The Relationship Between Immunosenescence and Inflammaging

Immunosenescence is the age-related incapacity of the immune system, while inflammaging is the age-related overactivity of the immune system, overreacting to signals of damage in the body. Both are disruptive to tissue function, health, and odds of survival in later life. They are flip sides of the same coin, labels for emergent properties of the combined interactions of many forms of damage and dysfunction that accumulate with age. The decline of the immune system is clearly important in the onset and progression of many age-related conditions; more resources should be devoted to approaches capable of immune rejuvenation, such as thymic regrowth, restoration of hematopoietic stem cell populations, and the like.

The relationship between immunosenescence and inflammageing is complex, involving the interplay between innate and adaptive arms of the immune system, together with senescent cells from non-immune system lineages, in a potentially vicious cycle. Inflammageing promotes senescence and impedes adaptive immune responses, while this impairment may lead to a greater mobilisation of innate immune cells, thereby favouring inflammageing. With the ageing of the immune system, immunosurveillance becomes less efficient, leading to failure to remove senescent cells. These in turn contribute locally and systemically to inflammation. The evidence discussed above demonstrates an overall imbalance in inflammatory processes, tilting progressively towards increasing inflammation with age, with failure of anti-inflammatory molecules to counteract this. The important interconnections between inflammation, immunosenescence, frailty, and age-related disease have been highlighted further by the development of an accurate ageing clock (iAge) based on inflammatory signatures.

The need to improve immune health and resistance to infectious diseases in older adults has been brought into sharp focus by the COVID-19 pandemic. Herein, we have outlined several strategies to improve elderly immune function and decrease inflammation. Of these, spermidine treatment, mTOR inhibition, and the selective removal of senescent cells using senolytics are most strongly supported by model organism studies and human clinical trial data, with significant scope for immune benefit even against severe infections, such as that caused by SARS-CoV-2. It is possible that combinations of these therapies may be needed to address immunosenescence and inflammageing in the context of an ageing body burdened with accumulated senescent cells.

We recommend that clinical trials of drugs for age-related diseases routinely include analysis of inflammatory mediators in order to determine whether the treatment has the added benefit of ameliorating inflammageing. We conclude that it is essential to investigate a diverse set of inflammation-related molecules to properly analyse the development of chronic inflammation with ageing; new proteomics platforms that permit simultaneous measurement of thousands of factors from very small samples should greatly facilitate such analysis and enable personalised interventions to reduce inflammation and support healthy immune function even in old age.


Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.