Your immune system’s ability to combat COVID-19, like any infection, largely depends on its ability to replicate the immune cells effective at destroying the SARS-CoV-2 virus that causes the disease.
These cloned immune cells cannot be infinitely created, and a key hypothesis of a new University of Washington study is that the body’s ability to create these cloned cells falls off significantly in old age.
According to a model created by UW research professor James Anderson, this genetically predetermined limit on your immune system may be the key to why COVID-19 has such a devastating effect on the elderly.
Anderson is the lead author of a paper published March 31 in The Lancet eBioMedicine detailing this modeled link between aging, COVID-19 and mortality.
“When DNA split in cell division, the end cap – called a telomere – gets a little shorter with each division,” explains Anderson, who is a modeler of biological systems in the School of Aquatic and Fishery Sciences. “After a series of replications of a cell, it gets too short and stops further division. Not all cells or all animals have this limit, but immune cells in humans have this cell life.”
The average person’s immune system coasts along pretty good despite this limit until about 50 years old. That’s when enough core immune cells, called T cells, have shortened telomeres and cannot quickly clone themselves through cellular division in big enough numbers to attack and clear the COVID-19 virus, which has the trait of sharply reducing immune cell numbers, Anderson said.
Importantly, he added, telomere lengths are inherited from your parents. Consequently, there are some differences in these lengths between people at every age as well as how old a person becomes before these lengths are mostly used up.
Anderson said the key difference between this understanding of aging, which has a threshold for when your immune system has run out of collective telomere length, and the idea that we all age consistently over time is the “most exciting” discovery of his research.
“Depending on your parents and very little on how you live, your longevity or, as our paper claims, your response to COVID-19 is a function of who you were when you were born,” he said, “which is kind of a big deal.”
To build this model the researchers used publicly available data on COVID-19 mortality from the Center for Disease Control and US Census Bureau and studies on telomeres, many of which were published by the co-authors over the past two decades.
Assembling telomere length information about a person or specific demographic, he said, could help doctors know who was less susceptible. And then they could allocate resources, such as booster shots, according to which populations and individuals may be more susceptible to COVID-19.
“I’m a modeler and see things through mathematical equations that I am interpreting by working with biologists, but the biologists need to look at the information through the model to guide their research questions,” Anderson said, admitting that “the dream of a modeler is to be able to actually influence the great biologists into thinking like modelers. That’s more difficult.”
One caution Anderson has about this model is that it might explain too much.
“There’s a lot of data supporting every parameter of the model and there is a nice logical train of thought for how you get from the data to the model,” he said of the model’s power. “But it is so simple and so intuitively appealing that we should be suspicious of it too. As a scientist, my hope is that we begin to understand further the immune system and population responses as a part of natural selection.”
Co-authors include Ezra Susser, Mailman School of Public Health, Columbia University; Konstantin Arbeev and Anatoliy Yashin, Social Science Research Institute, Duke University; Daniel Levy, National Heart, Lung, and Blood Institute, National Institutes of Health; Simon Verhulst, University of Groningen, Netherlands; Abraham Aviv, New Jersey Medical School, Rutgers University.
The termini of linear chromosomes are called telomeres, consisting of an array of DNA repeats [(TTAGGG)n in mammals] and a number of telomere binding proteins [1;2]. The incomplete replication of chromosomal ends during cell division results in loss of a small fraction of telomere DNA and makes telomere length a marker of the biological age of cells, tissues/organs, and probably of humans .
Telomeric DNA is synthesized by telomerase which maintains telomere function via compensating the loss of telomeric DNA resulting from cell-division. Telomerase consists of two core components: telomerase reverse transcriptase (TERT) and telomerase RNA template (TERC).
Telomerase activity is tightly regulated as most mature cells express very little telomerase, with the exception of germline cells, stem cells, and lymphocytes.
Telomere length attrition has been well documented during continued in vitro replication of cultured human cells, including fibroblasts and lymphocytes [4;5]; and in leukocytes and fibroblasts with progressive age [6–8] both in normal individuals and at an accelerated rate in the presence of some genetic abnormalities, disease states, or environmental stressors [9–11]. A large body of research has established that intact telomere function is essential for cell proliferation and that impaired telomere maintenance has a severe detrimental impact for cells such as stem cells which rely on proliferation for their function.
Blood leukocytes are composed of multiple cell types that derive from two hematopoietic lineages. Myeloid derived cells include granulocytes (neutrophils, basophils and eosinophils) and monocytes/macrophages, whereas lymphoid derived cells include T cells, B cells, and NK cells. The proportions of these different cell types in blood undergo changes with age, including increased monocytes, decreased lymphocytes, a decrease in naïve lymphocytes, and an increase in memory lymphocytes .
Because the mature myeloid lineage cells are non-dividing cells, whereas mature lymphocytes undergo extensive cell division in mediating their function, telomere length measured for leukocytes reflect sums or averages over cells with potentially very different replicative histories. Furthermore, telomeres are on average longer in naïve than in memory T cells [4;7], and are longer in CD28+ than in more differentiated CD28− CD8+ T cells . Therefore, measuring telomeres in defined cell populations whenever possible will facilitate a more informative interpretation of results.
Defects in telomeres cause severe problems in hematopoietic and other systems
The in vivo role of telomeres in cellular replication is best demonstrated from the studies of genetic disorders that impair various components of telomerase and telomeres [9;10]. The first genetic disorder reported to be associated with short telomeres is Dyskeritosis congenita (DC), a rare syndrome with abnormalities of the skin, nails, mucous membranes, and bone marrow .
A number of different genetic mutations in components of either telomerase ribonucleoprotein complex (DKC1, TERT, TERC, NOP10, and NHP2) or telomere binding protein-associated protein (TIN2) have been subsequently found in DC families [9;14]. In addition, genetic mutations of telomerase components, with consequent short telomeres, have also been found in association with idiopathic fibrosis of lung , fibrosis/cirrhosis of liver [16;17], and hereditary cancer risk . Together, these mutations show defects in the maintenance of telomere maintenance (short telomeres), accompanied by replicative dysfunction in stem cells , the hematopoietic system (bone marrow failure) , lung (idiopathic pulmonary fibrosis) and liver (cirrhosis), and predisposition of cancer.
A striking feature of these genetic defects and diseases is the phenomenon of genetic anticipation. This is the appearance of progressively shorter telomeres in DC patients and earlier onset of disease manifestations from generation to generation within the same family. It is telomere length, in the presence of an identical genetic mutation, that appears to explain an earlier onset age and severity of the disease in later generations. Thus, genetic and clinical evidence indicates that short telomeres cause genomic instability and lead to cellular dysfunction in those highly proliferative tissues and organs [9;10].
Short telomeres of leukocytes associated with aging and immune dysfunctions
Cellular proliferation is a key component of an effective adaptive immune response. Therefore, the role of telomeres in leukocytes, particularly in lymphocytes, is of great interest . A number of intriguing observations have indicated that a shortening of telomeres occurs in cells of the human immune system as a function of in vivo lineage differentiation and with aging, as well as during in vitro culture.
The loss of telomeres has been observed during naïve T cell differentiation to memory T cells [4;7], during CD28+ to CD28− CD8 T cell differentiation , in long-term cultured T cells [4;5], and in chronic viral infections . In the cultured CD8 T cells, significantly shortened telomeres appear to be to cause senescence as the ectopic expression of telomerase is capable of rescue telomere shortening and prolong their proliferation .
Furthermore, cross-sectional analyses show that telomere shortening occurs in leukocytes or PBMC and in isolated granulocytes and lymphocytes (CD4, CD8 T cells and B cells) with age [6–8]. Collectively, these findings show that telomere attrition occurs in blood leukocytes of both myeloid and lymphoid lineages, and that telomere length associates with leukocyte differentiation and age. However, the degree to which telomere attrition contributes to the overall decline of immune function with age remains to be determined.
Short telomeres of leukocytes or PBMC have also been described in association with a number of immune-related diseases . Patients with some common autoimmune syndromes including rheumatoid arthritis , and diabetes mellitus (type 1 and type 2) [26;27] display significantly shortened telomeres in leukocytes or PBMC compared to age-matched healthy controls.
In addition, patients with viral infections including HIV, EBV, and CMV undergo extensive proliferative response of T cells in response to these infections, and it has been observed that viral reactive T cells have short telomeres associated with replicative impairment [22;28]. A common pathological basis of these immune dysfunctions is the extensive proliferation of lymphocytes, leading to the exhaustion of telomeres and replicative potential.
Finally, short telomeres of leukocytes or PBMC are also found in patients with malignancies and as a risk factor for some type of tumors, whether or not the malignancies are of immune cell lineages  or other cell types . In malignancies of immune cell origin such as leukemia, it is currently unclear whether short telomeres contribute causally to leukemia pathogenesis or are the consequence of extensive proliferation of tumor cells, or both.
Even less is known about the cause of short telomeres of leukocytes or PBMC in patients with tumors of non-immune cells. Whether the burden of tumor bearing affects immune cell function, and more specifically how telomere maintenance is affected requires further study. Nevertheless, these findings suggest that telomere shortening may be a cause and/or a consequence of immune cell dysfunction.
Some known factors influencing telomere lengths in blood leukocytes
An increasing number of publications in recent years show that various physiological and/or psychological factors have an impact on overall health as well as an effect on telomere length of peripheral blood leukocytes [31–36]. Early studies showed an association of sustained stress, such as that experienced by the mothers of sick children or the caregivers of Alzheimer’s diseases, with short telomere length in leukocytes or PBMC compared to healthy controls [31;32].
Individuals with major depression over a long period of time have also been reported to have shorter telomeres in leukocytes than healthy controls . More recently, short telomeres have also been found in the offspring of mothers who had experienced a severe stressor in the index pregnancy, suggesting that prenatal stress exposure is linked to subsequent shorter telomere length in offspring .
Other studies have shown that a healthy lifestyle such as exercise, healthy weight, lower meat and higher fruit/vegetable consumption is linked to longer telomeres of leukocytes  whereas obesity is associated with shorter telomeres . It has further been suggested that a sustained healthy lifestyle may even attenuate the effect of stressors on telomere length .
These epidemiological analyses of mostly case-control studies reveal a correlative link between telomere length of leukocytes and various health conditions. Considering that telomere length is highly polymorphic in the population, a large sample size and preferably a longitudinal follow-up will be needed to further test these findings.
More importantly, it will be critical to understanding the underlying mechanism of these correlative findings. Do these physiological and/or psychological factors affect the length of telomeres by actual shortening/lengthening of telomeres in leukocytes, or do they alter telomere length in heterogeneous leukocyte populations by altering the relative proportions of different cell types known to differ in telomere length?
A parallel analysis of telomere length and leukocyte composition, or more rigorously still, a direct analysis of telomere length in leukocyte subsets with longitudinal follow-up may provide some answers. Only limited studies to date have carried out any longitudinal analysis of leukocyte subsets , and still more refined subpopulation analysis will be necessary to better define the potentially complex effects of telomere length change.
It has also been suggested that the length of individual telomeres in a cell, rather than the overall average of telomere length, may be important to function . It remains to be determined whether this is in fact relevant to normal and pathological human conditions. As noted in the summary of available methodologies, measurement of this parameter remains highly challenging in human population studies.
Comprehensive assessment of immune function including telomere length
Whether telomere length of leukocytes can be a useful parameter for predicting health and diseases is a subject of current debate [39;40]. Here we focus on whether telomere length of leukocyte or PBMC is a useful measure for assessing the competence of immune system function. From the study of genetic syndromes of telomere/telomerase dysfunction that were described above, there is little question that telomere length can influence bone marrow function. However, it remains to be determined whether there are measurable effects of telomere length on immune function, either with normal aging, during normal immune responses, or in defined pathologic states.
It has been shown that patients with various genetic defects in telomere maintenance have leukocyte/PBMC telomere length in the lower 10% of the age-matched normal population . Therefore, telomere length equal to the lower 10% or 5% in a population of a given age could be used as an operational criterion of short telomeres (Figure 1). Considering the variation of telomere length in populations, applying this criterion requires establishing a standard telomere length range of leukocytes and/or PBMC in the normal population and its change with age. As telomere length of leukocytes and PBMC is dynamic [42;43], repeated measurements of telomere length over time (months to years) is necessary to accurately determine the rate of telomere length change, a parameter that has critical value in assessing the telomere status in addition to the absolute length.
Considering the heterogeneous nature of cell lineages, types, and proliferative history, and the heterogeneity of telomere length on individual chromosomes within a cell, the measurement of average telomere length of heterogeneous cell populations alone is likely to be insufficient for assessing immune competence. As the adaptive immune response is antigen-specific, an average telomere length does not always predict the telomere length of those antigen-reactive lymphocytes which represent a small percentage of total lymphocytes.
The most specific assessment of telomere function in a specific response thus must be conducted by analysis of antigen-specific populations. A more comprehensive assessment of immune function in human must also include other measures, such as detailed analysis of composition of different cell type such as monocytes and lymphocytes, and the relative percentages of naïve, effector, and memory cells, and levels of cytokine/chemokines . Integrating these measures will reveal new insight into the human immune system and its change with age (Table 1). This in turn will help to further assess how telomere length may contribute in predicting immune competency.
Suggested panel of tests for evaluating the status of human immune function
|Blood cell counts of all types of leukocytes||CBC|
|Telomere length of leukocytes or PBMC||qPCR or Flow-FISH|
|Leukocyte composition including lymphocyte subsets||Multi-color flow cytometry|
|Serum cytokine profile||Multiplex assay|
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423542/#:~:text=Highlights-,Telomeres%20are%20essential%20for%20the%20integrity%20of%20chromosomes%20and%20for,hematopoietic%20and%20other%20proliferating%20cells.
More information: James J. Anderson et al, Telomere-length dependent T-cell clonal expansion: A model linking ageing to COVID-19 T-cell lymphopenia and mortality, eBioMedicine (2022). DOI: 10.1016/j.ebiom.2022.103978