Serum Albumin Decreases During Aging: Can Diet Help?

Levels of serum albumin peak at about 20 years old (~4.6 g/dL for males, ~4.4 g/dL for females), then decrease during aging, as shown for the 1,079,193 adults of Weaving et al. (2016):

Screen Shot 2018-07-04 at 1.19.29 PM.png

Similar age-related decreases for serum albumin albumin have also been reported in smaller studies: Gom et al. 2007 (62,854 subjects); Dong et al. 2010 (2,364 subjects); Le Couteur et al. 2010 (1,673 subjects); Dong et al. 2012 (1,489 subjects).

Why is it important that serum levels of albumin decrease during aging? Reduced levels of albumin are associated with an increased risk of death from all causes. For example, in the 1,704,566 adults of Fulks et al. 2010, serum albumin levels > 4.4 g/dL and 4.5 g/dL for females and males, respectively, were associated with maximally reduced risk of death from all causes, regardless of age (younger than 50y, 50-69y, or 70y+):

The association between reduced levels of serum albumin with an increased risk of death from all causes have also been found in smaller studies. In a ~9 year study of 7,735 men (age range, 40-59y), when serum albumin was less than 4 g/dL, the mortality rate was 23/1000/per year, compared with 4/1000/per year for subjects with values greater than 4.8 g/dL (Phillips et al. 1989):

albumin 3 mort

Similarly, in older adults (average age, ~80y, 672 subjects), serum albumin levels greater than 4.5 g/dL (equivalent to 45 g/L) were associated with significantly reduced all-cause mortality risk, when compared with compared with < 4.1 g/dL (equivalent to 41 g/L, Takata et al. 2010):

albumin 2 mort

Decreased levels of serum albumin (less than 4 g/dL) being associated with an increased all-cause mortality risk was also identified in a 12-year study of 287 older adults (average age, ~75y, Sahyoun et al. 1996).

Can the age-related decrease in serum albumin be minimized, or prevented? Shown below is my data for serum albumin since 2005, when I was 32y:

alb

First, note the period from when I was 32y until 40y. No age-related decrease! My average albumin value over 7 measurements was 4.74 g/dL. Unfortunately, I didn’t track my dietary info during that time.

Also note the period from 43y to 45y. First, my albumin levels are significantly higher than the first period, 4.92 g/dL (p=0.027)! Second, again note the absence of an age-related decrease. Based on the data of Weaving et al. (2016), my albumin levels should be around 4.4 g/dL, but I’ve got them going in the opposite direction! How have I been able to do that?

Since April 2015, with use of a food scale, I’ve been tracking my daily dietary intake, including macro and micronutrients (54 variables). For each orange data point in the second period, I have an average dietary intake for each of the 54 variables that I can use to correlate with serum albumin. Based on that data, I can make an educated guess at what could potentially increase, or decrease it.

Of the 54 dietary variables that I track, only 3 were significantly correlated with albumin: positive associations for alpha-carotene (r = 0.66, p = 0.027), beta-carotene (r = 0.75, p =0.007), and a negative association for Vitamin K (r = -0.64, p = 0.03). Shown below is the strongest correlation of the three, beta-carotene, vs. serum albumin.

bcarot alb.png

The majority of my alpha and beta-carotene intake comes from carrots, with a smaller amount coming from butternut squash. Interestingly, beta-cryptoxanthin, a Vitamin A metabolite that is abundant in butternut squash, was not significantly associated with serum albumin. Butternut squash is also a good source of alpha- and beta-carotene, so if butternut squash was driving the correlation between the carotenes with albumin, I’d expect beta-crypoxanthin to also be significantly associated with it. However, since it’s not, carrots are the most likely source driving the association. Also note that the my average intake of Vitamin K is dramatically higher (1410 mcg; range, 1080-2203 mcg) than the RDA or AI, which are ~100-120 mcg/day. The negative association between my Vitamin K intake with albumin suggests that I should keep it closer to 1100 mcg/day to potentially keep my albumin levels high.

If you’re interested, please have a look at my book!

References

Dong MH, Bettencourt R, Barrett-Connor E, Loomba R. Alanine aminotransferase decreases with age: the Rancho Bernardo Study. PLoS One. 2010 Dec 8;5(12):e14254.

Dong MH, Bettencourt R, Brenner DA, Barrett-Connor E, Loomba R. Serum levels of alanine aminotransferase decrease with age in longitudinal analysis. Clin Gastroenterol Hepatol. 2012 Mar;10(3):285-90.e1.

Gom I, Fukushima H, Shiraki M, Miwa Y, Ando T, Takai K, Moriwaki H. Relationship between serum albumin level and aging in community-dwelling self-supported elderly population. J Nutr Sci Vitaminol (Tokyo). 2007 Feb;53(1):37-42.

Dong MH, Bettencourt R, Barrett-Connor E, Loomba R. Alanine aminotransferase decreases with age: the Rancho Bernardo Study. PLoS One. 2010 Dec 8;5(12):e14254.

Fulks M, Stout RL, Dolan VF. Albumin and all-cause mortality risk in insurance applicants. J Insur Med. 2010;42(1):11-7.

Le Couteur DG, Blyth FM, Creasey HM, Handelsman DJ, Naganathan V, Sambrook PN, Seibel MJ, Waite LM, Cumming RG. The association of alanine transaminase with aging, frailty, and mortality. J Gerontol A Biol Sci Med Sci. 2010 Jul;65(7):712-7.

Phillips A, Shaper AG, Whincup PH. Association between serum albumin and mortality from cardiovascular disease, cancer, and other causes. Lancet. 1989 Dec 16;2(8677):1434-6.

Sahyoun NR, Jacques PF, Dallal G, Russell RM. Use of albumin as a predictor of mortality in community dwelling and institutionalized elderly populations. J Clin Epidemiol. 1996 Sep;49(9):981-8.

Takata Y, Ansai T, Soh I, Awano S, Sonoki K, Akifusa S, Kagiyama S, Hamasaki T, Torisu T, Yoshida A, Nakamichi I, Takehara T. Serum albumin levels as an independent predictor of 4-year mortality in a community-dwelling 80-year-old population. Aging Clin Exp Res. 2010 Feb;22(1):31-5.

Weaving G, Batstone GF, Jones RG. Age and sex variation in serum albumin concentration: an observational study. Ann Clin Biochem. 2016 Jan;53(Pt 1):106-11.

PRAL, Mortality Risk, and Lifespan

Within the body, meat, grains, and nuts are generally acid-forming, whereas vegetables and fruits are alkaline-forming. Is the distinction between whether your diet is acid- or alkaline-forming important for optimal health and lifespan? In an earlier post, I discussed the importance of PRAL (potential renal acid load) by correlating it with serum bicarbonate and mortality risk (https://michaellustgarten.com/2016/02/07/using-diet-to-optimize-circulating-biomarkers-serum-bicarbonate/).

More recent data (a 15-year study of 81, 697 older adults; average age ~61y; Xu et al. 2016) has examined the association between PRAL with risk of death from all causes. In women, acidic PRAL values ( > 0) were associated with a significantly increased risk of death from all causes, as were alkaline PRAL values (< -5.6). In addition, very acidic (~40) and very alkaline (-30) PRAL values were associated with the highest risk for all-cause mortality:

pral-acm-men

Similarly, in men, when compared with a PRAL = 0, both alkaline (PRAl < -5.6) and acidic (> 29.8) values were associated with increased all-cause mortality risk.

pral-acm-women

While this data suggests that eating too much meat, grains, and/or nuts may not be optimal for health, it also suggests that eating too much alkaline-forming food, including veggies and fruits, may also not be optimal! My high veggie-based diet yields a very negative PRAL, ~-120 (~ -0.05 PRAL units/calorie), which would seem to put me at increased all-cause mortality risk. To further investigate, I decided to look at the PRAL values of long-lived societies.

The PRAL formula, as reported by Remer and Manz (1994) is:

PRAL = (0.49 * protein intake in g/day) + (0.037 * phosphorus intake in mg/day) – (0.02 * potassium intake in mg/day) – (0.013 * calcium intake in mg/day) – (0.027 * magnesium intake in mg/day).

Life expectancy for Seventh-Day Adventist women is 85 years, a value that is the highest in the world (Fraser and Shavlik 2001). What’s the average daily PRAL value for that population?

Average daily dietary data in both vegetarian and non-vegetarian Seventh-Day Adventist women (average age, ~72y) has been reported (Nieman et al. 1989). For vegetarians, total calories = 1452; protein = 47g; phosphosphorus = 889 mg; potassium = 2628 mg; calcium = 628 mg; magnesium = 283 mg. These values yield an alkaline PRAL = -33.2. Because higher amounts of these nutrients can result from an increased calorie intake, it’s important to divide PRAL by the average daily calorie value, thereby yielding PRAL/calorie. For vegetarian Adventists, this value = -0.02.
In non-vegetarian Adventists, total calories = 1363; protein = 55g; phosphosphorus = 892 mg; potassium = 2342 mg; calcium = 633 mg; magnesium = 228 mg. These values also yield an alkaline PRAL = -25.5, and PRAL/calorie = -0.019.

Life expectancy for those who live on the island of Okinawa is among the longest in the world (Miyagi et al. 2003). What’s the average daily PRAL value for Okinawan older adults?

The average daily dietary data for 75-year old Okinawans has been reported (Willcok et al. 2007): total calories, 1785; protein, 39g; phosphosphorus, 864 mg; potassium, 5200 mg; calcium, 505 mg; magnesium, 396 mg. These values also yield an yield a very alkaline PRAL value = -87.4, and PRAL/calorie = -0.049. Interestingly, these values are very close to my very alkaline PRAL values of -121, and PRAL/calorie = ~-0.05!

My goal is not just to get to 75 in great health, but to live past 100 (and far beyond). What’s the data in centenarians? Unfortunately, I could only find 2 studies that included dietary data for that age group.

In a study of 30 Chinese centenarians (average age, 103y), daily dietary values of 1220 calories, 39g protein, 603 mg phosphorus, 1433 mg potassium, 482 mg calcium, and 355 mg magnesium were reported (Cai et al. 2016), thereby yielding an average daily PRAL value = -20.3, and PRAL/calorie = -0.017.
Similarly, in a larger study of 104 Japanese centenarians (average age, 100y), daily dietary values of 1137 calories, 44g protein, 676 mg phosphorus, 1695 mg potassium, 414 mg calcium, and 154 mg magnesium were reported (Shimizu et al. 2003), thereby yielding an average daily PRAL value = -16.3, and PRAL/calorie = -0.014.

In contrast to the data of Xu et al. (2016), these data suggest that an alkaline diet may indeed be optimal for lifespan.

So what’s your dietary PRAL value?

If you’re interested, please have a look at my book!

References

Cai D, Zhao S, Li D, Chang F, Tian X, Huang G, Zhu Z, Liu D, Dou X, Li S, Zhao M, Li Q. Nutrient Intake Is Associated with Longevity Characterization by Metabolites and Element Profiles of Healthy Centenarians. Nutrients. 2016 Sep 19;8(9).

Fraser GE, Shavlik DJ. Ten years of life: Is it a matter of choice? Arch Intern Med. 2001 Jul 9;161(13):1645-52.

Miyagi S, Iwama N, Kawabata T, Hasegawa K. Longevity and diet in Okinawa, Japan: the past, present and future. Asia Pac J Public Health. 2003;15 Suppl:S3-9.

Nieman DC, Underwood BC, Sherman KM, Arabatzis K, Barbosa JC, Johnson M, Shultz TD. Dietary status of Seventh-Day Adventist vegetarian and non-vegetarian elderly women. J Am Diet Assoc. 1989 Dec;89(12):1763-9.

Remer T, Manz F. Estimation of the renal net acid excretion by adults consuming diets containing variable amounts of protein. Am J Clin Nutr. 1994;59:1356-1361.

Shimizu K, Takeda S, Noji H, Hirose N, Ebihara Y, Arai Y, Hamamatsu M, Nakazawa S, Gondo Y, Konishi K. Dietary patterns and further survival in Japanese centenarians. J Nutr Sci Vitaminol (Tokyo). 2003 Apr;49(2):133-8.

Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He Q, Curb JD, Suzuki M. Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world’s longest-lived people and its potential impact on morbidity and life span. Ann N Y Acad Sci. 2007 Oct;1114:434-55.

Xu H, Åkesson A, Orsini N, Håkansson N, Wolk A, Carrero JJ. Modest U-Shaped Association between Dietary Acid Load and Risk of All-Cause and Cardiovascular Mortality in Adults. J Nutr. 2016 Aug;146(8):1580-5.

Calorie Restriction Pioneer Roy Walford: Where Did He Go Wrong?

With the goal of improving health and extending lifespan, Roy Walford was a pioneer in terms of studying (and implementing) a diet that is calorie restricted but that also contains optimal nutrition (CRON). Unfortunately, Walford died at age 80 from complications related to Amyotrophic Lateral Sclerosis (ALS). Were there any factors in his nutritional approach that increased his risk for developing ALS?

On Walford’s website, www.walford.com, he listed 2 sample days of both food intake and his resulting macro- and micronutrient composition:

day 1.png

Although several micronutrients (calcium, sodium, zinc) are below the RDA on day 1, Walford’s 2-day average bring these values close to the RDA. However, his Vitamin E intake on day 1 and day 2 (shown below) are glaringly deficient. On day 1, his Vitamin E intake was only 2.8 mg. On day 2, it was 6.1 mg, for a 2-day average value of 4.5 mg. The RDA for Vitamin E was updated in 2000 (Food and Nutrition Board, 2000) from 8 mg to the current 15 mg-he wasn’t close to either value!

Dietary Vitamin E has been reported to be decreased in patients with ALS, when compared with ALS-free controls, as shown below (Veldink et al. 2007). Although the subjects of Veldink et al. had an increased calorie intake when compared with Walford (2842 and 2938 calories in controls and in ALS patients, respectively), when scaled down to Roy’s 1500 calorie intake, a dietary Vitamin E intake of 9 mg would be found in ALS patients, with 10.8 mg found in the controls. For comparison, Walford’s 2-day Vitamin E intake was only 6.1 mg! Interestingly, the only other dietary nutrient category that was significantly different between ALS patients and controls was polyunsaturated fat (PUFA) intake, which was also low (8.8g) in Walford’s 2-day diet.

I’m not at all saying that Walford’s dietary deficiencies in Vitamin E and PUFA caused his ALS. It’s also unknown whether the 2 days that he posted on his website are representative of his overall CRON approach. But it’s an interesting observation, isn’t it?

If you’re interested, please have a look at my book!

References

Food and Nutrition Board, Institute of Medicine. Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, D.C.: National Academy Press; 2000:186-283.

Freedman MD, Kuncl RW, Weinstein SJ, Malila N, Virtamo J, Albanes D. Vitamin E serum levels and controlled supplementation and risk of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 May;14(4):246-51

Veldink JH, Kalmijn S, Groeneveld GJ, Wunderink W, Koster A, de Vries JH, van der Luyt J, Wokke JH, Van den Berg LH. Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2007 Apr;78(4):367-71.

The Essential Fatty Acid, Linoleic Acid: Dietary Intake And Circulating Values, What’s Optimal For Health?

Linoleic acid (C18:2, n-6) is an essential fatty acid that must be obtained from the diet, because our body can’t make it. How much linoleic acid should we eat every day for optimal health? To answer this question, I’ll investigate the association between circulating levels of linoleic acid with all-cause mortality risk, followed by identification of a corresponding dietary intake. Let’s have a look!

First, are circulating levels of linoleic acid associated with all-cause mortality risk? 4 studies have investigated this issue:

In a 15-year study of 1,551 middle-aged men (average age, 52y), increased circulating linoleic acid was associated with significantly reduced all-cause mortality risk in 3 of the 4 multivariable-adjusted models (Laaksonen et al. 2005).
In a 15-year study of 4,232 older adults (60y) elevated circulating linoleic acid was associated with significantly reduced all-cause mortality risk in men, but not women (Marklund et al. 2015).
In a 34-year study of 2,009 middle-aged men (average age, 50y) increased circulating linoleic acid was associated with significantly decreased risk of all-cause mortality (Warensjö et al. 2008). For example, shown below is the association between the risk of death from cardiovascular-related disease with the circulating linoleic acid concentration. At both 20 and 30 years after study onset, subjects that had circulating linoleic values above the median had approximately half of the mortality risk from CVD, when compared with below-median values for linoleic acid.

In a 13-year study that included both older men and women (average age, 74y), and, more subjects (2,792) than the studies of Laaksonen and Warensjöet combined, plasma phospholipid percentages of linoleic acid greater than ~21-24% were associated with significantly reduced all-cause mortality risk:

Colectively, these 4 studies show that increased circulating levels of linoleic acid are associated with reduced all-cause mortality risk. How much linoleic acid should we eat to achieve optimal circulating values? In other words, what dietary intake of linoleic acid corresponds to 21%+ of plasma phospholipid linoleic acid? Based on the data below, dietary intakes of linoleic acid that are greater than 14% of total calories are associated with circulating linoleic acid values of 21% (Wu et al. 2014).

On my ~2300 calorie diet, that translates into 322 calories (36g) from linoleic acid. I get a significant amount of dietary linoleic acid from one of the best linoleic acid food sources, walnuts, which contain 5.8 grams of linoleic acid per 100 calories (see Lipids, C18:2, http://ndb.nal.usda.gov/ndb/foods/show/3690?fg=&man=&lfacet=&count=&max=&qlookup=&offset=&sort=&format=Full&reportfmt=other&rptfrm=&ndbno=&nutrient1=&nutrient2=&nutrient3=&subset=&totCount=&measureby=&_action_show=Apply+Changes&Qv=.152&Q6919=1&Q6920=1&Q6921=1&Q6922=1&Q6923=1&Q6924=1).

Just using walnuts alone, I’d need ~700 calories per day to reach 14% dietary linoleic acid! Although I’m always interested in dietary strategies that may reduce all-cause mortality risk, allocating ~30% of my daily calories to only walnuts is not ideal for my high-fiber approach to health (https://michaellustgarten.com/2015/07/17/on-a-paleo-diet-not-if-you-fiber-intake-is-less-than/), nor would it satiate me, as high-volume vegetable meals are best for that. A more reasonable dietary linoleic acid target (for now) is ~8%, the point at which plasma linoleic acid mostly plateaus (see the plot above). 8% on my 2300 calorie diet translates into 20 grams of linoleic acid per day. I should note that I also get a good amount of linoleic acid (6.4 grams) from the 30 grams of sesame seeds that goes into my giant salad’s dressing, which I eat 2-3x per week. When combined with ~300 calories from walnuts/day, that gets me to at least 8% of my daily calories from linoleic acid.

If you’re interested, please have a look at my book!

References:

Laaksonen DE, Nyyssönen K, Niskanen L, Rissanen TH, Salonen JT. Prediction of cardiovascular mortality in middle-aged men by dietary and serum linoleic and polyunsaturated fatty acids. Arch Intern Med. 2005 Jan 24;165(2):193-9.

Marklund M, Leander K, Vikström M, Laguzzi F, Gigante B, Sjögren P, Cederholm T, de Faire U, Hellénius ML, Risérus U. Polyunsaturated Fat Intake Estimated by Circulating Biomarkers and Risk of Cardiovascular Disease and All-Cause Mortality in a Population-Based Cohort of 60-Year-Old Men and Women. Circulationz 2015 Aug 18;132(7):586-94.

Warensjö E, Sundström J, Vessby B, Cederholm T, Risérus U. Markers of dietary fat quality and fatty acid desaturation as predictors of total and cardiovascular mortality: a population-based prospective study. Am J Clin Nutr. 2008 Jul;88(1):203-9.

Wu JH, Lemaitre RN, King IB, Song X, Psaty BM, Siscovick DS, Mozaffarian D. Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the CardiovascularHealth Study. Circulation. 2014 Oct 7;130(15):1245-53

Vitamin C: Dietary Intake And Plasma Values, What’s Optimal For Health?

How much Vitamin C (ascorbic acid) is optimal for health? To answer this question, I’ll examine the association between circulating levels of Vitamin C with all-cause mortality risk. Then, which dietary Vitamin C intake corresponds to optimal plasma levels? Let’s have a look!

A variety of studies have investigated associations between plasma (or serum) Vitamin C with all-cause mortality risk:

In a 4-year study of 1,115 older adults (average age ~79y), plasma vitamin C values greater than 66 uM (micromolar) were associated with significantly decreased all-cause mortality risk, when compared with values less than 17 uM (Fletcher et al. 2003).
In a 12-year study of 725 older adults (average age, 73y), plasma vitamin C values greater than 52 uM were associated with significantly reduced all-cause mortality risk (Sahyoun et al. 1996). Interestingly, the most reduced mortality risk was found in those with plasma Vitamin C values greater than 89 uM, a value that can only be attained with dietary Vitamin C intakes greater than 1000 mg/day (more on this below!).
In a 16-year study of 8,453 middle-aged adults (average age ~49y), serum Vitamin C values greater than 45 uM were associated with significantly reduced all-cause mortality risk, when compared with values less than 17 uM (Simon et al. 2001).
In a 13-year study of 948 older adults (average age, 67y), serum Vitamin C values greater than 55 uM were associated with significantly reduced all-cause mortality risk, when compared with values less than 13.5 uM (Wang et al. 2018).
In a 13-year study of 1,054 older adults (average age ~76y), elevated plasma levels of Vitamin C (risk ratios were reported without the actual Vitamin C concentration) were associated with significantly decreased all-cause mortality risk (Bates et al. 2011).
In a 4-year study of 19,496 older adults (average age ~59y), plasma Vitamin C values greater than 48 uM in men and 59 uM in women (both in quintile 3, shown below) were associated with significantly reduced all-cause mortality risk (Khaw et al. 2001). The most reduced all-cause mortality risk included average Vitamin C values of 73 uM for men and 85 uM for women (shown below in quintile 5), values which require greater than 500 mg of dietary Vitamin C/day (more on this also below!).

Studies that show weaker or no association between the plasma Vitamin C concentration with all-cause mortality risk include Loria et al. (2000) and Jia et al. (2007). In Loria et al. (2000), 9,450 middle aged adults (~48y) were followed for 12-16 years. Men in the highest Vitamin C quartile (> 74 uM) had significantly reduced all-cause mortality risk, when compared with men in the low plasma Vitamin C group (< 28 uM). Although a similar association was identified for women, significance was lost after multivariable adjustment. In Jia et al. (2007), although plasma Vitamin C values less than 61 uM were associated with increased all-cause mortality risk in older adults (median age, ~80y) that were studied for ~7.5 years, these data were not statistically significant (p-value = 0.18). However, the study sample size (398 subjects) may have been too small to detect significant effects.

Collectively these studies show that low circulating levels of Vitamin C may be related to increased mortality risk, whereas plasma values greater than ~50 uM are consistently associated with reduced all-cause mortality risk. How much dietary vitamin C is required to attain 50 uM+?

As shown below, the RDA for dietary Vitamin C is 90 mg for males and 75 mg for females older than 19 years (Institute of Medicine 2000).

If you consume the RDA for Vitamin C, what plasma Vitamin C concentration will that yield? Shown below is how the plasma Vitamin C concentration varies according to ingested dose (Levine et al. 1996). Consuming the RDA value for Vitamin C yields a plasma Vitamin C value of 20-30 uM. From the studies listed above, that would put you in the increased all-cause mortality risk group! How much dietary Vitamin C would be needed to achieve plasma values greater than 50 uM? From the plot, we see that a dietary Vitamin C intake at double the RDA would be necessary. Furthermore, because 2 studies have reported decreased all-cause mortality risk at plasma Vitamin C values greater than 66 uM, dietary intakes intake between 500-1000+ mg/day may be necessary:

Which foods are Vitamin C-rich? As shown below, sweet peppers (yellow, red, and green) are the All-Stars for Vitamin C content per 100 calories:

What’s my average daily Vitamin C intake? Shown below is my average daily Vitamin C intake, 875 mg/day, separated by month. Based on that value, my plasma Vitamin C concentration should be ~ 70 uM, which may be associated with maximally reduced all-cause mortality risk.

With the goal of optimizing plasma Vitamin C, it is also important to monitor dietary sodium intake. Intestinal absorption of Vitamin C requires dietary sodium (Friedman and Zeidel 1999). As shown below, 1 ascorbate ion (asc-) is absorbed from the intestinal lumen into intestinal epithelial cells in the presence of 2 sodium (Na+) ions. Vitamin C can then diffuse into the blood as Asc- or as dehydroascorbate (DHA):

na asc transport

Accordingly, based on my average dietary Vitamin C intake of 875 mg/day, to maximize absorption, a corresponding dietary sodium intake of 1750 mg would also be necessary.

If you’re interested, please have a look at my book!

References

Bates CJ, Hamer M, Mishra GD. Redox-modulatory vitamins and minerals that prospectively predict mortality in older British people:the National Diet and Nutrition Survey of people aged 65 years and over. Br J Nutr. 2011 Jan;105(1):123-32.

Fletcher AE, Breeze E, Shetty PS. Antioxidant vitamins and mortality in older persons: findings from the nutrition add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Am J Clin Nutr. 2003 Nov;78(5):999-1010.

Friedman PA, Zeidel ML. Victory at C. Nat Med. 1999 Jun;5(6):620-1.

Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press, 2000.

Jia X, Aucott LS, McNeill G. Nutritional status and subsequent all-cause mortality in men and women aged 75 years or over living in the community. Br J Nutr. 2007 Sep;98(3):593-9.

Khaw KT, Bingham S, Welch A, Luben R, Wareham N, Oakes S, Day N. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 2001 Mar 3;357(9257):657-63.

Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3704-9.

Loria CM, Klag MJ, Caulfield LE, Whelton PK. Vitamin C status and mortality in US adults. Am J Clin Nutr. 2000 Jul;72(1):139-45.

Sahyoun NR, Jacques PF, Russell RM. Carotenoids, vitamins C and E, and mortality in an elderly population. Am J Epidemiol. 1996 Sep 1;144(5):501-11.

Simon JA, Hudes ES, Tice JA. Relation of serum ascorbic acid to mortality among US adults. J Am Coll Nutr. 2001 Jun;20(3):255-63.

Wang SM, Fan JH, Taylor PR, Lam TK, Dawsey SM, Qiao YL, Abnet CC.vAssociation of plasma vitamin C concentration to total and cause-specific mortality: a 16-year prospective study in China. J Epidemiol Community Health. 2018 Dec;72(12):1076-1082.

Drink Green Tea, Reduce All-Cause Mortality Risk?

Is green tea consumption associated with reduced risk of death risk from all causes? To investigate this question, Tang et al. (2015) performed a meta-analysis of 5 studies, including 200,884 subjects. As shown below, drinking 5 cups (40 oz.) or less per day is associated with reduced all-cause mortality risk. Drinking 2-3 cups (16-24 oz.) of green tea per day was associated with maximally decreased all-cause mortality risk, ~10%.

If you’re interested, please have a look at my book!

Reference

Tang J, Zheng JS, Fang L, Jin Y, Cai W, Li D. Tea consumption and mortality of all cancers, CVD and all causes: a meta-analysis of eighteen prospective cohort studies. Br J Nutr. 2015 Jul 23:1-11.

Vitamin D: What’s an optimal daily intake and blood value?

How much Vitamin D is optimal for health? To answer this question, today I’ll examine the association between a circulating marker of Vitamin D, 25-hydroxyvitamin D, with all-cause mortality risk. Then, I’ll examine the literature to estimate a dietary intake that can achieve an optimal circulating 25-hydroxyvitamin D concentration.

Circulating 25-hydroxyvitamin D is the most commonly measured vitamin D metabolite because of its greater half life (~3 weeks) and up to 1000-fold higher serum levels compared with the physiologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D (Zerwekh 2008). So what’s the evidence for the association between circulating 25-hydroxyvitamin D with all-cause mortality risk?

In a meta-analysis of 95 studies including 880,201 subjects, circulating 25-hydroxyvitamin D levels greater than 30 ng/mL (75 nmol/L) are associated with significantly reduced risk of death from all causes when compared with values less than 30 (<10, 20-29; Chowdhury et al. 2014):

Does the meta-analysis data for 25-hydroxyvitamin D mean that any values higher than 30 ng/mL are optimal for health? Maybe not. As shown below, although data from 11,315 subjects in the NHANES III study suggests that values between 30-40 ng/mL (75-99 nmol/L) may be optimal for decreased all-cause mortality risk (Sempos et al. 2013), 25-hydroxyvitamin D values greater than 48 ng/mL (120+ nmol/L) were associated with an increased all-cause mortality risk. Interestingly, in agreement with the Chowdhury meta-analysis data, this graph shows also increased mortality risk at values less than 30-40 ng/mL (75-99 nmol/L):

However, whether increased circulating 25-hydroxyvitamin D is associated with increased all-cause mortality risk is debatable. In another meta-analysis (Garland et al. 2014), although circulating 25-hydroxyvitamin D values less than 30 ng/mL were again associated with increased risk, in contrast, values greater than 48 ng/mL were not. Interestingly, values as high as 70 ng/mL (175 nmoL) were not associated with increased risk, either:

D UPDATED META

Aside from our skin making Vitamin D from sunlight during the summer months, what dietary intake can achieve the seemingly optimal 30-40 ng/mL (75-99 nmol/L) concentration for 25-hydroxyvitamin D in the winter? The RDA for Vitamin D is 600 IU for everyone older than 1 but younger than 70 (Institute of Medicine, 2010). If you’re over 70, the RDA is 800 IU. My average dietary intake is only ~170 IU-how can I increase this to at least the RDA, to achieve circulating values between 75-99 nmol/L?

Decent dietary sources of vitamin D include fish: salmon, sardines, mackerel, and tuna. Based on the table below (Holick 2007), eating ~3.5 ounces of wild salmon every day would achieve the RDA for vitamin D intake. In contrast, my daily tin of sardines puts me ~300 IU away from the RDA value! I could double my fish intake to ~8 oz./day, but I’d like to limit my animal protein intake, and, the extra ~200 calories would limit other nutrients that I’d like to enrich in my diet, like fiber.

Are there other, less calorie dense dietary sources of vitamin D? It’s important to note that dietary vitamin D can be found in 2 forms, D3, which is shown above, and D2. Which foods are rich in vitamin D2? Shown below is a picture of the best plant-based source of vitamin D2, maitake mushrooms:

The Vitamin D2 content of maitake mushrooms is 36 IU/calorie, whereas wild salmon only has 3.2 IU of vitamin D per calorie! Other “exotic” mushrooms (anything other than white button mushrooms is exotic to me!) like Chanterelle and Morel contain decent amounts of vitamin D2:

Before adding maitake and other “exotic” mushrooms into my nutritional plan for their vitamin D content, it’s important to ask, “does D2 increase circulating 25-hydroxyvitamin D to an equal extent as D3”? Unfortunately, the answer is no: although D2 and D3 both increase circulating 25-hydroxyvitamin D levels, D2-based sources increase 25-hydroxyvitamin D level about half as effectively as D3 (Trang et al. 1998). So, instead of consuming ~35g of maitake mushrooms to add 400 IU of vitamin D into my diet (to achieve the RDA of 600 IU), I’ve added ~70g/day.

12/29/2015 Update: Because of Maitake’s relatively high cost, $5 for only 100g, and the burden of having to eat it every day, for the past ~3 months I switched to Vitamin D supplements to achieve a D intake of ~1100 IU/day. Blood testing showed that this intake yielded a circulating 25-hydroxyvitamin D winter concentration of 31 ng/mL, putting me at low risk for all cause mortality, based on the meta-analysis D data.

8/23/2016 Update: I stopped supplementing with 1000 IU of Vitamin D in June 2016, to explore the effect of 3-4 hours of weekly sun exposure on my circulating Vitamin D levels. My unsupplemented, circulating 25-hydroxyvitamin D level was 41 ng/mL in my 8/2016 blood test. Accordingly, I intend on increasing my Vitamin D intake to 1600 IU (1400 supplemental, ~200 dietary)/day to achieve a circulating winter 25-hydroxyvitamin D level that is similar my the summer value.

11/12/2017 Update: I’ve been supplementing with 2000 IU of D3/day, bringing my average daily total to ~2200 IU/day. Based on that, my latest circulating 25-hydroxyvitamin D level (tested in October, 2017) was 39 ng/mL .

If you’re interested, please have a look at my book!

References

Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, Khan H, Baena CP, Prabhakaran D, Hoshen MB, Feldman BS, Pan A, Johnson L, Crowe F, Hu FB, Franco OH. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014 Apr 1;348:g1903.

Garland CF, Kim JJ, Mohr SB, Gorham ED, Grant WB, Giovannucci EL, Baggerly L, Hofflich H, Ramsdell JW, Zeng K, Heaney RP. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Public Health. 2014 Aug;104(8):e43-50.

Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.

Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.

Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, Yetley EA, Looker AC, Schleicher RL, Cao G, Burt V, Kramer H, Bailey RL, Dwyer JT, Zhang X, Gahche J, Coates PM, Picciano MF. Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES. J Clin Endocrinol Metab. 2013 Jul;98(7):3001-9.

Trang HM, Cole DE, Rubin LA, Pierratos A, Siu S, Vieth R. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr. 1998 Oct;68(4):854-8.

Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr 2008;87:1087S-91S.

Selenium: Dietary Intake And Plasma Values, What’s Optimal For Health?

How much selenium is optimal for health? To address this question, I’ll examine the association between circulating levels of selenium with all-cause mortality risk. Then, I’ll identify a dietary selenium intake that corresponds to optimal plasma selenium levels. Let’s have a look!

A variety of studies have investigated associations between plasma (or serum) selenium with risk of death from all causes:

In a 9-year study of 1,389 older adults (average age, 65y) plasma selenium values less than 1.09 micromolar (uM) were associated with significantly increased all-cause mortality risk, when compared with values greater than 1.22 uM (Akbaraly et al 2005):

In a 6-year study of 1,042 older adults (average age, 76y), plasma selenium values less than 0.83 um were associated with significantly increased all-cause mortality risk, when compared with values greater than 1.0 uM (Lauretani et al. 2008):

In a 5-year study of 632 older women (average age, 74y), serum selenium values less than 1.38 uM were associated with significantly increased all-cause mortality risk, when compared with the other 3 quartiles (1.38 to 1.52, 1.53 to 1.67, and >1.68 uM; Ray et al. 2006):

In a 12-year study of 13,887 middle aged adults (average age, 45y), serum selenium values between 130-150 ng/mL (equivalent to 1.65-1.9 uM) were associated with reduced all-cause mortality risk (Bleys et al. 2006). Increased mortality risk was associated with serum selenium values less than 1.3 uM (~102 ng/mL):

These data were confirmed in the same cohort (16,008 adults) that were followed for an additional 2 years (14 years total; Goyal et al. 2013). Baseline serum selenium values greater than 1.4 uM were associated with significantly reduced all-cause mortality risk, compared with values less than1.38 uM.

Finally, in a 13-year study of 1,054 older adults (average age ~76y), elevated plasma levels of selenium (risk ratios were reported without the corresponding selenium concentration) were associated with significantly decreased all-cause mortality risk (Bates et al. 2011).

Studies that show weaker or no association between circulating values of selenium with all-cause mortality risk include Gonzalez et al. (2007) and Wei et al. (2004). In Gonzalez et al. (2007), serum selenium values greater than 1.26 uM were associated with decreased all-cause mortality risk for older women (average age, 76y), but not men, during a 4-year follow-up. However, Gonzalez et al. (2007) may have been underpowered to detect significant associations with mortality risk because of the small study size (215 total subjects). In Wei et al. (2004), a younger cohort (average age, 56y) of 1,115 subjects were followed for 15 years, and no association between serum selenium with all-cause mortality was found. However, only 4% of the population (~46 subjects) had serum selenium values greater than 1.19 uM, a finding that suggests that this study was additionally under-sized to detect significant associations.

Collectively, these studies suggest that circulating selenium values greater than at least 1.0 uM (and up to ~1.9 uM) are optimal for reducing all-cause mortality risk. What dietary intake of selenium can achieve these circulating values?

Shown below is the correlation between dietary selenium with serum selenium in 205 older adults (average age ~75y; González et al. 2006). Let’s start with the RDA selenium value for adults older than 19 years, 55 micrograms (mcg; Institute of Medicine, 2000). 55 mcg of dietary selenium is correlated with a serum selenium value of ~80 ug/L (~1 uM). In support of this correlation, a dietary selenium intake of ~47 ug/day has been shown to correlate with a circulating selenium concentration of 0.95 uM (Navarro et al. 1995). Based on the evidence already presented, eating only the RDA for selenium and achieving circulating selenium values less 1 uM would be associated with increased risk of death from all causes in 6 of the 7 studies! Based on its association with all-cause mortality risk, the RDA selenium value of 55 mcg/day is too low.

Determining which dietary selenium intake is optimal for maximally reduced all-cause mortality risk depends on how you interpret the literature. Four of previously mentioned studies showed circulating selenium values greater than 1.2 uM (95 ug/L) to be associated with reduced all-cause mortality risk. Based on the plot of González et al. (2006), ~130 ug of dietary selenium is necessary to achieve a circulating selenium concentration of 1.2 uM. Three studies showed decreased all-cause mortality risk at circulating selenium levels > 1.38 uM (110 ug/L). The dietary selenium intake that corresponds to that concentration is ~180 ug of selenium/day. Accordingly, a dietary selenium intake between 130-180 ug/day may be optimal for reducing all-cause mortality risk.

Which foods are selenium rich? Brazil nuts are the best dietary source of selenium, as 1 Brazil nut (4 g) contains 77 mcg of selenium (http://ndb.nal.usda.gov/ndb/foods/show/3641?fg=&man=&lfacet=&count=&max=&qlookup=&offset=&sort=&format=Full&reportfmt=other&rptfrm=&ndbno=&nutrient1=&nutrient2=&nutrient3=&subset=&totCount=&measureby=&_action_show=Apply+Changes&Qv=.04&Q6825=1&Q6826=1&Q6827=1). To achieve a dietary selenium intake between 130-180 mcg/day, every day I eat 1 or 2 Brazil nuts. It’s important to note that selenium toxicity can occur at intakes ~400 mcg (Food and Nutrition Board 2000), so keeping an eye on Brazil nut intake is probably a good idea.

If you’re interested, please have a look at my book!

References:

Akbaraly NT, Arnaud J, Hininger-Favier I, Gourlet V, Roussel AM, Berr C. Selenium and mortality in the elderly: results from the EVA study. Clin Chem. 2005 Nov;51(11):2117-23.

Bates CJ, Hamer M, Mishra GD. Redox-modulatory vitamins and minerals that prospectively predict mortality in older British people: the National Diet and Nutrition Survey of people aged 65 years and over. Br J Nutr. 2011 Jan;105(1):123-32.

Bleys J, Navas-Acien A, Guallar E.Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Arch Intern Med. 2008 Feb 25;168(4):404-10.

Broome CS, McArdle F, Kyle JA, Andrews F, Lowe NM, Hart CA, Arthur JR, Jackson MJ. An increase in selenium intake improves immune function and poliovirus handling inadults with marginal selenium status. Am J Clin Nutr. 2004 Jul;80(1):154-62.

Food and Nutrition Board, Institute of Medicine. Selenium. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, D.C.: National Academy Press; 2000:284-324.

González S, Huerta JM, Fernández S, Patterson EM, Lasheras C. Food intake and serum selenium concentration in elderly people.Ann Nutr Metab. 2006;50(2):126-31.

González S, Huerta JM, Fernández S, Patterson AM, Lasheras C. Homocysteine increases the risk of mortality in elderly individuals. Br J Nutr. 2007; 97:1138–1143.

Goyal A, Terry MB, Siegel AB. Serum antioxidant nutrients, vitamin A, and mortality in U.S. adults. Cancer Epidemiol Biomarkers Prev. 2013 Dec;22(12):2202-11.

Hurst R, Armah CN, Dainty JR, Hart DJ, Teucher B, Goldson AJ, Broadley MR, Motley AK, Fairweather-Tait SJ. Establishing optimal selenium status: results of a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2010 Apr;91(4):923-31.

Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press, 2000.

Lauretani F, Semba RD, Bandinelli S, Ray AL, Ruggiero C, Cherubini A, Guralnik JM, Ferrucci L. Low plasma selenium concentrations and mortality among older community-dwelling adults: the InCHIANTI Study. Aging Clin Exp Res. 2008 Apr;20(2):153-8.

Navarro M, López H, Ruiz ML, González S, Pérez V, López MC. Determination of selenium in serum by hydride generation atomic absorption spectrometry for calculation of daily dietary intake. Sci Total Environ. 1995 Dec 15;175(3):245-52.

Ray AL, Semba RD, Walston J, Ferrucci L, Cappola AR, Ricks MO, Xue QL, Fried LP. Low serum selenium and total carotenoids predict mortality among older women living in the community: the women’s health and aging studies. J Nutr. 2006 Jan;136(1):172-6.

Swanson CA, Longnecker MP, Veillon C, Howe M, Levander OA, Taylor PR, McAdam PA, Brown CC, Stampfer MJ, Willett WC. Selenium intake, age, gender, and smoking in relation to indices of selenium status of adults residing in a seleniferous area. Am J Clin Nutr. 1990 Nov;52(5):858-62.

Wei WQ, Abnet CC, Qiao YL, Dawsey SM, Dong ZW, Sun XD, Fan JH, Gunter EW, Taylor PR, Mark SD. Prospective study of serum selenium concentrations and esophageal and gastric cardia cancer, heart disease, stroke, and total death. Am J Clin Nutr. 2004 Jan;79(1):80-5.

Eat more green leafy vegetables, reduce mortality risk?

Vitamin K is found in 2 predominant forms, Vitamin K1 (phylloquinone), found almost exclusively in green leafy vegetables, and Vitamin K2 (Menaquinone), found in fermented foods, organ meats, meat, butter and eggs. In the data below (Juanola-Falgarona et al. 2014), we see that Vitamin K1 (phylloquinone) is negatively associated with death from all causes:

Death from all causes was assessed based on the average value for four groups of Vitamin K1 intake: 171 ug/day = blue line, 276 ug/day =red line, 349 ug/day = green line and 626 ug/day = the yellow line. In the data above, Vitamin K1 values less than 349 ug/day are about the same in terms of all-cause mortality risk. However, those who ate 626 ug/day of Vitamin K1 had about half of the mortality risk compared to the lower K1 intake groups! Interestingly, the RDA for Vitamin K, at 90 ug/day seems to be outdated, based on the data above. Also, Vitamin K2 was not associated with all-cause mortality risk, as shown below:

Based on the K1 mortality data, 626 ug/day seems like a good goal. However, osteocalcin is a Vitamin K-dependent protein that has been shown to be maximally active in the presence of 1000 ug of Vitamin K1 (Binkley et al. 2002)! Osteocalcin is involved in pathways that decline with aging: insulin secretion and β-cell proliferation in the pancreas, energy expenditure by muscle, insulin sensitivity in adipose tissue, muscle and liver, and increased testosterone production (Karsenty and Ferron 2012). Therefore, getting 1000 ug+ per day of Vitamin K1 may optimize all of these functions and, decrease mortality risk!

What’s the take home from these data? Eat more leafy greens! How much is needed to get 1000 ug per day? Shown below is a short list of foods rich in Vitamin K and the serving size needed to reach 1000 ug. Approximately 4 ounces of cooked kale or 7 oz. of raw spinach will suffice, and at a low calorie yield. Other foods, like broccoli, brussel sprouts or romaine lettuce would need to be consumed in far greater amounts to reach 1000 ug.

What’s my daily K1 intake? Shown below is my 7-day average (7/16/2015 – 7/22/2015) for K intake, derived almost exclusively from plant sources. 1379 ug/day puts me well above the 626 ug/day that was associated with reduced mortality risk, and above the 1000 ug/day needed for maximal osteocalcin activation.

If you’re interested, please have a look at my book!

References:

Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW. A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation. Am J Clin Nutr. 2002 Nov;76(5):1055-60.

Juanola-Falgarona M, Salas-Salvadó J, Martínez-González MÁ, Corella D, Ostrich R, Ros E, Fitó M, Arós F, Gómez-Gracia E, Fiol M, Lapetra J, Basora J, Lamuela-Raventós RM, Serra-Majem L, Pintó X, Muñoz MÁ, Ruiz-Gutiérrez V, Fernández-Ballart J, Bulló M. Dietary intake of vitamin K is inversely associated with mortality risk. J Nutr. 2014 May;144(5):743-50.

Karsenty G, Ferron M. The contribution of bone to whole-organism physiology. Nature. 2012 Jan 18;481(7381):314-20.

Is coffee associated with reduced mortality risk?

Data from large epidemiological studies can be used to guide decisions about health. There’s a lot of confusion about coffee consumption in terms of health…What does the epidemiological data say?

Crippa et al. (2014) pooled the results from 21 studies that included almost 1 million subjects (997,464 to be exact). As shown below, 4 cups of coffee per day (~32 oz, about 1 Liter) is associated with ~15% reduced risk of death from all causes.

More specifically, what about coffee consumption and risk of death from heart disease and cancer? As shown below, ~3 cups of coffee per day is associated with reduced risk of death from heart disease (CVD). Interestingly, CVD risk increases at coffee consumption >3 cups per day:

What about coffee consumption and cancer risk? As shown below, although the association between coffee and cancer was not statistically significant, it looks like ~3 cups of coffee is associated with reduced cancer risk, whereas risk begins to increase in amounts greater than 3 cups.

I hope this clears up some of the confusion that exists about coffee consumption and health!

If you’re interested, please have a look at my book!

Reference

Crippa A, Discacciati A, Larsson SC, Wolk A, Orsini N. Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis. Am J Epidemiol. 2014 Oct 15;180(8):763-75.

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