Singapore Immunology Network (SIgN)
Agency for Science Technology and Research
According to United Nation estimates, approximately 1,000,000,000 human beings will be aged 60 years and older by 2020. The graying of the population will affect most countries; developing countries and all continents. This phenomenon reflects the progresses in medical care, hygiene conditions, wealth and biomedical discoveries over the past century. The increasing number of elderly individuals may not be a problem per se but societies should be better prepared for this demographic change. For instance, despite the progresses in medicine it has been recently shown that the increased life-span (Singapore data: 85 years for females and 80 for males in 2010) in the past decades was not associated with increased health-span. In males, the number of years spent with disability in 1990 was 8.8 while in 2010, males spent 10.7 years with disability. This is counter-intuitive as we often associate longevity with healthy aging. This clearly suggests that progress in medicine and research have not been focused enough in the identification of markers of healthy aging, causes for unsuccessful aging and ways to prevent it. In fact, approximately 70% of those aged 85 years or older require frequent and long hospitalizations. The problem is that with aging, the human being is more susceptible to diseases such as cancer, neurodegenerative, cardio-vascular, metabolic and infectious diseases. Ultimately, the growing number of elderly individuals with single/multiple co-morbidities is problematic for the elderly themselves (less autonomy, poor health, depression), for society (time/cost for parental care), the economy (low income/high cost population) and medical institutions (filling ward space, multiple conditions requiring intense care).
Many ways are being tested to prevent, slow and reverse aging and its associated diseases however we have to admit that the scientific and medical community is very far from the "fountain of youth". Nevertheless, one very effective way exists to prevent infections and their adverse effects in the elderly: vaccination. Influenza vaccination is a straightforward, minimally invasive and beneficial intervention to protect against flu disease and its complications, by inducing robust immune responses. Studies have shown that the flu vaccination campaigns was able to reduce the all-cause mortality of the elderly population during the Flu-peak season by 50%. Vaccination was able to protect the elderly from influenza itself but the main effect was avoiding or reducing the potential adverse effects of influenza infection. Elderly individuals experiencing the influenza infection have significantly higher susceptibility for hospitalization, which in turn is associated with increased risks for nosocomial infections and pneumonia. Overall, influenza infection is a risk factor associated with irreversible sequels.
Hypo-responsiveness to Vaccinations
As human beings age, their immune system becomes poorly functional, which explains why elderly individuals show hypo-responsiveness to vaccination with age. This is one direct consequence of the aging of the immune system. The loss of immune function with age, called immunosenescence, was identified decades ago following the observation of impairment in the antibody response. The changes in the antibody response with aging are both qualitative and quantitative (lower numbers and lower quality). The numbers of germinal centers as well as the number of progenitors responsible for antibody-producing B lymphocytes have been reported to decline in human tonsils. This may explain the age-related decreased number of circulating B lymphocytes. In a study on pneumococcal vaccination of elderly individuals, the frequency of IgM memory B lymphocytes were shown to decline. This correlates with lower anti-pneumococcal IgM levels in the elderly compared to younger individuals. The reduced antibody response with aging was attributed to defects in T lymphocyte regulation. T lymphocytes are central players of the immune response and are helping B lymphocytes to mount an efficient response to protect the host. In elderly individuals the number of naïve T lymphocytes produced by the thymus is highly reduced due to thymic involution. Moreover, the series of pathogens seen during life, especially persistent infections, are impacting on the immune compartment. Altogether this leads the number of T lymphocytes with a senescent profile to be elevated in aged individuals. While senescent T lymphocytes lose their capacity to proliferate they gain in the ability to secrete mediators of inflammation. This phenomenon is observed in various cell types during senescence and has been described as the Senescence-Associated Secretory Phenotype. Aging is associated with increased levels of pro-inflammatory molecules, named "Inflammaging", that affect many systems. Most elderly individuals display sub-clinical symptoms such as higher C-reactive protein, IL-6, or TNF-a. These three inflammatory markers are present individually or in combination in the majority of age-related conditions. The coexistence of a pro-inflammatory profile together with loss of immune function with aging may be explained by molecules such as cortisol which directly modulates metabolism, bone density, strength, exercise tolerance and cognitive function, ultimately driving pathophysiological conditions. Aging can also negatively affect the function of hematopoietic stem cells suggesting that altered stemness could be the starting point of aging and age-related conditions.
Research studies identified risk profiles associated with mortality in the elderly. Some of the profiles include immune status such as number of T (senescent) and B lymphocyte populations and seropositivity to chronic infections. Thus, immune senescence, inflammation and chronic infections are linked by their association with morbidity and mortality. However, the causes for poor response to vaccination and adverse effects of influenza vaccination are not limited to the erosion of the immune system and the above-mentioned biomarkers or risk profiles are not always specific. Indeed, aging is a complex phenomenon that should be studied with a holistic approach. Beside the immunological alterations observed, aging is associated with a loss of biological reserves in general. The cardio-vascular, respiratory, bone, muscle, hypothalamic-pituitary-adrenal axis, metabolic and cognitive functions show significant loss of reserve leading to poor resilience of the elderly population. One important condition in the elderly linked to loss of reserves is frailty, a geriatric syndrome associated with low functional capacities, exhaustion, poor resilience, altogether increasing the risk for adverse outcomes and death. The concept of frailty emerged as a clinically measurable syndrome, based on experiences of geriatricians. The term frailty may apply to different clinical settings but mainly describes a physical/functional decline, which may occur as a consequence of certain diseases, but also independently of specific disease. The overall consequences of this physiologic loss of reserves and resilience, which are not diseases per se, are higher risks for chronic diseases, disability and death. Although frailty assessment could be an elegant way to stratify the elderly population, there is currently little consensus in the literature concerning the biological parameters associated with and for determining frailty. Still, studies are emerging that demonstrate that a lower antibody titers against influenza in frail patients, which suggests that a better stratification of the elderly population should enable to identify populations at risk (validation studies are still required). There are many other ways to stratify the elderly population and adjust potential confounding factors in the analysis of vaccination data in a more systematic way, the "Systems Vaccinology". This includes gender, ethnicity, socio-economical status, history of chronic infections, co-morbidities, cognitive status, among others. Many immune-gerontological studies have been performed using the SENIEUR protocol which is able to clinically identify healthy elderly and reduce discrepancies in inclusion/exclusion criteria and selection processes. However, based on the inconsistency in the literature it is very likely that the SENIEUR protocol is not routinely used for all studies. Studied have shown that SENIEUR elderly responded to vaccination, while hypo-responsiveness was associated with circulatory diseases and cognition. To date, very few numbers of clinical trials are performing such stratifications and this may be a significant limit to the understanding of hypo-responsiveness to some vaccines. A comprehensive review of the immunological studies involving SENIEUR versus non-SENIEUR would be necessary to better evaluate the age-associated changes versus age-related conditions such as frailty.
Adaptation of Vaccines to Populations
As aging is accompanied with a progressive decline in functional capacities leading to loss of resilience and immune senescence, it is possible that both might play an important role in the reduced response to vaccination in the elderly. In this regard, adapting vaccines to the populations at risk could be of great importance. Reduced response to vaccinations in the elderly calls for more strategies to improve the effectiveness of vaccines in this growing population. Selected examples of strategies include i) the glucopyranosyl lipid adjuvant stable emulsion improves the antigen-presenting capacity and T cell immune response increased the production of pro-inflammatory cytokines when added to influenza split virus vaccine ii) the use of MF59 adjuvenated vaccine offers a broader range of protection for multiple strains iii) the change of delivery route, for instance from intramuscular to intradermal injection which has improved immunogenicity in elderly individuals. Many strategies such as caloric restriction, hormone therapy, cytokine therapy or stem cell approaches were shown to partially restore immunity in animal models, but may prove difficult to perform in humans due to lack of consensus. One typical example is iv) the potential benefit of caloric restriction in nonhuman primates versus the higher mortality of mice with dietary restriction during influenza infection due to lack of reserves v) reversing thymic involution might also be a significant strategy as animal models administrated with growth factors displayed increased thymic functions and suppression of senescence-associated genes such as Ink4a.
Limitations still exist in using animal models to compare a complex phenomenon such as aging. Moreover, a combination of several ways to improve vaccines may be necessary for the elderly population, especially the at-risk category, to fully respond to influenza vaccination. The stratification of the target population is becoming a necessity, especially in the case of elderly. Indeed, there is not one aging profile and the inter-individual differences of biological parameters observed in the young population significantly increase with aging and are affected by the series of events that happen in the course of life. These events may involve immunological challenges as well as other stressors. This leads to a wide heterogeneity of the aging population. Research of the Aging/Immunity Program at SIgN (A*STAR) is currently looking at this aspect.
About the Author
Dr. Anis Larbi completed his Ph.D in Immunology at the Faculty of Medicine of Sherbrooke University (Canada). His studies were performed at the Sherbrooke Research Center on Aging, a multidisciplinary Institute dedicated to aging research. After a post-doctoral at the University of Tubingen (Germany) where he studies the impact of persistent viral infections on the immune system he joined the Singapore Immunology Network (2010). Since then he has set up the Aging/Immunity Program. His research interest is human aging and the immune system. His laboratory is interested in the process of immune senescence and its clinical implications. Recently, his team launched the first clinical trial in Singapore to investigate the hypo-responsiveness to Flu vaccination in elderly individuals. His team is part of the Singapore Longitudinal Aging Study (SLAS) led by the Gerontological Research Program at NUS. Dr Larbi is an Adjunct Assistant Professor at NTU and NUS and a Scholar of the International Society for the Advancement of Cytometry.
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