Immunosenescence and susceptibility to respiratory viruses: a state-of-the-art review

Abstract

The global rise in the older population poses novel challenges in healthcare systems. Ageing is associated with immunosenescence, a progressive decline and remodelling of the immune system, and with inflammageing, a chronic, low-grade inflammatory process. Both states are associated with increased susceptibility to infections and adverse outcomes, especially in the context of infections. In this review, we examine the molecular and cellular pathophysiological mechanisms of immunosenescence and inflammageing that predispose older adults to increased morbidity and mortality from respiratory viral infections. We also outline the clinical implications of the ageing immune system, along with the most up-to-date evidence on possible biomarkers, preventative measures and treatment options aimed at mitigating the effects of immunosenescence on the vulnerability of older adults in respiratory viral infections.

Shareable abstract

Ageing increases vulnerability to respiratory viruses via remodelling of innate and adaptive immunity (immunosenescence) and by driving chronic inflammation (inflammageing). Understanding these mechanisms enables targeted vaccination and age-adapted care. https://bit.ly/4s8YL2U

Introduction

Advances in healthcare technologies and pharmacotherapies have significantly accelerated the pace of global population ageing [1]. Every country around the globe is facing continuous growth in both the size and the proportion of older people; by 2050, the global population aged 60 years and above is projected to double, reaching approximately 2.1 billion people [1]. As the population shifts towards older ages, new challenges are emerging, including increased healthcare demands. Among these challenges is “the destruction and remodelling of immune organ structure as well as innate and adaptive immune dysfunction with ageing”, so-called immunosenescence, alongside inflammageing, a characteristic inflammatory state in which high levels of pro-inflammatory molecules are expressed [2]. Both states predispose older adults to dysregulated immune responses and, inadvertently, to increased proportions of adverse outcomes, especially in the context of infections such as respiratory viral infections [3].

With sustained post-pandemic pressures on intensive care units (ICUs) and general respiratory care for older adults, clinicians urgently need to be aware of immunosenescence and its consequences in their daily practice. While numerous reviews have previously addressed the broad themes of ageing, immunosenescence and infection, few have focused specifically on respiratory viral infections in older adults and on integrating disease mechanisms with clinical implications and health policy considerations. Herein, we present a timely, practice-focused overview that complements existing literature of how immunosenescence shapes risk stratification, vaccination choices (e.g. high dose, adjuvant formulations), early antiviral implementation and supportive measures in the population ≥65 years old. Specifically, the aims of this narrative review are to 1) explain the pathogenetic mechanisms by which immunosenescence and inflammageing increase susceptibility to respiratory viruses in older adults; 2) associate these mechanisms with potential phenotypes and respective outcomes; 3) summarise candidate biomarkers and future research needs; and 4) translate findings into clinical practice insights for respiratory clinicians.

Methods

We conducted free searches on PubMed from inception until 10 September 2025, using several combinations of the following concepts, including their related keywords, synonyms and Medical Subject Heading (MeSH) terms: Concept 1: elderly patients; Concept 2: immune senescence; Concept 3: respiratory viruses; Concept 4: inflammageing. We searched references from retrieved articles to identify articles not captured in our PubMed search. Two authors independently screened all retrieved studies. We included peer-reviewed original articles and reviews in older adults (≥65 years old), clinical guidelines and high-quality preclinical (animal and in vitro) studies directly informing human disease. No restrictions were applied in terms of clinical site (hospitalised versus outpatient) or severity of respiratory infections. Non-English papers, case reports, conference abstracts and book chapters were excluded.

The burden of respiratory viruses in older adults

At present, no studies provide unified estimates of the total burden of all respiratory viral infections in older adults. Influenza alone demonstrates the scale of illness: data from the US Centers for Disease Control and Prevention (CDC) show up to 2 000 000 hospitalisations and 47 000–71 000 deaths annually among US adults [4]. Older adults, especially those with COPD, diabetes or multimorbidity, are at greatest risk. Individuals ≥65 years old have the highest influenza-associated hospitalisation rates; about one third develop pneumonia and ∼90% of influenza-related deaths occur in this group [4].

The pattern for older adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is similar. CDC data indicate that >81% of all COVID-19-related deaths occur in people ≥65 years old, and mortality in this age group is nearly 100-fold higher than in adults 18–29 years old [5]. In addition, a large cohort study published in 2024, which followed more than 80 000 individuals previously hospitalised with COVID-19, found that older adults continued to face substantially increased risks of death as well as cardiovascular, respiratory, metabolic, neurocognitive and mental health complications when compared with matched noninfected controls; notably, many of these elevated risks persist for more than 2 years after the initial infection [6].

Respiratory syncytial virus (RSV) also contributes substantially to morbidity in this age group. In industrialised countries, incidence reaches 600.7 per 100 000 person-years, with 157 hospitalisations per 100 000 among older adults [7]. The true burden is likely underestimated because testing in adults is limited. In-hospital mortality varies widely and may reach 9.1% in some low-resource settings [7]. Two recently approved RSV vaccines show efficacies of up to 94.1% [7]. Recent data from England (2023/2024) report 58.3 RSV-associated and 114.6 influenza-associated hospitalisations per 100 000 adults, with rates rising with age [8]. Exacerbation of chronic disease was common (33.1 per 100 000). Most hospitalised adults had one or more comorbidity (81%), and 26% were immunosuppressed. Clinical severity was comparable between RSV and influenza, with a 30-day mortality of 10.6% versus 8.7% (adjusted hazard ratio 0.85, 95% CI 0.6–1.2) [8]. RSV is an increasing cause of admission to the ICU among older adults [9].

Human metapneumovirus also imposes a notable burden. A recent meta-analysis estimated 231 (95% CI 41–421) hospitalisations per 100 000 adults ≥65 years old in the US, corresponding to ∼122 000 admissions in 2019 [10]. Human metapneumovirus has also been consistently reported among older adults admitted with community-acquired pneumonia and acute respiratory syndrome [11].

Immunosenescence: a hallmark of ageing

Overview of the ageing immune system

Immunosenescence is associated with a gradual weakening of immune competency. While immune system ageing is universal, the predominance and composition of immune cell subsets, and the associations between immunosenescence and mortality, are not uniform across genders or racial/ethnic groups [12, 13]. Both innate and adaptive immune systems are affected, particularly the functions of follicular T-helper cells and natural killer (NK) cells [14]. It has been proposed that one of the primary mechanisms reducing the quantity and variety of naïve T-cells is thymic involvement [15, 16]. Additionally, B-cell function is compromised; B-cell defects increase, while immunoglobulin class switching and antibody affinity maturation are impaired, all of which lead to reduced humoral responses [17, 18].

The innate immune system declines with age, showing reduced dendritic cell antigen presentation, impaired neutrophil chemotaxis and altered macrophage polarisation [19, 20]. In addition, inflammageing is characterised by increased levels of pro-inflammatory markers, including interleukin (IL)-6 and tumour necrosis factor-α (TNF-α) [21].

Key molecular and cellular mechanisms

After childhood, the thymus gland gradually shrinks and loses its ability to function, resulting in both a reduction of thymic epithelial cells and the generation of new T-cells. As the thymus becomes smaller, its structure declines and its ability to recover after impairment is limited. This process is known as thymic involution.

Another significant molecular mechanism in highly proliferative immune cells, particularly T-lymphocytes, is telomere shortening. Progressive telomere damage causes replicative senescence, characterised by loss of CD28 and upregulation of CD57 expression, a definitive characteristic of senescent T-cells [22].

Accumulation of senescent cells in various tissues may result in release of the senescence-associated secretory phenotype, which is characterised by the production of extracellular vesicles, cytokines, chemokines and proteases that impact the tissue microenvironment [23]. The senescence-associated secretory phenotype disrupts tissue homeostasis and causes age-related chronic inflammation [24, 25]. Additionally, age-related senescent cell accumulation leads to systemic toxicity, which is defined by impaired tissue recovery and healing and, thus, a higher risk of age-related illnesses [26].

Ageing is accompanied by a chronic, low-grade inflammatory state known as inflammageing, characterised by elevated levels of pro-inflammatory mediators such as IL-6, IL-1β, TNF-α and fibrinogen (figure 1). Although the underlying drivers of inflammageing are unknown, proposed contributors include impaired autophagy of damaged cells, microbial translocation and gut dysbiosis, mitochondrial dysfunction, and the accumulation of terminally differentiated or senescent T-cells. Elevated serum levels of IL-6, TNF-α and IL-1β in older adults are associated with frailty, cognitive decline and increased mortality [21, 27]. Moreover, chronic activation of NF-κB and p38 mitogen-activated protein kinase (p38-MAPK) pathways in senescent immune cells induces persistent senescence-associated secretory phenotype expression, while mitochondrial dysfunction, reactive oxygen species and inflammasome activation, particularly the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, further intensify this vicious cycle [20, 25, 28].

FIGURE 1.

Mechanisms linking immunosenescence to increased susceptibility and severity of respiratory viral infections in older adults. Ageing impairs mucosal defences via reduced mucociliary clearance, epithelial barrier defects and alveolar lining fluid (ALF) dysfunction. Alveolar macrophages and dendritic cells acquire senescence-like features, compromising viral clearance. T-cells and B-cells show reduced diversity, functional decline and pro-inflammatory skewing. “Inflammageing” and a senescence-associated secretory phenotype (SASP) further exacerbate dysregulated responses, contributing to increased severity of viral respiratory infections. BAFF: B-cell activating factor; CDH1: cadherin-1; GM-CSF: granulocyte–macrophage colony-stimulating factor; IFN: interferon; TCR: T-cell receptor. Figure created with BioRender.

Mechanisms linking immunosenescence with increased susceptibility to respiratory viruses

Lung function and innate immune responses

Lung function declines with age owing to several structural and physiological changes in the respiratory system rather than just molecular or inflammatory factors. These changes include the gradual loss of lung elasticity, reduced blood flow leading to decreased mucosal perfusion of the airways, less efficient mucus clearance and a diminished capacity for tissue repair, all of which contribute to prolonged recovery from injury [29]. Innate immunity, orchestrated by the lung epithelial barrier, the resident alveolar macrophages and other immune cells including dendritic cells, constitutes the first line of defence against respiratory viruses (figure 2). Ageing is associated with a deficient mucociliary clearance capacity and reduced ciliary beat frequency, which, in combination with insufficient cough, hampers the ability to expel infectious particles, increasing viral access to the lower airways [30]. Gene expression and protein interaction analysis has recently shown that, with ageing, lower expression of cadherin-1, a key regulator of lung mucosa stability and integrity, can lead to defects in epithelial barrier formation [31]. As ageing progresses, heightened inflammation and oxidative stress also disrupt the homeostasis of alveolar lining fluid, diminishing its proteolytic capacity and compromising key innate soluble defences against respiratory pathogens [32].

FIGURE 2.

The interplay of immunosenescence, inflammageing, frailty and viral outcomes. The figure represents a schematic interplay speculating on the association between immunosenescence, inflammageing and frailty with adverse outcomes in respiratory viral disease among older adults. “Susceptibility” and “severity” refer to infection. IL-6: interleukin-6; NF-κΒ: nuclear factor κ-light-chain-enhancer of activated B-cells; NK: natural killer cells; TNF-α: tumour necrosis factor-α.

Alveolar macrophages are resident immune cells that preserve tissue homeostasis, regulate immune cell responses and surfactant production, and remove apoptotic cells and debris [33]. These cells maintain their ability for proliferation and self-renewal because they originate from fetal monocyte precursors and are dependent on granulocyte–macrophage colony-stimulating factor (GM-CSF) for differentiation and survival [34]. With advancing age, alveolar macrophages acquire senescent-like features, including insensitivity to GM-CSF, cell-cycle arrest, senescence-associated secretory phenotype and reduced ability to clear apoptotic neutrophils (figure 2) [35]. Reduced expression of transcription factors, such as core binding factor-β, has been shown to mediate decreased alveolar macrophage proliferation and renewal [36]. Further, downregulation of the myelocytomatosis oncogene and upstream stimulatory factor-1 has been observed in older mice and human alveolar macrophages and is associated with impaired phagocytosis and chemotaxis [37]. Compromised viral sensing and clearance are particularly relevant to the increased severity of viral respiratory infections, such as influenza and SARS-CoV-2 among older adults [38, 39].

Ageing leads to blunted type I and III interferon (IFN) responses to viral insults, which weakens early antiviral defence and contributes to the higher severity of respiratory viral infections in older adults [40]. Recent research shows that monocytes from older adults have internal defects in both primary and secondary retinoic acid-inducible gene I signalling pathways. This is mainly caused by increased degradation of the TNF receptor-associated factor 3 (TRAF3) protein and poor induction of the transcription factor IFN regulatory factor 8 (IRF8), resulting in a much lower IFN response following viral detection [40]. Moreover, it has been suggested that, in older adults, plasmacytoid dendritic cells, which are major producers of type I IFN, undergo a reprogramming process towards a more specialised, conventional phenotype, with reduced capacity to secrete type I IFN [41]. The importance of type I and III IFN responses in antiviral immunity is underscored by recent research that uncovered the detrimental effects of IFN-neutralising autoantibodies on viral respiratory pathogens, such as influenza, Middle East respiratory syndrome coronavirus and SARS-CoV-2 [42]. Neutralising type I IFN autoantibodies, a consequence of impaired immune tolerance, are strongly associated with critical influenza and COVID-19 and their prevalence increases with age, reaching at least 5% in older adults [43–45].

Deficits in adaptive immune responses

Adaptive immune responses are also affected by ageing, undermining both acute virus control and immune memory. Age-dependent thymic involution results in a reduced pool of naïve T-cells, limiting the ability to recognise newly encountered viral pathogens. Simultaneously, T-cells are skewed towards effector memory and senescent phenotypes, with reduced capacity for expansion and altered cytokine production programming [46]. Moreover, decreased T-cell receptor repertoire diversity together with the clonal expansion of exhausted T-cells with ageing (especially in the context of cytomegalovirus latency) limit the ability of the adaptive immune system to respond to novel antigens [47]. This has been convincingly shown to interfere with the immune response to influenza infection and vaccination [48].

The B-cell compartment also exhibits age-related functional impairments, which lead to diminished antibody quality and quantity, contributing to delayed viral clearance and prolonged inflammatory responses. Class switch recombination and antibody affinity maturation through somatic hypermutation are particularly affected owing to the downregulation of the transcription factor E47 and the subsequent decrease in activation-induced cytidine deaminase function that mediates these processes [49]. In addition, B-cell activating factor production decreases with age, leading to impaired B-cell survival and maturation [50]. The increase and accumulation of age-associated B-cells, a subset of non-classical B-cells that are not dependent on B-cell activating factor activation and that displace naïve and follicular B-cells, contributes to immune senescence via altered primary and memory responses and inflammatory cytokine production [50]. Given that advanced age is associated with a higher prevalence of comorbidities, which themselves are linked to various innate and adaptive immune deficits against respiratory pathogens, these factors may represent additional indirect compromises to immune function in older adults [51].

Dysregulated inflammatory responses

Besides the elevated levels of pro-inflammatory mediators, characteristic of the inflammageing state, the age-related expansion of immune and non-immune cell populations expressing a senescence-associated secretory phenotype also plays a vital role [52, 53]. Cells exhibiting the senescence-associated secretory phenotype secrete a pro-inflammatory milieu rich in cytokines, chemokines and proteases, which not only perpetuate systemic inflammation but also locally disrupt alveolar epithelial integrity and induce secondary senescence in neighbouring cells [54]. This environment contributes to immune dysregulation and impairs antiviral defence mechanisms.

Many factors, such as immunosenescence, loss of elasticity and strength in the lungs, slower healing and the presence of other chronic diseases, play a role in making older adults more vulnerable to respiratory infections and their complications. Some adjustments in the immune system may be normal responses to lifelong exposures, while others might reduce the ability to fight new infections; how much these changes, alone or together, actually weaken protection against respiratory viruses in later life is still being studied [2].

Clinical implications

Increased severity and mortality

The global ageing trend has led to a growing proportion of older patients admitted to hospitals and ICUs [55], with respiratory infections accounting for a significant share of these admissions [56, 57]. These infections in older adults are associated with increased in-hospital and long-term mortality, greater healthcare utilisation and accelerated functional decline, particularly in patients ≥80 years old [56, 58]. This increased vulnerability is driven by multiple factors, including the burden of comorbidities, frailty, frequent atypical clinical presentations delaying diagnosis, reduced vaccine efficacy and duration of protection due to immunosenescence (figure 1) [59].

Influenza disproportionately affects older adults, with a substantial majority of influenza-related deaths occurring in this population [58]. It has been reported that C-reactive protein, ferritin and human leukocyte antigen-DR (monocytes) were present in higher levels in the oldest patients who died among adults hospitalised with influenza H1N1 infection, highlighting immunoparalysis and hyperinflammation as major mortality drivers [60]. Influenza heterogeneity was partially explained by early specific host-response dysregulations, which should be considered when designing personalised approaches to adjunctive therapy [60].

RSV, long considered primarily a paediatric pathogen, was identified in 12.5% of hospitalised older adults with influenza-like symptoms [61]. It is recognised as a significant cause of severe respiratory illness in older adults, with levels of morbidity and mortality comparable to those caused by influenza [62]. RSV infections can lead to decompensation of comorbidities, especially respiratory conditions, and cardiovascular complications [63]. They can involve cardiovascular events across several mechanisms, including inflammation-driven plaque instability, increased risk of thrombosis, increased cardiac demand due to respiratory stress and direct myocardial injury [64]. Moreover, inflammation may increase the risk of severe disease and complications. High IL-6 levels have been correlated with severity in RSV infection [65].

The COVID-19 pandemic further underscored this statement, with older adult patients experiencing markedly higher ICU admission and mortality rates [66]. The ageing of the immune system, especially the decline in CD4 and CD8 T-cells, the decreased phagocytic and migratory capacity of macrophages, the excessive IL-6 production inhibiting IFN-γ (important for CD8 activation) and the progressive loss of NK cell function, leads to more severe illness, greater risk of complications and increased mortality in older adults [67]. An important consideration is that treatment efficacy may vary with age; e.g. while dexamethasone showed benefit in younger patients, its efficacy in those >70 years old remains controversial [68, 69].

Vaccination challenges

Vaccination is an effective and safe preventative measure. However, vaccinating adults ≥65 years old is a challenge because of reduced vaccine efficacy, vaccine hesitancy, access to vaccines, and regular changes in recommendations and differences between countries.

Immunogenicity, efficacy and effectiveness are lower for some vaccines in older adults, such as influenza and COVID-19 vaccines [70, 71]. Beyond chronological age, studies have shown that frailty and environmental factors such as exposure to infectious diseases could affect their efficacy [72]. Various approaches have been implemented to strengthen immune responses in older adults, e.g. administering higher doses, increasing the number of doses, using multivalent vaccines and adding adjuvants [73]. High-dose influenza vaccines contain four times more haemagglutinin antigen compared to standard doses, which allows for better immunogenicity and effectiveness [74, 75]. In a systematic review and meta-analysis of a high-dose inactivated influenza trivalent vaccine, Lee et al. [76] showed that its relative effectiveness against influenza-like disease was 15.9% (95% CI 4.1–26.3%). A higher dose in older adults was associated with lower incidence rates of hospitalisation for pneumonia or influenza and all-cause hospitalisation compared with a standard dose [77]. Adjuvanted vaccines contain substances to boost vaccine immunogenicity by increasing antigen presentation and activating the innate immune system. The MF59 adjuvanted influenza vaccine was more effective than the standard dose inactivated vaccine and similar to that of the high-dose vaccine [78]. Regarding RSV, adjuvanted and non-adjuvanted vaccines (i.e. RSVPreF3 and RSVpreF) showed lasting effectiveness in a cohort of older adults despite their advanced age [79], and a single dose of mRNA vaccine showed efficacy versus placebo in adults >60 years old [80].

Strategies to enhance vaccine-induced immune responses in older adults include reducing chronic inflammation and oxidative stress and increasing immunogenicity with anti-inflammatory interventions and antioxidants. These include oleuropein, a secoiridoid extracted from extra-virgin olive oil, alone or in combination with BIRB 796, a potent inhibitor of the p38-MAPK pathway, to improve influenza vaccine formulations [81].

Repeated administration of COVID-19 vaccine doses aims to restore the immunogenicity of these vaccines, particularly in a frail older population, enhancing protection against severe disease and hospitalisation in this vulnerable population [72].

After respiratory viral infections, older people are exposed to an increased risk of bacterial infections, especially to pneumococcal ones [82]. Pneumococcal conjugate vaccines (PCV) contain multiple antigen subtypes protecting against serotypes of Streptococcus pneumoniae commonly found in older adults. A 21-valent PCV was specifically tailored to cover serotypes affecting older adults and has already been approved by the US Food and Drug Administration (FDA) [83].

Immune vaccine responses can be improved by maintaining a good lifestyle, i.e. avoiding vitamin D and C deficiencies, partaking in stimulating sports activities and having good sleep [84, 85]. The timing of vaccination, such as administering vaccines in the morning versus the afternoon, may influence immunogenicity in older adults, as shown for influenza [85, 86]. However, the priority is to not miss out on vaccination opportunities.

Trained immunity, a phenomenon by which innate immune cells such as monocytes, dendritic cells and NK cells increase their capacity to respond to a second infection with the same or a different pathogen, could be an effective way to improve vaccine response in adults >65 years old [87]. In the future, identifying strategies that simultaneously counteract immunosenescence in antigen-presenting cells and T-cells to enhance vaccine-induced protection should be a key objective.

Therapeutic considerations

New immunological concepts in immunomodulation and repair and new treatment targets have been recently reported in sepsis and in respiratory viral infections [88]. Treatment in respiratory viral infections consists of antiviral drugs, if available, that target the responsible virus. These are initiated soon after illness onset, particularly in people at high risk for complications, to stop the replication cycle and reduce viral load (figure 3). Moreover, management of severe infections in older patients often requires more frequent supportive care, including treatment of complications such as secondary bacterial infections, respiratory support and management of cardiovascular events.

FIGURE 3.

Treatment options for respiratory viral infections in older adults. The figure summarises current therapeutic strategies, including antiviral agents, immunomodulators for severe viral infections, supportive care and additional treatments such as inhaled therapies. Future directions, such as senolytic drugs, are also noted. IL: interleukin; JAK–STAT: Janus kinase–signal transducer and activator of transcription; mTOR: mammalian target of rapamycin; RSV: respiratory syncytial virus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

There is no evidence for effective antiviral treatments on the market for the treatment of RSV infection in older adults, despite the emergence of candidates [89]. Aerosolised or systemic ribavirin is recommended in high-risk haematological patients (allogeneic haematopoietic stem cell transplantation), added to intravenous immunoglobulin, but with no specific evidence in adults >65 years old [90]. The oral formulation appears to be a safe and cost-effective alternative to aerosolised ribavirin [91].

COVID-19 antivirals should be offered to all adults with risk factors for severe disease, including those ≥65 years old, regardless of vaccination status, and even in the outpatient setting, to reduce the risk of all-cause mortality and hospital admission, with careful consideration of potential drug interactions [92, 93]. Since the beginning of the pandemic, many drugs initially prescribed have been discarded. According to meta-analyses and using COVID-19-related hospitalisation or death from any cause as the principal outcome, remdesivir, nirmatrelvir/ritonavir and monoclonal antibodies such as casirivimab/imdevimab or sotrovimab were the drugs with the greatest body of evidence [94].

Concerning influenza, antivirals such as oseltamivir, zanamivir and, more recently, baloxavir marboxil, a cap-dependent endonuclease inhibitor, are effective and safe [95], and should be started as early as possible in people at high risk for complications, including adults ≥65 years old [96]. Further studies assessing their efficacy, including randomised clinical trials in older hospitalised patients, are still needed.

Alongside antivirals, immunopathological host responses have been managed using systemic corticosteroids, macrolides, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-influenza immune plasma and vitamin C, as well as inhaled steroids, long-acting β2-agonists, long-acting muscarinic antagonists and mucolytic agents. Their use depends on the aetiological agents and stage of the infections (early or later stage), especially in severe viral respiratory infections [97]. These agents reduce the production of virus-induced mediators, such as cytokines and mucins, and their anti-inflammatory effects may provide clinical benefits by alleviating symptoms, improving quality of life, and lowering hospitalisation and mortality rates [97]. Among the immunomodulatory drugs, immunosuppressive agents such as IL-6 inhibitors, Janus kinase–signal transducer and activator of transcription (JAK–STAT) kinase inhibitors and corticosteroids have been used as therapy for severe COVID-19 cases [92, 98].

Lastly, the development of novel treatments (e.g. monoclonal antibodies and adoptive T-cell therapies) and strategies (e.g. inhalable formulations, repurposing existing drugs and investigating natural or peptide-based compounds) may be useful tools in improving the management of severe infections in vulnerable and older populations [99–101]. Over the next few years, senolytics and rejuvenation therapies may also play an important role in the treatment of respiratory infections in older adults.

Implications in health policy

With the continuously rising population ≥65 years old, health policymakers and stakeholders should adapt the healthcare frameworks accordingly. The increased burden of respiratory viral infections in older adults and the higher associated mortality and morbidity warrant prioritisation of age-specific vaccination programmes (including high-dose, adjuvanted and multivalent vaccines) and tailored antiviral treatments focusing on this heterogenous population.

Older adult patients are often under-represented in clinical trials, as was the case during the COVID-19 pandemic, limiting the generalisability of findings to this population [101]. Increasing the inclusion of geriatric patients in clinical studies is essential to promote health equity and improve outcomes. Strengthening geriatric and respiratory care capacity in hospitals, alongside expanding training in geriatrics and immunosenescence for medical and nursing staff, are vital health policy priorities. Additionally, policies that support healthy ageing, through investment in nutrition, physical activity, air quality, social connectivity and equitable access to care, including telemedicine, are key to reducing the burden of respiratory viral infections in older adults.

Emerging research and future directions

Biomarkers of immunosenescence

Numerous biomarkers of immunosenescence reflect chronic, low-grade inflammation and age-related immune remodelling, often referred to as inflammageing [102, 103]. A large population-based study in Brazil demonstrated that serum levels of cytokines, chemokines and growth factors vary with age. Pro-inflammatory markers such as IL-6, IL-17, IL-2, TNF-α and C-X-C motif chemokine ligand 10 (CXCL10), as well as regulatory markers including IL-4 and C-C motif chemokine ligand 11 (CCL11), were significantly elevated in older adults [103]. Another study reported that IL-8, IL-15, soluble glycoprotein 130, soluble CD30 and monocyte chemoattractant protein-1 (MCP-1) increased with age [102]. Interestingly, in a systematic review of 44 studies, IL-6 and C-reactive protein were most consistently associated with frailty, while TNF-α showed a weaker association [104]. Although T-lymphocyte subpopulations were investigated in a few studies, evidence remains inconclusive due to small sample sizes and methodological heterogeneity [104, 105].

An immune risk phenotype associated with increased mortality included inversion in the CD4/CD8 ratio, expansion of terminally differentiated cytotoxic T-cells, cytomegalovirus (CMV) positivity and a high level of pro-inflammatory cytokines in serum [106]. The interaction between CMV and the human immune system is complex. CMV latent infection contributes to the accumulation of highly differentiated effector memory CD8 T-cells [107]. NK cells play a key role in the destruction of virus-infected cells. NK cell compartments undergo remodelling, with a decrease in immature NK cells [108].

Biomarkers could help identify older patients with immune ageing and recognise them as a high-risk group. However, further prospective research is needed to validate their clinical relevance, determine optimal biomarker combinations and establish meaningful thresholds for clinical application.

Senolytics and rejuvenation therapies

Ageing is a major risk factor for poor outcomes following respiratory tract infections. Cellular senescence, defined as irreversible cell-cycle arrest, contributes to inflammageing and age-related diseases [109]. Reducing the senescent cell burden with senolytic compounds improved the immune response and reduced mortality in mice infected with SARS-CoV-2 [110]. Luna et al. [111] reported that senolytic compounds decreased immune cell infiltration without improving influenza outcomes in aged mice. A few senolytic drugs have been tested in preclinical trials for age-related pathologies, such as dasatinib, quercetin, metformin, fisetin and UBX0101 [111, 112], while some clinical trials are ongoing in humans.

Personalised medicine approaches

A one-size-fits-all treatment approach is unlikely to be effective for respiratory infections [113], and this is even more true in older adults [114]. First, priority should be given to personalised sepsis diagnosis, by classifying patients according to immune status phenotypes, and developing a panel of biomarkers to target immunomodulatory interventions [88]. Seymour et al. [115] reported four clinical phenotypes correlating with host-response patterns and clinical outcomes in patients with sepsis. However, longitudinal biological data are still lacking. Encouragingly, genetic associations underlying susceptibility to pneumonia and COVID-19 have been reported [116, 117].

Second, screening for frailty and immunosenescence, vaccinating and promoting healthy ageing are crucial in the older population. Vaccination has indirect benefits, such as preventing long-term complications related to infections but also infection-independent cardioprotective effects [118], reducing the risk of major adverse cardiovascular events such as myocardial infarction [119]. In the same way, COVID-19 vaccination reduces the risk of major adverse cardiovascular events, myocardial infarction and ischaemic stroke after SARS-CoV-2 infection [120, 121]. The efficacy of multimodal interventions jointly on frailty and immunosenescence should be investigated using randomised controlled studies on an older adult population.

Third, a personalised immunisation strategy is crucial to improve vaccine efficacy and effectiveness, reduce side effects and assure healthy ageing. This strategy, based on individual characteristics, should optimise types, formulation, doses and schedules of vaccines (timing, intervals between vaccine doses) [122]. A personalised immunisation strategy will improve disease prevention and public health outcomes. To predict immune response to vaccination, a systems biology approach to examine gene signatures and molecular pathways could be developed [123, 124].

Conclusion

Age-related immune alterations affect susceptibility, disease progression and responses to treatment and vaccination in older populations. Respiratory viral infections in older adults are associated with frailty, increased morbidity and mortality, and lower quality of life among survivors. Personalised therapeutic strategies may be required for different respiratory viruses. Older adults are often under-represented in clinical trials; however, as the population ages, detecting and addressing immunosenescence should become a research priority. Moreover, the integration of frailty, inflammation and immunosenescence screening into clinical guidelines is imperative to guide treatment intensity, vaccination decisions and risk stratification. Funding for age-adapted antiviral treatments and immunomodulatory drugs suitable for older adults is important in this respect.

Points for clinical practice

• Immunosenescence and inflammageing increase the susceptibility to and severity of respiratory viral infections in older adults.

• Frailty assessment should be incorporated into respiratory practice, because frail patients experience higher hospitalisation and mortality risks than those matched by age alone.

• Early antiviral initiation is critical in high-risk older adults regardless of vaccination status.

• Supportive and adjunctive measures and careful management of cardiovascular complications remain essential.

• Integrated care models linking geriatric, respiratory and infectious disease expertise are key to reducing morbidity and mortality in ageing populations.

Questions for future research

• Which biomarkers may reliably predict severe viral outcomes in older adults?

• How can frailty and biological age metrics be incorporated into vaccine and antiviral trial designs to improve generalisability?

• Can precision immunisation strategies overcome immunosenescence?

• Do senolytic or immune-modulating therapies translate into clinically meaningful improvements in viral defence in older adults?

• How can real-world data and pragmatic trials be leveraged to assess absolute risk reductions, cost-effectiveness and optimal combinations of preventative strategies in geriatric respiratory viral infections?