Immunosenescence — Weaker Immune System of the Elderly Explained

Figure 1.  Diversity and clonal selection in the human T-cell receptor repertoire^[1] 

Key Points

1. T-Cell Receptor Diversity:

• As we age, T-cell receptor diversity declines due to shrinking thymus function.
• Thymus involution (thymus shrinkage) leads to fewer new T cells.

2. Immunosenescence:

• Immunosenescence refers to the age-related weakening of the immune system.
• It includes:
• Accumulation of dysfunctional memory T cells.
• Shortened telomeres (reduced cell lifespan).
• Impaired immune regulation.

3. Overall Changes:

• Aging results in:
• Weaker immune responses to new infections and vaccines.
• A shift toward inflammation.
• Increased susceptibility to autoimmune diseases, cancers, infections, and other age-related conditions.

4. Potential Solutions:

• Biomarkers (like CXCL9) can help identify individuals at risk for immunosenescence.
• Dietary interventions (such as prolonged fasting cycles) may alleviate immunosenescence.

5. COVID-19 and Aging:

• Older individuals are more vulnerable due to:
• Reduced T cell diversity and function.
• T cell senescence (contributing to ineffective immune response and inflammation).
• Lymphopenia (decreased lymphocyte count).

Understanding the aging-immune system connection is crucial for promoting healthy aging and addressing vulnerabilities.

TCR Diversity

T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens (vs. self antigens), is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells (see Figure 1).

Immunosenescence

Immunosenescence is linked to:

• Functional decline associated with the passage of time 
• Antigen burden to which an individual has been exposed during lifetime

Some immunological parameters are commonly notably reduced in aged people. The principal immunosenescence hallmarks are represented by:^[2-5]

• Thymic involution
• The shrinking (involution) of the thymus with age
• T-cells are named for the thymus where T-lymphocytes migrate from the bone marrow to mature.
• Effects of the involution:
• Decreased new T cell generation and hematopoietic stem cell dysfunctions, decreased naïve and increased memory lymphocytes with accumulation of dysfunctional senescent cells with shortened telomeres.
• Defects in apoptotic cell death, mitochondrial function and stress responses
• Malfunctioning of immune regulatory cells

Loss of thymic function and T-cell receptor (TCR) diversity is thought to contribute to weaker immunosurveillance of the elderly, including increasing instances of diseases such as cancers, autoimmunity, and opportunistic infections. 

Senescent Immune System

A senescent immune system is characterized by continuous reshaping and shrinkage of the immune repertoire by persistent antigenic challenges. 

These changes lead to:

• A poor response to newly encountered microbial antigens, including vaccines
• A shift of the immune system towards an inflammatory, autoimmune, Th2 profile. 

This immune dysregulation provides the background for an increased susceptibility to 

• Autoimmune diseases
• Cancer
• Metabolic diseases
• Osteoporosis
• Neurological disorders
• Allergic inflammation 
• Infection

Accordingly, the severity of many infections is higher in the elderly compared to younger adults and infectious diseases are frequently associated with long-term complications and frailty.^[6–10] Reciprocally, an immune good function is tightly correlated to health status, as depicted in centenarian offspring.^{[11, 12]}

Biomarker for Immunosenescence

In Stanford's study on inflammatory clock (i.e., iAge), they have found a robust marker—chemokine CXCL9:

Which was involved in cardiac aging, affected vascular function, and down-regulated Sirtuin-3, a longevity-associated molecule.

for chronic inflammation that could be potentially used to identify individuals with a decline in immunological function (immunosenescence), as well as those at risk for chronic disease and premature cardiovascular aging.

Can Prolonged Fasting Cycles Reverse Immunosenescence?

In one study,^[17] it indicates that cycles of an extreme dietary intervention represent a powerful mean to modulate key regulators of cellular protection and tissue regeneration but also provide a potential therapy to reverse or alleviate the immunosuppression or immunosenescence caused by chemotherapy treatment and aging, respectively, and possibly by a variety of diseases affecting the hematopoietic and immune systems and other systems and organs.

Roles of Aging Played in the Severity of COVID-19

Advanced age is a common co-morbidity for severity of disease during respiratory viral infections, and disease severity may be associated with altered T cell responses.^[13,14]

In summary, ageing can:^[15]

• Lag behind children in pre-activated antiviral innate immunity in the upper airways^[19]
• Affect T cell repertoire diversity
• For both CD4+ T cells and for CD8+ T cells.
• This age-related reduction in T cell clonal diversity is associated with impaired responses to viral infections such as influenza.
• Be associated with T cell senescence
• Advanced age can also be associated with T cell senescence, which perhaps contributes to ineffective responses to infections.
• Senescent T cells may also paradoxically be pro-inflammatory and therefore perhaps contribute to immunopathology.
• Be associated with lymphopenia
• Older patients experience more severe lymphopenia during COVID-19, although it is not clear whether ageing-associated lymphopenia is causal to disease severity or vice versa.

References

1. Diversity and clonal selection in the human T-cell repertoire 
2. Immune-inflammatory responses in the elderly: an update
3. Wistuba-Hamprecht K, Haehnel K, Janssen N, Demuth I, Pawelec G. Peripheral blood T-cell signatures from high-resolution immune phenotyping of γδ and αβ T-cells in younger and older subjects in the berlin aging study II. Immun Ageing. 2015;12:25. 6. 
4. Caruso C, Accardi G, Virruso C, Candore G. Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? Immun Ageing. 2013;10:20. 7. 
5. Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing. 2012;9:15.
6.  Caruso C, Vasto S. Immunity and aging. In: Ratcliffe MJH, editor. Encyclopedia of Immunobiology, Vol. 5, pp. Oxford: Academic Press; 2016. p. 127–32.
7. Wistuba-Hamprecht K, Haehnel K, Janssen N, Demuth I, Pawelec G. Peripheral blood T-cell signatures from high-resolution immune phenotyping of γδ and αβ T-cells in younger and older subjects in the berlin aging study II. Immun Ageing. 2015;12:25. 
8. Caruso C, Accardi G, Virruso C, Candore G. Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? Immun Ageing. 2013;10:20. 
9. Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing. 2012;9:15. 
10. Caruso C, Candore G, Cigna D, DiLorenzo G, Sireci G, Dieli F, Salerno A. Cytokine production pathway in the elderly. Immunol Res. 1996;15:84–90
11.  Bucci L, Ostan R, Cevenini E, Pini E, Scurti M, Vitale G, Mari D, Caruso C, Sansoni P, Fanelli F, Pasquali R, Gueresi P, Franceschi C, Monti D. Centenarians’ offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview. Aging (Albany NY). 2016;8:510–9. 
12. Pellicanò M, Buffa S, Goldeck D, Bulati M, Martorana A, Caruso C, ColonnaRomano G, Pawelec G. Evidence for less marked potential signs of T-cell immunosenescence in centenarian offspring than in the general agematched population. J Gerontol A Biol Sci Med Sci. 2014 May;69(5):495–504.
13. Lee, N., Shin, M. S. & Kang, I. T-cell biology in aging, with a focus on lung disease. J. Gerontol. A Biol. Sci. Med. Sci. 67, 254–263 (2012).
14. Goronzy, J. J. & Weyand, C. M. Successful and maladaptive T cell aging. Immunity 46, 364–378 (2017).
15. T cell responses in patients with COVID-19
16. An Inflammatory Clock Predicts Multi-morbidity, Immunosenescence and Cardiovascular Aging in Humans
17. Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression
18. Can Intermittent Fasting Reset Your Immune System?
19. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children