The impact of ageing on monocytes and macrophages
Introduction
Ageing populations are becoming a global trend [1], however increasing lifespan is outstripping health-span. This results in people living longer with chronic health conditions adversely impacting on quality of life. Older adults are at increased risk of hospitalisation and death from primary infections such as influenza [2], reactivation of latent infections such as shingles caused by Varicella-Zoster virus (VZV) [3], and are often living with chronic inflammatory diseases such as type 2 diabetes and rheumatoid arthritis. Although four vaccinations (Influenza, tetanus-reduced diphtheria-acellular pertussis [TdaP], Pneumococcal, and Herpes Zoster) are recommended for older individuals (>65 years) in the UK, vaccine efficacy decreases significantly with age [[4], [5], [6]].
All these age-related changes suggest that there are alterations in immunity which result in poorer antigen-specific immune responses and worse vaccine efficacy. To date the majority of the research has focussed on the adaptive immune system which has been reviewed extensively [7,8]. Although T and B cell changes are important in ageing, there is clearly also a role for innate immune cells. In this review we discuss age-related inflammation and how monocytes and macrophages contribute to these inflammatory processes. We then focus on what defines monocytes and macrophages, then what changes occur in these cells with age, and how this underlies diseases commonly associated with ageing.
Ageing is arguably primarily characterised by the accumulation of cells which have undergone the process of permanent cell cycle arrest, termed senescence [9]. Senescence can occur in all cells in the body, meaning that all tissues can contain senescent cells. Structural stromal cells, such as fibroblasts, show high levels of senescence with age. In the immune system, senescence has been shown in multiple cell types including macrophages and T cells [[10], [11], [12]]. However there is evidence, certainly in T cells, that what has been defined as senescence can be reversed with the addition of p38 MAP kinase inhibitors, begging the question if this is proper senescence or indeed if senescence is not always a state of permanent cell cycle arrest [12]. Senescence occurs as a result of irreparable cellular insults, such as excessive DNA damage, telomere erosion, or oxidative stress [13]. Senescent stromal cells do not divide and are apoptosis resistant [14]. They can be characterized by the expression of the CDK inhibitors p16INK4A and/or p21, telomere associated γH2AX foci and/or β-galactosidase expression. However, there is no single definitive marker of senescence and this subject has been reviewed extensively previously [13].
Systemic increases in senescent cell populations are closely linked to age-related pathology and inflammageing, which is the chronic low-grade inflammation observed with age in humans [15]. Senescent cells themselves secrete a raft of inflammatory mediators, termed the senescence associated secretory phenotype (SASP) [16]. The SASP can drive paracrine senescence perpetuating an increasingly senescent and inflammatory tissue environment [17]. Importantly, while the SASP is a profound source of inflammatory mediators, it does not encompass all mediators that are increased with age.
Inflammageing is characterised by an increase in circulating inflammatory mediators such as C Reactive protein (CRP), Interleukin (IL)-6 and Tumour Necrosis Factor (TNF)α [18]. Although acute inflammation is important for clearance of infection or facilitating wound healing, it is becoming increasingly clear that chronic inflammation is detrimental to a functioning immune response and health of the individual. Indeed, older people who have elevated circulating IL-6, CRP, TNFα, IL-1β or inflammasome-related genes have higher chance of all-cause mortality [[19], [20], [21]]. Conversely, lower levels of inflammatory cytokines in the peripheral blood correlate with good health outcomes, longevity, and reduced risk of death of older adults [22]. Not all older people age similarly - one such example is frailty, which is the individual’s biological age rather than chronological, and is considered to be an excellent guide for establishing the health of the individual. Inflammation is a strong predictor for frailty, and those older individuals who are most frail have highest levels of circulating CRP, IL-6 and IL-8 [23]. In addition, excessive inflammation has been shown to reduce vaccine efficacy [24,25], antigen-specific immunity [26] and increased immunoregulatory mechanisms to combat the increased inflammation [27].
The source of the inflammatory cytokine production during ageing is believed to be multi-factorial. SASP is an obvious contributor to this, but additional mechanisms have been proposed. Geriatric mice have been shown to have increased gut permeability which results in bacterial lipopolysaccharide (LPS) leakage into the blood stream and activation of mononuclear phagocytes via binding to Toll-like receptor (TLR)4 [28,29]. Older adults exhibit increased visceral adiposity; visceral fat is an inflammatory site as infiltrating immune cells, including mononuclear phagocytes, secrete a raft of inflammatory mediators [30]. Additionally, aged mice have elevated damage-associated molecular patterns (DAMPs), suggesting that human ageing may also lead to increased DAMP production [31]. DAMPS bind to a range of pattern recognition receptors (PRRs) on innate cells leading to a cascade of inflammatory cytokine production. Finally, the most recent proposed mechanism for increased inflammation with age is a failure of inflammatory resolution in older adults. The onset of inflammation is a highly active process, involving multiple cell types and mediators. We now appreciate that switching off inflammation is an equally involved process with distinct signalling and effector pathways all of which impact downstream immune responses [32]. We recently showed that although the onset of inflammation is similar between old and young, the resolution of inflammation was defective in older people leading to a prolonged inflammatory response [33]. Mononuclear phagocytes, consisting of monocytes and macrophages, were unable to engulf apoptotic immune cells following an inflammatory insult. This resulted in an accumulation of apoptotic cells, cellular debris, and mononuclear phagocytes that did not switch to a pro-resolution phenotype. Ultimately this kind of mechanism, of failed resolution, might underlie chronic inflammation such as that seen in aged people [33].
When Franceschi and colleagues coined the term inflammageing in 2000 [15], they suggested the root of age-related chronic inflammation was chronic activation of the macrophage. Whilst more recent data suggests that macrophages are not the sole source of inflammageing, it is clear that monocytes and macrophages are the central component in initiating the phenomenon. Although the effect of ageing on monocyte and macrophages has been studied and will be discussed in detail in this review, there are clearly facets of ageing in this context that are poorly understood. The focus of this review is an overview of the current knowledge of the impact of ageing on monocytes and macrophages, and how these cells can contribute to the inflammageing. In addition, this review will highlight areas of monocyte and macrophage biology where more research is required.
Section snippets
Macrophage phenotype and function
Macrophages are tissue resident cells known for phagocytosis, their name being derived from Greek meaning “big eaters”, first coined by Eli Metchnikoff in the late 19th century. He observed this population of cells in starfish larvae which had been pierced by tiny thorns going on to show that macrophages and the process of phagocytosis formed the “essence” of inflammation [34]. However, even following Metchnikoff’s Nobel prize in 1908 [35], the macrophage had long been undervalued and
Monocytes
Here follows a discussion of what is known with regards to monocytes during ageing. Ageing results in a plethora of phenotypic and functional changes in monocyte populations. These will be discussed in turn and are summarised in Fig. 2.
Future perspectives
Although many studies have been performed to look at the effects of age on monocyte and macrophage function, there are still many unknowns within the field of ageing. Macrophage ontogeny experiments are carried out in young mouse models, so there is a lack of data on if the origin of macrophage populations changes as we reach advanced age. We do not know whether there is a change in the monocyte contribution to the macrophage pool with advanced age. Also we do not know how age influences
Funding
This work was funded by a Barts Charity Lectureship (MGU045 to ESC).
Declaration of Competing Interest
The authors declare that they have no competing interests related to this work.
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