of Aging": molecularly, profoundly, understandably.

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217. https://doi.org/10.1016/j.cell.2013.05.039


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