Dietary Cholesterol Vs. Plasma Cholesterol: My n=1 Data

With use of a food scale,  I’ve been tracking my daily macro- and micronutrient intake every day since April 2015. In addition, I have 15 blood test measurements during that period, and accordingly, I’m able to examine correlations between my dietary intake with my circulating biomarkers. In this post, I’ll address the question, is my dietary cholesterol intake significantly correlated with plasma levels of cholesterol?

1. Plasma levels of total cholesterol vs. dietary cholesterol:

tc.png

In the plot we see a borderline significant (p = 0.06), moderate correlation (r = 0.5) between my plasma total cholesterol with my dietary cholesterol intake. However, note that total cholesterol is comprised of “good” and “bad” parts, with HDL as the “good”, and with non-HDL cholesterol, including LDL and VLDL, as the “bad”. What does that data look like?

2. Plasma levels of non-HDL (LDL+VLDL) cholesterol vs. dietary cholesterol:

nonhdl.png

In the plot we see a highly significant (p = 0.006), strong correlation (= 0.67) between my non-HDL cholesterol levels with my dietary cholesterol intake. It’s not possible to show causation via correlation, but this data suggests that my dietary cholesterol intake may be driving increased levels of non-HDL cholesterol.

3. Plasma levels of HDL cholesterol vs. dietary cholesterol:

hdl.png

In the plot, first note that in contrast with the positive correlations between total and non-HDL cholesterol with my dietary cholesterol intake, the correlation between HDL with my dietary cholesterol intake is negative (i.e., going in the opposite direction; r = 0.51), and borderline significant (p = 0.054).

Cumulatively, it looks like my dietary cholesterol intake may be related to increased “bad” cholesterol and decreased “good” cholesterol. As a limitation of this approach, although I’ve shown blood test data for 15 measurements (which is a decent sample size), I only have 4 measurements with an average daily cholesterol intake around 200 mg or greater. In the near future, I expect to average 200 mg of daily cholesterol (or more) per day, so let’s see if these correlations hold up!

 

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

 

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.

Reducing Homocysteine? Updates.

In an earlier post I wrote about the association between elevated circulating levels of homocysteine with an increased risk of death from all causes (https://michaellustgarten.com/2017/11/22/homocysteine-and-all-cause-mortality-risk/). I started to post updates in that link, but I’ve decided to move them to here.

As of 6/2018, I now have tracked dietary data (I weigh all my food and record the values in cronometer.com) that corresponds to 7 homocysteine measurements:
Picture1

12/5/2017: Despite 42 days of 800 micrograms of supplemental folic acid, bringing my average daily folate intake to 2026 micrograms/day, my plasma homocysteine was essentially unchanged at 11.7 uMoL, when compared with my baseline value of 11.8 uMol.What’s next on the list to reduce it? Trimethylglycine, also known as betaine. I’m a proponent of using diet as a first strategy,  and to increase my dietary betaine levels, I’ll eat beets and quinoa, bringing my daily betaine levels to ~500 mg/day. Let’s see how it turns out on my next blood test!

1/2/2018: ~500 mg/day of betaine from beets and quinoa did absolutely nothing to my homecysteine levels. In fact, it got worse (15.3 uMoL)! To test the hypothesis that it wasn’t enough betaine, next I tried 4 grams/day of betaine (also known as trimethylglycine, TMG).

2/20/18: Supplemental TMG did absolutely nothing in terms of reducing my homocysteine to values below baseline! Also note that there is evidence that TMG increases blood lipids, including LDL and triglycerides (TG; Olthof et al. 2005), and that’s exactly what it did to me. My average LDL and TG values since 2015 (11 measurements) are 77 and 50 mg/dL, respectively. On TMG, these values increased to 92 and 72 mg/dL, respectively, making them my highest values over 11 individual blood tests (with the exception of 1 day with an LDL of 93 mg/dL). Next, I tried a stack that included 50 mg of B6, 1000 mcg of B12, and 400 mcg of methylfolate, as supplementation with these B-vitamins has been shown to lower homocystine (Lewerin et al. 2003).

3/20/18: Finally, some progress! My homocysteine levels were reduced during the B-vitamin supplementation period. I’ve written it like that because I’m not sure if it was the B-vitamins that caused it. For example, in the image below, we see the correlation between my dietary B6 intake with homocysteine. The trendline is down, which I would expect if B6 supplementation actually is playing a role in reducing my homocysteine levels. However, note that the correlation between my dietary B6 levels with homocysteine is not very strong (= .48), resulting in a moderate R2 of 0.23 (similar data was obtained for B12 and folate). With 5 blood test measurements corresponding to 5 dietary periods, if B6 is playing a role, I would expect a stronger correlation. Nonetheless, with more data, the correlation may strengthen, so stay tuned for that!

b6hcy.png

5/14/2018: I changed B6-B12-methylfolate supplements so that I’d only have to take pills from 1 bottle instead of from 3. That supplement, however, had 1.5 mg of B6 instead of the 50 mg that was in my original supplement. Less B6 didn’t result in a higher homocysteine value-in fact, it went down (slightly), from 10.8 to 10.6. If an increased amount of B6 was causing lower levels of homocysteine, I would’ve expected higher, not (barely) lower homocysteine levels. This suggests that maybe my B6 intake has nothing to do with my homocysteine levels.

6/4/2018: Despite no changes to my supplements, my homocysteine came down a little more, to 10.2. Interestingly, the correlation (r) between homocysteine with my total dietary (diet + supplements) intake of B6, B12, and methylfolate is 0.39, 0.68, 0.29, respectively. The correlation between my B12 intake with homocysteine looks moderately strong, whereas the correlations for B6 and folate are weak. Based on this data, it’s possible I had a mild B12 deficiency that was causing elevated homocysteine. Note that my average B12 intake, without supplements is ~8 mcg/day, which is more than 3-fold higher than the RDA.

In looking at the association between my dietary data with homocysteine, a stronger correlation (r = 0.91; R2 = 0.83) has emerged…for my protein intake! In other words, a higher protein intake is more strongly correlated with lower homocysteine than B12:

Picture2

7/11/2018: To explore the strong association between my protein intake with homocysteine, I increased my protein intake from an average value of 104 g/day for the period that preceded my June measurement (5/15/2018 – 6/4/2018) to 136 g/day for the period up to my 7/11/2018 measurement (6/5/2018 – 7/10/2018). The result? Lower homocysteine, to 8.2 uMol/L! Interestingly, the correlation between my dietary protein intake with homocysteine remained strong (r = 0.86, R2 = 0.73, n = 7 measurements).

What about my B6, methyl-B12, methyl-folate stack? I’m still taking it, although it looks like methyl-B12 may be the only factor that is associated with my homocysteine levels. In support of that, the correlation between each with homocysteine is = 0.02, 0.73, 0.36, respectively.

Because I now have my homocysteine < 9 umol/L, it may be time to optimize other variables (in addition to the metabolic panel and CBC). Stay tuned!

 

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

 

References

Lewerin C, Nilsson-Ehle H, Matousek M, Lindstedt G, Steen B. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6: a randomised trial.vEur J Clin Nutr. 2003 Nov;57(11):1426-36.

Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med. 2005 May;2(5):e135.

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.

Using Diet to Optimize Circulating Biomarkers: Serum Bicarbonate

In an earlier post, I wrote about the association between biomarkers of systemic acid-base balance (serum bicarbonate, the anion gap, urinary pH) with all-cause mortality risk (https://michaellustgarten.wordpress.com/2015/08/28/serum-bicarbonate-and-anion-gap-whats-optimal/). Based on these data, systemic acidity may not be optimal for health and longevity, when compared with more alkaline values. Can circulating acid-base biomarkers be optimized through diet?

One way to optimize serum bicarbonate is with a low dietary PRAL (potential renal acid load). For a given food, PRAL is a measure of how much acid or base that the kidney will see. In subjects with normal kidney function (or with chronic kidney disease, CKD), a low dietary PRAL (alkaline-forming) is associated with high serum bicarbonate, whereas a high dietary PRAL (acid-forming) is associated with reduced serum bicarbonate (Ikizler et al. 2015):

bicarb pral

So how can we achieve a low dietary acid intake (low PRAL), with the goal of increasing serum bicarbonate? The answer is to abundantly consume foods with a low PRAL (vegetables), while minimizing foods with a high PRAL (animal products, grains). Let’s have a look at the PRAL values for several food groups (Remer and Manz, 1995):

All of the meat and meat products shown below have acid-forming, positive PRAL values:

PRAL meat

Similarly, fish have acid-forming, positive PRAL values:

fish pral

While PRAL values for milk, dairy, and eggs are generally acid-forming, there is a wider range, compared with meat and fish. For example, parmesan and cheddar cheese have high PRAL values (34.2, 26.5, respectively), whereas milk and yogurt have PRAL values ~1:

dairy pral

Grains are similar to animal products in terms of their PRAL values:

grain pral

In contrast, all of the vegetables on the list below have very low, alkaline-forming PRAL values. The All-Star for a low PRAL is spinach (-14):
veg pral

Similarly, most fruits have alkaline forming, low PRAL values. Although raisins seem to be the PRAL All-Star, their data (and all of the other foods on the list) are based on 100g (299 calories for raisins). For an equivalent amount of calories for strawberries, their PRAL equates to -20.6, which is similar to the raisin PRAL. Also included on the list are nuts, which contain a range of PRAL values from negative (hazelnuts) to positive (walnuts, peanuts):

fruit pral

What’s my dietary PRAL? To determine that, it’s first important to define the PRAL equation: 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; Remer and Manz, 1994). Using my latest 7-day average dietary data yields a very low, alkaline-forming PRAL, -121.9: (protein, 88g; phosphorus, 2038 mg; potassium, 9868 mg; calcium, 1421 mg; magnesium, 901 mg)! It’s important to note that the major contributor to my very low PRAL value comes from the potassium term. Because of my abundant vegetable intake, my potassium intake is very high, resulting in a highly alkaline PRAL. Considering that PRAL values of -40 were associated with serum bicarbonate values of ~28, my serum bicarbonate value of 31 on my last blood test (8/2015) may in part be explained by my very low dietary PRAL value, -121.9.

Another measure of dietary acid load is NEAP (net endogenous acid production). In subjects with normal (and reduced, CKD) kidney function, a high NEAP diet (acid-forming) is associated with reduced serum bicarbonate, whereas a low NEAP diet (alkaline-forming) is associated with higher serum bicarbonate values (Ikizler et al. 2015):

neap bicarb

NEAP is more easily calculated than PRAL-all you need to know are your dietary protein and potassium intakes: NEAP = (54.5 * protein intake in grams/day)/(potassium intake in mEq/day) -10.2 (Frassetto et al. 1999). To convert your daily potassium intake from mg to mEq, divide by 39.1. Using my 7-day average protein and potassium intake data yields a NEAP = (54.5 * 88)/(9868/39.1) – 10.2 = 8.8. Based on the plot above for NEAP vs. serum bicarbonate, that again puts me on the far left, which is associated with serum bicarbonate values greater than 28.

Collectively, eating more potassium-rich vegetables will reduce PRAL and NEAP, which is associated with systemic alkalinity, as measured by an elevated serum bicarbonate. Because high serum bicarbonate levels are associated with reduced all-cause mortality risk, this may be an important strategy for improving health and longevity!

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

References

Frassetto LA, Todd KM, Morris RJC, Sebastian A. Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents. Am J Clin Nutr. 1998;68:576-583.

Ikizler HO, Zelnick L, Ruzinski J, Curtin L, Utzschneider KM, Kestenbaum B, Himmelfarb J, de Boer IH. Dietary Acid Load Is Associated With Serum Bicarbonate but not Insulin Sensitivity in Chronic Kidney Disease. J Ren Nutr. 2016 Mar;26(2):93-102.

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.

Remer, T. and Manz, F. Potential renal acid load of foods and its influence on urine pH. Journal of the American Dietetic Association 1995 ;95(7), 791-797.

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.

Blood Testing: What’s An Optimal Value For Triglycerides?

In terms of all-cause mortality risk, is the reference range for circulating triglycerides (TG, <150 mg/dL) optimal?

A meta-analysis of 38 studies in 360,556 subjects with a median age of 48y and a 12-year follow-up reported lowest all-cause mortality risk for subjects with TG values less than 90 mg/dL (equivalent to ~1 mmol; Liu et al. (2013)). As shown below, each successive 90 mg/dL increase was associated with a 12% higher all-cause mortality risk. A person with a value closer to the high end of the reference range, ~150 would have a ~7% increased mortality risk compared someone with a value ~90. In other words, there would be 7 more deaths per 100 total people at a TG value of 150, compared with the death rate for people with values less than 90.

tg mortal

Added importance for the association between TG values less than 90 with all-cause mortality risk come from studies of people who have lived longer than 100 years, centenarians. As shown below, triglyceride values less than 101 mg/dL have been reported in 9 of 11 centenarian studies:

tg mort

What’s my TG value? On my latest blood test (8/2015), it was 42. I’ve measured my TGs 11 times over the past 10 years-my average value for those measurements is 62. Based on the meta-analysis and centenarian data, that would put me in the lowest risk category for all-cause mortality.

tg mort

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

References

Arai Y, Hirose N, Yamamura K, Shimizu K, Takayama M, Ebihara Y, Osono Y. Serum insulin-like growth factor-1 in centenarians: implications of IGF-1 as a rapid turnover protein. J Gerontol A Biol Sci Med Sci. 2001 Feb;56(2):M79-82.

Baranowska B, Bik W, Baranowska-Bik A, Wolinska-Witort E, Szybinska A, Martynska L, Chmielowska M. Neuroendocrine control of metabolic homeostasis in Polish centenarians. J Physiol Pharmacol. 2006 Nov;57 Suppl 6:55-61.

Barbagallo CM, Averna MR, Frada G, Noto D, Cavera G, Notarbartolo A. Lipoprotein profile and high-density lipoproteins: subfractions distribution in centenarians. Gerontology 1998;44(2):106–10.

Bik W, Baranowska-Bik A, Wolinska-Witort E, Kalisz M, Broczek K, Mossakowska M, Baranowska B. Assessment of adiponectin and its isoforms in Polish centenarians. Exp Gerontol. 2013 Apr;48(4):401-7.

Chan YC, Suzuki M, Yamamoto S. Dietary, anthropometric, hematological and biochemical assessment of the nutritional status of centenarians and elderly people in Okinawa, Japan. J Am Coll Nutr. 1997 Jun;16(3):229-35.

Chan YC, Suzuki M, Yamamoto S. A comparison of anthropometry, biochemical variables and plasma amino acids among centenarians, elderly and young subjects. J Am Coll Nutr. 1999 Aug;18(4):358-65.

Liu J, Zeng FF, Liu ZM, Zhang CX, Ling WH, Chen YM. Effects of blood triglycerides on cardiovascular and all-cause mortality: a systematic review and meta-analysis of 61 prospective studies. Lipids Health Dis. 2013 Oct 29;12:159.

Magri F, Muzzoni B, Cravello L, Fioravanti M, Busconi L, Camozzi D, Vignati G, Ferrari E. Thyroid function in physiological aging and in centenarians: possible relationships with some nutritional markers. Metabolism. 2002 Jan;51(1):105-9.

Paolisso G, Ammendola S, Del Buono A, Gambardella A, Riondino M, Tagliamonte MR, Rizzo MR, Carella C, Varricchio M. Serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function. J Clin Endocrinol Metab. 1997 Jul;82(7):2204-9.

Thillet J, Doucet C, Chapman J, Herbeth B, Cohen D, Faure-Delanef L. Elevated lipoprotein(a) levels and small apo(a) isoforms are compatible with longevity: evidence from a large population of French centenarians. Atherosclerosis 1998;136:389–94.

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.

Willcox DC, Willcox BJ, Wang NC, He Q, Rosenbaum M, Suzuki M. Life at the extreme limit: phenotypic characteristics of supercentenarians in Okinawa. J Gerontol A Biol Sci Med Sci. 2008 Nov;63(11):1201-8.