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Genomic instability: a force behind aging and cancer

Article
April 9, 2022
By
Olena Mokshyna, PhD.

Aging and cancer are strongly connected to genomic instability and the accumulation of harmful mutations in cells.

Highlights:

 

  • Genomic instability is a phenomenon of the high frequency of mutations within the genome
  • One of the main reasons behind genomic instability is replication stress that results from DNA damage
  • Genomic instability is considered a primary hallmark of aging and one of the hallmarks of cancer

Introduction

Each cell undergoes up to one million DNA changes per day, and though most of them are rapidly repaired, but the accumulation of the damage can lead to grave consequences. Genomic instability is a term used to describe a high frequency of mutations within the genome (all genetic information of an organism). Such mutations can occur through various mechanisms, including changes in nucleic acid sequences, chromosomal rearrangements, or aneuploidy (abnormal number of chromosomes in a cell). Though crucial for genetic diversity and evolution, genomic instability was linked to carcinogenesis in multicellular organisms. Genomic instability has also been connected to multiple pathologies in humans, including neurodegenerative and neuromuscular diseases. Genomic instability is considered a primary hallmark of aging due to its detrimental influence on cell and organism functionality.

DNA

           

Why does genomic instability occur?

Cell cycle involves multiple fine-tuned processes that ensure genome integrity. The key to the proper flow of these processes is efficient and error-free DNA replication. The main reason behind genomic instability is DNA replication stress, which occurs to the cell undergoing replication and can stall this process. Replication stress can occur due to many factors, among them (1):

  • Damaged or unusual DNA structure,
  • Common fragile sites,
  • Overexpression of oncogenes, 
  • Conflicts between replication and transcription.

Irreversible DNA damage is considered the main cause of genomic instability, which, in turn, encompasses multiple genetic alterations from point mutations to chromosome rearrangements. Depending on the consequences of replication stress event, genomic instability can be divided into two main classes (2):

  • Chromosomal instability (CIN) that leads to chromosome gain or loss;
  • Micro- and minisatellite instability (MIN) that increases the tendency to DNA mutations due to the errors in the mismatch repair mechanism (DNA repair mechanism that fixes erroneous insertion, deletion, and misincorporation of bases). MIN is linked to satellites - areas of DNA where certain motifs are repeated.

Damaged DNA

DNA damage occurs from both endogenous and exogenous factors. On average, the human genome accumulates around 105 DNA lesions per day (3). Endogenous agents that cause DNA damage include mainly reactive oxygen species (ROS), reactive nitrogen species , and environmental sources are DNA damaging agents, such as radiation, chemical mutagens, and carcinogens. 

There are several main types of DNA damage (4): 

  • Oxidative damage caused by ROS, an example being oxidation of guanine; 
  • Alkylation of bases, the most common type being methylation;
  • Base loss caused by hydrolysis of either purine or pyrimidine base that can happen eiether spontaneously or due to the errors in DNA repair;
  • Bulky adduct formation happens when a big reactive molecule (such as the components of cigarette smoke) attaches itself to one of the DNA strands and branches out from it;
  • DNA crosslinking, when chemical agents react with two nucleotides and form a link between them either within the same strand (intrastrand) or between two opposite strands (interstrand);
  • DNA strand breaks when one or both DNA strands break entirely.

Despite the high DNA damage rate, most DNA lesions do not convert into DNA mutations due to a range of sophisticated DNA-damage sensing and repairing mechanisms. Most of them are rapidly corrected (5), but some – such as single-strand (SSB) and double-strand (DSB) DNA breaks – are extremely dangerous. Among the repair mechanisms, nucleotide excision repair (NER) is targeted mainly at bulky lesions. Small base damages and SSB are fixed by base excision repair (BER), which is critically important during embryogenesis. During replication, the mismatch repair pathways (MMR) are activated, which can correct nucleotide misincorporation. DSBs are repaired by two major mechanisms - homologous recombination (HR) and non-homologous end-joining (NHEJ). HR is a highly accurate mechanism, which can use a sister chromatid (one half of a duplicated chromosome, an identical copy created during DNA replication of a chromosome) as a template. Unlike HR, NHEJ is a simpler mechanism that directly reconnects two broken DNA ends without a homologous template. NHEJ can result in small deletions or translocations, but it appears to be a major repair mechanism in non-dividing somatic cells (i.e., skin cells and neurons). Highly toxic DNA intra- or inter-strand crosslinks can be removed by HR pathways in symphony with other pathways such as NER (6). 

Irreversible DNA damage 

Even the highly efficient mechanism of repairment can malfunction, and then DNA damage can cause mutations in critical genes (such as tumor suppressor genes). In most cases, when a cell suffers DNA damage that is beyond repair, it is disposed of through apoptosis (a programmed cell death) or becomes senescent (7). Both apoptosis and senescence are heavily regulated through tumor protein p53, known as the guardian of the genome. Autophagy - a process of cellular self-degradation - can also be triggered by DNA damage (8). However, if these cellular response malfunctions, the mutated cells are accumulated and continue to proliferate, potentially leading to cancer. 

Other factors of replication stress

Fragile sites are specific loci in the human genome that are particularly difficult to replicate. They can be either common or rare. Common fragile sites are present in almost all individuals, whereas rare fragile sites are found in less than 5% of the population (9). These sites are characterized by trinucleotide repeats, most commonly CGG, CAG, GAA, and GCN (N standing for A or G), which can form into hairpin-like structures, leading to difficulty of replication (10). Common fragile sites are prone to replication stress-induced DNA DSBs. 

Another replication stress factor is overexpression of oncogenes such as cyclin E, which leads to normal replication perturbation, activation of the DNA damage response, and cellular arrest or senescence (11). c-Myc is another oncogene able to activate a DNA damage response and increase genomic instability (12).

Collisions between transcription and replication are an additional factor of genomic instability. In higher eukaryotes, replication and transcription are coordinated and occur within spatially and temporally separated domains. Nevertheless, if the transcription of a particularly large gene occurs during more than one cell cycle (13), it can lead to a collision and formation of DNA–RNA hybrids (R-loops).

 

Genomic instability and aging

One common denominator of aging is the accumulation of genetic damage (14) linked to genomic instability, which is considered one of the primary hallmarks of aging (15).

Under normal conditions, cells recover effectively and rapidly after DNA damage. The repair capacity far exceeds the DNA damage rate at a young age. However, as organism ages, bursts of DNA damage (for example, from inflammation) give rise to an increasingly high rate of apoptosis, cellular senescence, or mutations. Age-related decline in genome maintenance mechanisms may intensify genomic instability. Studies show that multiple DNA damage repair functions become compromised and more error-prone with aging (16), among them BER and NHEJ. 

The frequency of genome rearrangements increases exponentially at old age, while cellular responses such as apoptosis become less efficient (17). Altogether, this increases the accumulation of damaged cells in tissues and organs. Moreover, even if DNA damage gets repaired at an older age, the frequency of errors made by DNA repair mechanisms also increases, leading to the accumulation of irreversible mutations.

Genomic instability and cancer

Aging and cancer are frequently regarded as two different manifestations of the same underlying process - the accumulation of cellular damage. In addition, several pathologies associated with aging, such as atherosclerosis and inflammation, involve uncontrolled cellular overgrowth or hyperactivity (18). Thus, genomic instability also presents one of the leading hallmarks of cancer.

Almost all human cancers are characterized by genomic instability. Most cancers are impacted by the CIN form of instability connected to the high rate by which chromosome structure and number change over time in cancer cells compared with normal cells. However, recent research shows that MIN also plays its role. Genomic instability is present in all stages, from precancerous lesions to advanced stages of the disease (19). The molecular basis is well understood only in hereditary cancers, in which it has been linked to mutations in DNA repair genes. However, the molecular basis of genomic instability in sporadic cancers is much less well defined. 

Can we stabilize the genome?

The stability of the genome can be estimated via the biomarkers of genome integrity, including telomere length. These biomarkers have been recently utilized to establish whether optimizing diet and nutrient intake can help to stabilize the genome (20). Though the research is ongoing, some promising results are already available. These findings also have prompted the development of nutrigenomics – a field that aims to determine how a particular genotype and expression profile are connected to nutrient metabolism and absorption (21).

There is limited evidence both from animal studies and human trials demonstrating the putative genome-stabilizing role of carotenoids and vitamin A (22–24), range of B vitamins (including niacin, folate, and vitamin B12) (25), vitamin D (26), and minerals such as iron (27), selenium (28), and zinc (29). Another positively influencing dietary factor is a diet high in plant-based food (30). ​​There is some, albeit limited evidence, that consumption of products, such as blueberry juice (31) and olive oil (32), can also counteract DNA damage.

A range of therapeutics targeted at various mechanisms of DNA repair and damage is being researched to decrease genomic instability (33). Among already known drugs, metformin, the diabetes drug, was shown to reduce DNA damage by a not yet completely understood mechanism (34).

While mitigating genomic instability is not a straightforward task, the factors that increase the risks are well-known – smoking, exposure to industrial chemicals, and extensive UV exposure. All these factors increase the risks of increasing DNA damage and, correspondingly, inducing genomic instability.

Conclusions

Genomic integrity is one of the crucial conditions for adequate cell proliferation and organism functioning. When this integrity is threatened, the organism becomes vulnerable to multiple diseases. Aging and cancer are strongly connected to genomic instability and the accumulation of harmful mutations in cells. Though the evidence is limited for effective prevention and treatment of genomic instability, the research is being actively carried out in this direction. Some data points towards the benefits of a healthy diet to maintain genomic integrity, and the benefits of avoiding harmful factors such as smoking are beyond doubt.

References

 

1.         Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014 Jan;16(1):2–9.

2.         Aguilera A, Gómez-González B. Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet. 2008 Mar;9(3):204–17.

3.         Fakouri NB, Hou Y, Demarest TG, Christiansen LS, Okur MN, Mohanty JG, et al. Toward understanding genomic instability, mitochondrial dysfunction and aging. FEBS J. 2019 Mar;286(6):1058–73.

4.         Flatt PM. DNA Damage and Repair. In: BIOCHEMISTRY - DEFINING LIFE AT THE MOLECULAR LEVEL [Internet]. Western Oregon University, Monmouth, OR (CC BY-NC-SA); 2019. Available from: https://wou.edu/chemistry/courses/online-chemistry-textbooks/ch450-and-ch451-biochemistry-defining-life-at-the-molecular-level/?preview_id=4919&preview_nonce=cca8f0ce36&preview=true

5.         Li W, Vijg J. Measuring Genome Instability in Aging – A Mini-Review. Gerontology. 2012;58(2):129–38.

6.         Ho TV, Schärer OD. Translesion DNA synthesis polymerases in DNA interstrand crosslink repair. Environ Mol Mutagen. 2010;NA-NA.

7.         White RR, Vijg J. Do DNA Double-Strand Breaks Drive Aging? Mol Cell. 2016 Sep;63(5):729–38.

8.         Vicencio JM, Galluzzi L, Tajeddine N, Ortiz C, Criollo A, Tasdemir E, et al. Senescence, Apoptosis or Autophagy? Gerontology. 2008;54(2):92–9.

9.         Mazouzi A, Velimezi G, Loizou JI. DNA replication stress: Causes, resolution and disease. Exp Cell Res. 2014 Nov;329(1):85–93.

10.       Durkin SG, Glover TW. Chromosome Fragile Sites. Annu Rev Genet. 2007 Dec 1;41(1):169–92.

11.       Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006 Nov;444(7119):633–7.

12.       Reimann M, Loddenkemper C, Rudolph C, Schildhauer I, Teichmann B, Stein H, et al. The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo. Blood. 2007 Oct 15;110(8):2996–3004.

13.       Helmrich A, Ballarino M, Tora L. Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes. Mol Cell. 2011 Dec;44(6):966–77.

14.       Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, et al. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev. 2013 Mar;12(2):661–84.

15.       López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013 Jun;153(6):1194–217.

16.       Gorbunova V, Seluanov A, Mao Z, Hine C. Changes in DNA repair during aging. Nucleic Acids Res. 2007 Nov 26;35(22):7466–74.

17.       Suh Y, Lee K-A, Kim W-H, Han B-G, Vijg J, Park SC. Aging alters the apoptotic response to genotoxic stress. Nat Med. 2002 Jan;8(1):3–4.

18.       Blagosklonny MV. Aging: ROS or TOR. Cell Cycle. 2008 Nov;7(21):3344–54.

19.       Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability — an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010 Mar;11(3):220–8.

20.       Ferguson LR, Chen H, Collins AR, Connell M, Damia G, Dasgupta S, et al. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol. 2015 Dec;35:S5–24.

21.       Neeha VS, Kinth P. Nutrigenomics research: a review. J Food Sci Technol. 2013 Jun;50(3):415–28.

22.       Sram RJ, Farmer P, Singh R, Garte S, Kalina I, Popov TA, et al. Effect of vitamin levels on biomarkers of exposure and oxidative damage—The EXPAH study. Mutat Res Toxicol Environ Mutagen. 2009 Jan;672(2):129–34.

23.       Cho S, Lee DH, Won C-H, Kim SM, Lee S, Lee M-J, et al. Differential Effects of Low-Dose and High-Dose Beta-Carotene Supplementation on the Signs of Photoaging and Type I Procollagen Gene Expression in Human Skin in vivo. Dermatology. 2010;221(2):160–71.

24.       van Helden YGJ, Keijer J, Heil SG, Pico C, Palou A, Oliver P, et al. Beta-carotene affects oxidative stress-related DNA damage in lung epithelial cells and in ferret lung. Carcinogenesis. 2009 Dec 1;30(12):2070–6.

25.       The Micronutrient Genomics Project Working Group, van Ommen B, El-Sohemy A, Hesketh J, Kaput J, Fenech M, et al. The Micronutrient Genomics Project: a community-driven knowledge base for micronutrient research. Genes Nutr. 2010 Dec;5(4):285–96.

26.       Nair-Shalliker V, Armstrong BK, Fenech M. Does vitamin D protect against DNA damage? Mutat Res Mol Mech Mutagen. 2012 May;733(1–2):50–7.

27.       Prá D, Franke SIR, Henriques JAP, Fenech M. Iron and genome stability: An update. Mutat Res Mol Mech Mutagen. 2012 May;733(1–2):92–9.

28.       Ferguson LR, Karunasinghe N, Zhu S, Wang AH. Selenium and its’ role in the maintenance of genomic stability. Mutat Res Mol Mech Mutagen. 2012 May;733(1–2):100–10.

29.       Sharif R, Thomas P, Zalewski P, Fenech M. The role of zinc in genomic stability. Mutat Res Mol Mech Mutagen. 2012 May;733(1–2):111–21.

30.       Lim U, Song M-A. Dietary and Lifestyle Factors of DNA Methylation. In: Dumitrescu RG, Verma M, editors. Cancer Epigenetics [Internet]. Totowa, NJ: Humana Press; 2012 [cited 2022 Mar 9]. p. 359–76. (Methods in Molecular Biology; vol. 863). Available from: http://link.springer.com/10.1007/978-1-61779-612-8_23

31.       Wilms LC, Boots AW, de Boer VCJ, Maas LM, Pachen DMFA, Gottschalk RWH, et al. Impact of multiple genetic polymorphisms on effects of a 4-week blueberry juice intervention on ex vivo induced lymphocytic DNA damage in human volunteers. Carcinogenesis. 2007 Aug;28(8):1800–6.

32.       Weinbrenner T, Fitó M, Torre R de la, Saez GT, Rijken P, Tormos C, et al. Olive Oils High in Phenolic Compounds Modulate Oxidative/Antioxidative Status in Men. J Nutr. 2004 Sep 1;134(9):2314–21.

33.       Bielski CM, Taylor BS. Homing in on genomic instability as a therapeutic target in cancer. Nat Commun. 2021 Dec;12(1):3663.

34.       Najafi M, Cheki M, Rezapoor S, Geraily G, Motevaseli E, Carnovale C, et al. Metformin: Prevention of genomic instability and cancer: A review. Mutat Res Toxicol Environ Mutagen. 2018 Mar;827:1–8.

Highlights:

 

  • Genomic instability is a phenomenon of the high frequency of mutations within the genome
  • One of the main reasons behind genomic instability is replication stress that results from DNA damage
  • Genomic instability is considered a primary hallmark of aging and one of the hallmarks of cancer

Introduction

Each cell undergoes up to one million DNA changes per day, and though most of them are rapidly repaired, but the accumulation of the damage can lead to grave consequences. Genomic instability is a term used to describe a high frequency of mutations within the genome (all genetic information of an organism). Such mutations can occur through various mechanisms, including changes in nucleic acid sequences, chromosomal rearrangements, or aneuploidy (abnormal number of chromosomes in a cell). Though crucial for genetic diversity and evolution, genomic instability was linked to carcinogenesis in multicellular organisms. Genomic instability has also been connected to multiple pathologies in humans, including neurodegenerative and neuromuscular diseases. Genomic instability is considered a primary hallmark of aging due to its detrimental influence on cell and organism functionality.

DNA

           

Why does genomic instability occur?

Cell cycle involves multiple fine-tuned processes that ensure genome integrity. The key to the proper flow of these processes is efficient and error-free DNA replication. The main reason behind genomic instability is DNA replication stress, which occurs to the cell undergoing replication and can stall this process. Replication stress can occur due to many factors, among them (1):

  • Damaged or unusual DNA structure,
  • Common fragile sites,
  • Overexpression of oncogenes, 
  • Conflicts between replication and transcription.

Irreversible DNA damage is considered the main cause of genomic instability, which, in turn, encompasses multiple genetic alterations from point mutations to chromosome rearrangements. Depending on the consequences of replication stress event, genomic instability can be divided into two main classes (2):

  • Chromosomal instability (CIN) that leads to chromosome gain or loss;
  • Micro- and minisatellite instability (MIN) that increases the tendency to DNA mutations due to the errors in the mismatch repair mechanism (DNA repair mechanism that fixes erroneous insertion, deletion, and misincorporation of bases). MIN is linked to satellites - areas of DNA where certain motifs are repeated.

Damaged DNA

DNA damage occurs from both endogenous and exogenous factors. On average, the human genome accumulates around 105 DNA lesions per day (3). Endogenous agents that cause DNA damage include mainly reactive oxygen species (ROS), reactive nitrogen species , and environmental sources are DNA damaging agents, such as radiation, chemical mutagens, and carcinogens. 

There are several main types of DNA damage (4): 

  • Oxidative damage caused by ROS, an example being oxidation of guanine; 
  • Alkylation of bases, the most common type being methylation;
  • Base loss caused by hydrolysis of either purine or pyrimidine base that can happen eiether spontaneously or due to the errors in DNA repair;
  • Bulky adduct formation happens when a big reactive molecule (such as the components of cigarette smoke) attaches itself to one of the DNA strands and branches out from it;
  • DNA crosslinking, when chemical agents react with two nucleotides and form a link between them either within the same strand (intrastrand) or between two opposite strands (interstrand);
  • DNA strand breaks when one or both DNA strands break entirely.

Despite the high DNA damage rate, most DNA lesions do not convert into DNA mutations due to a range of sophisticated DNA-damage sensing and repairing mechanisms. Most of them are rapidly corrected (5), but some – such as single-strand (SSB) and double-strand (DSB) DNA breaks – are extremely dangerous. Among the repair mechanisms, nucleotide excision repair (NER) is targeted mainly at bulky lesions. Small base damages and SSB are fixed by base excision repair (BER), which is critically important during embryogenesis. During replication, the mismatch repair pathways (MMR) are activated, which can correct nucleotide misincorporation. DSBs are repaired by two major mechanisms - homologous recombination (HR) and non-homologous end-joining (NHEJ). HR is a highly accurate mechanism, which can use a sister chromatid (one half of a duplicated chromosome, an identical copy created during DNA replication of a chromosome) as a template. Unlike HR, NHEJ is a simpler mechanism that directly reconnects two broken DNA ends without a homologous template. NHEJ can result in small deletions or translocations, but it appears to be a major repair mechanism in non-dividing somatic cells (i.e., skin cells and neurons). Highly toxic DNA intra- or inter-strand crosslinks can be removed by HR pathways in symphony with other pathways such as NER (6). 

Irreversible DNA damage 

Even the highly efficient mechanism of repairment can malfunction, and then DNA damage can cause mutations in critical genes (such as tumor suppressor genes). In most cases, when a cell suffers DNA damage that is beyond repair, it is disposed of through apoptosis (a programmed cell death) or becomes senescent (7). Both apoptosis and senescence are heavily regulated through tumor protein p53, known as the guardian of the genome. Autophagy - a process of cellular self-degradation - can also be triggered by DNA damage (8). However, if these cellular response malfunctions, the mutated cells are accumulated and continue to proliferate, potentially leading to cancer. 

Other factors of replication stress

Fragile sites are specific loci in the human genome that are particularly difficult to replicate. They can be either common or rare. Common fragile sites are present in almost all individuals, whereas rare fragile sites are found in less than 5% of the population (9). These sites are characterized by trinucleotide repeats, most commonly CGG, CAG, GAA, and GCN (N standing for A or G), which can form into hairpin-like structures, leading to difficulty of replication (10). Common fragile sites are prone to replication stress-induced DNA DSBs. 

Another replication stress factor is overexpression of oncogenes such as cyclin E, which leads to normal replication perturbation, activation of the DNA damage response, and cellular arrest or senescence (11). c-Myc is another oncogene able to activate a DNA damage response and increase genomic instability (12).

Collisions between transcription and replication are an additional factor of genomic instability. In higher eukaryotes, replication and transcription are coordinated and occur within spatially and temporally separated domains. Nevertheless, if the transcription of a particularly large gene occurs during more than one cell cycle (13), it can lead to a collision and formation of DNA–RNA hybrids (R-loops).

 

Genomic instability and aging

One common denominator of aging is the accumulation of genetic damage (14) linked to genomic instability, which is considered one of the primary hallmarks of aging (15).

Under normal conditions, cells recover effectively and rapidly after DNA damage. The repair capacity far exceeds the DNA damage rate at a young age. However, as organism ages, bursts of DNA damage (for example, from inflammation) give rise to an increasingly high rate of apoptosis, cellular senescence, or mutations. Age-related decline in genome maintenance mechanisms may intensify genomic instability. Studies show that multiple DNA damage repair functions become compromised and more error-prone with aging (16), among them BER and NHEJ. 

The frequency of genome rearrangements increases exponentially at old age, while cellular responses such as apoptosis become less efficient (17). Altogether, this increases the accumulation of damaged cells in tissues and organs. Moreover, even if DNA damage gets repaired at an older age, the frequency of errors made by DNA repair mechanisms also increases, leading to the accumulation of irreversible mutations.

Genomic instability and cancer

Aging and cancer are frequently regarded as two different manifestations of the same underlying process - the accumulation of cellular damage. In addition, several pathologies associated with aging, such as atherosclerosis and inflammation, involve uncontrolled cellular overgrowth or hyperactivity (18). Thus, genomic instability also presents one of the leading hallmarks of cancer.

Almost all human cancers are characterized by genomic instability. Most cancers are impacted by the CIN form of instability connected to the high rate by which chromosome structure and number change over time in cancer cells compared with normal cells. However, recent research shows that MIN also plays its role. Genomic instability is present in all stages, from precancerous lesions to advanced stages of the disease (19). The molecular basis is well understood only in hereditary cancers, in which it has been linked to mutations in DNA repair genes. However, the molecular basis of genomic instability in sporadic cancers is much less well defined. 

Can we stabilize the genome?

The stability of the genome can be estimated via the biomarkers of genome integrity, including telomere length. These biomarkers have been recently utilized to establish whether optimizing diet and nutrient intake can help to stabilize the genome (20). Though the research is ongoing, some promising results are already available. These findings also have prompted the development of nutrigenomics – a field that aims to determine how a particular genotype and expression profile are connected to nutrient metabolism and absorption (21).

There is limited evidence both from animal studies and human trials demonstrating the putative genome-stabilizing role of carotenoids and vitamin A (22–24), range of B vitamins (including niacin, folate, and vitamin B12) (25), vitamin D (26), and minerals such as iron (27), selenium (28), and zinc (29). Another positively influencing dietary factor is a diet high in plant-based food (30). ​​There is some, albeit limited evidence, that consumption of products, such as blueberry juice (31) and olive oil (32), can also counteract DNA damage.

A range of therapeutics targeted at various mechanisms of DNA repair and damage is being researched to decrease genomic instability (33). Among already known drugs, metformin, the diabetes drug, was shown to reduce DNA damage by a not yet completely understood mechanism (34).

While mitigating genomic instability is not a straightforward task, the factors that increase the risks are well-known – smoking, exposure to industrial chemicals, and extensive UV exposure. All these factors increase the risks of increasing DNA damage and, correspondingly, inducing genomic instability.

Conclusions

Genomic integrity is one of the crucial conditions for adequate cell proliferation and organism functioning. When this integrity is threatened, the organism becomes vulnerable to multiple diseases. Aging and cancer are strongly connected to genomic instability and the accumulation of harmful mutations in cells. Though the evidence is limited for effective prevention and treatment of genomic instability, the research is being actively carried out in this direction. Some data points towards the benefits of a healthy diet to maintain genomic integrity, and the benefits of avoiding harmful factors such as smoking are beyond doubt.

References

 

1.         Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014 Jan;16(1):2–9.

2.         Aguilera A, Gómez-González B. Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet. 2008 Mar;9(3):204–17.

3.         Fakouri NB, Hou Y, Demarest TG, Christiansen LS, Okur MN, Mohanty JG, et al. Toward understanding genomic instability, mitochondrial dysfunction and aging. FEBS J. 2019 Mar;286(6):1058–73.

4.         Flatt PM. DNA Damage and Repair. In: BIOCHEMISTRY - DEFINING LIFE AT THE MOLECULAR LEVEL [Internet]. Western Oregon University, Monmouth, OR (CC BY-NC-SA); 2019. Available from: https://wou.edu/chemistry/courses/online-chemistry-textbooks/ch450-and-ch451-biochemistry-defining-life-at-the-molecular-level/?preview_id=4919&preview_nonce=cca8f0ce36&preview=true

5.         Li W, Vijg J. Measuring Genome Instability in Aging – A Mini-Review. Gerontology. 2012;58(2):129–38.

6.         Ho TV, Schärer OD. Translesion DNA synthesis polymerases in DNA interstrand crosslink repair. Environ Mol Mutagen. 2010;NA-NA.

7.         White RR, Vijg J. Do DNA Double-Strand Breaks Drive Aging? Mol Cell. 2016 Sep;63(5):729–38.

8.         Vicencio JM, Galluzzi L, Tajeddine N, Ortiz C, Criollo A, Tasdemir E, et al. Senescence, Apoptosis or Autophagy? Gerontology. 2008;54(2):92–9.

9.         Mazouzi A, Velimezi G, Loizou JI. DNA replication stress: Causes, resolution and disease. Exp Cell Res. 2014 Nov;329(1):85–93.

10.       Durkin SG, Glover TW. Chromosome Fragile Sites. Annu Rev Genet. 2007 Dec 1;41(1):169–92.

11.       Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006 Nov;444(7119):633–7.

12.       Reimann M, Loddenkemper C, Rudolph C, Schildhauer I, Teichmann B, Stein H, et al. The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo. Blood. 2007 Oct 15;110(8):2996–3004.

13.       Helmrich A, Ballarino M, Tora L. Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes. Mol Cell. 2011 Dec;44(6):966–77.

14.       Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, et al. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev. 2013 Mar;12(2):661–84.

15.       López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013 Jun;153(6):1194–217.

16.       Gorbunova V, Seluanov A, Mao Z, Hine C. Changes in DNA repair during aging. Nucleic Acids Res. 2007 Nov 26;35(22):7466–74.

17.       Suh Y, Lee K-A, Kim W-H, Han B-G, Vijg J, Park SC. Aging alters the apoptotic response to genotoxic stress. Nat Med. 2002 Jan;8(1):3–4.

18.       Blagosklonny MV. Aging: ROS or TOR. Cell Cycle. 2008 Nov;7(21):3344–54.

19.       Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability — an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010 Mar;11(3):220–8.

20.       Ferguson LR, Chen H, Collins AR, Connell M, Damia G, Dasgupta S, et al. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol. 2015 Dec;35:S5–24.

21.       Neeha VS, Kinth P. Nutrigenomics research: a review. J Food Sci Technol. 2013 Jun;50(3):415–28.

22.       Sram RJ, Farmer P, Singh R, Garte S, Kalina I, Popov TA, et al. Effect of vitamin levels on biomarkers of exposure and oxidative damage—The EXPAH study. Mutat Res Toxicol Environ Mutagen. 2009 Jan;672(2):129–34.

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Dr. Ana Baroni MD. Ph.D.

Scientific & Medical Advisor
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Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.

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