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+):

albumin mort.png

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 populationsJ 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.

Homocysteine and All-Cause Mortality Risk

On a recent blood test, my plasma level of homocysteine (Hcy) was 11.9 uMol. Is that optimal minimizing disease risk and maximizing longevity? Let’s have a look at the literature.

A 2017 meta-analysis of 11 studies including 27,737 participants showed an increased risk of death from all causes (“all-cause mortality”; ACM) as circulating levels of homocysteine increase (Fan et al. 2017):

hcy acm.png

When looking at meta-analyses, it’s important to examine each of the individual studies. Here are the data for the 11 included studies:

  • Kark et al. 1999: 1,788 older adults, average age 65y, followed for 9-11 years. Compared with values less than 8.5 uMol, subjects with elevated homocysteine (> 14.7) had a 2-fold higher risk of death from all causes.
  • Bostom et al. 1999: 1,933older adults, verage age, 70y, median follow-up, 10y. Subjects with values > 14.3 uMol had 2-fold ACM risk, when compared with < 14.3.
  • Hoogeveen et al. 2000: 811 older adults (average age, 65y), 5 yr follow-up. Non- diabetics had a 34% increased ACM risk (p=0.08), but diabetics had 2.5-fold increased ACM risk after a 5-yr follow-up.
  • Vollset et al. 2001: 4,766 older adults (age range, 65-67y at study entry), median 4 yr follow-up. Compared with 5.1-8.9 uMol, values greater than 12 were significantly associated with a 2.4-4.5 increased ACM risk.
  • Acevedo et al. 2003. 3,427 subjects, average age 56y, ~3yr follow-up. ACM risk lowest for < 9.4 uMol, compared with > 14.4.
  • González et al. 2007: 215 older adults (average age, 75y), median 4 yr follow-up. Compared with < 8.7 uMol, values > 16.7 had 2.3-fold increased ACM risk.
  • Dangour et al. 2008: 853 older adults (average age, 79y), ~7.6y follow-up. Homocysteins > 19.4 uMol associated with ~2-fold higher ACM risk, when compared with < 9.8.
  • Xiu et al. 2012: 1,412 older adults (average age, ~75y), up to 10 year follow-up. 1.8-fold higher ACM risk comparing those with >14.5 uMol with < 9.3.
  • Waśkiewicz et al. 2012: 7,165 middle aged adults, ~5yr follow- up. 1.8-fold increased ACM risk for subjects with homocysteine > 10.5 uMol(average age, 52y) when compared with < 8.2 (avg age, 40y).
  • Wong et al. 2013: 4,248 older men, average age ~77y, ~5yr follow-up. 1.5-fold increased ACM risk for homocysteine values > 15 uMol.
  • Swart et al. 2012: 1,117 older adults (average age, 75y), up to a 7yr follow-up. In 543 men, homocysteine was not associated with ACM risk. In 574 women, 1.7 to 1.9-fold higher ACM risk when comparing  > 12.7 and >15.6 vs < 10.3 uMol.

Not included in their analysis:

  • Petersen et al. 2016: 670 subjects, average age 65y, average follow-up 14.5y. Subjects with homocysteine values ≥ 10.8 μmol/l  had a significant higher incidence of all-cause mortality:

hcy 2

In sum, the evidence appears consistent across these 12 studies that elevated homocysteine is associated with an increased risk of death from all causes. Based on the Fan et al. (2016) meta-analysis, lower appears better, with values < 5 uMol associated with maximally reduced ACM risk. Also based on that data, my ACM risk is ~1.5-fold increased!

To see how dietary changes and supplements have impacted my homocysteine levels, see this link: https://michaellustgarten.com/2018/03/23/reducing-homocysteine-updates/

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

 

References:

Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D’Agostino RB, Wolf PA, Jacques PF, Wilson PW. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999 May 24;159(10):1077-80.

Dangour AD, Breeze E, Clarke R, Shetty PS, Uauy R, Fletcher AE. Plasma homocysteine, but not folate or vitamin B-12, predicts mortalityin older people in the United Kingdom. J Nutr. 2008 Jun;138(6):1121-8.

Fan R, Zhang A, Zhong F. Association between Homocysteine Levels and All-cause Mortality: A Dose-Response Meta-Analysis of Prospective Studies. Sci Rep. 2017 Jul 6;7(1):4769.

González S, Huerta JM, Fernández S, Patterson AM, Lasheras C. Homocysteine increases the risk of mortality in elderly individuals. Br J Nutr. 2007 Jun;97(6):1138-43.

Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study. Circulation. 2000 Apr 4;101(13):1506-11.

Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999 Sep 7;131(5):321-30.

Petersen JF, Larsen BS, Sabbah M, Nielsen OW, Kumarathurai P, Sajadieh A. Long-term prognostic significance of homocysteine in middle-aged and elderly. Biomarkers. 2016 Sep;21(6):490-6.

Swart KM, van Schoor NM, Blom HJ, Smulders YM, Lips P. Homocysteine and the risk of nursing home admission and mortality in older persons. Eur J Clin Nutr. 2012 Feb;66(2):188-95.

Waśkiewicz A, Sygnowska E, Broda G. Homocysteine concentration and the risk of death in the adult Polish population. Kardiol Pol. 2012;70(9):897-902.

Wong YY, Almeida OP, McCaul KA, Yeap BB, Hankey GJ, Flicker L. Homocysteine, frailty, and all-cause mortality in older men: the health in men study. J Gerontol A Biol Sci Med Sci. 2013 May;68(5):590-8.

Vollset SE, Refsum H, Tverdal A, Nygård O, Nordrehaug JE, Tell GS, Ueland PM. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001 Jul;74(1):130-6.

 

Platelets and All-Cause Mortality Risk

Have you had a blood test and aren’t sure what values for platelets may be optimal for health? The reference range is 150-400 platelets per nanoliter (*10^9/L). Within that range, what’s optimal?

In a study of 21,635 adults older than 35y (average age wasn’t reported) with a 7.6-year follow-up, platelets between 230-270 was associated with maximally reduced risk of death from all causes (Bonaccio et al. 2016):

platets acm

In a study of 21, 252 adults (average age 53y) with an average follow-up of 3.5y, values ~250 were associated with maximally reduced risk of death from all causes Vinholt et al. (2017) :

plat2 acm

What about in older adults? In a study of 159, 746 postmenopausal women (average age, 63y) with a 16-year follow up, maximally reduced risk of death from all causes was associated with platelet values between 200-256 (Kabat et al. 2017).

In a study of 36, 262 older adults (average age, 71y) with an 11-year follow-up, platelet values ~250 were associated with maximally reduced risk for all-cause mortality. Interestingly, even at platelet values ~250, mortality risk was highest for non-Hispanic whites, when compared with non-Hispanic blacks and Hispanics (Msaouel et al. 2014):

plat ethnicity

In 5,766 older adults (average age, 73y) that were followed for 12-15 years, values higher than 200-300 had an increased risk of death from all causes (van der Bom et al 2009). Risk for values between 100-199 was not different when compared against 200-299, but there was a non-significant trend towards increased risk (1.05, 95% CI: 0.97, 1.14).

In 131,308 older adults (~73y) with a 6-yr follow-up, maximally reduced risk of death from all causes was associated with values between 200-300, whereas risk significantly increased below and above that range, respectively Tsai et al. (2015):

plat eld

In sum, the data suggests that platelet values ~250 may be optimal for heath, with 200-300 as the “optimal range” within the 150-400 reference range. What are your values?

 

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

 

References

Bonaccio M, Di Castelnuovo A, Costanzo S, De Curtis A, Donati MB, Cerletti C, de Gaetano G, Iacoviello L; MOLI-SANI Investigators. Age-sex-specific ranges of platelet count and all-cause mortality: prospective findings from the MOLI-SANI study. Blood. 2016 Mar 24;127(12):1614-6.

Kabat GC, Kim MY, Verma AK, Manson JE, Lin J, Lessin L, Wassertheil-Smoller S, Rohan TE. Platelet count and total and cause-specific mortality in the Women’sHealth InitiativeAnn Epidemiol. 2017 Apr;27(4):274-280.

Msaouel P, Lam AP, Gundabolu K, Chrysofakis G, Yu Y, Mantzaris I, Friedman E, Verma A. Abnormal platelet count is an independent predictor of mortality in the elderly and is influenced by ethnicityHaematologica. 2014 May;99(5):930-6.

Tsai MT, Chen YT, Lin CH, Huang TP, Tarng DC; Taiwan Geriatric Kidney Disease Research Group. U-shaped mortality curve associated with platelet count among older people: a community-based cohort study. Blood. 2015 Sep 24;126(13):1633-5.

van der Bom JG, Heckbert SR, Lumley T, Holmes CE, Cushman M, Folsom AR, Rosendaal FR, Psaty BM. Platelet count and the risk for thrombosis and death in the elderlyJ Thromb Haemost. 2009 Mar;7(3):399-405.

Vinholt PJ, Hvas AM, Frederiksen H, Bathum L, Jørgensen MK, Nybo M. Thromb Res.Platelet count is associated with cardiovascular disease, cancer and mortality: A population-based cohort study. 2016 Dec;148:136-142.

Total Cholesterol: What’s Optimal For Longevity?

On my latest blood test (August 2015), my total cholesterol was 127 mg/dL-is that value optimal for health and longevity?

Based on data for 1,104,294 men younger than 60y (median age, 40y) that were followed for up to 14 years (Fulks et al. 2009), my 127 mg/dL value (1 – 2.4%) puts me relatively close to maximally reduced all-cause mortality risk, which occurs at 146-158 mg/dL (5-9% on the graph below):

c hdl mort

But what about the data for men older than 60?

In a 10-year study of 2,277 older adults (average age, ~77y), total cholesterol levels less than 175 mg/dL were associated with ~2-fold higher risk of all-cause mortality, compared with values greater than 226 mg/dL (Schupf et al. 2005):

tc less 175 acm

Similarly, in a 10-year study of even older adults (median age, 89y; 724 subjects), all-cause mortality risk was significantly increased in subjects with total cholesterol values less than 193 mg/dL (dark black line below), compared with values greater than 251 mg/dL (dashed line; Weverling-Rijnsburger et al. 1997). In addition, subjects with cholesterol values greater than 251 mg/dL lived ~2 years longer than those with values less than 191 mg/dL. So higher cholesterol in very old adults…increased lifespan! Does that mean I should alter my dietary approach to increase my circulating cholesterol levels after I reach 60?

chol 89y mort.png

To address that issue, it’s important to understand why cholesterol increases during aging. One possible mechanism involves the role of cholesterol in immune defense against infectious agents (bacteria, viruses, parasites, etc.). Obviously, our immune system is supposed to eliminate these pathogens, but immune function decreases with age (Targonski et al. 2007). As a compensatory mechanism, cholesterol can protect against infectious agents. For example, LDL cholesterol binds to and partially inactivates Staphylococcus aureus (Bhakdi et al. 1983). Staphylococcus aureus infection increases during aging, as its incidence rate is ~3-fold higher in adults older than 60y, when compared with younger subjects (Laupland et al. 2008). In addition, LDL cholesterol inhibits bacterial endotoxin (Weinstock et al. 1992), whose presence in the blood increases during aging (Ghosh et al. 2015). In support of the link between circulating cholesterol with infectious agents, in the older adults of Weverling-Rijnsburger et al. (1997), cholesterol values greater than 251 mg/dL (solid black line) were associated with significantly decreased infectious disease-related mortality, when compared with values less than 193 mg/dL:

infect mort

So if we’re better able to keep infectious agents out of our blood, that would be expected to reduce the need for elevated circulating cholesterol during aging. How can we do that?

One approach involves increased dietary fiber. Fermentation of dietary fiber by gut bacteria produces short-chain fatty acids, which improve gut barrier function (Chen et al. 2013), and decrease cholesterol synthesis (Wright et al. 1990). However, older adults do not eat high-fiber diets, as values of only ~19g/day have been reported (Lustgarten et al. 2014). In contrast, dietary fiber intakes greater than only 29g/day are associated with less infectious disease (and all-cause mortality) risk (Park et al. 2011). So definitely eating at least 29g fiber/day is important, but is that amount optimal to minimize the need for elevated cholesterol during aging?

In a 2-week study of the role of dietary fiber on circulating cholesterol, subjects that ate only 10g fiber/1000 calories did not significantly reduce their baseline total cholesterol values from ~182 mg/dL (Jenkins et al. 2001). In contrast, a dietary fiber intake of 19g/1000 calories reduced baseline total cholesterol from 185 to 150 mg/dL, and subjects that ate even more fiber than that, 55g/1000 calories reduced their total cholesterol values from ~182 to 142 mg/dL, a drop that was also significantly different compared with the 19g fiber/1000 calorie group.

Collectively, these data suggest that to maximally boost gut barrier function, thereby minimizing circulating infectious agents and the need for elevated circulating cholesterol during aging, a very-high fiber-diet may be important. Accordingly, my average daily fiber intake is ~100 g/day on a 2300 calorie diet, resulting in ~43g fiber/1000 calories. Based on this, I don’t expect for my total cholesterol values to change during aging, as my gut barrier function will be optimal, and infectious agents in my blood will be minimized.

To add some specificity to this approach, 2 additional measurements may be important: serum albumin and HDL cholesterol. In agreement with the studies of Weverling-Rijnsburger et al. and Schupf et al., in a 5-year study of 4,128 older adults (average age, ~79y), those with total cholesterol values less than 160 mg/dL had significantly higher all-cause mortality risk, compared with values greater than 240 mg/dL (Volpato et al. 2001):

low tc mortl

However, when considering subjects’ albumin and HDL cholesterol levels, the differential mortality risk was abolished. Subjects that had low total cholesterol but also high (within-range) albumin and HDL had improved survival compared to the higher cholesterol groups:

adj tc mort for alb hdl

If your total cholesterol values are less than 160 mg/dL, what serum albumin and HDL values should you shoot for? As shown below, albumin levels greater than 38 g/L and HDL values greater than 47 mg/dL were associated with maximally reduced all-cause mortality risk in subjects with total cholesterol values less than 160 mg/dL (Volpato et al. 2001):

volpato

My albumin values are consistently between 46-48 g/L, but during recent measurements my HDL levels have been lower than optimal (35 mg/dL on 8/2015). The good news is that I was able to increase my HDL from 28 (7/2013 measurement) to 35 mg/dL by adding ~4 oz of fish every day! To further increase my HDL, I’ve doubled my fish oil intake (~3.3 g of combined EPA + DHA per day, from 5-9 g of cod liver oil). I’ll test the effect of this on my circulating biomarkers in a couple of months, so stay tuned!

3/23/2016 Update: Because of concerns that the pre-formed Vitamin A (that is found in cod liver oil) may negate the potential health-promoting effects of optimal Vitamin D levels (Schmutz et al. 2016), I stopped taking cod liver oil during the 3-month period that preceded my latest blood test (3/23/2016). However, I was able to increase my HDL from 35 to 53 mg/dL! I attribute this increase to the daily inclusion of ~60g/walnuts per day. In doing that, although I only replaced ~200 calories from carbohydrates with fat, lower carbohydrate diets have been shown to increase HDL (Manor et al. 2016).

Nonetheless, in terms of the all-cause mortality data that includes total cholesterol (137 mg/dL), albumin (51 g/L), and HDL (53 mg/dL), based on my latest blood test results, my risk is now maximally low!

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

References

Bhakdi S, Tranum-Jensen J, Utermann G, Füssle R. Binding and partial inactivation of Staphylococcus aureus alpha-toxin by human plasma low density lipoprotein. J Biol Chem. 1983 May 10;258(9):5899-904.

Chen H, Mao X, He J, Yu B, Huang Z, Yu J, Zheng P, Chen D. Dietary fibre affects intestinal mucosal barrier function and regulates intestinal bacteria in weaning piglets. Br J Nutr. 2013 Nov;110(10):1837-48.

Eaton SB, Eaton SB 3rd, Konner MJ. Paleolithic nutrition revisited: A twelve-year retrospective on its nature and implications. Eur J Clin Nutr. 1997 Apr;51(4):207-16.

Fulks M, Stout RL, Dolan VF. Association of cholesterol, LDL, HDL, cholesterol/ HDL and triglyceride with all-cause mortality in life insurance applicants. J Insur Med. 2009;41(4):244-53.

Ghosh S, Lertwattanarak R, Garduño Jde J, Galeana JJ, Li J, Zamarripa F, Lancaster JL, Mohan S, Hussey S, Musi N. Elevated muscle TLR4 expression and metabolic endotoxemia in human agingJ Gerontol A Biol Sci Med Sci. 2015 Feb;70(2):232-46.

Jenkins DJ, Kendall CW, Popovich DG, Vidgen E, Mehling CC, Vuksan V, Ransom TP, Rao AV, Rosenberg-Zand R, Tariq N, Corey P, Jones PJ, Raeini M, Story JA, Furumoto EJ, Illingworth DR, Pappu AS, Connelly PW. Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function. Metabolism. 2001 Apr;50(4):494-503.

Laupland KBRoss TGregson DBStaphylococcus aureus bloodstream infections: risk factors, outcomes, and the influence of methicillin resistance in Calgary, Canada, 2000-2006. J Infect Dis. 2008 Aug 1;198(3):336-43.

Lustgarten MS, Price LL, Chalé A, Fielding RA. Metabolites related to gut bacterial metabolism, peroxisome proliferator-activated receptor-alpha activation, and insulin sensitivity are associated with physical function in functionally-limited older adults. Aging Cell. 2014 Oct;13(5):918-25.

Mansoor N, Vinknes KJ, Veierød MB, Retterstøl K. Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials. Br J Nutr. 2016 Feb;115(3):466-79.

Park Y, Subar AF, Hollenbeck A, Schatzkin A. Dietary fiber intake and mortality in the NIH-AARP diet and health study. Arch Intern Med. 2011 Jun 27;171(12):1061-8.

Schmutz EA, Zimmermann MB, Rohrmann S. The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements. Eur J Nutr. 2016 Feb;55(1):393-402.

Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship Between Plasma Lipids and All-Cause Mortality in Nondemented Elderly. J Am Geriatr Soc. 2005 Feb;53(2):219-26.

Targonski PV, Jacobson RM, Poland GA. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine. 2007 Apr 20;25(16):3066-9.

Vasto S, Scapagnini G, Rizzo C, Monastero R, Marchese A, Caruso C. Mediterranean diet and longevity in Sicily: survey in a Sicani Mountains population. Rejuvenation Res. 2012 Apr;15(2):184-8.

Volpato S, Leveille SG, Corti MC, Harris TB, Guralnik JM. The value of serum albumin and high-density lipoprotein cholesterol in defining mortality risk in older persons with low serum cholesterolJ Am Geriatr Soc. 2001 Sep;49(9):1142-7.

Weinstock C, Ullrich H, Hohe R, Berg A, Baumstark MW, Frey I, Northoff H, Flegel WA. Low density lipoproteins inhibit endotoxin activation of monocytes. Arterioscler Thromb. 1992 Mar;12(3):341-7.

Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE, Westendorp RG. Total cholesterol and risk of mortality in the oldest old. Lancet. 1997 Oct 18;350(9085):1119-23.

Wright RS, Anderson JW, Bridges SR. Propionate inhibits hepatocyte lipid synthesis. Proc Soc Exp Biol Med. 1990 Oct;195(1):26-9.

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.

LA CVD mortality

  • 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:

LA total mort

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).

LA dietary in PL

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.wordpress.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 StudyCirculation. 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 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!).

C risk

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).

C RDA

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:

C dose

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:

C foods

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.

C intake

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 overBr 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 volunteersevidence 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.

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%.

green tea

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):

d mort

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):

d mortality

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.

d

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:

maitake

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:

mush

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 D2Am 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.