Our immune system is shaped by its encounters throughout life, much like we are. Dr. Claudio Franceschi from the Italian National Research Centre on Aging at the University of Bologna coined the term “immunobiography” to describe the complexity of the immune system’s chronological exposure to different types of stimuli of varying doses and intensity. Additionally, our individual immunobiography is influenced by our biology, socioeconomic and psychological status, temporal and geographic location, nutrition, as well as the microbiota living within and on us.
WHAT HAPPENS TO THE IMMUNE SYSTEM OVER TIME?
How your immune system functions depends on your age. Newborns need to become accustomed to the world around them and learn what is and what is not pathogenic; at this time the immune system promotes tolerance. During childhood, the immune system focuses on establishing memory to encountered pathogens. In adulthood, the immune system largely maintains homeostasis and fends off the occasional pathogen until it begins to shift its focus once again. The immune system of middle-aged adults differs from their younger counterparts due to changes in cell senescence, the accumulation of memory cells, and differences in composition and homeostasis. Immune cells retain a record of previously encountered antigens and situations, and so over time, the immune system’s original naïveté transitions to an experienced memory-rich state with higher proportions of memory B- and T-cells, as well as experienced innate cells. Long-lived cells undergo senescence which affects their reactivity, and both long- and short-lived cells are influenced by the aged environment in which they reside. At the same time, an overall shift in immune homeostasis occurs. Dr. Franceschi describes this phenomenon as “inflammaging”, a low-grade inflammatory state common in old age that is associated with increased levels of pro-inflammatory cytokines due to a hyperactivated innate immune response, the pro-inflammatory effects of increased cell death with age, and increased pro-inflammatory cytokine secretion from senescent cells. Inflammaging has also been correlated with increased incidence of cardiovascular disease, and higher rates of mortality.
While the immune system of elderly adults (aged 70 and above) is still responsive and able to combat infections, a decline in these abilities is evident. For example, an older person’s immune system does not respond to vaccines in the same way as it once did. The diminished might of the aged immune system is also apparent in the much higher risk of complications or even fatality in the elderly population infected with pathogens like influenza, which is often easily cleared by a young person’s immune system. Additionally, since the immune system weakens with age, the clearing of cancerous cells in the elderly is also impaired. Consequently, with an aging population, it is of utmost importance to understand how our immune systems age. And yet, gaining insight into this complex process is quite difficult.
SNAPSHOTS OF AGING. HOW TO STUDY AGING OF THE HUMAN IMMUNE SYSTEM
Blood samples from elderly donors can only give us a glimpse of a small part of the immunological landscape. We can form only a limited picture of the immune cells circulating through the blood system at the time of sampling, as well as what immunological modulators happen to be present in circulation. Moreover, isolating cells from the body can select for the fittest cells and changes can occur in their state of activation not to mention the abundance of cells we miss that are snugly located in their respective organs and tissues.
Dr. Donna Farber’s group at Columbia University in New York City takes a more comprehensive approach when studying the human immune system. Instead of relying on blood samples, the group has gained access to tissue samples from organ donors of a variety of ages. While the information they collect lacks a truly longitudinal examination of the same individuals over time, it does give us indications as to how the immune system changes with time. Naïve T-lymphocyte production is highest at the beginning of life, decreasing very gradually with time until the age of 40 where it nearly instantaneously plummets. During this time, Dr. Farber’s group saw the launch of the already known phenomenon of thymus involution, i.e. the downsizing of the T-cell factory. However, they were still able to find high numbers of naïve T-cells in lymphoid and mucosal tissues. In their hands, these naïve T-cells still seemed to display a functional immune response and diversity their antigen response. Having said this, it is possible that this swift antigenic response may be aided by the existing experienced T-cells in a tissue specific manner to novel pathogen invasion.
MODELLING IMMUNE AGING
Due to the severe limitations and difficulties of studying human immunology in humans, many scientists turn to animal models, which are much more amenable to experimental manipulation, organ sampling, and longitudinal studies. Yet, many immunologists’ favourite animal model, the laboratory mouse, is raised in the typical specific-pathogen-free research environment with limited microbial exposures. As a result, lab mice have a significantly different immune system than their dirtier pet store counterparts. In particular, research mice exhibit a more immature immune profile than those found in the wild or even pet stores. Having said that, raising research mice protected from pathogenic insults, and from a plethora of additional stressors that can affect research results, is important for conducting well-controlled experiments. But how can we then study immune system aging knowing that the immune system is shaped by a lifetime of exposures? When we age clean mice in a nearly sterile environment, are we truly able to make inferences about the aged human immune system from them?
In an effort to move towards a model that allows for a better controlled study of the human immune system, a novel way to study human immune aging was proposed by Dr. David Harris at the University of Arizona. Dr. Harris established the first cord blood bank in the United States, and one of the ways these cells have been used is by introducing human cord-blood-derived hematopoietic stem cells into mice lacking an immune system of their own, thus Creating “humanized mice”. The reconstitution of a human immune system in mice is a powerful system for the study of human immune cells in a controlled system, including for the study of aging which is what Dr. Harris decided to pursue. The primary purpose of the study was to look at the long-term survival of these humanized mice, and thus establish whether they are useful for studying immune system aging. Indeed, Dr. Harris’s group found that 38% of the humanized mice survived beyond one year of age. They also found that the initially naïve T cells in these mice displayed a more memory-like phenotype with age, yet this was not further explored to establish definitive causality. Additional preliminary results suggested some similarity of immune cell aging in humanized mice with what we know about aging in humans.
Our immune system contains a wealth of information recorded over a lifetime. Scientists’ ability to understand and access this information is increasing, thus helping shed some powerful insights into the aging process. Nevertheless, intensive scrutiny and meticulous experimentation are required to adequately make interpretations which can then be applied to human health. With advancing technology, personalized approaches based on individual immune memoirs may soon play a leading role in treating aging-related immunodeficiency and disease.
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