A year-long intervention trial was conducted to characterise the responses of multiple biomarkers of Se status in healthy American adults to supplemental selenomethionine (SeMet) and to identify factors affecting those responses. A total of 261 men and women were randomised to four doses of Se (0, 50, 100 or 200 mg/d as L-SeMet) for 12 months. Responses of several biomarkers of Se status (plasma Se, serum selenoprotein P (SEPP1), plasma glutathione peroxidase activity (GPX3), buccal cell Se, urinary Se) were determined relative to genotype of four selenoproteins (GPX1, GPX3, SEPP1, selenoprotein 15), dietary Se intake and parameters of single-carbon metabolism. Results showed that supplemental SeMet did not affect GPX3 activity or SEPP1 concentration, but produced significant, dose-dependent increases in the Se contents of plasma, urine and buccal cells, each of which plateaued by 9 -12 months and was linearly related to effective Se dose (mg/d per kg 0·75 ). The increase in urinary Se excretion was greater for women than men, and for individuals of the GPX1 679 T/T genotype than for those of the GPX1 679 C/C genotype. It is concluded that the most responsive Se-biomarkers in this non-deficient cohort were those related to body Se pools: plasma, buccal cell and urinary Se concentrations. Changes in plasma Se resulted from increases in its non-specific component and were affected by both sex and GPX1 genotype. In a cohort of relatively high Se status, the Se intake (as SeMet) required to support plasma Se concentration at a target level (Se pl-target ) is: Se in ¼ ½ðSe pl2target 2 Se pl Þ=ð18:2 ng d kg 0:75 =ml per mgÞ .Key words: Selenium: Biomarkers: Selenoprotein P: Glutathione peroxidase: Genotype: Supplementation Se is an essential mineral nutrient required to support the expression of some twenty-five proteins, each of which contains selenocysteine residues as essential constituents (1) . These selenoproteins have diverse functions including antioxidant protection (2) , thyroid hormone metabolism (3) and Se transport (4) . Selenoprotein expression can be reduced by deprivation of Se. SNP can also affect selenoprotein function, as in the case of cytosolic glutathione peroxidase (GPX1) (5) . In fact, GPX1 genotype has been associated with cancer risk (6) .High Se status has been associated with reduced cancer risk, and perhaps increased risk of type 2 diabetes. The Nutritional Prevention of Cancer (NPC) Trial showed that increasing Se intake could reduce colon and prostate cancer risk (7) , at least for individuals with plasma Se levels , 106 ng/ml (8) . However, the same study indicated that Se-supplemented subjects whose plasma Se levels had increased to 180-200 ng/ml may have had increased risk of type 2 diabetes (9) . Elevated diabetes risk was observed for subjects in the upper quintile of plasma Se ($ 137·7 ng/ml) in the third National Health and Examination Survey (NHANES) (10) , and among subjects in the upper quartile of plasma Se ($ 147 ng/ml) in NHANES 2003-4 (11) . While increased diabete...

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ᮀ Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to show that the selenium dose that minimizes prostatic DNA damage also maximizes apoptosis-a cancer-suppressing death switch used by prostatic epithelial cells. These provocative findings suggest a new line of thinking about how selenium can reduce cancer risk. Mid-range selenium status (.67-.92 ppm in toenails) favors a process we call "homeostatic housecleaning"-an upregulated apoptosis that preferentially purges damaged prostatic cells. Also, the U-shaped relationship provides valuable insight into stratifying individuals as selenium-responsive or seleniumrefractory, based upon the likelihood of reducing their cancer risk by additional selenium. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a robust experimental approach bridging the gap between laboratory and human studies that can help to define the optimal doses of cancer preventives for large-scale human trials. Moreover, our observations bring much needed clarity to the null results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and set a new research priority: testing whether men with low, suboptimal selenium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation.

To better understand the potential trade-off between female reproductive investment and longevity in an emerging model of human healthspan, we studied pet dogs to determine whether intensity of reproduction (total number of offspring) encumbered the likelihood of exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, including complete reproductive histories, for a cohort of canine "centenarians" -exceptionally long-lived Rottweiler dogs that lived more than 30 % longer than the breed's average life expectancy. Reproductive intensity (number of litters, total number of pups) and tempo of reproductive effort (age at first reproduction, mean interbirth interval, age at last reproduction) in 78 exceptionally long-lived female Rottweilers (>13 years old) were compared to a cohort of 97 female Rottweilers that had usual longevity (age at death 8.0-10.75 years). We found no evidence that a mother's physiological investment in offspring was associated with disadvantaged longevity. Instead, similar to some studies in women, our data showed an inverted U-shaped trend, suggesting that moderate investment in reproduction may promote longevity. Late reproductive success, a much-studied surrogate of maternal fitness in women, was not a strong predictor of longevity in this canine cohort. Instead, independent of reproductive investment, the duration of lifetime ovary exposure was significantly associated with highly successful aging. Our results from exceptionally long-lived pet dogs provide rationale for further investigative efforts to understand the ovary-sensitive biological factors that promote healthy longevity in women and pet dogs.