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Immunosenescence research: the fight for healthy ageing

The January issue of the BSI’s official journal Clinical & Experimental Immunology is a special issue on immunosenescence, containing a fascinating set of review articles summarising our current knowledge in this area and what we still need to find out.  Here, BSI member Dr Natalie Riddell, Lecturer in Immunology, University of Surrey, discusses the key papers highlighted in this issue.

The key to successful ageing is to ‘die young as late as possible’ (adapted from Ashley Montagu), but only those who maintain a robust and regulated immune system in their later years are likely to achieve this. This month’s Clinical & Experimental Immunology is a special issue highlighting the current state of play in immunosenescence research.

Intrinsic & extrinsic factors that contribute towards immune senescence. From Masters et al. doi: 10.1111/cei.12851
Intrinsic & extrinsic factors that contribute towards immune senescence (12)

Immunosenescence describes the complex set of changes that occur in all components of the immune system, as well as the local environment, that result in loss of immune function as we age. It is a double-edged sword that is characterised by reduced immune protection to infections and cancers, along with concomitant increased inflammation and age related inflammatory disease. Demographic predictions for the UK suggest that more than 25% of the population will be over 65 years old by 2030, and most individuals are expected to live to at least 80 (Office for National Statistics, National Life Tables 2012–2014). Despite advances in medicine, many older adults currently still endure ill health for at least the last decade of life. Thus the aim of immunosenescence research is not to extend lifespan, but to extend healthy lifespan in the older population.

 

Feeling the effects of infections

A chief indicator that immune function is lost with ageing is the increased incidence and severity of some infections. One such infection is West Nile virus, which is an emerging virus that is asymptomatic in 80% of infections.1 However, the incident of severe infection is raised by 20% in the over 60s, as discussed by Montgomery in this CEI review. The rate and severity of illness to established infections such as influenza, varicella zoster virus (shingles), Streptococcus pneumonia and tetanus is also increased in the older population.2-4 Increased illnesses correlates with lower cell-mediated immunity and/or lower antibody responses to these infections in the elderly. Repeated vaccination throughout life may maintain immunity and limit gaps in immune protection.3   

 

Understanding the dynamics of age and vaccine effectiveness

Repeated vaccination, however, is not a straightforward solution. Vaccinating older individuals is problematic, as the effectiveness of most vaccines decrease with age, with maximal responses often as low as 30% in the over 70s.5 Nevertheless, vaccination programmes demonstrate the ability to reduce disease burden in the elderly as well as offering a tool to observe immune responses in vivo in humans.

Kim et al. suggest that moving away from empirical research to either systems analysis or hypothesis driven approaches may advance our vaccinology understanding.5 Interrogation of peripheral blood responses following vaccination, termed ‘systems vaccinology’, has led to the identification of immune signatures and pathways that are correlated to immune responses. Systems analysis can extend further than vaccinology in immunosenescence research and, indeed, the emerging and exciting field of ‘immunomics’ has vast potential for characterising age-associated alterations in immune function.

 

Of mice and men

Hypothesis driven approaches to vaccinology can utilise the knowledge gained from mechanistic mouse models and our molecular understanding of intrinsic defects to human cells.5 However, caution is required when extrapolating data from murine models, as there are substantial differences between immune ageing in mice and humans.6 Nevertheless, model systems and ex vivo analyses of molecular alterations in aged human cells have identified multiple changes in the vaccination response with age and the aged immune system in general. The most striking alterations occur within the adaptive immune compartment, and have been better characterised within T cells. They include reduced lymphocyte repertoire, increasing clonality and increasing autoreactivity.5,7,8 Recent work has focused on intrinsic cell defects, which alter T cell activation threshold, induction of cellular senescence and differentiation into short-lived effector or long-lived memory cells.

 

Converging pathways

Importantly, several of the review articles in this special issue demonstrate that nutrient sensing (AMPK), activation signalling (pERK, Akt/mTOR),  senescence signalling (p38) and inhibitory receptor signalling (KLRG1, PD-1) appear to converge and are actively maintained in senescent T cells and are not a passive response induced by cellular dysfunction.5,9,10 Thus, these signalling pathways are potential therapeutic targets to improve functional responses when desired, for example during vaccination or cancer therapy. Such approaches are yet to be tested in vivo and the potential to cause collateral damage by removing the brake on potent inflammatory cells must be considered. Nutrient availability (ATP/AMPK), cellular metabolism (mTORC) as well as local environmental cues (cytokine data from murine models) are also paramount to the lineage commitment of activated cells and alter the production of T regulatory, T effector and T memory response.5

 

Inflamm-ageing

It’s become increasingly apparent that innate immunity also changes with age and contributes to immunosenecence. This may be of particular importance in the ageing lung as pulmonary infections are the primary cause of morbidity and mortality in the elderly, as discussed by Boe et al.11 Innate cells appear to have reduced TLR signalling via MAPK and NFƙB resulting in reduced inflammatory cytokine production as well as altered chemotaxis responses, decreased phagocytosis and antigen presentation capacity. Evidence suggests that the resolution of infection and thus inflammation is prolonged due to reduced clearance of apoptotic cells and debris by macrophages.11 These age-associated alterations in innate immunity may contribute to increased systemic inflammation termed ‘inflamm-ageing’ observed in aged tissues.10

Innate immune functions of alveolar macrophages. From Boe et al. Clin Exp Immunol doi: 10.1111/cei.12881
Innate immune functions of alveolar macrophages.
From Boe et al. Clin Exp Immunol doi: 10.1111/cei.12881

 

The stromal microenvironment

Masters et al. discuss the often overlooked contribution of the stromal microenvironment as an extrinsic factor to immunosenescence and inflammation.12 Accumulation of senescent stromal cells which demonstrate the senescent associated secretory phenotype (SAPS), may alter tissue structure and function, and increase local inflammation.13 The impact of altered lymphoid stromal microenvironment may be widespread and include altered haematopoiesis, reduced lymphatic flow and disrupted secondary lymphoid organisation, which consequently will alter antigen transportation and presentation to T cells.12  

Altered stromal microenvironments in non-lymphoid organs may also impact immune function. For example, low grade inflammation in the tumour microenvironment can attract detrimental regulatory cells and neutrophils which can inhibit tumour immunity and promote tumorigenic factors.14

 

Similarities between ageing and other conditions

Lastly, increased systemic inflammation seen during ageing is also apparent in chronic infections such HIV or cytomegalovirus,10,15 obesity7 and individuals enduring chronic psychological stress.16 Similarly, the main features of immunosenescence are apparent in many of these conditions, including decreased antibody responses, increased infections, malignancies and also incidences of inflammatory associated disorders such as cardiovascular disease.7,10,15,16 Inflammation and premature immunosenescence are, therefore, prevalent features of many common conditions of modern life, such as obesity and stress, and could have negative health consequences for large proportions of society well before old age is reached. Thus potential preventative therapies as well as treatment or interventions aimed at reversing immunosenescence will have widespread implications for the improved health of old as well as some younger individuals. 

Natalie Riddell, Lecturer in Immunology, University of Surrey

 

Clinical & Experimental Immunology’s January 2017 special issue on immunosenescence can be downloaded from their website. All papers included in it are free to access.

 

References

  1.  Montgomery RR 2016 Age-related alterations in immune responses to West Nile virus infection. Clinical & Experimental Immunology doi:10.1111/cei.12863
  2.  Arnold N & Messaoudi I 2016 Herpes zoster and the search for an effective vaccine. Clinical & Experimental Immunology doi:10.1111/cei.12809
  3.  Weinberger B 2016 Adult vaccination against tetanus and diphtheria: the European perspective. Clinical & Experimental Immunology doi:10.1111/cei.12822
  4.  Fleming DM & Elliot AJ 2005 The impact of influenza on the health and health care utilisation of elderly people. Vaccine 23 Suppl 1, S1–9 doi:10.1016/j.vaccine.2005.04.018
  5.  Kim C et al. 2016 The life cycle of a T cell after vaccination – where does immune ageing strike? Clinical & Experimental Immunology doi:10.1111/cei.12829
  6.  Smithey MJ et al. 2015 Lost in translation: mice, men and cutaneous immunity in old age. Biogerontology 16 203–208 doi:10.1007/s10522-014-9517-0
  7.  Frasca D et al. 2016 Ageing and obesity similarly impair antibody responses. Clinical & Experimental Immunology doi:10.1111/cei.12824
  8.  Dunn-Walters DK 2016 The ageing human B cell repertoire: a failure of selection? Clinical & Experimental Immunology 183 50–56 doi:10.1111/cei.12700
  9.  Akbar AN 2016 The convergence of senescence and nutrient sensing during lymphocyte ageing. Clinical & Experimental Immunology doi:10.1111/cei.12876
  10.  Fulop T et al. 2016 Intracellular signalling pathways: targets to reverse immunosenescence. Clinical & Experimental Immunology doi:10.1111/cei.12836
  11.  Boe DM et al. 2016 Innate immune responses in the ageing lung. Clinical & Experimental Immunology doi:10.1111/cei.12881
  12.  Masters AR et al. 2016 Immune senescence: significance of the stromal microenvironment. Clinical & Experimental Immunology doi:10.1111/cei.12851
  13.  Tchkonia T et al. 2013 Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. Journal of Clinical Investigation 123 966–972 doi:10.1172/JCI64098
  14.  Hurez V et al. 2016 Considerations for successful cancer immunotherapy in aged hosts. Clinical & Experimental Immunology doi:10.1111/cei.12875
  15.  Nasi M et al. 2016 Ageing and inflammation in patients with HIV infection. Clinical & Experimental Immunology doi:10.1111/cei.12814
  16.  Bauer ME et al. 2015 Neuroendocrine and viral correlates of premature immunosenescence. Annals of the New York Academy of Sciences 1351 11–21 doi:10.1111/nyas.12786