**5. What can be done to help maintain telomere length?**

Diet is known to play an important role in telomere maintenance and personalized nutrition is a growing and promising field to prevent DNA damage [40]. A proper diet combined with physical exercises seems to prevent genomic instability, possibly providing a proper intake of antioxidants and reduction of inflammation levels [40, 53, 106, 107]. Several intervention studies have been performed to challenge the common sense that telomeres only shorten during a lifetime. According to literature, dietary patterns and individual micronutrients can influence telomere length and function. A recent review reported that individuals undergoing the following lifestyle interventions presented increased telomerase activity: practice of physical exercise, diet micronutrient supplementation, yoga, and mindfulness meditation [74].

exposure to ionizing radiation led to longer telomeres through telomerase activation, which could potentiate carcinogenesis [93]. Even so, it is possible to highlight that most occupational

Environmental factors can also trigger epigenetic changes [94], which can also be related to telomere maintenance [67, 95]. Previous studies suggested that DNA methylation plays an important role in maintaining genomic stability, and is highly sensitive to environmental exposure [96, 97]. The impact of adverse exposure on telomere shortening starts at a very early developmental stage. Environmental exposure to lead in children appears to be associated with shorter telomeres [98], as prenatal exposure to toxic agents also seems to be a predictor of telomere imbalance. Neonatal umbilical cord blood showed a positive association between shortened fetal telomere length and smoking during pregnancy [99]. Even with the concept that high variation in telomere length between individuals is already present before birth and could increase due to environmental exposure, 128 Indian newborns from high‐level natural background radiation areas showed no evidence of telomere length attrition [100]. On the other hand, placental tissues of over 200 twins were evaluated with regard to telomere length [101]. The aim was to verify if maternal residential traffic exposure was associated with telomere length. Maternal residential proximity to a major road was linked to shortened placental telomere length, while maternal residence closer to more wooded sites increased placental telomere length by 3.6%. As traffic exposure is an important source of free radicals that are known for accelerating aging, the air pollution‐related adverse outcomes started early in life

A group of Italian pregnant women living close to waste landfill sites was analyzed with regard to telomere length to investigate if pollution, as an environmental stressor, could affect their health. The authors observed that pollution from illegal waste sites was significantly associated with shorter telomere length, higher oxidative stress levels, and lower telomerase activity, which are known factors of cellular senescence and aging‐related meiotic dysfunction in women [102]. Even low levels of cadmium shortened buccal cell telomere length in adolescents environmentally exposed to this metal [103]. Arsenic exposure to drinking water increased telomere length in individuals from West Bengal, India. This effect was telomerase‐dependent but did not exhibit an overexpression of alternative lengthening of telomere‐associated proteins TRF1 and TRF2 [104]. Some environmental toxic metals can produce epigenetic changes, such as DNA methylation, loss of expression of tumor suppressor gene *p16*, among

Diet is known to play an important role in telomere maintenance and personalized nutrition is a growing and promising field to prevent DNA damage [40]. A proper diet combined with physical exercises seems to prevent genomic instability, possibly providing a proper intake of antioxidants and reduction of inflammation levels [40, 53, 106, 107]. Several intervention studies have been performed to challenge the common sense that telomeres only shorten

others [105], eventually leading to telomere dynamics alterations.

**5. What can be done to help maintain telomere length?**

exposures induce telomere shortening.

172 Telomere - A Complex End of a Chromosome

[101].

Folate is an important vitamin required for DNA synthesis, one‐carbon metabolism and repair. When there is folate deficiency, the incorporation of uracil instead of thymine in DNA is increased [108]. Plasma homocysteine concentration, which is increased when folate and vitamin B12 are deficient, seems to be inversely associated with telomere length. On the other hand, homocysteine and folate are inversely correlated [109]. Low levels of folate were associated with shorter telomeres in an older male cohort, although this effect was not observed either in female subjects or younger adults [108]. Another study showed that the MTHFR C677T polymorphism of the folate metabolism gene, which may raise plasma homocysteine, was weakly associated with increased telomere length at below‐median folate levels [110]. A recent study showed that folate deficiency leads to long but dysfunctional telomeres, associ‐ ated with increased chromosome instability, possible due to DNA hypomethylation [107]. Some molecular mechanisms have been proposed on how folate deficiency induces telomere shortening, such as (a) abnormal epigenetic state of subtelomeric DNA; (b) ineffective binding of shelterin complex proteins to telomeric DNA due to decrease affinity to uracil; (c) the increased excision of uracil in the telomere structure that generates abasic sites and DNA breaks. Therefore, folate status modifies telomere length by affecting DNA integrity and the epigenetic regulation of telomere length through DNA methylation [111].

As discussed earlier in this chapter, DNA damage in adulthood may originate in early life [98, 101], as lifelong dietary patterns are established in childhood. Yet, most studies with regard to telomere length in children are conducted on the effects of environmental exposure and socioeconomic and psychological status [72, 73, 98, 99, 101, 103]. A recently published study analyzed whether nutritional factors are associated with telomere length in children [112]. Between 2009 and 2011, 437 children aged 3, 6, and 9, were sampled and telomere length and micronutrient levels were measured. After adjustment for several parameters, telomere length was inversely associated with plasma levels of zinc. Also, children with the homozygous mutant genotype of the *RFC* G80A (rs1051266) polymorphism presented the shortest telomere. The RFC (reduced folate carrier) gene encodes for an enzyme required for bioavailability and metabolism of folate and vitamin B12. The chosen polymorphism is known to reduce the activity of the enzyme; indeed, the *RFC G80AA* genotype was associated with a 26 kb/diploid genome telomere loss when compared to the *RFC 80GG* genotype. Although the association between zinc levels and telomere length is still not clearly understood, the authors suggest that the inverse relationship between the two parameters may be a result of an increase in telomere sequence deletions by labile zinc induction of oxidative stress [112, 113].

High levels of plasma vitamin D were associated with longer telomeres in women, with evidence of a dose‐response relationship [114]. Vitamin D is known for reducing inflammation and cell proliferation. Because both increased inflammation and enhanced cell proliferation accelerate telomere attrition [8, 56, 57], vitamin D seems to improve telomere biology through anti‐inflammation and antiproliferative mechanisms [114]. Individuals treated daily with vitamin preparations are characterized by 273 bp longer telomeres than those who are not treated [115]. Vitamins C and E have also shown associations with longer telomeres [115]. It is relevant that both ascorbic acid (vitamin C) and tocopherol (vitamin E) are recognized antioxidants [116–119] that can prevent ROS generation, therefore increasing oxidative stress. For patients with Alzheimer's disease, elevated oxidative stress levels were found, besides shorter telomeres [120]. When vitamin E was administered to these patients, although there was no significant difference in telomere length after 6 months, levels of oxidative stress were lower [120].

Iron is a biologically very important trace element for maintaining metabolic homeostasis and genome stability. Nevertheless, it is required in a relatively narrow range, otherwise iron becomes a high potential generator of ROS [121]. Iron catalyses the Fenton reaction by generating the 8‐hydroxy‐guanine adduct, one of the most common DNA oxidative damages [13], found also in telomeres [17]. Iron overload induces DNA hypermethylation and can shorten telomere length [122], although the relationship between iron status and telomere dynamics is not totally clear. Shortened telomeres were found in patients with primary hematochromatosis and in patients taking supplements containing iron [123]. In women using iron preparations, telomeres were shortened by 9% when compared to non‐users [115].

A low fat diet has also been associated with improvements in telomere dynamics. Men with prostate cancer who changed their lifestyle to a low fat diet, increased activity and stress reduction, presented increased peripheral blood mononuclear cells telomerase activity [124]. Also, polyunsaturated fatty acid intake was inversely associated with telomere length after multivariate adjustment in a group of 2284 American women [125]. The practice of physical exercise is well known as an important resource for a healthier life. Considering its effect on telomere length, some studies have reported no effect at all. One study observed a significant moderating effect of vigorous physical activity in protecting telomeres against cellular stress in women [126]. Endurance exercises were also relevant for older athletes. When compared to individuals of the same age, but low levels of exercise, older athletes had longer telomere length. Yet, among younger athletes, this difference was not observed regardless of endurance or practicing lower levels of exercise [106]. This result suggests that the lifetime practice of exercises might help the slower shortening of telomere length.
