Interconnections between Inflammageing and Immunosenescence during Ageing

Abstract

Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, or the dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults, including centenarians, is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing-it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity, and mortality risk. While inflammageing was initially thought to be caused by "continuous antigenic load and stress", reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and the ageing of the immune system. In this review, we explore some of the main sources and consequences of inflammageing in the context of immunosenescence and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise, and pharmacological interventions can reduce inflammageing and thus, improve later life health.

Keywords: SASP; ageing; cytokines; immunosenescence; immunosurveillance; inflammageing; inflammation; senescence.

Figure 1

Cell senescence plays a central role in inflammageing. Cell senescence is promoted by a variety of stressors including age-related telomere attrition, DNA damage, oxidative stress, proteostatic stress, and oncogene activation. Senescence of immune cells can lead to immune failure, while age-related decreased immunity results in the poor immunological clearance of senescent cells. Obesity is associated with a pro-inflammatory state that can drive senescence, with senescent cells detected in adipose tissue; it also predisposes sufferers to diabetes, wherein altered blood sugar control may trigger senescence through glycation and metabolic stress. Inflammation is a primary response to infection, but some inflammatory signals (e.g., IL-6) can promote cell senescence. Moreover, certain viral and bacterial infections can also drive senescence. The pro-inflammatory secretome produced by senescent cells is associated with age-related diseases. Hence, senescent cells lie at the heart of a multi-faceted vicious circle leading to increased inflammation, age-related diseases, and ultimately, death.

Figure 2

Pro-inflammatory signature of inflammageing. Orange oval shows factors most strongly associated with age-associated inflammation. Some cytokines usually considered pro-inflammatory can have anti-inflammatory activities, e.g., IL-6 produced as a cytokine through NFKB signalling pathways is pro-inflammatory, while IL-6 produced as a myokine following exercise is anti-inflammatory. Some factors may be anti-inflammatory in children and young adults but pro-inflammatory in later life; biological sex is also important in determining whether the factors act in a pro- or anti-inflammatory manner (see text for details). Hence, factors that overlap between pro- (orange) and anti-inflammatory activity (green) may be informative for the inflammatory signature.

Figure 3

Epithelial barriers and innate and adaptive immunity constitute three major components of the immune system. Epithelial and endothelial barriers form an essential but often overlooked first line of defence in immunity. The senescence of epithelial and endothelial cells forming such barriers can lead to decreased protection (e.g., through diminished mucous secretions or ciliary activity), ‘leakiness’ through the loss of tight junctions and altered properties, including excess inflammation and tissue damage through the SASP. The second pillar of immunity, the innate immune response, is rapid-onset and, though fairly non-specific, can often be sufficient to prevent pathogens from causing disease, though senescence can lead to non-resolving inflammation. The final pillar of the adaptive immune system involves a slower-onset but highly specific response to infection; however, the senescence of these cells greatly reduces overall immune responses and may contribute to inflammageing (see text for further details).

Figure 4

Cross-talk between cells of the innate and adaptive immune systems. Innate cells are labelled in red, with adaptive in green. Both innate and adaptive arms arise from haematopoietic stem cells (HSCs) in the bone marrow. The first line of defence is provided by the rapidly-acting PAMP/DAMP-sensing innate system, with innate cells presenting antigens to adaptive cells; this stimulates rapid proliferation of adaptive cells bearing receptors cognate for the antigen. T cells are ‘educated’ in the thymus to eliminate cells that recognise ‘self’, so that the immune system is self-tolerant. Breakage of this tolerance leads to autoimmunity, wherein the immune system attacks specific molecules or cells of the body as if they were infectious pathogens. Notably autoimmunity rises significantly with increasing age.

Figure 5

Inflammageing arises from increased cell senescence across many tissues, as well as age-related changes to the bone marrow niche and individual innate and adaptive immune cells. Together this leads to inappropriately high levels of sterile inflammation, with a number of secreted factors that may serve as a signature of inflammageing.