Protective Effects of Micronutrient Supplements, Phytochemicals and Phytochemical-Rich Beverages and Foods Against DNA Damage in Humans: A Systematic Review of Randomized Controlled Trials and Prospective Studies.

Accumulation of deoxyribonucleic acid (DNA) damage diminishes cellular health, increases risk of developmental and degenerative diseases, and accelerates aging. Optimizing nutrient intake can minimize accrual of DNA damage. The objectives of this review are to: 1) assemble and systematically analyze high-level evidence for the effect of supplementation with micronutrients and phytochemicals on baseline levels of DNA damage in humans, and 2) use this knowledge to identify which of these essential micronutrients or nonessential phytochemicals promote DNA integrity in vivo in humans. We conducted systematic literature searches of the PubMed database to identify interventional, prospective, cross-sectional, or in vitro studies that explored the association between nutrients and established biomarkers of DNA damage associated with developmental and degenerative disease risk. Biomarkers included lymphocyte chromosome aberrations, lymphocyte and buccal cell micronuclei, DNA methylation, lymphocyte/leukocyte DNA strand breaks, DNA oxidation, telomere length, telomerase activity, and mitochondrial DNA mutations. Only randomized, controlled interventions and uncontrolled longitudinal intervention studies conducted in humans were selected for evaluation and data extraction. These studies were ranked for the quality of their study design. In all, 96 of the 124 articles identified reported studies that achieved a quality assessment score ≥ 5 (from a maximum score of 7) and were included in the final review. Based on these studies, nutrients associated with protective effects included vitamin A and its precursor ß-carotene, vitamins C, E, B1, B12, folate, minerals selenium and zinc, and phytochemicals such as curcumin (with piperine), lycopene, and proanthocyanidins. These findings highlight the importance of nutrients involved in (i) DNA metabolism and repair (folate, vitamin B12, and zinc) and (ii) prevention of oxidative stress and inflammation (vitamins A, C, E, lycopene, curcumin, proanthocyanidins, selenium, and zinc). Supplementation with certain micronutrients and their combinations may reduce DNA damage and promote cellular health by improving the maintenance of genome integrity.

Current State of Saliva Biomarkers for Aging and Alzheimer's Disease.

INTRODUCTION: Aging is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases such as Alzheimer's Disease (AD). AD is a progressive degenerative disorder of the brain and is the most common form of dementia. METHODS: To-date no simple, inexpensive and minimally invasive procedure is available to confirm with certainty the early diagnosis of AD prior to the manifestations of symptoms characteristic of the disease. Therefore, if population screening of individuals is to be performed, easily accessible tissues would need to be used for a diagnostic test that would identify those who exhibit altered or aberrant aging profiles that may be indicative of AD risk, so that they can be prioritized for primary prevention. This need for minimally invasive tests could be achieved by targeting saliva, since it is now well recognized that many aging diseases including AD are associated with peripheral biomarkers that are not only restricted to pathology and biomarkers within the brain. RESULTS: Therefore, the aim of this review is to summarize some of the main findings of salivary biomarkers of aging and AD; including various proteins, metabolites, and alterations to DNA and miRNA. The future of healthy aging resides in innovative platforms, biosensors and point-of-care devices that can extract real time information on the health status of an individual. Those platforms may be achieved through the development and validation of novel biomarkers of health using saliva which, although being the least explored for biomedical purposes, has the distinct advantage that it can be self-collected in a non-invasive manner.

Folate deficiency induces dysfunctional long and short telomeres; both states are associated with hypomethylation and DNA damage in human WIL2-NS cells.

The essential role of dietary micronutrients for genome stability is well documented, yet the effect of folate deficiency or excess on telomeres is not known. Accordingly, human WIL2-NS cells were maintained in medium containing 30, 300, or 3,000 nmol/L folic acid (FA) for 42 days to test the hypothesis that chronic folate deficiency would cause telomere shortening and dysfunction. After 14 days, telomere length (TL) in FA-deficient (30 nmol/L) cultures was 26% longer than that of 3,000 nmol/L FA cultures; however, this was followed by rapid telomere attrition over the subsequent 28 days (P trend, P < 0.0001); both long and short telomere status was positively correlated with biomarkers of chromosome instability (P ≤ 0.003) and mitotic dysfunction (P = 0.01), measured by the cytokinesis-block micronucleus cytome (CBMN-cyt) assay. The early increase in TL was associated with FA-deficiency-induced global DNA hypomethylation (P = 0.05), with an effect size similar to that induced by the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine. Quantitative PCR analysis indicated a negative association between FA concentration and uracil incorporation into telomeric DNA (r = -0.47, P = 0.1), suggesting a possible plausible mechanism for uracil as a cause of folate deficiency-induced telomere dysfunction or deletion. Peptide nucleic acid-FISH (PNA-FISH) analysis showed that FA deficiency resulted in 60% of micronuclei containing acentric terminal fragments, an observation consistent with the 3-fold increase in terminal deletions (P = 0.0001). Together, these results demonstrate the impact of folate deficiency on biomarkers of telomere maintenance and integrity, and provide evidence that dysfunctional long telomeres may be as important as critically short telomeres as a cause of chromosomal instability.

Folate deficiency is associated with the formation of complex nuclear anomalies in the cytokinesis-block micronucleus cytome assay.

Chromosomal instability (CIN) is an important hallmark to oncogenesis and can be diagnosed morphologically by the presence of nuclear anomalies such as micronuclei (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBuds). We have identified additional nuclear anomalies formed under folate-deficient conditions, defined as "fused" nuclei (FUS), "circular" nuclei (CIR), and "horse-shoe" nuclei (HS) and investigated their suitability for inclusion as additional CIN biomarkers in the lymphocyte cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. Although the morphological appearance of FUS, CIR, and HS suggested an origin from multiple NPB in the fusion region between the two nuclei, the very low frequency of dicentric chromosomes in metaphase spreads from these cultures did not support this model. Fluorescence in situ hybridization (FISH) analysis of cytokinesis-blocked binucleated (BN) cells with peptide nucleic acid probes for telomeres and centromeres (PNA-FISH) revealed a high proportion of fusion regions contained both centromeric and telomeric DNA. This suggests that folate deficiency may disrupt the process of sister chromatid separation and chromosome segregation during mitosis. It was concluded that the FUS, CIR, and HS morphologies represent promising biomarkers of CIN that are sensitive to folate deficiency, and further validation and investigation of the mechanisms responsible for their formation is warranted.

Application and adaptation of the in vitro micronucleus assay for the assessment of nutritional requirements of cells for DNA damage prevention.

DNA damage is a fundamental cause of developmental and degenerative diseases. The in vitro cytokinesis-block micronucleus cytome (CBMN-Cyt) assay is an established comprehensive method for assessing cytostasis and chromosome stability in cells. Originally developed to study the acute effects of single environmental genotoxicants, creative applications and adaptations to the basic protocol have allowed its use in evaluating the impacts of dietary micronutrients and micronutrient combinations (nutriomes) on DNA damage. In this review, we examine some of these studies and the important findings they have generated with respect to nutrient/nutrient, nutrient/genotype and nutrient/genotoxicant interactions, as well as assessment of the carcinogenic (or protective) potential of whole dietary patterns. In addition, we outline current knowledge gaps and technical limitations and propose future adaptations to enhance the applicability of the CBMN-Cyt method for in vivo predictions.

Telomere length in lymphocytes of older South Australian men may be inversely associated with plasma homocysteine.

Deficiencies in folate (FOL) and vitamin B12 (B12) result in increased chromosomal aberrations, a validated biomarker of cancer risk. Telomeres, the regions of DNA that cap the ends of each chromosome, are critical for maintaining chromosomal stability but the impact of micronutrients on telomere structure and function remains unclear. We hypothesized that telomere length maintenance might be compromised if the status of FOL and B12 was inadequate and plasma homocysteine (HCY) was increased. We investigated the relationship between telomere length in peripheral blood lymphocytes and plasma FOL, B12, and HCY status, and tested whether any such relationship was dependent on age, gender, body mass index, and common polymorphisms in folate metabolism genes. A single blood sample was collected from 43 younger (18-32 years) and 47 older (65-83 years) adults in South Australia. The younger cohort consisted of 18 males and 25 females, whereas the older group included 24 males and 23 females. Telomere length was determined in lymphocytes by flow cytometry. Telomere length in the younger cohort was 11.52% greater than in the older cohort (p = 0.015). In the older cohort, telomere length in females was 12.5% greater than in males (p = 0.028). In older males, there was a significant inverse correlation between telomere length and HCY (r = -0.57, p = 0.004), but this effect was not observed in the younger cohort or in the older female group. These results provide evidence that telomere length of lymphocytes in older men may be adversely affected by HCY in vivo.