Immunosenescence and How to Manage it.

Feeling old? Consider the redwoods in the USA. Reaching heights of more than 350 feet, the world’s tallest trees have been on this planet since the days of the dinosaurs. A single specimen can live more than 2,000 years. That’s old enough to make it through from the Roman Empire to the British Empire and an assortment of presidents and prime ministers! Yet the mycelial population that connects all trees and arguably is the formative source of all life, is even older.

These trees are biologically resilient in part because of their intricate nutrient sourcing and immune flexibility, derived in large part from the mycelium! Whilst a tree and fungi are not human, their ability to survive over centuries and millennia is impressive.

Biological resilience for modern humans is the innate ability to mount a complex and dynamic process to survive in the face of adversity. Such as stressful life events, significant threats, environmental pressures, or trauma. It is best conceptualised as a continuum, with potential for change across our life span.

The decline of the immune system with age is reflected in the increased susceptibility to infectious diseases, poorer response to vaccination, increased prevalence of cancer, autoimmune, and other chronic diseases[1],[2]. The innate and adaptive immune responses are also affected by the aging process; however, the adaptive response seems to be more affected by the age-related changes in the immune system.

Additionally, aging tends to present a chronic low-grade inflammatory state that has been implicated in the pathogenesis of many age-related diseases (atherosclerosis, Alzheimer's disease, osteoporosis, autoimmunity, and diabetes etc.)

Why are we interested in Immunosenescence?

Immunosenescence is modifiable and should be a primary focus for the adoption of lifestyle and nutrition-orientated strategies. The slowing down of immune decline is intimately linked to a higher quality of life, reduction of disease, and greater capacity to adapt to challenges.

For example, contact with nature and associated physical activities have been shown to boost immunity in older adults and may be promoted in a variety of ways including horticultural therapy[3]. Dietary interventions such as intermittent fasting, food selection, and supplementation also have a role in the preservation of immune competence and represent low risk, easy to apply, interventions[4].

Reflecting on the clinical findings obtained to date concerning SARS-CoV-2 infection and reports of diseases of a similar aetiology, it appears evident that the Immunosenescence process, particularly the increased production of inflammatory cytokines resulting from ‘inflammaging’, plays a role in determining the prognosis of COVID-19 in older individuals, and those with compromised immune responses[5].

Nutrition Can Reverse Immunosenescence

Our understanding of the rationale and relevance of nutrition to human health has been profoundly enhanced in recent decades. It is steadily becoming apparent that nutrition-based natural compounds represent a fundamental class of modulatory factors which in?uence several facets of human health[6].

A diet rich in bioactive nutraceuticals and phytocompounds is likely to convey long-term health bene?ts to the elderly and the young. Consumption of fruit, vegetables, and an olive oil rich Mediterranean diet has been shown to induce bene?cial changes in innate immune cell phenotype and response, as well as the gut microbiome, resulting in lower prevalence of in?ammation, thus promoting healthier aging and reduction in immune-related decline[7].

There is little argument that deficiency in both macronutrients and micronutrients causes immune function impairment, which can be reversed by nutrient repletion. Nutritional deficiencies are still prevalent in less developed regions but can also be found across all developed countries’ populations and are a main contributor to a high incidence of morbidity and mortality from infectious diseases. Even in developed countries where general nutritional deficiencies are less common, nutrition issues such as specific nutrient deficiencies, less than ideal diet composition, and excess calorie consumption are still a challenging reality that drives immunosuppression[8].

The GI connection

The gastrointestinal tract has a significant role to play in immune function and the related gut microbiome also undergoes dynamic changes through time as it integrates and responds to signals from the environment[9]. Diet, drug use, physical activity, and social environment are among the factors that constantly shape the composition and function of the gut microbiome. An imbalance in the microbial community structure, referred to as dysbiosis, is a common accomplice of age-related disorders that collectively represent the leading cause of disability and mortality worldwide[10]. Subclinical changes in intestinal integrity may promote microbial migration to systemic sites, systemic low-grade inflammation, onset of chronic inflammatory disease, and premature mortality[11]. Probiotics and prebiotics are known to down-regulate the inflammatory response and improve innate immune efficiency in the elderly[12].

Strategic Applications

Phytonutrients, polyphenols, and others confer an advantage to the immune system by facilitating the limitation of inappropriate inflammation and support the adequacy of the immune system. Resveratrol for example is a polyphenol typically found in red wine, grape skins, and berries, and induces a significant increase in T helper cells and in the delayed-type hypersensitivity response of aged rats[13].

Fatty acids including the long-chain PUFAs of the omega-3 (n-3) and omega-6 (n-6) classes impact on immune suppression. n-6 PUFAs, derived from plants and land animals, have minimal effects on immune response. n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found mainly in fish and fish products and in some plants (flax seeds), have the most significant impact on immune cells[14].

Micronutrients as well as macro nutrients also play a part in resisting immune senescence. Zinc deficiency for example can cause decreased levels of serum thymulin, a zinc dependent peptide hormone produced by thymic epithelial cells, with an activity that is progressively reduced with age, with a peak in pre-adolescence. The active form of thymulin induces the expression of markers of T lymphocyte activation, promoting T-mediated functions, acting both on the early and on the late phases of lymphocyte differentiation, essential for immune resilience[15].

Conclusion

As we are uncovering the mycelium and its vital role in plants, and its unique relationship with us and our world. It may be viewed through the lens of the human immune system which similarly intertwines itself around all tissue in our body, transferring resources where needed and is co-dependent on our environment and nutrient availability. Yet, its very complexity, means we are constantly learning about how to enhance our related resiliency. Interestingly many of our immune cells have receptors for mycelial by-products, and much is being learned of the role of mushrooms on immune health and mental health[16]. Suggesting that our very own survival and development was likely intimately linked to the oldest edible kingdom known to man, and that means there is much more yet to be discovered.

The role of nutrition in the management of the severity of COVID-19 and the recovery of surviving patients is currently under investigation; in particular, supplementation of vitamins C, D, and zinc to improve patient health, restore immune homeostasis and reduce the risk of infection for healthy individuals, and probiotics to improve gastrointestinal symptoms in COVID-19 patients[17]. Never before has so much attention been paid to the relationship between nutrition and immunity. Let’s hope it continues.

References

[1] Jack Feehan, Nicholas Tripodi, Vasso Apostolopoulos, The twilight of the immune system: The impact of immunosenescence in aging, Maturitas, Volume 147, 2021, Pages 7-13,

[2] Allen JC, Toapanta FR, Chen W, Tennant SM. Understanding immunosenescence and its impact on vaccination of older adults. Vaccine. 2020 Dec 14;38(52):8264-8272. doi: 10.1016/j.vaccine.2020.11.002. Epub 2020 Nov 21.

[3] Glenn Choon Lim Wong, PhD, Ted Kheng Siang Ng, PhD, Jia Le Lee, PhD, Pei Yi Lim, Sean Kai Jie Chua, Crystal Tan, BSc, Michelle Chua, Bsc, Janice Tan, BSc, Samantha Lee, BSc, Angelia Sia, MSc, Maxel K W Ng, MSc, Rathi Mahendran, MBBS, Ee Heok Kua, MD, Roger C M Ho, MBBS, MD, Anis Larbi, PhD, Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial, The Journals of Gerontology: Series A, Volume 76, Issue 2, February 2021, Pages 307–317

[4] Longo VD, Cortellino S. Fasting, dietary restriction, and immunosenescence. J Allergy Clin Immunol. 2020 Nov;146(5):1002-1004. doi: 10.1016/j.jaci.2020.07.035. Epub 2020 Aug 24. PMID: 32853639

[5] Pietrobon AJ, Teixeira FME, Sato MN. I mmunosenescence and Inflammaging: Risk Factors of Severe COVID-19 in Older People. Front Immunol. 2020 Oct 27;11:579220.

[6] Sharma R, Padwad Y. Nutraceuticals-Based Immunotherapeutic Concepts and Opportunities for the Mitigation of Cellular Senescence and Aging: A Narrative Review. Ageing Res Rev. 2020 Nov;63:101141.

[7]?Ghosh TS, Rampelli S, Jeffery IB, et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut 2020;69:1218-1228.

[8] Wu D, Lewis ED, Pae M, Meydani SN. Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance. Front Immunol. 2019 Jan 15;9:3160.

[9] DeJong EN, Surette MG, Bowdish DME. The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host Microbe. 2020;28:180–9

[10] GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–8

[11] Moger-Reischer RZ, Lennon JT. Microbial ageing and longevity. Nat Rev Microbiol. 2019;17:679–90.

[12] Arthur C. Ouwehand, Nynke Bergsma, Riikka Parhiala, Sampo Lahtinen, Miguel Gueimonde, Harriet Finne-Soveri, Timo Strandberg, Kaisu Pitk?l?, Seppo Salminen, Bifidobacterium microbiota and parameters of immune function in elderly subjects, FEMS Immunology & Medical Microbiology, Volume 53, Issue 1, June 2008, Pages 18–25

[13] Yuan J, Lu L, Zhang Z, Zhang S. Dietary intake of resveratrol enhances the adaptive immunity of aged rats. Rejuv Res. (2012) 15:507–15.

[14] Calder PC. The 2008 ESPEN Sir David Cuthbertson Lecture: fatty acids and inflammation–from the membrane to the nucleus and from the laboratory bench to the clinic. Clin Nutr. (2010) 29:5–12.

[15] Fraker PJ, King LE. Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr. (2004) 24:277–98.

[16] https://www.statnews.com/2020/01/07/transforming-psychedelics-into-mainstream-medicines/ accessed 9.8.2021

[17] Moscatelli F, Sessa F, Valenzano A, Polito R, Monda V, Cibelli G, et al. COVID-19: Role of Nutrition and Supplementation. Nutrients (2021)