Research Blog
Welcome to the concluding segment of ODX's "Biological Age Biomarkers" Series. In this tenth installment, delve into the world of the White Blood Cell and discover why an increased WBC count is associated with age-related factors, including all-cause mortality, hypertension, cardiovascular risk, and ischemic stroke.
The ODX Biological Age Biomarkers Series
Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN
- Biological Age Biomarkers Part 1: Introduction and Overview
- Biological Age Biomarkers Part 2: Fasting Glucose
- Biological Age BioMarkers Part 3: C-Reactive Protein (CRP)
- Biological Age Biomarkers Part 4: Albumin
- Biological Age BioMarkers Part 5: Alkaline Phosphatase
- Biological Age BioMarkers Part 6: Creatinine
- Biological Age BioMarkers Part 7: Red Cell Distribution Width (RDW)
- Biological Age BioMarkers Part 8: Mean corpuscular volume (MCV)
- Biological Age BioMarkers Part 9: Lymphocytes
- Biological Age BioMarkers Part 10: WBCs
White blood cell (WBC) count reflects immune function and inflammation
Physiological changes associated with total white blood cell count
White blood cells (WBCs), also called leukocytes, are immune cells produced in the bone marrow. They are used to fight infections, promote an inflammatory immune response to pathogens, and regulate the cellular response to injury (Tigner 2021).
Aging is associated with dysregulation of the immune system which progresses over time and is often marked by a low-grade chronic inflammatory state called “inflammaging” (Desai 2010). An elevated total WBC count (leukocytosis) is a non-specific marker of systemic inflammation that can occur in response to pathogens and toxins, including cigarette smoke (Kabat 2017).
Leukocytosis may reflect immune activation, infection, and physical or emotional stress. However, a low WBC count may indicate bone marrow failure, severe infection, autoimmunity, or malnutrition (Pagana 2022).
Total white blood cell count and cognitive decline
Total white blood cell counts, likely due to increased inflammation, can be associated with cognitive decline, including in neurodegenerative diseases such as Alzheimer's and Parkinson’s. Peripheral immune activation, characterized by elevated WBCs, is thought to trigger central nervous system immune activation, reactive oxygen species, cytokines, etc. In a large retrospective study of 4,417 Alzheimer’s and 2,995 Parkinson’s patients, leukocytosis was the most prevalent anomaly observed. It was associated with worsening neurocognitive decline and is considered an independent risk factor for Parkinson’s dementia (Unda 2021).
A higher total WBC, even within the normal range, was associated with cognitive decline in an analysis of NHANES data for 1,670 older adults. DSST cognitive test scores steadily decreased as WBC counts increased (Kao 2011).
A meta-analysis of 36 studies found that subjects with mild cognitive impairment, as well as Alzheimer’s, had significantly increased total WBCs, neutrophils, and neutrophil:lymphocyte ratio than healthy controls (Huang 2022).
Total white blood cell count and biological age
Increased WBCs are associated with age-related factors, including all-cause mortality, hypertension, cardiovascular risk, ischemic stroke (Leng 2005), inflammation (Gkrania-Klotsas 2010), and atherosclerosis, as well as myocardial infarction and mortality with WBCs above 9.4 k/cumm (Horne 2005).
White blood cell counts helped predict mortality in the Women’s Health and Aging Studies cohort study. A significantly increased mortality risk was associated with WBCs above 7.0 versus the lowest mortality risk in those with the lowest WBCs, i.e., below 5.6 k/cumm (Leng 2005).
Elevated total WBCs are independently associated with mortality. In population-based studies of subjects with and without a history of CVD, an increased WBC count doubled total mortality and increased CVD incidence and mortality. The association between total WBCs and mortality parallels or exceeds that of total cholesterol, LDL cholesterol, and hypertension (Kabat 2017).
In a large prospective study of 29,526 coronary angiography subjects, the lowest incidence of mortality was observed with a total WBC of 6.0 k/cumm or below. An elevated WBC count may independently predict cardiovascular events, even in healthy individuals (Anderson 2007).
The lowest mortality risk observed was associated with a WBC count of 3.5-6 in the 44-year Baltimore Longitudinal Study of Aging. Individuals with WBCs above 10 had a 2-fold increased mortality, while those with WBCS below 3.5 had a 3-fold increased mortality. Those who died were more apt to smoke, be less physically active, and have a worse cardiovascular health profile than survivors (Ruggiero 2007).
Early research of 2,011 healthy men in the longitudinal Normative Aging Study concluded that an elevated WBC count was an independent predictor of all-cause mortality. A total WBC above 9000/mm3 was associated with a 1.8-2.5 times greater mortality risk (de Labry 1990).
References
Anderson, Jeffrey L et al. “Usefulness of a complete blood count-derived risk score to predict incident mortality in patients with suspected cardiovascular disease.” The American journal of cardiology vol. 99,2 (2007): 169-74. doi:10.1016/j.amjcard.2006.08.015
de Labry, L O et al. “White blood cell count as a predictor of mortality: results over 18 years from the Normative Aging Study.” Journal of clinical epidemiology vol. 43,2 (1990): 153-7. doi:10.1016/0895-4356(90)90178-r
Desai, Anjali et al. “Leukocyte function in the aging immune system.” Journal of leukocyte biology vol. 87,6 (2010): 1001-9. doi:10.1189/jlb.0809542
Gkrania-Klotsas, Effrossyni et al. “Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies.” PloS one vol. 5,10 e13405. 18 Oct. 2010, doi:10.1371/journal.pone.0013405
Horne, Benjamin D et al. “Which white blood cell subtypes predict increased cardiovascular risk?.” Journal of the American College of Cardiology vol. 45,10 (2005): 1638-43. doi:10.1016/j.jacc.2005.02.054
Huang, Le-Tian et al. “Association of Peripheral Blood Cell Profile With Alzheimer's Disease: A Meta-Analysis.” Frontiers in aging neuroscience vol. 14 888946. 6 May. 2022, doi:10.3389/fnagi.2022.888946
Kabat, Geoffrey C et al. “White Blood Cell Count and Total and Cause-Specific Mortality in the Women's Health Initiative.” American journal of epidemiology vol. 186,1 (2017): 63-72. doi:10.1093/aje/kww226
Kao, Tung-Wei et al. “White blood cell count and psychomotor cognitive performance in the elderly.” European journal of clinical investigation vol. 41,5 (2011): 513-20. doi:10.1111/j.1365-2362.2010.02438.x
Leng, Sean X et al. “Baseline total and specific differential white blood cell counts and 5-year all-cause mortality in community-dwelling older women.” Experimental gerontology vol. 40,12 (2005): 982-7. doi:10.1016/j.exger.2005.08.006
Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.
Ruggiero, Carmelinda et al. “White blood cell count and mortality in the Baltimore Longitudinal Study of Aging.” Journal of the American College of Cardiology vol. 49,18 (2007): 1841-50. doi:10.1016/j.jacc.2007.01.076
Shankar, Anoop et al. “The association between circulating white blood cell count, triglyceride level and cardiovascular and all-cause mortality: population-based cohort study.” *Atherosclerosis*, vol. 192, no. 1, 2007, doi:10.1016/j.atherosclerosis.2006.04.029.
Tigner, Alyssa, et al. “Histology, White Blood Cell.” StatPearls, StatPearls Publishing, 19 November 2021.
Unda, Santiago R et al. “Peripheral Leukocytosis Predicts Cognitive Decline but Not Behavioral Disturbances: A Nationwide Study of Alzheimer's and Parkinson's Disease Patients.” Dementia and geriatric cognitive disorders vol. 50,2 (2021): 143-152. doi:10.1159/000516340
Wang, Tao et al. “White blood cell count and all-cause and cause-specific mortality in the Guangzhou biobank cohort study.” *BMC public health*, vol. 18, no. 1, 2018, doi:10.1186/s12889-018-6073-6.
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Biomarkers
