Hallmark 1: Genomic instability
What exactly is going on inside our bodies to cause ageing? According to a groundbreaking paper by Lopez-Otin et al., ageing is caused by the accumulation of damage in our cells, which compromise integrity and overall functionality. The key factors that orchestrate this decline are called the 12 Hallmarks of Ageing.
Genomic instability is the first hallmark and it refers to the gradual accumulation of errors and damage in DNA* over time. Alongside telomere shortening, epigenetic alterations, loss of proteostasis, and disabled macroautophagy, which we’ll get to—this DNA damage is categorized as a primary hallmark, which means that it is a core contributor to cellular damage during the ageing process.
DNA Damage and Skin
Perhaps the easiest thing to see as a consequence of DNA damage with age is sun- exposed skin. We all have seen the results of too much sun worship. UV light, which accompanies sunshine, is the most prevalent human carcinogen. UV light can directly damage our DNA, creating harmful changes known as DNA lesions - think of them like tiny dents or scratches on the genetic material inside our cells. The two main types of damage caused by UV light have complicated names: cyclobutane pyrimidine dimers and 6–4 photoproducts.
In normal physiological circumstances, our bodies have a built-in repair system that can spot and fix this damage, kind of like a mechanic repairing dents in a car. This process is called nucleotide excision repair, which cuts out the damaged part of the DNA and replaces it with healthy DNA. But if this repair system doesn’t work properly, the damage adds up. People with a rare condition called xeroderma pigmentosum have a faulty repair system, which makes them extremely sensitive to sunlight. As a result, they can develop premature skin ageing and have a 10,000 times higher risk of skin cancer compared to people without the condition.
This highlights how critical DNA repair is in preventing genomic instability. When DNA damage isn’t properly fixed, it leads to unstable, faulty genetic material, which can drive both premature ageing and disease.
How does DNA Become Damaged?
The integrity and stability of all your cells’ DNA is under constant threat by both external agents - physical, chemical, and biological, and internal threats - DNA replication errors, spontaneous reactions with water molecules, and reactive oxygen species (ROS) [2]. These changes can disrupt vital genes* or interfere with the mechanisms cells use to read and use their instruction manual. If such damaged or dysfunctional cells are not removed, they can undermine the balance and health of tissues and the entire body (think disease).
The Hallmarks of Ageing Criteria
Fulfilling the First Criteria
It should naturally occur as part of the ageing process.
DNA Repair Mechanisms
Although the types of DNA damage can vary widely, not to worry - your cells have evolved sophisticated ways to manage and fix these issues! In fact, they have three levels of defence in place:
Regulating harmful molecules: The first line of defence. Your cells work proactively to minimise the production of harmful molecules, like reactive oxygen species (ROS), that could damage DNA. If these molecules do form, cells have mechanisms to neutralise or eliminate them before they cause trouble [3].
Repairing DNA damage: If damage does occur, your cells have a toolbox of repair systems designed to fix it. These repair mechanisms can identify and correct errors, like mismatched base pairs or breaks in the DNA strands, to restore the integrity of the genetic code [4].
Post-repair defence: If a cell accumulates too much DNA damage—damage that can’t be effectively repaired—it moves on to the final line of defence. The cell is either directed to self-destruct (a process called apoptosis) or to stop dividing permanently (a state known as senescence). This helps prevent damaged cells from causing further harm to surrounding tissues or even contributing to diseases like cancer [4].
However, as a natural part of ageing, DNA damage does tend to accumulate and the effectiveness of these repair mechanisms can decline. This gradual loss of genomic stability therefore becomes a key factor in the development of age-related conditions.
Fulfilling The Second Criteria:
If genomic instability is experimentally accelerated, then ageing will increase.
There’s ample evidence that by accelerating DNA damage, animals age prematurely; this is largely due to the failure of DNA repair mechanisms. But, in humans, it would be unethical to introduce such defects purposefully. Instead, scientists have to look at defects that occur naturally in an attempt to draw conclusions on this criteria. A major review paper on protecting the ageing genome [5] highlights one of the clearest examples of this: people with inherited problems in their DNA repair systems often age faster than usual. But the way they age depends on which repair system is affected. For example, people with Cockayne syndrome—caused by changes in the ERCC6 and ERCC8 genes—experience early ageing symptoms in their nervous system, affecting their brain and nerves. Those with Werner syndrome—caused by a change in the WRN gene—show signs of premature ageing in their heart and blood vessels. In fact scientists have identified over 50 different DNA repair disorders, but no single one causes full- body ageing in the exact way normal ageing does. Instead, each defect leads to different symptoms in specific parts of the body, helping researchers slowly piece together how DNA damage contributes to this process.
Fulfilling The Third Criteria:
“If the hallmark is experimentally stopped or reduced, then ageing will decrease”
In their earlier work, López-Otín and colleagues had limited experimental evidence directly supporting this idea. Their strongest example came from a 2013 study by Baker and colleagues, which involved genetically modified mice that produced extra amounts of a protein crucial for proper cell division. This protein helped prevent mistakes in chromosome numbers, a form of genomic instability [6]. The result? These mice not only had lower rates of cancer and fewer chromosome abnormalities but also lived longer, healthier lives. More recent studies have provided even stronger evidence. But what about humans? While direct experimental evidence in people is limited, as for obvious reasons we can’t genetically modify humans for research, there are clues from existing genetic disorders. Individuals with genetic disorders, namely Werner syndrome and Bloom syndrome, where DNA repair mechanisms are impaired, exhibit accelerated ageing, suggesting that defective DNA repair contributes to ageing. Conversely, certain genetic variants that enhance DNA repair are associated with healthier ageing and
increased longevity. For instance, research on centenarians has identified certain genetic variants in DNA repair genes [7]. These variants are thought to enhance the efficiency of DNA repair pathways, helping to maintain genomic integrity and reduce age-related genomic instability. Thus implying that improving DNA repair mechanisms could slow down ageing. Although not an "experimental" intervention in the strictest sense, these natural human models support the idea that enhancing DNA repair reduces ageing effects, fitting the criterion through anecdotal evidence. However, further research, perhaps using human cell lines, is needed to solidify this.
The Takeaway
The science is clear: protecting the genome is of fundamental importance for normal, healthy aging. Some DNA damage is preventable—think avoiding nuclear waste and wearing sunscreen—but certainly not all of it. While there are still many questions to be answered by scientists (keep going, scientists!), research continues to expand our understanding of DNA damage and its role in ageing. This knowledge may lead to the development of novel interventions promoting a lengthy healthspan.
As we continue exploring the remaining hallmarks of ageing, we'll see how genomic instability triggers and amplifies other hallmarks, painting a comprehensive picture of why and how we age. This deeper understanding not only advances our scientific knowledge but also empowers us with practical steps to promote healthier, more resilient ageing today.
Vocab Refresh:
*DNA: The molecule that carries the genetic instructions for life. It’s like a long, twisted ladder made up of chemical building blocks called base pairs, that form genes which are arranged in a specific sequence.
*Gene: A gene is a section of DNA that carries the instructions for making specific protein or group of proteins within your body. In humans, most genes differ slightly from person to person, often by just one to three tiny changes in the DNA sequence.
*Genome: A genome is an organism’s entire, complete set of DNA. The genome is the instruction manual for building and running the human body. Every cell in your body has its own copy of this manual, giving it the complete set of instructions it needs to play its part—whether that be a skin cell, a muscle cell, or a brain cell.
References:
Hallmarks of ageing paper: López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349.
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[3] Jena AB, Samal RR, Bhol NK, Duttaroy AK. Cellular Red-Ox system in health and disease: The latest update. Biomed Pharmacother. 2023 Jun;162:114606. doi: 10.1016/j.biopha.2023.114606. Epub 2023 Mar 28. PMID: 36989716
[4] Chen J, Potlapalli R, Quan H, Chen L, Xie Y, Pouriyeh S, Sakib N, Liu L, Xie Y. Exploring DNA Damage and Repair Mechanisms: A Review with Computational Insights. BioTech (Basel). 2024 Jan 16;13(1):3. doi: 10.3390/biotech13010003. PMID: 38247733; PMCID: PMC10801582.
[5] Petr MA, Tulika T, Carmona-Marin LM, Scheibye-Knudsen M. Protecting the Aging Genome. Trends Cell Biol. 2020 Feb;30(2):117-132. doi: 10.1016/j.tcb.2019.12.001. Epub 2020 Jan 6. PMID: 31917080.
[6] Kim HS, Kim BH, Jung JE, Lee CS, Lee HG, Lee JW, Lee KH, You HJ, Chung MH, Ye SK. Potential role of 8-oxoguanine DNA glycosylase 1 as a STAT1 coactivator in endotoxin-induced inflammatory response. Free Radic Biol Med. 2016 Apr;93:12-22. doi: 10.1016/j.freeradbiomed.2015.10.415. Epub 2015 Nov 11. PMID: 26496208
[7] Santos-Lozano A, Santamarina A, Pareja-Galeano H, Sanchis-Gomar F, Fiuza-Luces C, Cristi-Montero C, Bernal-Pino A, Lucia A, Garatachea N. The genetics of exceptional longevity: Insights from centenarians. Maturitas. 2016 Aug;90:49-57. doi: 10.1016/j.maturitas.2016.05.006
Authors: Katsume Stoneham & Georgia Pilling
