TABLE 5.

Epidemiologic studies evaluating the effect of blood nutrients on telomere length¹

Reference	Design	Population	Method	Factor	Results
Boccardi et al. 2019 (89)	Cross-sectional	68 subjects from the Geriatric Unit of Ospedale Maggiore Policlinico of Milan (2009–2016)	PCR-ELISA and qPCR	Plasma β-carotene	In all populations, β-carotene was significantly and positively correlated with telomerase activity, independent of gender. Subjects affected by AD had significantly lower concentrations of β-carotene and LTL compared with healthy controls
Julin et al. 2017 (90)	Cross-sectional	2483 men from a multiple nested case-control subcohort of the HPFS	PCR	Plasma vitamin D	Neither plasma 25(OH)D3 or 1,25(OH)2D3 were associated with LTL
Min and Min, 2016 (91)	Cross-sectional	3660 healthy subjects from the NHANES study (1999–2002)	PCR	Serum carotenoids	A doubling of blood α-carotene, β-carotene (trans + cis), and β-cryptoxanthin was associated with ∼2% longer telomeres. Compared with the lowest carotenoid quartile of α-carotene, β-carotene (trans + cis), and β-cryptoxanthin, telomere length for adults with the highest quartiles was significantly increased by 5–8%
Pusceddu et al. 2017 (92)	Cross-sectional	65 healthy subjects	PCR	Serum vitamin B-12, total serum folate	Age and gender-adjusted RTL correlated with total serum folate and 5-methyltetrahydrofolate
Richards et al. 2007 (93)	Cross-sectional	2160 healthy women	PCR	Serum vitamin D	Serum vitamin D concentrations were positively associated with LTL, and this relation persisted after adjustment for age and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 bp, which is equivalent to 5.0 y of telomeric aging. This difference was further accentuated by increased concentrations of CRP
O'Callaghan et al. 2014 (30)	Cross-sectional	89 healthy South Australian adults	PCR	Plasma magnesium and calcium	A negative association between telomere length and both plasma calcium and magnesium concentrations were reported in older females. These relations were not observed in the younger adults, nor in the older males
Sen et al. 2014 (94)	Cross-sectional	786 healthy subjects from the Austrian Stroke Prevention Study, a population-based cohort study on brain aging	PCR	Plasma lutein, zeaxanthin, and vitamin C concentrations	Of all micronutrients, the combination of lutein and zeaxanthin (Lu∼Zx) and vitamin C remained significantly and independently associated with LTL when adjusted for age and sex. After additional adjustment the relation between Lu and Zx and LTL became stronger, whereas the association between vitamin C and LTL remained virtually unchanged
Paul et al. 2015 (95)	Cross-sectional	1044 healthy subjects from the Framingham Offspring Study	PCR	Plasma folate	There was no significant positive association between plasma folate and leukocyte telomere length
Liu et al. 2016 (96)	Cross-sectional	1154 healthy subjects from the USRT study	PCR	Plasma 25(OH)D3	No significant association between continuous 25(OH)D3 and long LTL in all participants, nor in white females, white males, black females, or black males were reported. Vitamin D deficiency (defined as 25(OH)D3 <30 nmol/L), was significantly associated with shorter telomeres in whites, but not in other groups
Shin and Baik, 2016 (97)	Cross-sectional	798 healthy subjects	PCR	Serum vitamin B-12 and folate	In multiple adjusted models, no association was observed between LTL and serum folate and vitamin B-12
Williams et al. 2016 (98)	Cross-sectional	5096 healthy subjects from the Northern Finland Birth Cohort 1966	PCR	Plasma 25(OH)D3	No evident association between plasma 25(OH)D3 and telomere length was observed
Nomura et al. 2017 (99)	Cross-sectional	7826 healthy subjects from NHANES cohort data (1999–2002)	PCR	Serum folate, vitamin B-12, vitamin A, γ-tocopherol, α-tocopherol, and carotenoids	Serum vitamin A was positively associated and γ-tocopherol was inversely associated with LTL. Serum folate and α-tocopherol were marginally positively associated with LTL, whereas vitamin B-12 was not associated with LTL. Serum carotenoids were generally positively associated with LTL
Tucker 2017 (100)	Cross-sectional	5768 healthy subjects from NHANES cohort data (1999–2002)	PCR	Blood γ-tocopherol, blood α-tocopherol, dietary vitamin E, dietary supplements	An inverse association between serum concentrations of γ-tocopherol and TL was observed. Telomeres were approximately 1 y shorter (15.6 bp) for each increment of 47.3 to 55.7 g/dL of γ-tocopherol in the blood, depending on the variables controlled
Liu et al. 2019 (101)	Cross-sectional	7336 healthy subjects from NHANES cohort data (1999–2002)	PCR	Serum ferritin	Low ferritin concentrations (iron deficiency) were not significantly associated with telomere length compared with normal ferritin concentrations
Mazidi et al. 2018 (102)	Cross-sectional	5446 healthy subjects from NHANES cohort data (1999–2000)	PCR	Plasma trans-fatty acids like palmitelaidic acid, elaidic acid, vaccenic acid, and linolelaidic acid	After adjusting for age, sex, ethnicity, education, marital status, subclinical inflammation, BMI, and smoking, only palmitelaidic acid and linolelaidic acid were negatively associated with TL
Farzaneh-Far et al. 2010 (14)	Prospective cohort	608 patients from the Heart and Soul Study	PCR	Serum marine ω-3 fatty acids	Those participants in the highest quartile of DHA3EPA experienced the slowest rate of telomere shortening

¹AD, Alzheimer's disease; CRP, C-reactive protein; DHA3EPA, docosahexaenoic acid eicosapentaenoic ω-3 fatty acid; HPFS, Health Professionals Follow-Up Study; LTL leukocyte telomere length; RTL, relative telomere length; TL, telomere length; USRT, US Radiologic Technologists Study; 1,25(OH)2D3,1,25-dihydroxyvitamin D; 25(OH)D3, 25 hydroxy-vitamin D.