Biogerontology (2018) 19:481–496 https://doi.org/10.1007/s10522-018-9771-7 (0123456789().,-volV)(0123456789().,-volV) REVIEW ARTICLE Reversing the immune ageing clock: lifestyle modifications and pharmacological interventions Niharika A. Duggal Received: 27 June 2018 / Accepted: 16 September 2018 / Published online: 29 September 2018 Ó The Author(s) 2018 Abstract It is widely accepted that ageing is Immune ageing and health accompanied by remodelling of the immune system, including reduced numbers of naı¨ve T cells, increased Over the past 250 years life expectancy has increased senescent or exhausted T cells, compromise to mono- dramatically and is still increasing at 2 years per cyte, neutrophil and natural killer cell function and an decade in most countries. Advancing age is accompa- increase in systemic inflammation. In combination nied by a compromised ability of older adults to these changes result in increased risk of infection, combat bacterial and viral infections (Gavazzi and reduced immune memory, reduced immune tolerance Krause 2002; Molony et al. 2017a, b), increased risk of and immune surveillance, with significant impacts autoimmunity (Goronzy and Weyand 2012), poor upon health in old age. More recently it has become vaccination responses (Del Giudice et al. 2017; Lord clear that the rate of decline in the immune system is 2013) and the re-emergence of latent infections to malleable and can be influenced by environmental produce conditions such as shingles (Schmader 2001). factors such as physical activity as well as pharmaco- All of this contributing towards increased morbidity logical interventions. This review discusses briefly our and mortality in older adults (Pera et al. 2015) and current understanding of immunesenescence and then indicative of reduced immunity. focuses on lifestyle interventions and therapeutic Another universal feature of physiological ageing is strategies that have been shown to restore immune an increase in circulating levels of pro-inflammatory functioning in aged individuals. cytokines (IL-1b, IL-6, IL8, TNFa, IFNc, and CRP) termed ‘‘Inflammaging’’ (Franceschi et al. 2007). Keywords Ageing Á Immunesenescence Á Importantly, a strong association has been reported Inflammaging between elevated pro-inflammatory cytokine levels in older adults and mortality (Cohen et al. 2003), frailty (Cesari et al. 2004), age-related chronic diseases (Ershler and Keller 2000) and cognitive impairment (Yaffe et al. 2003). Inflammaging is multifactorial with some of the factors proposed to contribute to inflammaging including: lifetime antigenic load N. A. Duggal (&) resulting in oxidative damage; increased DNA dam- MRC-Arthritis Research UK Centre for Musculoskeletal age, accumulation of senescent cells, increased vis- Ageing Research, Institute of Inflammation and Ageing, Birmingham University, Birmingham, UK ceral adipose tissue; decline in sex hormones and e-mail: [email protected] 123 482 Biogerontology (2018) 19:481–496 reduced immune regulation (Baylis et al. 2013; Singh resulting from reduced bioenergetics in neutrophils and Newman 2011). (Qian et al. 2014). Altered immunity with age is the result of remod- Circulating monocytes play a critical role in elling of both the innate and adaptive arms of the defence against invading pathogens being early immune system, collectively termed immunesenes- responders to infection and able to act as antigen cence. Delaying or reversing the effects of ageing on presenting cells. Ageing affects the distribution of the immune system could be extremely beneficial in monocyte subsets with a decline in classical mono- maximising health and improving quality of life in cytes (CD14?ve CD16-ve) and increase in intermedi- older adults (Dorshkind et al. 2009). For the cells of ate (CD14?ve CD16?ve) and non-classical monocytes the innate immune response the literature is clear that (CD14?ve CD16??ve) occurs with age (Seidler et al. their numbers increase with age but their function 2010). Interestingly, non-classical monocytes express upon challenge with pathogens declines. Thus age- high levels of miR-146a and exhibit a senescence associated defects have been observed in neutrophils, associated secretory phenotype (SASP), contributing monocytes/macrophages, NK cells and dendritic cells towards inflammaging (Ong et al. 2018). Also, age- (Fig. 1). Neutrophils are the primary immune defence associated changes in platelets also contribute towards against bacterial and fungal infections and recent inflammatory cytokine production by monocytes studies have revealed that in addition to the well (Campbell et al. 2018). However, monocyte cytokine documented reduction in phagocytosis and ROS secretion in response to stimulation via TLRs is generation, these cells also show reduced chemotaxis greatly reduced with age (Metcalf et al. 2017). A to a range of stimuli (Sapey et al. 2014) and a reduced notable exception is TLR5 expression that has been ability to extrude their DNA as NETs to entrap reported to increase with age, offering an opportunity bacteria extracellularly (Hazeldine et al. 2014). Addi- to develop improved vaccines for older adults (Qian tionally, an age-associated reduction in TLR1 expres- et al. 2012). Retinoic acid inducible gene 1 (RIG-1) sion on neutrophils has been associated with reduced like receptors play a key role in recognition of viral chemokine (IL8) production, reduced rescue from nucleic acids and older human monocytes have intact apoptosis and lower expression of activation markers, RIG1 signalling to activate pro-inflammatory cytoki- nes but have a diminished IFN response (Pillai et al. Neutrophil NK cell Numbers Neutrophilia dim Chemotaxis CD56 cells Phagocytosis NKp30 and NKp46 Superoxide generation Cytotoxicity NET generation Monocyte Dendritic cell Numbers Ageing Recruitment to Chemotaxis Lymphoid organs Phagocytosis Phagocytosis Superoxide generation Antigen Cytokine secretion presentation Fig. 1 Age related alterations in innate immune cells 123 Biogerontology (2018) 19:481–496 483 2016; Molony et al. 2017a). Cytosolic dsDNA recep- has been shown to decline with age, whereas NKG2D tor AIM2 triggers the inflammasome and is important expression remains unaltered (Solana et al. 2014), as for control of virus infections (Guo et al. 2015). NKG2D is required for the killing of senescent cells Recently, defects in AIM2 expression have been (Sagiv et al. 2016) this may affect the killing ability of reported in monocytes of older adults, impairments in NK cells towards senescent cells, though this has not caspase 1 activation upon stimulation of AIM2 has yet been shown. In this context, NK cell cytotoxicity been associated with reduced IL1b secretion (Wang towards cancer cells is mediated by granule exocytosis et al. 2016). These alterations in innate immune and is reduced with age (Almeida-Oliveira et al. 2011; responses to pathogens with ageing have conse- Hazeldine et al. 2012), due to reduced release of quences for the ability of older adults to respond to perforin (Hazeldine et al. 2012). In contrast, NK cell an infectious challenge. Other monocyte functions mediated antibody dependent cell cytotoxicity such as wound repair (Sebastia´n et al. 2005) and (ADCC) is preserved with age (Lutz et al. 2005). clearance of apoptotic cells (Aprahamian et al. 2008) Myeloid derived suppressor cells (MDSCs) are are also compromised in older adults. known to play an important role in suppression of T Dendritic cells play a key role in initiating cell responses (Gabrilovich and Nagaraj 2009). pathogen-specific adaptive immune responses and Importantly, ageing is accompanied by an increase have been divided into two subsets—myeloid DCs in MDSCs, which has been linked with a higher and plasmacytoid DCs. A reduction in plasmacytoid incidence of cancer and chronic inflammation in aged DCs and unaltered frequency of myeloid DCs have individuals (Enioutina et al. 2011). In the adaptive been reported in older adults (Garbe et al. 2012). immune system, the effects of age are also significant Recent data in this field has led to further division of (Fig. 2). The thymus is devoted to T lymphocyte myeloid DCs into two subsets; CD1c?ve and CD141?- differentiation and maturation and ageing is associated ve mDCs. Ageing is accompanied by a decline in with atrophy of the thymus (Mitchell et al. 2010). In peripheral CD141?ve DCs, whereas the CD1c?ve humans, thymic atrophy involves a decrease in both mDCs remain unaltered (Agrawal et al. 2016). Age stromal and thymocyte cellularity with infiltration of associated impairments occur in DC recruitment to adipocytes, loss of tissue organisation, reduced levels lymphoid organs post antigen exposure which has of cytokines and hormones essential for thymopoiesis been associated with mitochondrial dysfunction (e.g. IL-7, KGF and Ghrelin) and upregulation of (Chougnet et al. 2015). Surprisingly, the age associ- thymosuppressive cytokines (e.g. IL-6, TNFa) with ated ability of DCs to phagocytose C.albicans remains age (Palmer 2013; Ventevogel and Sempowski 2013). intact (Do Nascimento et al. 2015). Also, the ability of The net outcome of thymic involution is reduced naı¨ve DCs to induce T cell proliferation and IFNc secretion T cell output (Haines et al. 2009) which compromises is impaired in older adults, resulting in impairments in the ability to respond to new pathogens and vaccines. vaccine responses (Panda et al. 2010; Sridharan et al. Other hallmarks of T cell immunesenescence include: 2011). Another age associated dysfunction of DCs is accumulation