Monthly Archives: October 2019

Optimizing Biological Age With Aging.ai: Platelets

Platelets are one of the 19 variables that are included in the biological age calculator, aging.ai.  The reference range is 150-400 platelets per nanoliter (*10^9/L), but within that range, what’s optimal?

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

platets acm

Similarly, in a study of 21,252 adults (average age 53y), 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), maximally reduced risk of death from all causes was associated with platelet values between 200-256 (Kabat et al. 2017).

In a smaller study (36,262 older adults, average age, 71y), 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 lower mortality risk for non-Hispanic blacks and Hispanics (Msaouel et al. 2014):

plat ethnicity

In 5,766 older adults (average age, 73y), platelets higher than 200-300 was associated with 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), maximally reduced risk of death from all causes was associated with platelet 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 my values? Over the past 16 years, I’ve measured my platelets 25 times, and 6x, my platelets were below this 200-300 range. I’m not too worried about it, though, as most of my measurements are within that range!

plt.png

Are there any variables that are correlated with platelets? For me, the strongest correlation over 18 tracked blood tests from 2015 – 2019 is my body weight. As my weight increases, my platelets are higher (r = 0.64, p-value = 0.006)Platelets have been reported to increase in association with elevated inflammation (CRP; Izzi et al. 2018), but I only have 3 co-measurements for CRP with platelets. I have a blood test scheduled for next week, more data coming soon!

 

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.

Izzi B, Bonaccio M, de Gaetano G, Cerletti C. Learning by counting blood platelets in population studiessurvey and perspective a long way after BizzozeroJ Thromb Haemost. 2018 Sep;16(9):1711-1721. doi: 10.1111/jth.14202.

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’s Health 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.

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.

Circulating Biomarkers Associated With Coronary Artery Calcification

The coronary artery calcification (CAC) score is a measure of how much calcification is in the coronary arteries, and accordingly, is an in vivo measure of atherosclerosis. Why is the CAC score important? Besides its role in atherosclerosis, risk of death for all causes goes up at any age as the CAC score increases. For ex., in people younger than 50 (left side below), as the CAC score increases from 0 to 1-399, 400-999, and > 1000, risk of death for all causes increases by ~10-fold, from 2.3 per 1000 person years (PY) to 6.1/1000, 9.7/1000, and 22.7/1000. Similarly, for people older than 70y (right side below), as the CAC score increases, baseline all-cause mortality risk increases ~15-fold, from 5.6/1000 to 21.6/1000, 44.3/1000, and 76/1000, respectively (Hartaigh et al. 2016):

Screen Shot 2019-10-20 at 8.40.05 AM.png

Are blood biomarkers associated with CAC? When the CAC score was elevated, a greater percentage of white blood cells (WBCs) that were neutrophils and the red blood cell distribution width (RDW%) were higher, whereas lower CAC scores were associated with higher levels for the fraction of lymphocytes divided by total WBCs and higher total red blood cells (den Harder et al. 2018):

n l rdw cac

In agreement with these data, CAC scores > 100 were associated with a higher RDW% (13.0%) and a higher neutrophil/lymphocyte ratio (NLR; 1.54), when compared with CAC < 100 (RDW = 12.8%; NLR = 1.39; Gürel et al. 2019).

The findings that a higher RDW% and higher levels of neutrophils, but lower levels of lymphocytes are associated with a higher CAC score is in agreement with the data for how these variables change with aging and their associations with all-cause mortality risk. First, note that I previously reported that RDW% increases during aging and is associated with an increased risk of death from all causes (https://michaellustgarten.wordpress.com/2019/09/25/optimizing-biological-age-rdw/). Similarly, neutrophils increase, whereas lymphocytes decrease, thereby leading to a higher neutrophil/lymphocyte ratio during aging, which is associated with an increased all-cause mortality risk (https://michaellustgarten.wordpress.com/2019/10/10/neutrophil-lymphocyte-ratio-and-survival/).

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

References

den Harder AM, de Jong PA, de Groot MCH, Wolterink JM, Budde RPJ, Iŝgum I, van Solinge WW, Ten Berg MJ, Lutgens E, Veldhuis WB, Haitjema S, Hoefer IE, Leiner T. Commonly available hematological biomarkers are associated with the extent of coronary calcifications. Atherosclerosis. 2018 Aug;275:166-173. doi: 10.1016/j.atherosclerosis.2018.06.017.

Gürel OM, Demircelik MB, Bilgic MA, Yilmaz H, Yilmaz OC, Cakmak M, Eryonucu B. Association between Red Blood Cell Distribution Width and Coronary Artery Calcification in Patients Undergoing 64-Multidetector Computed TomographyKorean Circ J. 2015 Sep;45(5):372-7. doi: 10.4070/kcj.2015.45.5.372.

Hartaigh BÓ, Valenti V, Cho I, Schulman-Marcus J, Gransar H, Knapper J, Kelkar AA, Xie JX, Chang HJ, Shaw LJ, Callister TQ, Min JK. 15-Year prognostic utility of coronary artery calcium scoring for all-cause mortality in the elderly. Atherosclerosis. 2016 Mar;246:361-6. doi: 10.1016/j.atherosclerosis.2016.01.039.

Optimizing Biological Age: C-Reactive Protein (hs-CRP)

High sensitivity C-Reactive Protein (CRP) is one of the 10 variables included in the biological age calculator, PhenoAge (https://michaellustgarten.wordpress.com/2019/09/09/quantifying-biological-age/). The reference range for CRP is 0 – 3 mg/L, but within that range, what’s optimal? To answer that question, it’s important to know how CRP changes during aging, and what levels are associated with an increased risk of death for all causes.

First, CRP increases 3-5 fold during aging in women and men, respectively (Ferrucci et al. 2005):

crp age.png

Investigating further, CRP continues to increase from relatively low levels of 0.7 mg/L (equivalent to 0.07 mg/dL) in 85-99 year olds to 2.5 mg/L (equivalent to 0.25 mg/dL) in adults older than 110y (Arai et al. 2015):

crp cent.png

In support of this finding, the average CRP level in 98 centenarians (average age, 101y) was 5.4 mg/L, when compared with 3.2 mg/L in 70 year olds (Montoliu et al. 2014).

Based on the data for how CRP changes during aging, lower values would be expected to better in terms of risk of death for all causes. How low is optimal for CRP?

Several studies have investigated this issue. Risk of death for all causes was significantly reduced when CRP was < 3 mg/L, when compared with > 3 mg/L in the 11,193 subjects (average age 63y) of Oluleye et al. (2013). In terms of CRP values less than 3 mg/L, CRP < 1.0 mg/L was associated with significantly reduced risk of death for all causes in the 5,248 subjects (average age, 54y) of Hamer et al. (2010), in the 3,620 subjects (average age, 58y) of Koenig et al. (2008), in the 2,240 older adults (average age, 69y) of Elkind et al. (2009), and in the 1,519 subjects (average age 72y) of Kuoppamäki et al. (2015).

Similarly, CRP levels close to 1 mg/dL have also been associated with a significantly reduced risk of death for all causes, including < 0.86 mg/L in the 11,409 adults (average age, 59y) of Shen et al. (2019), and < 0.83 mg/L in the 1,476 men (average age, 53y) of Laaksonen et al. (2005).

In terms of the association between CRP with risk of death for all causes, can we go lower than ~0.8 mg/L? CRP values < 0.5 mg/L were associated with reduced all-cause mortality risk, whereas values > 3 mg/L were associated with increased risk in the 16,850 non-smokers and non-users of hormone replacement therapy (average age, 58y) of Ahmadi-Abhari et al. (2013). Similarly, CRP between 0.5 – 1 mg/L, the area on the chart (see below) where the black line and the shaded 95% confidence interval have a hazard ratio < 1, was associated with a significantly reduced risk of death for all causes, whereas CRP > 5 mg/L was associated with an increased all-cause mortality risk in the 7,015 subjects of Zuo et al. (2016):

Screen Shot 2019-10-18 at 7.58.58 AM

Going even lower, CRP < 0.33 mg/L (Tertile 1, white circle) was associated with a maximally reduced all-cause mortality risk when compared with values > 0.86 mg/L (Tertile 3, black circle) in the 1,034 older adults (average age, ~72y) of Shinkai et al. (2008):

crp mortal2.png

Similarly, CRP values between 0.03 – 0.33 mg/L in men and between 0.03 – 0.25 mg/L in women (blue lines for both men and women, Tertile 1) was associated with a significantly reduced risk of death for all causes in the 11,080 subjects (average age, 62y) of Nisa et al. (2016). In contrast, CRP > 0.85 mg/L in men and > 0.62 mg/L in women (close to significance in women, p=0.06; green lines for both, Tertile 3) was associated with an increased all-cause mortality risk:

Screen Shot 2019-10-16 at 7.27.39 AM

Lowest risk of death for all causes was also identified when CRP was between 0.1 – 0.3 mg/L (1st; Tertile 1), when compared with CRP > 0.8 mg/L (3rd; Tertile 3) in the 7,740 older adults (average age, 64y) of Makita et al. (2009):

Screen Shot 2019-10-17 at 8.01.02 PM.png

Can we go lower than 0.3 mg/L for CRP and all-cause mortality risk? Yes! CRP < 0.21 mg/L was associated with a maximally reduced risk of death for all causes, and mortality risk significantly increased above 0.44 mg/L in the 2,589 subjects (average age, 59y) of Arima et al. (2008):

Screen Shot 2019-10-17 at 7.34.48 PM.png

Collectively, based on these data, with the goal of optimal health and lifespan, I’d suggest that CRP levels should be as low as possible, and avoiding the age-related CRP increase.  What are my CRP values? I’ve only measured it 6x, including once in 2009 (0.2 mg/L), once in 2018 (0.67 mg/L), and 4x in 2019 (0.41, 0.34, 0.47, 0.29 mg/L). My average value for 2019 is 0.38 mg/L, and I’d like to cut that in half. I have a blood test scheduled for next week, so stay tuned for that data!

Here’s the short version of this post in video format!

 

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

 

References

Ahmadi-Abhari S, Luben RN, Wareham NJ, Khaw KT. Seventeen year risk of all-cause and cause-specific mortality associated with C-reactive proteinfibrinogen and leukocyte count in men and women: the EPIC-Norfolk studyEur J Epidemiol. 2013 Jul;28(7):541-50. doi: 10.1007/s10654-013-9819-6.

Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, Suematsu M, Hirose N, von Zglinicki T. Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians. EBioMedicine. 2015 Jul 29;2(10):1549-58. doi: 10.1016/j.ebiom.2015.07.029.

Arima H, Kubo M, Yonemoto K, Doi Y, Ninomiya T, Tanizaki Y, Hata J, Matsumura K, Iida M, Kiyohara Y. Highsensitivity C-reactive protein and coronary heart disease in a general population of Japanese: the Hisayama studyArterioscler Thromb Vasc Biol. 2008 Jul;28(7):1385-91. doi: 10.1161/ATVBAHA.107.157164.

Elkind MS, Luna JM, Moon YP, Liu KM, Spitalnik SL, Paik MC, Sacco RL. High-sensitivity C-reactive protein predicts mortality but not stroke: the Northern Manhattan Study. Neurology. 2009 Oct 20;73(16):1300-7. doi: 10.1212/WNL.0b013e3181bd10bc.

Kuoppamäki M, Salminen M, Vahlberg T, Irjala K, Kivelä SL, Räihä I. High sensitive C-reactive protein (hsCRP), cardiovascular events and mortality in the aged: a prospective 9-year follow-up studyArch Gerontol Geriatr. 2015 Jan-Feb;60(1):112-7. doi: 10.1016/j.archger.2014.10.002.

Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, Guralnik JM, Longo DL. The origins of age-related proinflammatory state. Blood. 2005 Mar 15;105(6):2294-9. Epub 2004 Nov 30.

Hamer M, Chida Y, Stamatakis E. Association of very highly elevated C-reactive protein concentration with cardiovascular events and all-cause mortality. Clin Chem. 2010 Jan;56(1):132-5. doi: 10.1373/clinchem.2009.130740.

Koenig W, Khuseyinova N, Baumert J, Meisinger C. Prospective study of high-sensitivity C-reactive protein as a determinant of mortalityresults from the MONICA/KORA Augsburg Cohort Study1984-1998Clin Chem. 2008 Feb;54(2):335-42.

Laaksonen DE, Niskanen L, Nyyssönen K, Punnonen K, Tuomainen TP, Salonen JT. C-reactive protein in the prediction of cardiovascular and overall mortality in middle-aged men: a population-based cohort study. Eur Heart J. 2005 Sep;26(17):1783-9.

Montoliu I, Scherer M, Beguelin F, DaSilva L, Mari D, Salvioli S, Martin FP, Capri M, Bucci L, Ostan R, Garagnani P, Monti D, Biagi E, Brigidi P, Kussmann M, Rezzi S, Franceschi C, Collino S. Serum profiling of healthy aging identifies phospho- and sphingolipid species as markers of human longevity. Aging (Albany NY). 2014 Jan;6(1):9-25.

Makita S, Nakamura M, Satoh K, Tanaka F, Onoda T, Kawamura K, Ohsawa M, Tanno K, Itai K, Sakata K, Okayama A, Terayama Y, Yoshida Y, Ogawa A. Serum C-reactive protein levels can be used to predict future ischemic stroke and mortality in Japanese men from the general populationAtherosclerosis. 2009 May;204(1):234-8. doi: 10.1016/j.atherosclerosis.2008.07.040.

Oluleye OW, Folsom AR, Nambi V, Lutsey PL, Ballantyne CM; ARIC Study Investigators. Troponin TB-type natriuretic peptideC-reactive protein, and cause-specific mortality. Ann Epidemiol. 2013 Feb;23(2):66-73. doi: 10.1016/j.annepidem.2012.11.004.

Nisa H, Hirata A, Kohno M, Kiyohara C, Ohnaka K. High-Sensitivity C-Reactive Protein and Risks of All-Cause and Cause-Specific Mortality in a Japanese Population. Asian Pac J Cancer Prev. 2016;17(5):2643-8.

Shen Y, Zhang Y, Xiong S, Zhu X, Ke C. High-sensitivity C-reactive protein and cystatin C independently and jointly predict all-cause mortality among the middle-aged and elderly Chinese population. Clin Biochem. 2019 Mar;65:7-14. doi:10.1016/j.clinbiochem.2018.12.012.

Shinkai S, Chaves PH, Fujiwara Y, Watanabe S, Shibata H, Yoshida H, Suzuki T. Beta2-microglobulin for risk stratification of total mortality in the elderly population: comparison with cystatin C and C-reactive protein. Arch Intern Med. 2008 Jan 28;168(2):200-6. doi: 10.1001/archinternmed.2007.64.

Zuo H, Ueland PM, Ulvik A, Eussen SJ, Vollset SE, Nygård O, Midttun Ø, Theofylaktopoulou D, Meyer K, Tell GS. Plasma Biomarkers of Inflammation, the Kynurenine Pathway, and Risks of All-CauseCancer, and Cardiovascular Disease Mortality: The Hordaland Health Study. Am J Epidemiol. 2016 Feb 15;183(4):249-58. doi: 10.1093/aje/kwv242.

Optimizing Biological Age: MCV

Mean corpuscular volume (MCV) is one of the 10 variables included in the biological age calculator, PhenoAge (see https://michaellustgarten.wordpress.com/2019/09/09/quantifying-biological-age/). It’s calculated by dividing the fraction of the blood that contains RBCs (hematocrit) by RBCs (MCV = hematocrit/RBC), thereby identifying the average volume contained within red blood cells. Although the MCV reference range is 80 – 100 femtoliters (10^-15L), what’s optimal in terms of a youthful biological age, and minimized disease risk?

MCV increases during aging. In support of this, using a small subset of samples from the Baltimore Longitudinal Study on Aging (values not in parentheses), MCV increased from average values of 88.8 in young (18-39y), to 91.3 in middle-aged (40-59y), to 92.4 in old (>60y) subjects. Similarly, MCV also increased in the full sample size from the Baltimore Longitudinal Study on Aging (values in parentheses) from 89.2 to 91.1 to 92.9 in young, middle-aged and old, respectively (Araki and Rifkind, 1984):

Screen Shot 2019-10-12 at 3.32.31 PM

In a larger study that included 3,358 subjects, MCV increased from median values of 92.2 in women and 93.4 in men younger than 60y to 94.2 and 95.7 in women and men older than 60y, respectively (Lee et al. 2018):

mcv age

When considering that MCV increases during aging, one would predict that higher levels would be associated with an increased risk of death of all causes. In support of this, in the 36,260 subjects of Yoon et al. (2016), MCV levels > 94.2 in women and > 95.8 in men (Tertile 4) were associated with a 55% and 44% increased risk of death from all causes, respectively, when compared with MCV values between 89.2 – 91.6 in women and 90.5 – 93 in men (Tertile 2):

mcv acm

Collectively, these data suggest that a lower MCV may be better in terms of biologic youth,  and for a lower risk of death from all causes. What are my MCV values? I’ve measured MCV 25 times over the past 16 years. In my 30’s, I measured it 7 times, with an average MCV = 90. In my 40’s, I’ve measured it 18 times, for an average value = 91.1. Although these 2 groups of data are not significantly different (p=0.09), the red trendline for these data is slightly up (R2=0.02), which suggests that my MCV is slowly increasing with age:

mcv me

Although my MCV values are seemingly far from the increased mortality risk of Yoon et al. (> 95.8), it increases during aging, so I’ve definitely got my eye on it. Should it start to increase, I’ll intervene with dietary changes. Stay tuned!

 

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

 

References

Araki K, Rifkind JM. Age dependent changes in osmotic hemolysis of human erythrocytes. J Gerontol. 1980 Jul;35(4):499-505.

Lee Eun-jin, Kim Mi-young, Lee Eun-yeop, Jeon Beom, Lee Ji-won, Kim Han-sung, Kang Hee-jeong, Lee Young-kyung, Eun Jin Lee, Miyoung Kim, Eunyup Lee, Kibum Jeon, Jiwon Lee, Han-Sung Kim, Hee Jung Kang, Young Kyung Lee.vEstablishment of reference section for general blood test in healthy elderly. Establishing Reference Intervals for Complete Blood Cell Count in Healthy Korean Elderly Individuals. J Lab Med Qual Assur 2018; 40: 27-37. doi.org/10.15263/jlmqa.2018.40.1.27.

Yoon HJ, Kim K, Nam YS, Yun JM, Park M. Mean corpuscular volume levels and all-cause and liver cancer mortality. Clin Chem Lab Med. 2016 Jul 1;54(7):1247-57. doi: 10.1515/cclm-2015-0786.

Optimizing Biological Age: White Blood Cells

Circulating levels of white blood cells (WBCs) are one of the 10 variables used to quantify biological age with PhenoAge (https://atomic-temporary-71218033.wpcomstaging.com/2019/09/09/quantifying-biological-age). The reference range for WBCs is 4.5 – 11 *10^9 cells/L, but within that range, what’s optimal?

Several studies have reported that WBCs greater than 5 are associated with an increased all-cause mortality risk (Ahmadi-Abhari et al. 2013, Samet et al. 2005, Weijenberg et al. 1996). While observational studies are important for identifying associations with mortality risk, stronger evidence is obtained when the data from the same subjects are tracked for a long time period. Perhaps the best evidence for the association between WBCs with mortality risk comes from the Baltimore Longitudinal Study on Aging (BLSA), which studied 2803 men and women over a period of 44 years (Ruggiero et al. 2007). As shown below, subjects that had circulating WBCs between 3.5 – 6 had the best survival, whereas WBCs below 3.5, between 6 – 10, and 10+ each had successively higher risk. The 0.5 point on the y-axis of the curve (survival) is defined as 50% mortality, and is the point where half of the study subjects died, whereas the remaining 50% were still alive. At that point, compared with subjects that had WBCs between 6 – 10, people that had WBCs between 3.5 – 6 lived ~7 years longer! So getting your WBC into that range may be a big deal for increasing life expectancy.

wbc ferr

How can you reduce circulating WBCs? One way to reduce WBCs is to eat less calories, thereby reducing your body weight. As shown below, eating less calories resulted in a decreased BMI and decreased WBCs in the Biosphere II project (Walford et al. 2002), almost exactly in the same pattern:

cr bmi

WBC Biosphere

Because calorie restriction reduced WBCs from ~6.8 to 4.6, should 4.6 be considered optimal? In support of this idea, calorie restriction is well documented to increase lifespan in a variety of organisms, including flies, worms, and rodents. Although there isn’t any evidence (yet) on the long-term effects of calorie restriction (CR) on lifespan in people, it has been shown to be protective against age-related diseases, including abdominal obesity, diabetes, hypertension, and cardiovascular disease (Omodei and Fontana 2011). Therefore, a reduced WBC level may be related to the positive health-related effects of CR. 

As an argument against using the CR-mediated reduction in WBC as a guide for what the optimal range should be, calorically-restricted mice have a decreased survival in response to infection (Goldberg et al. 2015):

cr survival

However, it’s important to note that infection-related survival was decreased in CR mice that were 40% restricted in terms of daily calories. Based on the Biosphere 2 data above, BMI was reduced from ~23 to 19, which translates into a 17% reduction. However, whether 17% CR is better for improving infection-related survival compared with 40% CR is currently unknown.

What’s my WBC level? Shown below is my WBC data for the past 16 years, including 25 measurements (average WBCs, 4.78 * 10^9 cells/L). The 2 red lines delineate the 3.5 – 6 range that was associated with an increased lifespan in the BLSA study (Ruggiero et al. 2007), and based on that, I’ve only had 1 measurement that was higher than that range.

wbc update

Starting from the red arrow below, WBCs increase during the 22-year period that precedes death (Ruggiero et al. 2007), so making sure that they don’t go up during aging is important!

wbc age

 

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

 

References

Ahmadi-Abhari S, Luben RN, Wareham NJ, Khaw KT. Seventeen year risk of all-cause and cause-specific mortality associated with C-reactive proteinfibrinogen and leukocyte count in men and women: the EPIC-Norfolk studyEur J Epidemiol. 2013 Jul;28(7):541-50.

Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Žugich J. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell. 2015 Feb;14(1):130-8.

Jee SH, Park JY, Kim HS, Lee TY, Samet JM. White blood cell count and risk for all-causecardiovascular, and cancer mortality in a cohort of KoreansAm J Epidemiol. 2005 Dec 1;162(11):1062-9.

Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic diseaseFEBS Lett. 2011 Jun 6;585(11):1537-42.

Ruggiero C, Metter EJ, Cherubini A, Maggio M, Sen R, Najjar SS, Windham GB, Ble A, Senin U, Ferrucci L. White blood cell count and mortality in the Baltimore Longitudinal Study of AgingJ Am Coll Cardiol. 2007 May 8;49(18):1841-50.

Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol A Biol Sci Med Sci. 2002 Jun;57(6):B211-24.

Weijenberg MP, Feskens EJ, Kromhout D. White blood cell count and the risk of coronary heart disease and all-cause mortality in elderly menArterioscler Thromb Vasc Biol. 1996 Apr;16(4):499-503.

Sarcopenia, Disease Risk, And The Neutrophil/Lymphocyte Ratio

In an earlier post, based on data from the Baltimore Longitidunal Study on Aging (BLSA), I suggested that total white blood cell (WBCs) counts between 3500 to 6000 cells per microliter of blood may be optimal for reducing disease risk and for maximizing longevity (https://michaellustgarten.wordpress.com/2015/08/13/blood-testing-whats-optimal-for-wbc-levels/).

However, within WBCs, neutrophils increase, whereas lymphocytes decrease during aging (Ruggiero et al. 2007, Starr and Dreary 2011). As a result, the ratio between neutrophils with lymphocytes (NLR) increases during aging from ~1.5 in 20 year olds to ~1.8 in adults older than 75y (Li et al. 2015):

Screen Shot 2019-10-06 at 3.40.06 PM

An increased neutrophil/lymphocyte ratio during aging may be bad for health and disease risk. First, a higher neutrophil/lymphocyte ratio is associated with sarcopenia (defined as the age-related loss of muscle mass and physical function) in older adults (average age, 72y; Öztürk et al. 2018):

Screen Shot 2019-09-13 at 7.46.06 AM

Second, risk of death for all causes is significantly increased for older adults (average age, 66y) that had higher NLR values (60-80%, >80%, equivalent to NLR = 1.92-2.41, > 2.41), when compared with lower NLR values (< 20%, 20-40%, 40-60%, equivalent to NLR < 1.90; Fest et al. 2019):

nlr

Similarly, all-cause mortality risk was 30% increased in older adults (average age, 54y) that had NLR values > 1.77, when compared with < 1.77, and 40% increased for NLR values > 2.15, when compared with < 2.15 (Kime et al. 2018).

What are my NLR values? Over 17 blood test measurements from 2015 – 2019, my average NLR is 1.11. So far so good!

nlr

 

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

 

References

Fest J, Ruiter TR, Groot Koerkamp B, Rizopoulos D, Ikram MA, van Eijck CHJ, Stricker BH. The neutrophil-to-lymphocyte ratio is associated with mortality in the general population: The Rotterdam Study. Eur J Epidemiol. 2019 May;34(5):463-470.

Kim S, Eliot M, Koestler DC, Wu WC, Kelsey KT. Association of Neutrophil-to-Lymphocyte Ratio With Mortality and Cardiovascular Disease in the Jackson Heart Study and Modification by the Duffy Antigen Variant. JAMA Cardiol. 2018 Jun 1;3(6):455-462. doi: 10.1001/jamacardio.2018.1042.

Li J, Chen Q, Luo X, Hong J, Pan K, Lin X, Liu X, Zhou L, Wang H, Xu Y, Li H, Duan C. Neutrophil-to-Lymphocyte Ratio Positively Correlates to Age in Healthy PopulationJ Clin Lab Anal. 2015 Nov;29(6):437-43. doi: 10.1002/jcla.21791.

Öztürk ZA, Kul S, Türkbeyler İH, Sayıner ZA, Abiyev A. Is increased neutrophil lymphocyte ratio remarking the inflammation in sarcopenia? Exp Gerontol. 2018 Sep;110:223-229.

Ruggiero C, Metter EJ, Cherubini A, Maggio M, Sen R, Najjar SS, Windham GB, Ble A, Senin U, Ferrucci L. White blood cell count and mortality in the Baltimore Longitudinal Study of AgingJ Am Coll Cardiol. 2007 May 8;49(18):1841-50.

Starr JM, Deary IJ. Sex differences in blood cell counts in the Lothian Birth Cohort 1921 between 79 and 87 years. Maturitas. 2011 Aug;69(4):373-6.

Resting Heart Rate: Year-Over-Year Update

A few months ago, I presented data that a resting heart rate (RHR) ~40 beats per min is associated with maximally reduced risk of death from all causes (https://michaellustgarten.wordpress.com/2019/02/02/resting-heart-rate-whats-optimal/). I started tracking my RHR data in August 2018, and I now have more than a full year of data. RHR increases during aging, so how does my RHR look over that past year+?

rhr

As you can see, the trend line (red) is down, not up, which suggests that my fitness program is on the right track. My improvements for RHR can be better illustrated by comparing year-over-year changes for August 2018 with August 2019, and similarly, for September:

rhr data

The challenge will be continuous improvement for RHR. Eventually it will plateau, and I’ll respond by modifying my fitness program to make further gains.

 

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

Optimizing Biological Age: Alkaline Phosphatase

Alkaline phosphatase (ALP) is one of the 10 variables used to quantify biological age with PhenoAge (https://michaellustgarten.wordpress.com/2019/09/09/quantifying-biological-age). The reference range for alkaline phosphatase is 20 – 140 IU/L*, but within that range, what’s optimal?

Two separate meta-analyses have investigated the association between serum levels of ALP with risk of death for all causes. First, in a meta-analysis of 4 studies that included ~9 million adults, ALP values greater than 48 IU/L were associated with a significantly increased all-cause mortality risk (Kunutsor et al. 2014):

Screen Shot 2019-10-06 at 1.30.37 PM

In another meta-analysis that included 24 studies and 147,634 subjects (Li et al. 2014), lowest risk of death for all causes was identified for ALP values ~50 IU/L:

Screen Shot 2019-10-05 at 8.00.38 AM

Note that mortality risk increased linearly up to 85 U/L (short dashed line, dark black line), but increased at a much greater rate for values greater than 85 U/L. In addition, the meta-analysis of Li et al. 2014 did not include the 8.9 million adults of Fulks et al. (2008), which were included in the Kunutsor meta-analysis. Nonetheless, the data from these 2 complimentary meta-analyses arrive at the same conclusion: lower ALP values may be better in terms of reducing risk of death from all causes.

Investigating further, ALP levels increase during aging from ~60-80 U/L in adults < 55y to > 80 U/L in adults > 55y (Strømme et al. 2005, Han et al. 2016), evidence that further suggests that lower may be better:

Screen Shot 2019-10-06 at 12.36.55 PM

What are my ALP values? As shown below, I’ve measured ALP 27 times over the past 13 years, with an average value of 49.4 U/L (black line). Also note the red dotted trend line, which is close to flat over that period. So far, so good for ALP!

alp

*Note that IU/L = U/L

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

References

Fulks M, Stout RL, Dolan VF. Using liver enzymes as screening tests to predict mortality risk. J Insur Med 2008;40:191–203.

Han L, Wang J, Zhang Q, Ke P, Wu X, Wan Z, Lin H, Zeng R, Huang X, Zhuang J. Development of reference intervals for serum alkaline phosphatase among adults in Southern China traced to the new IFCC reference measurement procedure. Clin Chem Lab Med. 2016 Apr;54(4):659-65. doi: 10.1515/cclm-2015-0732.

Kunutsor SK, Apekey TA, Seddoh D, Walley J. Liver enzymes and risk of all-cause mortality in general populations: a systematic review and meta-analysis. Int J Epidemiol. 2014 Feb;43(1):187-201.

Li JW, Xu C, Fan Y, Wang Y, Xiao YB. Can serum levels of alkaline phosphatase and phosphate predict cardiovascular diseases and total mortality in individuals with preserved renal function? A systemic review and meta-analysisPLoS One. 2014 Jul 17;9(7):e102276.

Strømme JH, Rustad P, Steensland H, Theodorsen L, Urdal P. Reference intervals for eight enzymes in blood of adult females and males measured in accordance with the International Federation of Clinical Chemistry reference system at 37 degrees C: part of the Nordic Reference Interval Project. Scand J Clin Lab Invest. 2004;64(4):371-84. Erratum in: Scand J Clin Lab Invest. 2005;65(1):83-4.

Blood glucose: What’s optimal?

The reference range for circulating levels of glucose is 70-130 mg/dL. That’s a wide range, so what’s optimal, especially considering that glucose is one of the variables used to quantify of biological age (https://michaellustgarten.wordpress.com/2019/09/09/quantifying-biological-age)?

In the largest study published for this subject (12,455,361 adults), risk of death for all causes was maximally reduced for glucose levels between 80-94 mg/dL (Yi et al. 2017). In contrast, mortality risk significantly increased when glucose levels were < 80 or > 100 mg/dL in both men and women:
bg

As glucose levels rise above 100 mg/dL, risk for Type II diabetes increases, which is one potential explanation for higher glucose levels being associated with a higher mortality risk. Why would glucose levels lower than 80 mg/dL also be associated with worse health? Interestingly, glucose levels < 80 mg/dL are associated with an increased risk of death from “total external causes” (left panel below), including unintentional accidents and transport accidents (middle, right panel below) in a relatively large study of 345,318 adults (Yi et al. 2019). In addition, an increased mortality risk from transport accidents involving pedestrians or cyclists was associated with glucose levels below 55 mg/dL (data not shown):

Screen Shot 2019-10-02 at 6.33.07 AM

Glucose levels increase during aging (Yi et al. 2017), evidence that adds further merit that lower is better (but not below 80 mg/dL!):

Screen Shot 2019-10-02 at 6.47.39 AM.png

What are my glucose levels? Shown below is my data for the past 13 years:

my bg

On the left side of the chart, I measured my glucose levels about once per year from 33-40y, resulting in an average value of 89 mg/dL. Since 2015 I started daily dietary tracking, and tested more often (19x), resulting in an average value of 87 mg/dL. The comparison between these 2 groups of data is not significantly different (p=0.19). Based on the data in Yi et al., my glucose levels should have increased from 92 to 96 mg/dL during the past 13 years. Instead, my glucose levels during that period are relatively stable, with average value (87.5 mg/dL) that would be expected for a 26y old. So far, so good!

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

 

References

Yi SW, Park S, Lee YH, Park HJ, Balkau B, Yi JJ. Association between fasting glucose and all-cause mortality according to sex and age: a prospective cohort studySci Rep. 2017 Aug 15;7(1):8194. doi: 10.1038/s41598-017-08498-6.

Yi SW, Won YJ, Yi JJ. Low normal fasting glucose and risk of accidental death in Korean adults: A prospective cohort studyDiabetes Metab. 2019 Jan;45(1):60-66. doi: 10.1016/j.diabet.2018.01.005.

Ending Aging-Related Diseases 2019: Lustgarten Presentation

In the first half of this presentation, I talk about my contribution to the gut-muscle axis in older adults, and in the second half, my personalized approach to optimal health!

Also, here’s the article that corresponds to the presentation:
https://www.leafscience.org/the-gut-microbiome-affects-muscle-strength-in-older-adults/

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