Low White Blood Cells: a longevity indicator?

When we first started living The CR Way 15 years ago, a frequent topic of conversation among CR practitioners was that reducing calories lowers white blood cells (WBCs). A normal white blood cell count ranges from 4,500 to 10,000 cells per microliter of blood. However, normal for someone following a limited-calorie diet ranges from approximately 3,000 to 4,000 cells per microliter.

At first glance, lower white blood cells might be cause for concern. After all, WBCs, also known as leukocytes, defend against all sorts of immune system challenges such as infectious disease and cancer. According to Mayo Clinic hematologist, Ruben Mesa, M.D., white blood cell count below 2,500 cells per microliter may increase the risk of serious infection. If you are concerned about your low WBC, take a moment to look at the rest of what Dr. Mesa and his colleagues have to say about it at http://www.mayoclinic.com/health/low-white-blood-cell-count/AN00726. Then check with your doctor to see if any of the conditions mentioned apply to you.

High WBC → Inflammation?

High white blood cell count can be an indicator of increased inflammation, which is associated with accelerated aging as well as age-related diseases. Dr. Russell Tracy, whose pioneering research helped demonstrate the role of inflammation in heart disease felt was quoted as saying “Inflammatory factors predict virtually all bad outcomes in humans…It predicts having heart attacks, having heart failure, becoming diabetic; predicts becoming fragile in old age; predicts cognitive function.¹

Higher WBC may also be an indicator of cancer risk. In several studies higher white blood cell count was associated with an increased risk of cancer and overall cancer mortality. See the following for more:

Association between circulating white blood cell count and cancer mortality: a population-based cohort study.

Anoop Shankar, Jie Jin Wang, Elena Rochtchina, Mimi C. Yu, Richard Kefford., Paul Mitchell.

Archives of Internal Medicine. 2006 Jan 23;166(2):188-94

“Conclusion: These data provide new epidemiological evidence of an association between circulating WBC count, a widely available marker of inflammation, and subsequent cancer mortality.”

PMID: 16432087

Prospective Study of Leukocyte Count as a Predictor of Incident Breast, Colorectal, Endometrial, and Lung Cancer and Mortality in Postmenopausal Women.

Karen L. Margolis, Rebecca J. Rodabough, Cynthia A. Thomson, Ana Maria Lopez, Anne McTiernan.

Archives of Internal Medicine. 2007;167(17):1837-1844.

“Conclusion: Postmenopausal women with higher WBC counts have a higher risk of incident invasive breast, colorectal, endometrial and lung cancer, as well as a higher risk of breast, lung, and overall cancer mortality.”

PMID: 17893304

Low White Blood Cell Count

A low white blood cell count provoked by living The CR Way may be an indication of less stress on the immune system. Limiting calories activates the longevity gene SIRT1 (Silencing Information Regulator Two, the 1 indicates its position on the chromosome), which reduces immune system stress by lowering inflammation. SIRT1 “silences” (decreases the activity) NFkB, (nuclear factor kappa B) a protein complex that is fundamental to inflammatory responses.² While NFκB is essential to life, it also plays a significant role in many disease states.

While we await more research about WBCs and longevity, new studies are demonstrating that CR has a very positive effect on white blood cells:

Long-term effects of caloric restriction or exercise on DNA and RNA oxidation levels in white blood cells and urine in humans.

Tim Hofer, Luigi Fontana, Stephen D. Anton, Edward P. Weiss, Dennis Villareal, Bhaskar Malayappan, Christiaan Leeuwenburgh.

Rejuvenation Research. 2008 Aug;11(4):793-9.

Abstract …Data from the present study provide evidence that negative energy balances induced through either CR or EX result in substantial and similar improvements in markers of DNA and RNA damage to white blood cells, potentially by reducing systemic oxidative stress.

PMID: 18729811

Immune Challenges?

For those who are facing immune system challenges, be assured that several foods and recipes from The CR Way have many immune system benefits. Here is an excerpt from one of our posts designed to help a CR friend in need:

Shiitake mushroom, broccoli, and onion soup may be immune booster choices. Fresh shiitake is expensive, but packages of frozen shiitakes for much less are available in many health food stores and supermarkets. Having the soup over hulled barley would be a way to add low-glycemic and high-taste calories and increase immune-boosting nutrients (beta-glucans) for a price (85 cents a pound) that is hard to beat. When evaluating immune function – our doctor, Steve Bock, who appears with us on television from time to time, looks at activity of WBC components such as natural killer cells. The idea for including shiitake in our regimen was Steve’s.

Here’s what Memorial Sloan Kettering Cancer Center says about shiitake: http://www.mskcc.org/mskcc/html/69377.cfm.

And the following study tests the effects of beta-glucans, the primary active substance of shiitake:

Dietary modulation of immune function by beta-glucans.

Julia J. Volman, Julian D. Ramakers, Jogchum Plat

Physiology & Behavior. 2008 May 23;94(2):276-84. Epub 2007 Dec 4.

Abstract The immune response can be modulated by nutrients like beta-glucans, which are glucose polymers that are major structural components of the cell wall of yeast, fungi, and bacteria, but also of cereals like oat and barley. There is a lot of structural variation in the beta-glucans from these different sources, which may influence their physiological functions. In this review the current status concern-ing possibilities to modulate immune function by beta-glucans is discussed. In vitro as well as in vivo studies in animals and humans show that especially beta-glucans derived from fungi and yeast have immune modulating properties.

Most frequently evaluated are effects on leukocyte activity, which has been suggested to contribute to the increased resistance against infections observed after beta-glucan interventions. Although most studies supply the beta-glucans parenteral (e.g. intravenous or subcutaneous), also enteral administrated (dietary) beta-glucan influence the immune response. Although more human studies are needed, it is tempting to suggest that dietary beta-glucans may be a useful tool to prime the host immune system and increase resistance against invading pathogens.

PMID: 18222501

One last comment: Although a low WBC count is almost certainly a general indicator of better health, that doesn’t mean lower and lower is better. Set limits. Always consult with your doctor for guidance.

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¹ McGowan, Kathleen, “Can We Cure Aging?” Health and Medicine / Aging DiscoverMagazine.com. 4 Dec. 2007 http://discovermagazine.com/2007/dec/can-we-cure-aging, accessed August 31, 2008

² Fan Yeung, Jamie E Hoberg, Catherine S Ramsey, Michael D Keller, David R Jones, Roy A Frye, and Marty W Mayo. “Modulation of NF-kB-dependent transcription and cell survival by the SIRT1 deacetylase.” EMBO Journal. 2004 June 16; 23(12): 2369–2380. © 2004, European Molecular Biology Organization, PMID: 15152190

Q: I’m new to CRON (Calorie Restriction Optimal Nutrition) and take multi-vitamins since I’m also vegan. Someone has mentioned that supplements may actually nullify what CR is doing. I was wondering if someone could point me to a study or explain to me how this is so. Does it have something to do with getting excess protein?

A: This is a great question - something that all serious CR folk ask at one time or another. An answer could have taken pages and pages were it not for the insightful work of an important scientist, Cynthia Kenyon, who changed history. In 1992, Dr. Kenyon found that by blocking the actions of daf-2 in round worms, their lifespan could be doubled:

Cynthia Kenyon, J Chang, E Gensch, A Rudner, R Tabtiang.

Department of Biochemistry and Biophysics, University of California at San

Francisco 94143-0554.

A C. elegans mutant that lives twice as long as wild type.

Nature. 1993 Dec 2;366(6454):461-4.

We have found that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type. This lifespan extension, the largest yet reported in any organism, requires the activity of a second gene, daf-16. Both genes also regulate formation of the dauer larva, a developmentally arrested larval form that is induced by crowding and starvation and is very long-lived. Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation. daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.

PMID: 8247153

Fortunately, the daf-2 pathway is conserved in all mammalian species including humans, where it is known as the insulin / IGF-I signaling pathway. Human CR has been shown to lower insulin and insulin-like growth factor 1 (IGF-I) - a common pattern for all animal studies that show life extension by calorie restriction.

Since Dr. Kenyon’s original work, many studies and review articles support her findings such as this excellent work by the esteemed longevity researcher Nir Barzilai:

http://sageke.sciencemag.org/cgi/content/full/2002/16/vp4

Insulin and IGF-I are very similar molecules with some similar actions. One of the most important is regulation of growth. When either of these molecules is stimulated, many actions occur - including increased cell proliferation, resulting in growth-related actions.

Now that you know that downregulation of the insulin/IGF-I signaling pathway is essential for CR’s age-slowing effect, you can systematically evaluate what supplements, macronutrient combinations, or lifestyle choices up-regulate insulin and /or IGF-I and, a related inquiry, which ones up-regulate growth.

Consider food choices for example. Since you are vegan, you are less likely than some to consume excessive protein, which can lead to significant stimulation of IGF-I¹. However, we are always surprised when vegans or anyone who is interested in longevity include high-glycemic food choices as a part of their meals. Fasting glucose above 100 is a risk factor for diabetes². On the other hand, lower glucose levels may facilitate activation of cell signals that increase longevity³. This is one reason that we devote a whole chapter in The CR Way to glucose control.

In September, we will be the initial CR cohort members to participate in the first in-depth exploration of the cell signaling patterns in long-term human CR. It is probable that this research will yield many new insights that can be practically applied to lifestyle choices for anyone interested in longevity. For now though, using the insulin / IGF-I signaling pathway as a guide for decisions about supplements, macronutrients and other choices will be a great help.

Wishing you the best of health,

Paul and Meredith

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¹ Luigi Fontana, Sam Klein, John O. Holloszy. “Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk.”

American Journal of Clinical Nutrition. 2006 Dec;84(6):1456-62. PMID: 17158430

² National Diabetes Education Program, a partnership of NIDDK the U.S. National Institute of Digestive and Diabetes and Kidney diseases, CDC: The Centers for Disease Control and Prevention, and 100s of health-related organizations. http://ndep.nih.gov/diabetes/WTMD/pre-diabetes.htm, accessed August 1, 2008

³ JT Rodgers, C Lerin, W Haas, SP Gygi, BM Spiegelman, P Puigserver. “Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.” Nature. 2005 Mar 3;434(7029):113-8. PMID: 15744310

For more, try this freely available full paper with many excellent references:

Michelangela Barbieri, Massimiliano Bonafè, Claudio Franceschi, and Giuseppe Paolisso

Department of Geriatric Medicine and Metabolic Diseases, University of Naples, 80138 Naples, Italy.

Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans

American journal of physiology. Endocrinology and metabolism. 2003 Nov;285(5): E1064-71

Although the underlying mechanisms of longevity are not fully understood, it is known that mutation in genes that share similarities with those in humans involved in the insulin/insulin-like growth factor I (IGF-I) signal response pathway can significantly extend life span in diverse species, including yeast, worms, fruit flies, and rodents. Intriguingly, the long-lived mutants, ranging from yeast to mice, share some important phenotypic characteristics, including reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-I plasma levels. Such genetic homologies and phenotypic similarities between insulin/IGF-I pathway mutants raise the possibility that the fundamental mechanism of aging may be evolutionarily conserved from yeast to mammals. Very recent findings also provide novel and intriguing evidence for the involvement of insulin and IGF-I in the control of aging and longevity in humans. In this study, we focus on how the insulin/IGF-I pathway controls yeast, nematode, fruit fly, and rodent life spans and how it is related to the aging process in humans to outline the prospect of a unifying mechanism in the genetics of longevity.

PMID: 14534077

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