Like many other systems, the immune system faces challenges and deficits with aging. As humans age, they face progressive declines in the immune system that contribute to increased incidence of disease and an impaired ability to fight infections. Immune aging can be detrimental, resulting in overall increased disease burden and decreased resilience.
Certain hallmarks and outcomes of aging, such as cellular senescence, inflammation, and compromised autophagy are also closely linked to immune function. It is therefore important to preserve immune resilience and health as you get older in order to be better equipped when facing the prospect of disease.
Basic Immune Biology
The immune system protects your body from pathogens such as bacteria, viruses, fungi, and parasites. It is composed of multiple cell types and organs that help your body fight disease and stay healthy. When you’re healthy and everything in your immune system is running smoothly, you may not even notice it working. However, when the immune system is not functioning properly or you’re faced with a particularly aggressive pathogen, you can become ill.
Germs that your body has never been exposed to are more likely to make you sick and will activate the immune system. Without an immune system, your body would not have a way to fight harmful invaders or be able to recognize malignant changes that occur inside the body.
The immune system has a few primary tasks that enable it to keep you healthy and fight disease. The main function is to fight off foreign invaders. Another is to recognize and neutralize potentially harmful substances or toxins such as those from the environment or generated from bacteria. Less commonly known, the immune system is also important in recognizing and fighting disease-causing changes that develop in the body, such as cancer.
As we age, these essential functions of the immune system become impaired. Although there is no simple solution to reverse aging, steps can be taken to boost your immune system. This can lead to increased resilience and health when facing disease.
The Two Arms of Immunity
There are two main arms of immunity: the innate (non-specific) immune system and the adaptive (specific) immune system. These two systems work in conjunction via distinct mechanisms to fight disease after a pathogen triggers the immune system.
The first line of defense against germs such as bacteria and viruses is the innate immune system. This arm of the immune system is composed of cell types such as monocytes, phagocytes (macrophages and neutrophils), dendritic cells, natural killer cells, mast cells, basophils, eosinophils, and innate lymphoid cells. The innate immune system provides a general defense against harmful pathogens and has also been termed the non-specific immune system. It mainly fights germs using “eating cells” such as natural killer cells or phagocytes that are able to degrade invading cells through a process termed phagocytosis – using their plasma membrane to engulf the invader. The main goal of the innate immune system is to clear potentially dangerous invaders once they enter the body through avenues such as the digestive system, mucus membranes, skin, or respiratory system.
The adaptive immune system is developed as your body is exposed to different pathogens. This arm of the immune system is composed of white blood cells, or lymphocytes, that consist of T lymphocytes (CD4 and CD8 T cells) as well as B cells. After initially encountering a pathogen, B cells make antibodies and use them to specifically fight that pathogen if it is ever re-encountered. CD8 T cells can also help provide protection against secondary infections and have an important role in the killing of infected cells and protective immunity. The adaptive immune system is constantly learning and adapting as you encounter new pathogens over the course of your life. It can also help the body fight viruses or bacteria that change or mutate over time.
The immune system is activated by numerous triggers that the body does not recognize as its own, termed antigens. Some examples of antigens include proteins on the surface of viruses, bacteria, and fungi. The immune system is initially activated when these surface proteins bind to receptors on immune cells and then trigger different responses from the body. Once the immune system is exposed to a new disease, it will store information about the germ and how to fight it. Then, if the body later encounters the same germ again, it will be able to recognize it right away and fight it faster.
What Is Immune Aging?
As people age, they face declining immune resilience resulting in greater disease burden and worse health outcomes. Older adults are particularly susceptible to disease and face increased challenges when dealing with pathogens such as viruses or bacterial infections. As highlighted by the COVID-19 pandemic, older adults are an especially vulnerable population due to immune system declines (Shahid et al., 2020). Not only are older adults more vulnerable to acute disease such as viral infections, they also have increased incidence of chronic diseases (Franceschi and Campisi, 2014).
Immune aging is not driven by a singular factor. In fact, a variety of age related systemic and cellular changes contribute to aging. Different players, such as age-associated inflammation and immunosenescence, drive immune aging and are known to contribute to the changes observed in older adults.
Immunosenescence is defined as the changes to the immune system with age (Aw et al., 2007). Aging is associated with remodeling of the immune system and alterations to the organs and cells associated with immunity (Aw et al., 2007). These changes result in a progressive deterioration that impairs the body’s ability to fight infections, respond to vaccination, deal with malignancies, and also increases susceptibility to age-associated inflammation (Aiello et al., 2019).
Cellular characteristics of immunosenescence include decreased peripheral naive immune cells as well as an increased number of terminally differentiated memory cells (Aiello et al., 2019). This means that there are less cells able to respond to new diseases and more cells that have already seen a pathogen and are specific to that particular germ.
The cells within both the innate and adaptive immune system exhibit altered phenotypes – cellular characteristics – and function with age (Aiello et al., 2019; Ponnappan and Ponnappan, 2011). These cellular changes impact how the body is able to respond to and fight disease. There is also a systemic increase in inflammation that promotes some of the age-associated alterations in the immune system (Aiello et al., 2019).
Inflammation and Immune Aging
Inflammation is known to contribute to both general aging as well as immune aging. As people get older, they face increased levels of blood inflammatory markers. This systemic increase in inflammation, termed “inflammaging”, is known to contribute to the incidence of numerous chronic diseases such as cardiovascular disease, diabetes, frailty, chronic kidney disease, dementia, cancer, and others (Ferruci and Fabri, 2018).
Inflammaging has recently been suggested to be added as one of the hallmarks of aging (Lopez-Otin et al., 2013; Schmauck-Medina et al., 2022). Inflammaging has been linked to a variety of age-related conditions and is partially mediated by immune system dysfunction (Ferruci and Fabri, 2018). Dysregulated immune cells can produce and contribute to the increased blood levels of pro-inflammatory markers and immunogenic stimulators. Although the exact role of age-associated inflammation in aging is still under investigation, it is clear that inflammaging has a causal role in immune system and general health decline.
Cellular Senescence and Immune Aging
Cellular Senescence, a hallmark of aging, also contributes to immune dysfunction (Lopez-Otin et al., 2013). Senescent cells arise from normal cells and are defined as cells that are no longer able to proliferate, but are still metabolically active (Di Mico et al., 2021). Many people use the term “zombie cells” when describing senescent cells, as they serve no function and only cause additional damage to nearby healthy cells.
With aging, senescent cells accumulate in the body, are unable to be cleared, and contribute to age related dysfunction (Di Mico et al., 2021). Senescent cells secrete what’s termed a senescence-associated secretory phenotype (SASP) that causes inflammation (Di Mico et al., 2021). Senescent cells and their SASP contribute to general impairments with aging as well as immune system declines. Much of the inflammaging seen in older adults is driven by SASP from senescent cells.
Loss of Proteostasis: Compromised Autophagy and Immune Aging
An aspect of the hallmark of aging known as loss of proteostasis, compromised autophagy is a direct consequence of aging and is driven by immune system dysregulation (Schmauck-Medina et al., 2022). Autophagy is a natural process where the body’s cells clean out any damaged and unnecessary components. Impaired autophagy is observed in numerous aging associated conditions such as immunosenescence and is also suggested to be considered as a hallmark of aging (Schmauck-Medina et al., 2022).
Interestingly, activation of autophagy was shown to promote longevity in animal models (Fernández et al., 2018). In regards to immune function, restoring autophagy can improve immune responses to vaccination in older adults by overcoming immunosenescence (Alsaleh et al., 2020).
Immunosenescence and Cancer
Immunosenescence with aging is also a key player in cancer development (Lian et al., 2020). With age, there is increased cancer incidence as well as elevated morbidity and mortality rates from this disease (Lian et al., 2020). The immune system has various roles in cancer including immune surveillance and in antitumor responses. Dysregulated immune responses are also closely associated with the initiation and the progression of tumors (Lian et al., 2020). Overall, immune system dysfunction with aging can contribute to general health declines and increased incidence of diseases such as cancer.
Measuring Immune Aging
Similar to how NOVOS Age measures biological age via the epigenome, scientists are now investigating ways to track and measure immune age. Recently, Sayed and colleagues aimed to identify biological biomarkers and other metrics associated with immune aging (Sayed et al., 2021). Immune aging is complex and not uniform between individuals. The aim of this study was to identify predictors of biological aging by evaluating inflammatory markers of over 1,000 individuals of ages ranging from 8-96 years old (Sayed et al., 2021). With information from these individuals, the group developed an inflammatory clock aging (iAGE). This clock is able to identify biomarkers, independent of chronological age, that directly correlate with general health and frailty.
Inflammation is known to be increased with progressive age (Ferrucci and Fabbri, 2018). The authors in this study identified circulating inflammatory cytokines, particularly the chemokine CXCL9, that correlated with health decline in aging (Sayed et al., 2021). Cytokines are a group of pro- or anti-inflammatory signaling molecules that are mainly secreted from immune cells. Chemokines are a subset of secreted proteins within the cytokine family whose usual function is to induce cell migration.
The findings in this study offer insight into tracking and measuring biological health with aging as well as a better understanding of how health and biological resilience are different from chronological age. The ability to measure your health and immune resilience independent of chronological age could be invaluable when making health choices.
How to Preserve Immune Health With Age
Even with tools to track and measure biological age, it is important to take steps to improve immune health and resilience with aging. There are scientifically proven steps that you can take to stay healthier and enhance your immune system over time.
The benefits of exercise for healthy aging have been extensively studied and are well known. Regular exercise in older adults can reduce risk of all-cause mortality, chronic disease, and premature death (Fleg, 2012; Mora and Valencia, 2018).
Lesser known is the fact that exercise is also important for immune health during aging. Consistent exercise has been associated with enhanced vaccination response, decreased levels of inflammation and inflammatory cytokines, decreased numbers of exhausted T cells, increased T cell proliferative capacity, increased neutrophil phagocytic capacity, longer leukocyte telomere lengths, and other immune benefits (Simpson et al., 2012). All of these positive changes indicate that regular exercise is important in regulating immune responses and preserving immune health with aging.
Along with exercise, diet has profound effects on the aging immune system (Weyh et al., 2020). There has been great interest in using dietary strategies in older adults to improve immunity. The elderly are more likely to have poor nutritional status, further impacting already impaired immune function (Weyh et al., 2020).
Although it’s unlikely that a single food will have immense effects on the immune system, an overall balanced and healthy diet is important for proper function of all cells. Diets that are lower in nutrients, such as ultra-processed foods can negatively impact the immune system. Additionally, traditional western diets that are high in refined sugar, starches, and meat and low in fruits and vegetables can result in inflammation, suppressed immunity, and disturbances in gut microbiota (Molendijk et al., 2019).
The microbiome, composed of numerous and varied microbes in our digestive system and body, interacts directly with the immune system (Belkaid and Hand, 2014). Therefore, eating prebiotic and probiotic foods can support a healthy microbiome and therefore immune system. Examples of probiotic foods include kefir, yogurt, tempeh, kombucha, kimchi, sauerkraut, and miso. Examples of prebiotic foods include garlic, onions, leeks, asparagus, bananas, and seaweed. In general, a diet including a variety of fruits, vegetables, beans, and whole grains is a good way to get a sufficient and diverse spectrum of dietary prebiotics.
Deficiencies in single nutrients can alter immune responses in the body. Studies have found that improper amounts of zinc, selenium, iron, copper, folic acid, and vitamins A, B6, C, D, and E can all impair immune responses (Chandra, 1997). These vitamins and minerals support the immune system through different mechanisms. They work as antioxidants to protect against reactive oxygen species and support the growth and function of immune cells.
Studies have also demonstrated that supplementation with vitamins such as vitamin C and D can be beneficial when facing viral challenges (Hemilä and Louhiala, 2013; Martineau et al., 2017). Overall, making sure that you are properly nourished and eating a balanced diet is a good way to support immune health.
The immune system plays an important role in fighting and clearing diseases. It helps protect your body against germs such as viruses or bacteria as well as generates immunity against pathogens that you previously encountered. As you are repeatedly exposed to new and emerging pathogens, your immune system must adapt and defend against a variety of diseases over the course of your lifetime.
Unfortunately, the immune system faces a decline with aging, leaving older adults more susceptible to infection and illness. This decline is mainly caused by a progressive deterioration in immune function, termed immunosenescence. Additional immune system dysfunction is driven by many of the hallmarks of aging such as inflammation, compromised autophagy, cellular senescence and others. Therefore, it is important to take steps to preserve immune health with aging in order to reduce disease risk and increase resilience.
Dominique Martin is a dual Biomedical Science PhD and MBA candidate at the University of Connecticut. Her current research at the UConn Center on Aging and Department of Immunology focuses on finding interventions to improve and rejuvenate the aging immune system. She has published research in journals such as Frontiers in Immunology, Immunity and Aging, Cell Metabolism, and Geroscience. Dominique Martin is a scientific professional with research experience in immunology, the biology of aging, animal science, and behavioral neuroscience. Dominique also holds a BS and MS in Animal Science from the University of Connecticut.
The Immune System and Immune Health
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