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 reduce my homocysteine level, I’ve added 800 mcg of folic acid, bringing my already high dietary folate intake to 2000 micrograms/per day. Stay tuned to see if my homocysteine levels are reduced in a couple of weeks!

12/8/2017 update: 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. What’s next on the list to reduce it? Trimethylglycine, also known as betaine, so stay tuned for those results in a couple of months!

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.

 

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.wordpress.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.