In this review we bring together evidence that (i) RNA viruses are a cause of chromosomal instability and micronuclei (MN), (ii) those individuals with high levels of lymphocyte MN have a weakened immune response and are more susceptible to RNA virus infection and (iii) both RNA virus infection and MN formation can induce inflammatory cytokine production. Based on these observations we propose a hypothesis that those who harbor elevated frequencies of MN within their cells are more prone to RNA virus infection and are more likely, through combined effects of leakage of self-DNA from MN and RNA from viruses, to escalate pro-inflammatory cytokine production via the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) and the Senescence Associated Secretory Phenotype (SASP) mechanisms to an extent that is unresolvable and therefore confers high risk of causing tissue damage by an excessive and overtly toxic immune response. The corollaries from this hypothesis are (i) those with abnormally high MN frequency are more prone to infection by RNA viruses; (ii) the extent of cytokine production and pro-inflammatory response to infection by RNA viruses is enhanced and possibly exceeds threshold levels that may be unresolvable in those with elevated MN levels in affected organs; (iii) reduction of MN frequency by improving nutrition and life-style factors increases resistance to RNA virus infection and moderates inflammatory cytokine production to a level that is immunologically efficacious and survivable.
The telomere and telomerase hypothesis of aging and cancer is based on the findings that most human tumors have telomerase activity while almost all normal human somatic cells do not. Telomeres are nucleoprotein structure that located 100-300 kb from the end of linear eukaryotic chromosomes (Blackburn et al, 2001; Yoo & Robinson, 2000). Human telomeres consist of thousand repetitive sequences TTAGGG with ranging from 5 to 20 kb (Figure 1) (Martin, 2002). In human cell, there are 92 telomeres which have several functions including protecting chromosome ends, to maintain chromosome stability, serve as an attachment point to the nuclear matrix and also involve in the cell replication.
Micronucleus (MN) assay has been widely used as a biomarker of DNA damage, chromosomal instability, cancer risk and accelerated aging in many epidemiological studies. In this narrative review and meta-analysis we assessed the association between lymphocyte micronuclei (MNi) and cancers of the skin, blood, digestive tract, and prostate. The review identified nineteen studies with 717 disease subjects and 782 controls. Significant increases in MRi for MNi were observed in the following groups: subjects with blood cancer (MRi = 3.98; 95 % CI: 1.98-7.99; p = 0.000) and colorectal cancer (excluding IBD) (MRi = 2.69; 95 % CI: 1.82-3.98, p
Folate and methionine are critical for one-carbon metabolism impacting DNA synthesis, repair, and methylation processes, as well as polyamine synthesis. These micronutrients have been implicated in colorectal cancer risk. There are, however, inconsistencies within the literature, with some studies showing restriction to have tumour-inhibitory effects, whereas others suggest excess to have adverse outcomes. We conducted a review of the published data to examine the accumulated evidence for involvement of dietary folate and/or methionine restriction or excess in intestinal tumour development in the Apc(Min/+) mouse model, which is genetically prone to develop such cancers. Thirteen publications were selected for evaluation based on the following inclusion criteria: (i) use of Apc(Min/+) mouse model; (ii) interventions using dietary folate and/or methionine; and (iii) primary outcome measures focused on intestinal tumour development. We found that nutritional modulation of folate and methionine was shown to have different effects on intestinal cancer in the Apc(Min/+) mouse, depending on the dosage, duration and timing of intervention, and interaction of the Apc(Min/+) genotype with other genetic factors affecting folate and DNA methylation metabolism. Although some studies showed that folate deficiency before tumorigenesis tended to increase risk of tumour formation, there are inconsistencies regarding whether excess folate post-weaning or after tumour initiation increases intestinal tumour burden. Altogether, the pooled data do not appear to indicate a difference in effect on intestinal tumour incidence between post-weaning diets that are folate deficient or folate adequate. The Apc(Min/+) mouse is a useful model for assessment of the impact of dietary folate on intestinal tumour development, but further research is required to understand the reasons for these inconsistencies amongst studies based on likely mechanisms, including modulation of nucleotide synthesis, DNA methylation, and chromosomal instability, which may affect the rate of cellular division and its control.