Can We Prevent Immune System Aging?
Could we eventually turn back time on our failing immune systems?
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The world’s population is aging rapidly – by 2050, 17% of people will be over 65, an estimated increase of almost ~100% from 2019.
While this will have significant effects on multiple sectors of society, one of the most concerning impacts is the huge increase in demand for healthcare. As people age, their susceptibility to infection increases – as does the likelihood of poorer outcomes to infection.
The idea of “healthy aging” – the ability to retain as much physical, mental and social ability as possible into old age – is therefore set to become a huge focus in aging research.
“If you look at recent aging report published by the House of Lords, there is a big gap between how long we are living and our actual health span,” says Dr. Niharika A Duggal, assistant professor in Immunity and Aging at the University of Birmingham, and trustee for the British Society of Research in Aging (BSRA). “The UK government is aiming to add an extra 5 years of good health within the average lifespan by 2035, but one of the key challenges obstructing this goal is immune aging and the increased risk of infections in those aged 75 and older.”
However, extensive research efforts are underway, investigating both pharmacological and non-pharmacological interventions that could reverse – or at least slow down – immune system aging. Could we eventually turn back time on our failing immune systems?
Hallmarks of immunosenescence
As the body ages, so too does the immune system. This immune aging results in a remodeling of the immune system and a reduced ability to mount a robust immune response, known as immunosenescence.
Symptoms of immunosenescence include degradation of immune organs and a loss of new lymphocytes, coupled with a chronic proinflammatory state known as “inflammaging”. Together, these lead to the onset of age-related diseases, poor vaccination outcomes and increased susceptibility to infectious disease and malignancies.
The effects of immunosenescence vary across both the innate and adaptive immune system, resulting in almost every component of the immune system displaying dysregulation of some form.
Dysregulation begins with stem cells in the bone marrow, with reduced production of adaptive immune cells, but increased production of innate immune cells. Although this means that the numbers of most innate cells remain stable during aging, their ability to function normally can be significantly impacted. For example, aged neutrophils exhibit a reduced ability to migrate towards the site of infection, coupled with impaired pathogen killing.
One particularly affected immune cell type is T cells. In addition to the reduction in overall numbers of new T cells produced by the bone marrow, changes in the thymus interfere with T cell maturation, as this is the organ where T cells complete their development and become fully functional. “As you age, the thymus involutes, meaning it shrinks,” says Dr. Leen Slaets, assistant professor at Hasselt University, whose research focuses on protective interventions against immune aging. “In addition, the specialized thymic epithelium is replaced with adipose (fat) tissue, so the final steps of T cell maturation will not occur as efficiently as in younger people.” This loss of new T cells means it’s much harder to fight off infections with new pathogens, which was nowhere more obvious than during the COVID-19 pandemic, when age was shown to be a significant risk factor for mortality.
However, it isn’t just new immune cells that are affected by immune aging. In older adults, memory cells – i.e., cells that have already encountered a pathogen and can mount a faster, stronger response on a repeat encounter with the same pathogen – become the dominant T cell population, but these cells also show signs of immunosenescence. “When T cells become senescent, they start to lose expression of co-stimulatory receptors, that help them recognise pathogens,” explains Slaets. “They also become more inflammatory – for example, T helper cells start to produce the kind of cytotoxic molecules that are normally only produced by killer T cells.”
What drives immune aging?
This shift towards a pro-inflammatory profile is echoed across the immune system. Senescent (aging) cells occur in all areas of the body and are characterized by DNA damage and morphological, phenotypic and functional changes. They can become highly pro-inflammatory, contributing to an overall increase in base-level inflammation – a state known as inflammaging.
Inflammaging not only alters the normal functions of the immune system, but can also increase the risk of chronic inflammatory and autoimmune diseases.
One facet of Duggal’s research looks at the role of immunosenescence in the age-associated onset of chronic inflammatory diseases, such as rheumatoid arthritis (RA), and the drivers behind this increase in inflammation. “As we age, we begin to see a state of dysbiosis in the microbiome, which contributes to an increase in the permeability of the intestinal barrier, and transfer of microbial products into circulation,” she explains. “A 2017 study recognized dysbiosis as a causal factor in inflammaging. The hypothesis is that microbial products might induce this pro-inflammatory state due to chronic antigen stimulation, and their ability to skew T cells towards more pro-inflammatory subsets.”
Immunosenescence can also drive aging in other organs and cell types. Studies in mice have shown that inducing targeted immunosenescence in young, otherwise healthy animals by deleting a DNA repair gene resulted in accelerated aging in other organs, including the liver and kidneys. These results demonstrated that the immune system plays a role in systemic aging, and suggest that improving immune function could contribute to improving health and wellbeing in older adults.
Slowing the clock: The effects of lifestyle
So, what can be done to mitigate immunosenescence, and boost the function of aging immune cells? According to research by both Duggal and Slaets, the answer may be simpler than first thought: diet and exercise.
“Adipose tissue is a big source of inflammaging and pro-inflammatory, senescent cells, and it also contributes to thymic involution,” says Duggal. “So, reducing adipose tissue is linked to maintaining a healthy immune system.”
Duggal’s research group recently published a study that revealed older adults who adhered to a Mediterranean diet had fewer features of immunosenescence, such as accumulation of senescent T cells. “We think that the mechanism for this link lies in the microbiome,” she explains. “We’ve done a study in mice that shows that preventing transfer of microbial products from the gut into the blood stream also prevents build-up of adipose tissue and aging cells in the thymus. This means that we can possibly preserve the functions of the thymus and proper T cell development.”
Her group is now looking at similar trends in humans. “We can broadly classify our older adults into those that show dysbiosis and high levels of gut leakage (i.e., transfer of microbial products across the intestinal barrier), and those that show low levels, and we’re seeing more evidence of immune aging in those with high gut leakage,” she says.
The protective effects of exercise against age-related diseases have long been established, however, exercise has also been shown to have direct ani-inflammatory and immunomodulatory impacts. “In cross-sectional studies, older adults who exercise regularly have lower numbers of senescent T cells and more new T cells that are still able to replicate well, compared to sedentary individuals,” says Slaets. Indeed, a study published by Duggal in 2018 showed that older adults who were avid cyclists exhibited higher levels of naïve T cells, immunoprotective elements and regulatory immune cells than their age-matched sedentary counterparts.
However, the molecular mechanisms are still unclear. “In general, regular periods of moderate exercise, whether aerobic exercise or resistance training, are associated with reductions in inflammatory markers,” Slaets goes on to explain. “We hypothesize that the metabolites produced by the muscles help reduce immunosenescence; for example, skeletal muscle is a major source of the amino acid glutamine, which has been shown to improve T cell proliferation.”
Another theory suggests that exercise flushes immune cells – particularly T cells – from lymphoid tissue into circulation, increasing their opportunities to attack and eliminate pathogens and malignant cells, while also increasing the turnover of senescent cells. Dr Slaets’ lab is currently investigating the effects of biological sex on T-cell senescence during exercise intervention.
Boosting immune function: Pharmaceutical interventions
As simple as these interventions sound, diet and exercise changes are not possible for everyone, and in some contexts – such as vaccination – the aging immune system may still need a pharmaceutical helping hand.
Dr. Jenna Bartley is an assistant professor at the Center of Aging, University of Connecticut, where her research focuses on boosting immune responses to vaccination in older adults. “When a younger person is vaccinated, we usually see a classical, textbook adaptive immune response,” she says. “But older adults have a reduced adaptive response, which means lower levels and a shorter duration of vaccine protection.”
Bartley’s research aims to improve vaccine responses in older adults, using specific pre-vaccination interventions. “A huge advantage for implementation would be to not need to reformulate vaccines, but rather give an intervention to an older adult prior to vaccination that would then induce a stronger, more youthful immune response.”
Metformin is one such potential intervention. Metformin is the first line medication for type 2 diabetes. However, the drug also targets many of the hallmarks of aging, including reducing metabolic dysregulation in immune cells, inflammation and immunosenescence.
“We showed that pre-treating older adults with metformin before influenza vaccination improves T helper cell responses,” she explains.
Although this was only a pilot study, metformin has also been shown to significantly reduce the risk of hospitalization and mortality in COVID-19 and influenza infections in older and otherwise vulnerable populations.
Another potential intervention is a class of drugs called senolytics, which target and kill senescent cells. Senescent cells express the senescence-associated secretory phenotype (SASP), characterized by the release of high levels of cytokines, chemokines and proteases. While this is beneficial in some roles, such as wound healing, if they are not cleared (i.e. due to immune aging), SASP components can contribute to immunosenescence and poor immune responses.
“The SASP contributes to the environment in the body being very pro-inflammatory and not conducive to a good immune response,” says Bartley. “I’m currently investigating whether eliminating these senescent cells prior to vaccination can improve vaccine response by reducing that pro-inflammatory, aged environment.”
Rather than directly targeting immune cells, Bartley’s research targets aging physiology as a whole. “The pillars that drive aging are things like cellular senescence, epigenetic alterations, deregulated nutrient sensing and altered intracellular communication,” she says. “My kind of research, called geroscience, looks at targeting those pillars with different interventions to try to delay aging physiology to improve immune function and overall health span.”
What does the future of aging hold?
Maintaining quality of life and independence are key concerns for healthy aging. Although there are contributing factors, such as genetics, limiting immunosenescence may be able to postpone the onset of age-related disease and improve recovery and outcomes from infectious diseases, increasing the health span of older adults.
“I think we have a lot of promising interventions coming up,” says Bartley. “But, I think that the best responses are going to be combinations of different things – optimizing exercise and nutrition, then considering pharmaceutical intervention – and it’s going to take a lot of research to figure out that personalized medicine approach.”
While pharmacological, specifically personalized support for immunosenescence may not be ready for clinical use just yet, all three researchers stressed that there is an easy, already available method to help delay immune aging: regular exercise!
