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Genomic Stability: United Nations' SDG "Good Health and Well-Being" Knowledge Series



Author:

Kenneth Kwok, Founder and CEO, Global Citizen Capital Co-President, AWAWA


This Knowledge Series is dedicated to my mother Ms. Evanda Li, my father Mr. Lawrence Kwok and to my late uncle Mr. KB Wong, who inspire me to become a better man every day, for myself, family, friends, community and world.


Overview of the Knowledge Series


To understand preventive healthcare, we have to first understand more about aging, which is the natural event occurring in all living organisms and can be defined as a deterioration of the cell functioning due to damage accumulation over time. This is an important biological, demographic and socio-economic issue all over the world. All living organisms have different longevity, indicating that evolution has played an important role in regulation and flexibilization of aging between species, in a relatively fast process. The understanding of the molecular basis of aging and longevity could let us manipulate it somehow in the future. In this regard, in the last 50 years numerous investigations related to aging have emerged, trying to explain this unstoppable process.


On this basis, preventive healthcare deals with the prevention of illness to decrease the burden of disease and associated risk factors. Preventive measures can be applied at all stages across the lifespan and along a disease spectrum, to prevent further decline over time. This 10 part series highlights the various key factors associated with aging and recommends examples of preventive recommendations, with a focus on affordability and access. Afterall, United Nations’ Sustainable Development Goal Number 3 – Good Health and Well-Being – targets ensuring healthy lives and promoting well-being for all at all ages.

Global Citizen Capital, in association with AWAWA, is honoured to participate in and contribute towards the combined UNDP, WHO and SDG initiatives to promote the conceptualization and commercialization of affordable preventive healthcare.


Knowledge Series - Part 1 - Genomic Instability


Introduction

One type of damage that occurs with aging is that errors tend to appear in our DNA. When DNA is replicated, the code might not always be copied correctly — parts could get misspelled, and sections could be accidentally inserted or deleted. These errors are not always caught by the mechanisms in our bodies that repair DNA. 


In the cell cycle, DNA is usually most vulnerable during replication. The replisome must be able to navigate obstacles such as tightly wound chromatin with bound proteins, single and double stranded breaks which can lead to the stalling of the replication fork. Each protein or enzyme in the replisome must perform its function well to result in a perfect copy of DNA. The genetic code is a cell's instruction manual, so as errors build up, they can cause disruptions. If the instructions become unclear or wrong over time, that could break down the cell and even make it turn cancerous. 


In old tissue, scientists have observed that many cells have a lot of accumulated genetic damage. If researchers can figure out how to improve the mechanism that repairs DNA, they could improve and possibly delay the aging process.


History of Research


In the last decade, several studies have demonstrated that autophagy or autophagic-related molecules act as a “safeguard” of genome stability both directly (DNA repair modulation) and indirectly (by acting as a homeostatic response). Several mouse models have provided substantial information regarding genomic instability and its connection with healthy and pathological aging (Folgueras AR et all, 2018)


Regarding oxidative stress and DNA damage, Reactive Oxygen Species (ROS) increase is thought to be mainly harmful for the mitochondrial DNA (mtDNA), generating the mutagenic 8-hydroxy-20-deoxyguanosine (8-OHdG), as well as mutations and deletions in mtDNA that result in a dysfunctional mitochondrion (Barja G, 2004). Moreover, mitochondrial dysfunction promotes telomere attrition, telomere loss, and chromosome alterations, culminating in apoptosis in mouse embryos . Besides, it has been demonstrated that, upon autophagic stimulation with an anti-lipolytic agent in 16-month-old rats, 8-OHdG accumulation in liver was successfully supressed, reaching the values obtained from young animals in only 6 h. When they measured the cytochrome c oxidase activity, they found that this decrease was not associated with lower mitochondrial enzyme activity, demonstrating the selective mitophagy of a small population of 8-OHdG-positive mitochondria and the importance of this proteostatic process in anti-aging mechanisms (Cavallini G. et all, 2007).


In the same way, dietary restriction reduced 8-OHdG levels in mitochondrial DNA (mtDNA) of aged rats and mice compared with those fed ad libitum (Van Remmen H. et all, 2003), supporting the importance of dietary restriction in prevention of mtDNA damage by ROS in aged animals. Notably, Sod2−/− mice accumulated high levels of 8-OHdG both in nuclear and mitochondrial DNA, compared with wild type mice. Nevertheless, they showed no changes in lifespan or age biomarkers. On the other hand, Atg7−/− mouse keratinocytes presented premature aging after oxidative stress induction, supporting the importance of autophagy in healthy aging (Song X. et all, 2017). In addition, Bender et al. found high levels of mtDNA deletions in dopaminergic neurons of PD patients, compared to controls. As we have already mentioned, PARKIN and PINK1 are mutated in PD, thus altered mitophagy can explain, in part, the accumulation of mtDNA damage in PD patients.


Autophagy has emerged as an important process in genome maintenance. After treatment with several cell cycle blockers, human osteosarcoma cells (U2OS) increased the micronuclei frequency as well as autophagosomes. Importantly, the authors observed a small but significant colocalization between them. Knockdown of Atg5 or Atg7 abolished this colocalization. Artificially aneuploid mouse cells showed increased autophagy to protect cells from genome instability (Ariyoshi K. et all, 2016).


Recommendations


There is growing evidence which shows that vitamins, minerals, and other dietary factors have profound and protective effects against cancer cells, whether they are grown in the lab, in animals, or studied in human populations. A better understanding of the effects and synergy of these dietary factors in the prevention and treatment of genomic instability is critical to the future reduction of mortality associated with cancer.


A range of B vitamins, including niacin (vitamin B3), folate (vitamin B9), and vitamin B12, significantly interact to maintain the stability of both nuclear and mitochondrial genomes. For example, a niacin deficiency, common in certain populations, impairs the function of the PARP family of enzymes, identified above as critical to DNA repair. A folate deficiency, especially in the presence of suboptimal levels of vitamin B6 and vitamin B12, may have significant effects on the expression of chromosomal fragile sites, leading to chromosome breaks, micronuclei and deletions of mtDNA. It may also lead to reduced telomere length. There are considerable interindividual differences in people's capacity to absorb and metabolize these vitamins, dependent upon genotype and epigenotype (B. van Ommen et al, 2010)


Vitamin C is considered an antioxidant, and is present at high concentrations (mM) in certain tissues such as the eye. Effects on various markers of genome stability were shown to depend on individual diet-derived vitamin C concentrations, and also on exposure to xenobiotics or oxidative stress (R.J. Sram et al, 2012). Vitamin D is also critical in the maintenance of genome stability, possibly through protection against oxidative stress, chromosomal aberrations, telomere shortening and inhibition of telomerase activity.

In terms of minerals, while a number of them are typically considered as toxicants, there are several that are essential micronutrients, albeit usually with a narrow window of efficacy as compared with toxicity. These include iron, selenium and zinc. As an example, Selenium provides a useful illustration of the complexities of reaching agreement on optimal population levels. The population as a whole shows a “U” shaped curve for functionality, where low and high selenium levels both increase genomic instability. Optimal levels of selenium may protect against DNA or chromosome breakage, chromosome gain or loss, damage to mtDNA, and detrimental effects on telomere length and function. One example of how selenium can function is by protecting genome stability through a BRCA1-dependent mechanism(L. Ferguson et all, 2012)


Diets high in plant-based foods have been associated with decreased cancer risks, and certain dietary components, common in plant foods, can alter DNA methylation levels, affecting genome stability and transcription of tumor suppressors and oncogenes (U. Lim et al, 2012). Hyperglycemia and a high fat diet have been shown to be positively correlated with an increased risk of cancers, such as breast and endometrial cancers.

All in all, this has launched the research labelled as nutrigenomics (sometimes also called nutritional genomics) which considers the interactions between foods or dietary supplements and an individual's genome and the consequent downstream effects on his or her phenotype. The field has the potential to provide tailored nutritional advice or develop specialist food products for populations or for individuals. It recognizes that appropriate dietary advice for one individual may be inappropriate or actually harmful to another. The potential is comparable to that of its sister field of pharmacogenomics, which considers individualized drug therapy.


Conclusion


There is extensive evidence that genomic damage accompanies aging and that its artificial induction can provoke aspects of accelerated aging. In the case of the machinery that ensures faithful chromosomal segregation, there is genetic evidence that its enhancement can extend longevity in mammals (Baker et al., 2013). Also, in the particular case of progerias associated with nuclear architecture defects, there is proof of principle for treatments that can delay premature aging. Similar avenues should be explored to find interventions that reinforce other aspects of nuclear and mitochondrial genome stability, such as DNA repair, that could have a positive impact on normal aging.


About Global Citizen Capital


As a social impact investment fund vehicle, Global Citizen Capital and its portfolio companies adhere to an united theme of “From Sustainability to Regeneration”, delivering high quality of life to mankind. it strives to connect with individuals, companies, organizations, foundations and funds with the intention to generate a measurable, beneficial social or environmental impact alongside a financial return. Impact investments made also provide capital to address social and/or environmental issues. Global Citizen Capital is a leader in investments across the fields of preventive medicine and regenerative healthcare, and is active in the areas of social impact bonds, health credit markets and public-private sector partnerships to achieve its mandates.


About AWAWA


Bridging impact investments with charitable initiatives, Asia World Anti-Aging and Well-Being Association (“AWAWA”) has been established to support the research, mentorship and social outreach programs related to preventive healthcare. Working closely with global non-profits who share a similar mindset, AWAWA is dedicated to increasing the scale and effectiveness of impact investing around the world, building critical infrastructure and promoting activities, education, and research that help accelerate the development of a coherent impact investing industry in healthcare. Knowing the core drivers of healthcare costs are health sector expenditures (hospitals and physician costs) and the prevalence of long-term conditions, AWAWA works to reduce the financial burden on the healthcare system which can be lessened when the population becomes healthier.


References

Folgueras AR, Freitas-Rodríguez S, Velasco G, López-Otín C. Mouse models to disentangle the hallmarks of human aging. Circ Res. (2018) 123:905–24. doi: 10.1161/CIRCRESAHA.118.312204

Barja G. The Cell Aging Regulation System (CARS). Barja G React Oxyg Species (2017) 148:148–83. doi: 10.20455/ros.2017.829

Cavallini G, Donati A, Taddei M, Bergamini E. Evidence for selective mitochondrial autophagy and failure in aging. Autophagy (2007) 3:26–7. doi: 10.4161/auto.3268

Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics (2003) 16:29–37. doi: 10.1152/physiolgenomics.00122.2003

Song X, Narzt MS, Nagelreiter IM, Hohensinner P, Terlecki-Zaniewicz L, Tschachler E, et al. Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo. Redox Biol. (2017) 11:219–30. doi: 10.1016/J.REDOX.2016.12.015

Ariyoshi K, Miura T, Kasai K, Fujishima Y, Oshimura M, Yoshida MA. Induction of genomic instability and activation of autophagy in artificial human aneuploid cells. Mutat Res Mol Mech Mutagen. (2016) 790:19–30. doi: 10.1016/J.MRFMMM.2016.06.001

B. van Ommen, A. El-Sohemy, J. Hesketh, J. Kaput, M. Fenech, C.T. Evelo, et al. The Micronutrient Genomics Project: a community-driven knowledge base for micronutrient research. Genes Nutr, 5 (2010), pp. 285-296 (R.J. Sram et al, 2012)

L.R. Ferguson, N. Karunasinghe, S. Zhu, A.H. Wang. Selenium and its’ role in the maintenance of genomic stability. Mutat Res, 733 (2012), pp. 100-110

L. Ferguson, R. Schlothauer The potential role of nutritional genomics tools in validating high health foods for cancer control: broccoli as exampleMol Nutr Food Res, 56 (2012), pp. 126-146

U. Lim, M.-A. Song. Dietary and lifestyle factors of DNA methylation. Cancer epigenetics. Springer (2012), pp. 359-376

Baker, D.J., Dawlaty, M.M., Wijshake, T., Jeganathan, K.B., Malureanu, L., van Ree, J.H., Crespo-Diaz, R., Reyes, S., Seaburg, L., Shapiro, V., et al. (2013). Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat. Cell Biol. 15, 96–102. Published online December 16, 2012

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