As the landscape of the Covid19 pandemic begins to alter due to developing immunity in the population from both natural infection and vaccination1, we now have a greater understanding of how the immune system adapts during exposure to infections. It is important to note that even though there may be light at the end of the tunnel, our immune response to exposure to the Sars-Cov2 virus is the most important factor as to how our bodies manage covid infections and whether we develop serious disease and/or complications.
Recent research has highlighted that each individual’s immune system is unique and therefore an immune response is difficult to predict2. At the same time the immune system is highly flexible and changes over a lifetime. This variability in immune response is thought to be a major factor in why some may experience asymptomatic disease while others develop severe disease and some of those die.
A study has identified that the same three key combinations of immune cell population frequencies can define an individuals immunotype and predict a diverse set of functional responses to cytokine situation (inflammation).2 Unrelated younger individuals have similar, homogenous, immunotypes, however as people age their immune systems become increasingly heterogenous, different from each other. This suggests that immunity is heavily influenced by the environment it is exposed to and it continues to alter as we age and how the immune system ages is essential for longevity and immune resilience. Changes to immunity due to aging also explains the greater incidence of significant disease from Covid infections in the elderly.2-4
It is understood that immune cell populations do not work in isolation and continuously depend on and regulate each other, thereby affecting systemic responses. Research is continuing as to how to best understand the immunotype of each individual to help predict host response and also to develop targeted therapeutics specific immunotypes. However, we can, from this, understand that supporting normal and healthy immunity throughout life and protecting against antecedents that may disrupt immune function is of paramount importance.2
Immuno-senescence and Inflammaging
A major factor in the decline in immunity as we age is immuno-senescence this is the age-associated decline of the immune system and host defense mechanisms. Immunosenescence results in increased susceptibility and severity of infectious diseases and non-communicable age-associated diseases, among them cancer, cardio-vascular disease, and autoimmunity. It manifests itself in both the innate and the adaptive immune branches.3
In adaptive immunity we see a reduction in thymic output and thymic epithelial cells in conjunction with an increase in thymic adiposity, known as thymic involution. This reduces the output of new naive T cells therefore reducing potential response to previously encountered infections. A lifetime of persistent pathogen exposures (e.g., chronic infections) leads to prioritising proliferation of memory T cells specific to those pathogens. These physiological mechanisms lead to an “imbalanced” repertoire of immune cells that is predominately populated by memory cells specific to frequently encountered pathogens, which limits the ability of the adaptive branch to respond to novel pathogens.3 It is therefore important to support immune response in early life to ameliorate chronic infections.
The innate immune system aging is associated with the development of a chronic low-grade inflammatory response which can occur without the presence of pathogen stimulation, this has been described as “inflammaging”. Elderly people often experience chronic inflammation and possess elevated levels of pro-inflammatory cytokines, associated with chronic disease and mortality. Theories suggest that inflammaging is facilitated by long-lasting pathogen encounters, cell debris and stress, and the reduced efficiency of the adaptive immune response, although mechanisms are still not fully understood.3-6
We know that inflammation plays a major role in the progression of chronic conditions, but as it additionally leads to the degradation of immunity, there is an increased need to ensure healthy inflammatory responses are supported throughout life.
Factors affecting inflammation
As we age increased levels of NF-kb have been observed.NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a major pro-inflammatory transcription factor, which is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. It plays a key role in regulating the immune response to infection. Incorrect regulation has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development as well as inflammaging. NF-kB can be induced by overeating, obesity, dysbiosis, psychological and chronic stress, vitamin D deficiency, circadian rhythm disturbance, aldosterone, angiotensin II, oxidized mitochondrial DNA.3
Molecules shown to downregulate NF-kB include alpha lipoic acid, vitamin C, vitamin E, NAC, cat’s claw, silymarin, Boswellia, resveratrol, green tea, gingko biloba and curcumin, as well as caloric restriction.7
Toll-like receptors (TLR) are receptors on the surface of cells which recognise pathogen patterns from viruses, bacteria, or fungi to induce NF-kB proinflammatory signaling. TLR inhibition is a potential target to alleviate inflammation. TLR4 is of particular interest in connection with aging, its activation leads to mitochondrial dysfunction and an inflammatory reaction, including in brain microglia. TLR4 is inhibited by substances from cocoa.3
Some polyphenols, including quercetin, naringenin and silymarin can suppress overexpression of inflammatory mediators through TLR4/NF-κB signaling intervention.3
It is highly probable that as immunotypes and the microbiome are so plastic throughout life,( as well as the myriad of studies that have observed these systems) the microbiome variation contributes to immune diversity. Hence the microbiome plays and essential role in healthy aging of the immune system and supporting immunological responses to infection and vaccination.
The gut microbiota has a central role in both inflammaging owing to its ability to release inflammatory products, contribute to circadian rhythms (thereby affecting cortisol levels) and crosstalk with other organs and systems.8
Studies have shown that dietary interventions to increase diversity of the microbiome have an impact on the immune system and demonstrate a reduction in inflammation.
It was found that9:
- Diet intervention with systems profiling reveals links in diet-microbiome-immune axis
- High-fiber diet changes microbiome function and elicits personalized immune responses
- Fermented-food diet increases microbiome diversity and decreases markers of inflammation
Hence long-term interventions and dietary support for gut flora can modulate immunity and reduce inflammaging.9-10
For further information about supporting microbial diversity in the gut, see our blogs The gut ecosystem and microbial diversity – Cytoplan and Prebiotics and latest research | Cytoplan blog
As mentioned, the status of gut microbiome is highly predictive of inflammatory markers and host responses to infection. Additionally, vitamin D has an influence on both the gut flora and immunity, it has an immunomodulatory function in innate and adaptive immune responses to viral infection. Anti-inflammatory functions of Vit D include regulation of gut microbiome and maintaining microbial diversity. It promotes growth of gut-friendly commensal strains of Bifida and Firmicutes species.11 Therefore, vitamin D status must be considered in everyone, the government recommends supplementing 10ug of vitamin D per day.
- Each individual’s immune system is unique and therefore an immune response is difficult to predict. At the same time the immune system is highly flexible and changes over a lifetime. This variability in immune response is thought to be a major factor in why some may experience asymptomatic disease while others develop severe disease and some of those die.
- A major factor in the decline in immunity as we age is immuno-senescence this is the age-associated decline of the immune system and host defence mechanisms.
- Immuno-senescence is exacerbated by inflammation, known as inflammaging.
- Increased expression of NF-kB and TLR4 are associated with inflammation.
- Polyphenols in the diet such as cocoa have been shown to inhibit TLR4.
- Molecules shown to downregulate NF-kB include alpha lipoic acid, vitamin C, vitamin E, NAC, cat’s claw, silymarin, Boswellia, resveratrol, green tea, gingko biloba and curcumin, as well as caloric restriction.7
- The gut microbiota has a central role in both inflammaging, studies have shown that supporting microbial diversity with high fibre and fermented foods can attenuate inflammation and support normal immune function.
- There is a strong correlation with vitamin D status and the gut microbiome both of which support immune funciton.
If you have questions regarding the topics that have been raised, or any other health matters, please do contact our team of Nutritional Therapists.
- Crotty, S. ‘Hybrid Immunity’, Science , Vol 372, Issue 6549, pp. 1392-1393
- Kaczorowski KJ, Shekhar K, Nkulikiyimfura D, Dekker CL, Maecker H, Davis MM, Chakraborty AK, Brodin P. Continuous immunotypes describe human immune variation and predict diverse responses. Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6097-E6106. doi: 10.1073/pnas.1705065114. Epub 2017 Jul 10. PMID: 28696306; PMCID: PMC5544312.
- Moskalev A, Stambler I, Caruso C. Innate and Adaptive Immunity in Aging and Longevity: The Foundation of Resilience. Aging Dis. 2020 Dec 1;11(6):1363-1373. doi: 10.14336/AD.2020.0603. PMID: 33269094; PMCID: PMC7673842.
- Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007 Jan;128(1):92-105. doi: 10.1016/j.mad.2006.11.016. Epub 2006 Nov 20. PMID: 17116321.
- Jones E, Sheng J, Carlson J, Wang S. Aging-induced fragility of the immune system. J Theor Biol. 2021;510:110473. doi:10.1016/j.jtbi.2020.110473
- Fülöp T, Larbi A, Witkowski JM. Human Inflammaging. Gerontology. 2019;65(5):495-504. doi: 10.1159/000497375. Epub 2019 May 3. PMID: 31055573.
- Bland J et al. Textbook of Functional Medicine.; 2008.
- Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018 Oct;14(10):576-590. doi: 10.1038/s41574-018-0059-4. PMID: 30046148.
- Wastyk HC, Fragiadakis GK, Perelman D, Dahan D, Merrill BD, Yu FB, Topf M, Gonzalez CG, Van Treuren W, Han S, Robinson JL, Elias JE, Sonnenburg ED, Gardner CD, Sonnenburg JL. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021 Aug 5;184(16):4137-4153.e14. doi: 10.1016/j.cell.2021.06.019. Epub 2021 Jul 12. PMID: 34256014.
- Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20(2):145-155. doi:10.1038/nn.4476
- Shenoy S. Gut microbiome, Vitamin D, ACE2 interactions are critical factors in immune-senescence and inflammaging: key for vaccine response and severity of COVID-19 infection. Inflamm Res. 2022;71(1):13-26. doi:10.1007/s00011-021-01510-w