Inflammaging and immunosenescence

The human body undergoes many changes during aging, remodelling of the immune system is a key part of this. The exact changes that the immune system undergoes have been analysed in different studies in order to understand why elderly people show reduced responses to vaccines. In this blog we will discuss the terms inflammaging and immunosenescence that are often used by researchers and how these play a role in vaccine efficacy. 

What is inflammaging?

Inflammaging is an age-related increase of pro-inflammatory markers in tissues and blood which is reflected by a chronic, sterile, low-grade inflammation in elderly people.¹ This includes higher levels of tumour necrosis factor (TNF), IL-6 and other pro-inflammatory cytokines.² The process of inflammaging contributes to the development of age related diseases.³ 

The key players in inflammaging are monocytes and macrophages. Mice studies have suggested that there is an increases output of myeloid progenitor cells and an elevated number of macrophages in the spleen and bone marrow of aged mice.⁴ Furthermore, macrophages residing in the tissue of old mice have demonstrated a more anti-inflammatory-pro-angiogenic phenotype compared to younger mice. ⁴

Several factors play a role in inflammaging such as genetics, obesity, viral and bacterial infections and immune cell dysregulation.¹ Unresolved viral or bacterial infections may lead to chronic stimulation of immune cells, as senescent immune cells retain the ability to recognise pathogen-associated molecular patterns supporting inflammaging.⁴ 

In addition, recent research has also shown that cell debris, misplaced self-molecules, and misfolded and oxidized proteins also play a key role in inflammaging.¹ The gut microbiome is an important factor as well, since it acts as the boundary between diet, metabolism and the innate immune response. These concepts relate to aging as the gut microbiome undergoes extensive remodelling with age.³ Additionally, the permeability of the gut to microbiota increases due to degeneration of tissues. This eventually results in a higher level of circulating LPS, contributing to inflammation.⁴

What is immunosenescence?

Immunosenescence is a term that was coined by Roy Walford, a professor of the pathology department of the University of California, Los Angeles School of Medicine. Walford first used the term immunosenescence in 1969 in his book "The Immunologic Theory of Aging" which discusses the relationship between the process of aging and dysfunctioning of the immune system.¹⁴

Immunosenescence is a process that leads to dysfunction of the innate and especially the acquired immune system.⁵ Immunosenescence mostly affects the T-lymphocytes. The key features of senescence are reduced naïve T-cell output from the thymus, the production of senescent T-cells and an increase in memory T-cells. 

In elderly people, a reduction of T-cell production takes place, which will primarily result in a reduction of naive T-cells. This phenomenon occurs most likely due to insufficient homeostatic proliferation and loss of the thymus. It mostly causes a reduction of naive CD8+ T-cells.⁶

Furthermore, senescent T-cells are T-cells that have abnormal phenotypes such as downregulation of CD27 and CD28 and upregulation of CD57.¹¹ This for example results in a decreased T-cell receptor function and diversity, leading to a reduced T-cell responsiveness with age.² Due to these phenotypic changes the T-cells defect in proliferation and effector functions and accumulate with age.⁷

Finally, an increased number of memory T-cells plays a role. To compensate for reduced naïve T-cell output from the thymus, existing naive T-cells increase homeostatic turnover. These cells differentiate into CD45RA+CD8+TEM cells upon antigen stimulation and take over the memory pool.¹² Furthermore, these cells have decreased T-cell responses since the CD28 co-stimulatory pathways are absent.¹

To summarize, the reduction of the amount of T-cells and the increase of dysfunctional T-cells contributes to aging of the immune system. This impacts the proper functioning of the immune system in elderly.

Not only T-cells undergo changes during immunosenescence. The innate immune system also changes, with alterations described in macrophages, dendritic cells, neutrophils and NK cells. NK cells show reduced cytokine and chemokine production, cytolytic potential and CD1 expression. Furthermore, neutrophils and macrophages display defective phagocytosis. Dendritic cells have reduced IFN production, CD25 expression lymphocyte cytotoxicity. Moreover, B-cells also undergo changes during aging, they decrease in number and show reduced diversity.¹³

Isidori A, Loscocco F, Ciciarello M, Corradi G, Lecciso M, Ocadlikova D, et al. Immunosenescence and immunotherapy in elderly acute myeloid leukemia patients: Time for a biology-driven approach. Cancers (Basel) [Internet]. 2018 [cited 2023 Oct 3];10(7):211. Available from: https://www.mdpi.com/2072-6694/10/7/211

Immunosenescence is influenced by numerous different factors. These include genetics and sex. There are also several extrinsic factors that affect the process of immunosenescence such as nutrition, comorbidities, exercise, previous exposure to microorganisms and pharmacological treatments.⁸

How are immunosenescence and inflammaging related to each other?

The occurrence of inflammaging can be viewed as the consequence of immunosenescence, as the changes in the immune system that occur during aging lead to dysregulation of the immune system and increased release of inflammatory mediators. During senescence functional decay, aging of anatomical barriers, neural and cardiovascular components aid the accumulation of DAMPs (damage-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns). This accumulation plays a role in chronic immune system activation, relating to immunosenescence and inflammaging.⁹

In addition, even though senescent T-cells have a decreased proliferation, they are still metabolically active. These cells show an increased production of pro-inflammatory cytokines, which could have damaging effects on the tissue microenvironment. This expression of pro-inflammatory cytokines contributes to the chronic low-grade inflammation occurring in inflammaging.² 

Literature

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