To our knowledge, this is the first study that has compared the levels of micronutrients among the oldest old with intact cognitive function (CDR = 0) cross–culturally. Contrary to our hypothesis, major differences were found in their circulating micronutrient levels.
The Oregon elders had much higher folate levels. This is likely due to the fact that it is mandatory in the United States to fortify cereals and flour with folate. According to recent National Health and Nutrition Examination Survey results (29
), red blood cell folate and serum folate levels among the U.S. population significantly increased after mandatory folate fortification in 1998. Serum folate levels increased with age among those aged 12 years and older according to National Health and Nutrition Examination Survey data (29
). The serum folate level of the Oregon elders examined in the current study was higher than those aged 60 years and older reported by National Health and Nutrition Examination Survey, probably due to the age of our cohort and their relatively high educational levels. The latter could result in better dietary habits with adequate micronutrients and a higher rate of supplementation.
Is such a high blood folate level among the Oregon cohort a positive health factor? A recent interventional study found that high serum folate increased risk for cancer and all-cause mortality in ischemic cardiac disease patients (30
). The increase in mortality was mainly due to cancer, but the putative mechanism(s) are not known. With regard to cognitive outcomes, the Cochrane Database of Systematic Reviews
on the association between folate supplementation and cognitive functions are inconclusive (31
). One study showed that those with low serum vitamin B12
status (<148 pmol/L) and high serum folate concentrations (>59 nmol/L) were at higher risk of cognitive impairment compared with those with low vitamin B12
, but with normal serum folate concentrations (32
). Also, a faster rate of cognitive decline was found among those with folate intakes exceeding 400 μg/day compared with those with lower intakes (33
). The Oregon cohort had high serum B12
(ranging from 155 to 3212 pg/mL; ie, 114–2369 pmol/L). Only six participants (5.2%) had a value lower than 148 pmol/L, with none having lower than the critical deficiency threshold of 111 pmol/L. By these criteria, there does not appear to be an increased risk among the Oregon cohort in the current study. However, considering that the consumption of folate is high in the United States due to fortification and personal use of supplements, it may be prudent to establish guidelines for the oldest old regarding the average intake of vitamin B12
and folate because elderly persons tend to lose intrinsic factors in the digestive system and often lack the acidity to properly absorb B12
). The proportion of those with hyperhomocysteinemia was lower among the Oregon cohort compared with the Okinawa cohort, possibly due to high folate intake in the United States. If Okinawa elders could increase their folate intake, their homocysteine levels may decrease, as indicated by our post hoc analysis.
Vitamin E also differed between Okinawans and Oregonians. Serum γ-tocopherol levels were significantly higher in Oregonians, even after adjustment for total cholesterol and/or triglycerides. Gamma-tocopherol is the major form of vitamin E in the U.S. diet and its antioxidative and anti-inflammatory properties beyond those found in α-tocopherol have been receiving attention recently (35
). Ford and coworkers (36
) studied the distribution of α- and γ-tocopherol levels among the U.S. population using data from the National Health and Nutrition Examination Survey. In Ford’s study, the mean α- and γ-tocopherol levels and those adjusted by total cholesterol among those aged 70 years and older, respectively, were 35.0 (α), 6.5 (α/total cholesterol), 4.2 (γ), and 0.8 (γ/total cholesterol). In our Oregon cohort, the comparable figures were 35.3, 6.7, 4.1, and 0.8, respectively, similar to the Ford study, but significantly higher than those found among the Okinawan group. Foods high in γ-tocopherol include hydrogenated corn and soybean oils; ingredients often included in processed foods, such as commercially baked goods (doughnut and other pastries, cookies, and crackers), deep-fried foods. snack foods such as potato chips, and some margarines. Morris and coworkers (37
) found that higher consumption of γ-tocopherol was associated with unhealthy dietary behaviors, including higher intakes of saturated and trans fats. In their population-based Italian cohort study, Ravaglia and coworkers (38
) showed that the beneficial effect of γ-tocopherol against dementia incidence was evident only in the middle tertile of γ-tocopherol. One of the potential explanations of this finding suggested by the authors is a poor diet possibly associated with high γ-tocopherol in the upper tertile. It is also possible that the high proportion of obesity observed in the Oregon cohort of oldest old could be partly due to a high consumption of processed foods that are convenient, highly available, and require little preparation.
Morris and coworkers (7
) found that high intake of vitamin E from food, but not from supplements, was inversely associated with AD incidence. One explanation of this finding is that several tocopherol forms rather than α-tocopherol alone may be necessary for vitamin E to have a protective effect on cognitive health (37
). The much lower γ-tocopherol levels found in the Okinawan cohort suggests that high serum levels of γ-tocopherol might not be necessary to achieve healthy cognitive aging. A controlled intervention study with γ-tocopherol would be required in order to more closely examine the effect of γ-tocopherol on cognitive health.
Finally, Oregon elders had a higher proportion of overweight and obese individuals based on the World Health Organization international standard classification. Obesity, especially midlife obesity, has been shown to have detrimental effects on cognitive health, along with higher risk of diabetes, a risk factor for not only vascular dementia but also for AD (39
). On the other hand, distinguishing midlife and late-life obesity, one study (41
) in the United States found that late-life underweight (BMI <20) increased risk of dementia over 5 years of follow-up, whereas being overweight (BMI 25.0–29.9) was not associated with an increased risk, and being obese (BMI ≥30) actually “reduced” the risk of dementia compared with having normal BMI in late life. Coinciding with this finding, a recent study based on Australian cohorts showed that for elders who had survived to the age of 70, mortality risk was lowest in those with a BMI classified as overweight over a 10-year period compared with those with normal weight or the obese participants (42
). They suggested that current BMI requirements might be too strict for seniors. It would be interesting to explore whether those overweight in the cohorts examined here actually survive longer with intact cognition compared with those of normal weight. Further follow-up would be required to examine this issue.
Our study strengths include the fact that we compared the micronutrient levels of rare survivors among the elders (oldest old with CDR = 0), a rarely studied group with regard to micronutrient analysis. Additionally, within-cultural comparisons (eg, examining whether or not a specific micronutrient is associated with cognitive well-being “within” one culture or cohort) could suffer from the potential ceiling effects of a specific micronutrient. That is, if the majority of the cohort members have high or low levels of specific micronutrients, we might not be able to find a significant association between that nutrient and health due to the lack of variability in a within-cohort study. Cross-cultural comparisons of the absolute levels of micronutrients are useful in that they have the potential to shed light upon areas that within-cultural studies may not. Our study limitations include small sample size, especially for the Okinawan cohort. Even though we used similar inclusion criteria between the two cohorts, and both groups are healthy volunteers, the study findings may not be completely free from sample selection bias. Vitamin supplementations were based on self-report in Okinawa, which could suffer from reporting errors. The potential effect of medications on micronutrients were reported, including a long-term use of proton pump inhibitors being associated with B12
deficiency and elevated homocysteine (43
) and drug-induced hypokalemmia (45
). We believe that the effect of medications among relatively healthy volunteers examined in this study is not substantial, but further studies are required to confirm this notion. Oregon micronutrient analyses were conducted using aliquots stored for more than 8 years. Previous studies have confirmed the stability of serum and plasma α-tocopherol stored up to 15 years (46
). Other studies have confirmed that vitamin B12
and homocysteine are stable for more than 29 years of storage (48
). Folate has been shown to degrade after 17 years of storage and appears stable for up to 6 years (48
). We may have underestimated the true difference in serum folate between our two cohorts because we cannot confirm that some folate degradation may have occurred in the Oregon samples as a consequence of storage duration in that cohort. Finally, this is a cross-sectional pilot study; although we excluded those with CDR ≥0.5, dementia-related pathology is known to start a decade or more before neurological symptoms become apparent. Therefore, reverse causation is also a possibility.
In sum, contrary to our hypothesis, there was no discernable protective micronutrient pattern. The Okinawan elders had lower folate and γ-tocopherol and a borderline higher proportion with hyperhomocysteinemia. The optimal lifestyle leading to healthy cognitive aging could consist of various components such as healthy diet, high physical activity, and social engagement, among other factors. Each component’s effect on overall cognitive health could vary and there could also be interaction effects among the components as shown in the study by Scarmeas and coworkers (49
) and/or or gene–environment interactions. The oldest old examined here likely achieved healthy cognitive aging due to various factors and the interactions of these factors over the life course. Some factors may include shared genetic traits among families (50
), whereas others may have unique social, historical, and epidemiological contexts, such as the population-wide experience of long-term caloric restriction among the Okinawans (51
) and the potential associated physiological benefits (52
). Some detrimental effects could be compensated for by protective factors. This means that there may potentially be many patterns that allow elders to survive with intact cognition, and we need to study the lifestyle “package” leading to healthy cognitive aging. Alternatively, we could explore the most effective means to sustain cognitive health within each component (nutrition, social engagement, physical activities, etc.) and recommend the best approach hoping that the interaction would yield combined and better outcomes. The results presented here are based on a pilot study. Follow-up of the current cohorts examined here and further cross-national comparisons of circulating micronutrients and other lifestyle factors could help clarify the lifestyle package leading to healthy cognitive aging.