Immune Aging & Therapeutic Targets

Senior couple in a restaurant with woman feeding her husband healthy food so they can increase their immune system and reduce aging.

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Aging is a natural process that is unique to each individual. The change in efficiency of the human immune system occurs in a non-monotonic manner with age.1 In infancy, the immune system is developing, and its function is dependent on maternal antibodies. As the innate and adaptive responses mature and as immune memory is accumulated, it grows stronger, but then it declines—sometimes rapidly—in the elderly.1 While some people will remain healthy into old age, others may experience alterations in the immune system (in both the innate and adaptive responses), and these changes can underlie many age-related diseases.2

Studies suggest that older, healthy individuals (60 years and above) may exhibit chronic, low-grade sterile inflammation characterized by high baseline serum concentrations of C-reactive protein (CRP) and cytokines, including interleukin-6 (IL-6) and IL-8. This “inflammaging”—a condition observed in aged individuals who experience chronic, low-grade inflammation, even in the absence of pathogens1—predicts earlier mortality.1,5 Inflammaging may arise as a result of multiple mechanisms, including the accumulation of misfolded proteins, compromised gut barrier function, and the deterioration of regulatory T-cell function.3

The impact of aging on the innate immune system remains insufficiently understood in the medical community; however, progress has been made in recent years.3 An overarching theme in the literature is a loss of function in adaptive immunity and a gain in nonspecific innate immunity, which may leave older individuals more susceptible to autoimmune diseases,4 cancer, and chronic tissue inflammation.3 While some people will remain healthy into old age, others may experience alterations in the immune system (in both the innate and adaptive responses), and these changes can underlie many age-related diseases.

COVID-19, Inflammation, and Older Adults

Inflammation in the presence of a pathogen in older adults is also under intense study, due to the emergence of COVID-19.6,7 The elderly tend to experience more inflammation in general than younger individuals, which may contribute to the greater morbidity and mortality among this group from COVID-19.8 2020 data shows that in the UK, over 90% of the COVID-19-related deaths have been in people over 60.9 This may be due, in part, to underlying conditions like diabetes and obesity, but some scientists suggest another driver of increased disease risk may be inflammation and the aging immune system.6 Scientists are beginning to understand how inflammation plays a part in the progression of this disease, as a hallmark of severe COVID-19 is inflammation.5

Researchers suspect that alteration of ACE2 receptor expression, oxidative stress, adipose tissue- and immune-senescent cell activity, and lack of vitamin D, as well as a decrease of autophagy and mitophagy, may contribute to high amplitude immune responses to external challengers in elderly adults.10 However, it is important to note that COVID-19 is not deadly in all elderly patients, in part because the aging process is dependent on several markers, including genes, lifestyle, and the individual variety of immune responses to challengers.10

Chronic, low-grade inflammation is associated with almost all conditions linked to older age, including type 2 diabetes, cardiovascular disease, cancer, and dementia.11 Low-grade inflammation also plays a leading role in certain autoimmune conditions that are more common in older adults, such as rheumatoid arthritis.11

Lifestyle Change: Embracing Exercise & Optimal Nutrition

A significant amount of evidence suggests that exercise has a profound effect on the functioning of the immune system.12,13 In 2018, researchers found that a high-intensity interval walking protocol in older adults with stable rheumatoid arthritis was followed by an improvement of oxidative burst and bacterial phagocytosis in neutrophils.14 It was also associated with reduced disease activity, improved cardiovascular fitness, and improved innate immune functions, which is indicative of reduced infection risk and inflammatory potential.14 Another recent study provides evidence to suggest that cytotoxic T cells become transiently reductive (stressed) in healthy individuals following a single bout of cycling.15 Overall, study results indicate that increasing physical activity enhances innate immune function, which is indicative of reduced infection risk and inflammatory potential.13 Further studies are needed to elucidate how a more active lifestyle may help to modulate the immune system for healthier aging.2

Taking a nutritional approach to improve immunity in older adults may include a focus on n-3 polyunsaturated fatty acids (PUFAs) and probiotics, among others.14 The dietary intake of PUFAs has been linked to decreased inflammation through their effects on leukocyte action, eicosanoid production, and T-cell proliferation.14 A combined exercise–n-3 PUFA intervention was recently shown to trigger local anti-inflammatory and growth responses. After six months of progressive resistance training combined with an n-3 PUFA-rich diet, gene expression of the proinflammatory cytokine IL-1? was downregulated and that of the regulator of cellular growth mechanistic target of rapamycin (mTOR) was upregulated in the skeletal muscle of older women.15,16

Strategies to combat metabolic inflammation associated with alterations in the gut microbiome may include time-restricted feeding, diets rich in fibers and restricted in carbohydrates, and the supplementation of probiotics.16 Probiotics have been found to modify the population of gut microflora and increase some aspects of mucosal and systemic immunity in healthy humans, such as altered cytokine production, increased natural killer cell cytotoxic activity, increased secretory immunoglobulin A (IgA) levels, and enhanced resistance to infections.16 Their effect on an aging immune system warrants further study.

Functional Medicine Considerations

Given that environmental factors, including diet and lifestyle, play an important role in shaping the gut microbiome, functional medicine provides the perfect opportunity to address dysbiosis and favorably impact the onset and progression of immune-related diseases. What other lifestyle changes can affect immune modulation? Learn more about the physiology and pathophysiology associated with immune dysregulation and their associations with systemic disease in IFM’s Immune Advanced Practice Module (APM). The Immune APM provides clinicians with an in-depth understanding of underlying immune mechanisms and effective interventions to support and balance immune function.


Related Articles

Innate Immunity: Diet and Lifestyle Support

The Role of the Microbiome in Immune-Related Diseases

Learn to Recognize and Reverse Immune Dysfunction


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  2. Fulop T, Larbi A, Hirokawa K, Cohen AA, Witkowski JM. Immunosenescence is both functional/adaptive and dysfunctional/maladaptive. Semin Immunopathol. 2020;42(5):521-536. doi:1007/s00281-020-00818-9
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  11.  Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822-1832. doi:1038/s41591-019-0675-0
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  15.  Wadley AJ, Holliday A, Morgan RG, et al. Preliminary evidence of reductive stress in human cytotoxic T cells following exercise. J Appl Physiol. 2018;125(2):586-595. doi:1152/japplphysiol.01137.2017
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