Functional Age BioMarkers Part 9: Lymphocytes

Welcome to part nine of ODX's "Functional Age Biomarkers" Series. In this ninth installment, delve into the world of lymphocytes and uncover the correlation between aging and the decline in B and T lymphocytes, leading to heightened vulnerability to cognitive decline, weakened immunity, and organ dysfunction.

The ODX Functional Age Biomarkers Series

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

1. Functional Age Biomarkers Part 1: Introduction and Overview
2. Functional Age Biomarkers Part 2: Fasting Glucose
3. Functional Age BioMarkers Part 3: C-Reactive Protein (CRP)
4. Functional Age Biomarkers Part 4: Albumin
5. Functional Age BioMarkers Part 5: Alkaline Phosphatase
6. Functional Age BioMarkers Part 6: Creatinine
7. Functional Age BioMarkers Part 7: Red Cell Distribution Width (RDW)
8. Functional Age BioMarkers Part 8: Mean corpuscular volume (MCV)
9. Functional Age BioMarkers Part 9: Lymphocytes
10. Functional Age BioMarkers Part 10: WBCs

Lymphocytes reflects immune function

Physiological changes associated with low lymphocytes

The primary job of lymphocytes, a type of white blood cell, is to fight chronic bacterial or acute viral infections. Lymphocytes facilitate adaptive immunity and include B cells and T cells. Antibody-producing B-cells participate in humoral immunity, while T-cells enable cellular-type immune reactions (Pagana 2022).

Aging is associated with an overall reduction in B and T lymphocytes (Cisneros 2022). This reduction impairs the immune system’s ability to clear viral and bacterial infections (naive lymphocytes) and decreases antibody response to vaccination and recurrent infection (memory lymphocytes). Although aging is associated with an overall reduction in lymphocytes, increased activation of lymphocytes, including natural killer lymphocytes, can be observed during the aging process (Corona 2012, Weng 2006). An aging immune system is also associated with impaired wound healing, unopposed tissue inflammation, cancer susceptibility, and reactivation of viral infections, including shingles (Weyland 2016).

A decreased lymphocyte count is associated with immune compromise and severe infection (Pagana 2022). However, it is also a marker for malnutrition, a risk factor for increased morbidity and mortality (Leandro-Merhi 2019). A low lymphocyte count is also associated with COVID-19. The SARS-CoV-2 virus that causes COVID-19 directly attacks lymphocytes, complicating recovery from this pandemic. A prospective study of 101 COVID-19 patients found that a decreased lymphocyte level was associated with malnutrition, anorexia, organ failure, diabetes, and cancer (Zhang 2022). Lower lymphocytes were associated with overall mortality in sepsis and all-cause mortality in COVID-19 (Seshadri 2023).

Lymphocytes and cognitive decline

Lymphocytes may help protect cognitive function and are higher in those with normal cognition. Decreased lymphocytes are associated with vascular cognitive impairment which correlates with inflammation and cerebral white matter injury in those with non-disabling cerebrovascular events (Li 2022).

A decrease in lymphocytes may be associated with the early cognitive impairment observed with Parkinson’s disease. Lower baseline circulating lymphocytes were associated with accelerated cognitive decline in individuals with Parkinson’s who carry the APOE4 gene. Although lower levels of lymphocytes in the blood were associated with decline, infiltration of T lymphocytes across the blood-brain barrier appears to be a part of the pathological mechanism (Tsukita 2021).

Lymphocytes and biological age

Aging is associated with diminishing immune system function which can increase vulnerability to infection and immune dysfunction. T lymphocytes are especially affected by physiological aging. T cell senescence occurs over time, while T cell exhaustion, characterized by dysfunctional T cells, can be accelerated by chronic disease or chronic antigen exposure (Jia 2023).

Aging, at any rate, is associated with an overall reduction in lymphocytes. Stress can hasten this decline and contribute to altered lymphocyte differentiation. Exposure to stress, especially chronic stress, can accelerate the aging process and contribute to immune impairment, organ dysfunction, and premature mortality. The adverse effects of stress on lymphocytes can impair the immune system's ability to fight off viruses such as cytomegalovirus (CMV) (Klopack 2022)

Lymphocyte reduction may be considered a biomarker of frailty, a hallmark of physiological aging. A lower lymphocyte count and lymphocyte percentage of white blood cells may be associated with an increased incidence and severity of frailty. Chronic stress and activation of the HPA access can magnify this effect, tying in elevated stress, elevated cortisol, decreased lymphocytes, and frailty. Conversely, physical activity, which is impaired or limited by frailty, is associated with higher lymphocyte counts in younger and older healthy individuals. A lower lymphocyte percentage was significantly associated with less physical activity and reduced muscle strength in a study of institutionalized women. A lower lymphocyte count coupled with a higher neutrophil count increases the neutrophil:lymphocyte ratio, a marker of inflammation and possible indicator of frailty. Inflammation is associated with free radicals and oxidative stress which can reduce lymphocytes and damage muscle tissue (Navarro-Martínez, Rut 2021). An absolute lymphocyte count below 1.54 k/cumm, was associated with increased all-cause mortality in older community-dwelling women aged 65-101 (Leng 2005).

The proliferation of lymphocytes can be considered a marker of health, biological age, and remaining lifespan as observed in a study of 140 subjects between 30 and 103 years old. Evaluating lymphocyte proliferation over time may help to track changes that occur with nutrition and lifestyle improvements designed to strengthen immunity and slow the aging process (Martínez de Toda 2016).

References

Cisneros, Bulmaro et al. “Immune system modulation in aging: Molecular mechanisms and therapeutic targets.” Frontiers in immunology vol. 13 1059173. 15 Dec. 2022, doi:10.3389/fimmu.2022.1059173

Corona, Angela W et al. “Cognitive and behavioral consequences of impaired immunoregulation in aging.” Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology vol. 7,1 (2012): 7-23. doi:10.1007/s11481-011-9313-4

Jia, Zhenghu et al. “Immune-Ageing Evaluation of Peripheral T and NK Lymphocyte Subsets in Chinese Healthy Adults.” Phenomics (Cham, Switzerland) vol. 3,4 360-374. 23 May. 2023, doi:10.1007/s43657-023-00106-0

Klopack, Eric T et al. “Social stressors associated with age-related T lymphocyte percentages in older US adults: Evidence from the US Health and Retirement Study.” Proceedings of the National Academy of Sciences of the United States of America vol. 119,25 (2022): e2202780119. doi:10.1073/pnas.2202780119

Leandro-Merhi, Vânia Aparecida et al. “NUTRITIONAL INDICATORS OF MALNUTRITION IN HOSPITALIZED PATIENTS.” Arquivos de gastroenterologia vol. 56,4 (2019): 447-450. doi:10.1590/S0004-2803.201900000-74

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

Li, Binghan et al. “Correlations among peripheral blood markers, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events.” Frontiers in aging neuroscience vol. 14 1023195. 2 Dec. 2022, doi:10.3389/fnagi.2022.1023195

Martínez de Toda, Irene et al. “Immune function parameters as markers of biological age and predictors of longevity.” Aging vol. 8,11 (2016): 3110-3119. doi:10.18632/aging.101116

Seshadri, Gokul et al. “Immune cells are associated with mortality: the Health and Retirement Study.” Frontiers in immunology vol. 14 1280144. 20 Oct. 2023, doi:10.3389/fimmu.2023.1280144

Navarro-Martínez, Rut, and Omar Cauli. “Lymphocytes as a Biomarker of Frailty Syndrome: A Scoping Review.” Diseases (Basel, Switzerland) vol. 9,3 53. 13 Jul. 2021, doi:10.3390/diseases9030053

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Tsukita, Kazuto et al. “Lower Circulating Lymphocyte Count Predicts ApoE ε4-Related Cognitive Decline in Parkinson's Disease.” Movement disorders : official journal of the Movement Disorder Society vol. 36,12 (2021): 2969-2971. doi:10.1002/mds.28799

Weyand, Cornelia M., & Jörg J. Goronzy. "Aging of the Immune System. Mechanisms and Therapeutic Targets." *Annals of the American Thoracic Society.*, vol. 13, Suppl 5, 2016, doi:10.1513/AnnalsATS.201602-095AW.

Weng NP. Aging of the immune system: how much can the adaptive immune system adapt? Immunity. 2006 May;24(5):495-9. doi: 10.1016/j.immuni.2006.05.001. PMID: 16713964; PMCID: PMC2266981.

Zhang, Kai et al. “Malnutrition Contributes to Low Lymphocyte Count in Early-Stage Coronavirus Disease-2019.” Frontiers in nutrition vol. 8 739216. 6 Jan. 2022, doi:10.3389/fnut.2021.739216