Ageing and its association with immune decline

Introduction

Ageing is a profoundly complex and integral part of human life. As pharmaceutical developments have occurred, introducing new medicines and therapies such as biologics and antibiotics within the last 100 years, research has begun to look at malignancy at a more macro scale. To be clear, while it has become easier to combat infectious diseases in recent times, the combating of diseases tied to our genetic composition is far more complicated, whether it be autoimmune diseases or onset conditions such as cases of dementia. 

Ageing is one such case of a process that is hard to combat because the mechanisms that cause it are diverse and currently not fully understood. Strides have been made under a concept known as senescence, which continues to enlighten researchers and the anti-ageing pharmaceutical industry. This article provides a short summary of what immunosenescence is and how we can utilise our understanding to develop therapies for human immunity.

What is immunosenescence?

Immunosenescence is the change from a healthy, active immune cell phenotype to one that is no longer conventionally active and begins to secrete inflammatory chemical messengers known as the senescence-associated secretory phenotype (SASP) (Figure 1). A most important aspect of senescence is that a cell undergoes cell cycle arrest, meaning it cannot proliferate. You may now question why cells are programmed to senesce if the outcomes are detrimental to the host? 

It prevents the continued proliferation of old or damaged cells, including cells with uncontrolled proliferation (such as cancer cells). If we stop senescence altogether, we run the risk of accumulating damaged and/or mutated cells, increasing the chances of disease progression, such as through fibrosis and tumorigenesis, so specific targeting and dosage of drug interventions have to be considered. 

The immune system in particular, displays biological changes that are indicative of senescent progression. These include thymic involution (shrinking of the thymus associated with a decrease in T cell production), inflammaging (chronic inflammation associated with SASP), an increase in mitochondrial stress through metabolic changes, and an increase in differentiated memory T cells (EMRA T cells). Knowledge of these changes can give insight into potential mechanisms to target for therapeutics. 

Current and developing therapies for immunosenescence

Given our expanding understanding of senescence, as of the time of writing, there are no clinically approved drugs for senescence specifically. The development of therapies for diseases such as cancer, heart disease and diabetes (diabetic patients tend to exhibit increased levels of cellular senescence owing to “accelerated ageing”) have been implicated with suppressing senescence. 

These drugs would be mTOR inhibitors such as Rapamycin, statins, P13K inhibitors, as well as immune checkpoint inhibitors for T cells, such as anti CTLA-4 PD-L1 and PD-L2, and the anti-diabetic metformin, which have all shown in vitro to be effective against high levels of senescent cells. There was also the development of the recent first senolytic drugs dasatinib and quercetin in 2015 that kill senescent cells selectively against non-senescent cells and stand to provide a proof of concept for targeting disease through senescent mechanisms.

Conclusion

The field of senescence is certainly one to keep an eye on, with a bibliometric analysis in 2023 showing an increase every year in the number of published papers (Figure 2). It may be sooner rather than later that we see this become a trending topic of discussion for treating an array of disease states. Continuous research into specific immune cell subtypes (B, T and NK cells) and their relation to a decline in immunity in response to age can tell us more about potential therapeutic pathways or lifestyle choices that can improve the health of the immunocompromised elderly.

One such example of this is Treg-mediated increased glucose consumption in the tumour microenvironment leading to an increase in cell senescence in effector T cells, suggesting that high sugar diets can accelerate tumorigenesis. Our understanding of ageing through senescence will help reduce the mortality rates of elderly groups in decades to come through knowing that mechanisms such as the SASP and altered immune cell function, which can promote disease states.

Written by Yaseen Ahmad

Related articles: Genetics of ageing and longevity / Accelerated ageing

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