Highlights
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LLD has unique clinical and biological features compared to depression in other periods of life.
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Low-grade systemic inflammation or inflammaging may underlie LLD onset and progression.
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Targeting aging-associated immune/inflammatory changes might be a promising therapeutic approach for LLD.
Summations
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Late life depression is associated with low-grade systemic inflammation or inflammaging.
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The pro-inflammatory profile may differ between early-onset versus late-onset depression.
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Diet and microbiota-targeted interventions may be promising in attenuating depression-related inflammation.
Considerations
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While the pathogenesis of the low-grade inflammation in LLD is still unclear, it is potentiated by the senescence of immune cells (that tend to assume a proinflammatory profile with ageing) and the burden of physical comorbidities like cardiovascular and metabolic diseases.
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To date studies have failed to report any meaningful differences in the pro-inflammatory profile between early-onset and late life depression.
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The majority of studies conducted in the field of nutrition psychiatry was with adult population. The benefits of diet and microbiota-target interventions in older adults and LLD remain to be established.
Introduction
Depressive disorders are one of the most common mental disorders across the lifespan. Late-life depression (LLD) refers to depressive disorders occurring in individuals aged 60 years or older. It encompasses a spectrum of depressive conditions, including major depressive disorder (MDD), persistent depressive disorder (dysthymia), and subsyndromal depression (American Psychiatric Association, 2013). LLD can either be a late-onset depression (LOD), when the first lifetime depressive episode began after age 60, or an early-onset depression (EOD), meaning that an older adult has experienced recurrent depressive episodes with a first episode occurring earlier in life. Depression is often perceived as an expected psychological reaction to the challenges associated with ageing. Older adults are commonly portrayed as depressed, lonely, and preoccupied with impending disability and death. However, older age is associated with increased subjective wellbeing and decreased negative affect. Older adults are also more likely to anticipate the occurrence of adverse events and rehearse the experience in their mind, which may lessen the psychological and emotional impact of the event, supporting the view that depression must not be seen as an unequivocal outcome of ageing (Richardson et al., Reference Richardson, Carr, Netuveli and Sacker2023).
The cross-sectional prevalence of MDD is estimated to be 3.8% in the whole population, affecting 5% of adults, and around 6% of adults older than 60 years based on representative surveys, medical data and statistical modelling (“Homepage | Institute for Health Metrics and Evaluation”, n.d.; Kok & Reynolds, Reference Kok and Reynolds2017). The rates of depressive disorders increase significantly in the oldest age groups, reaching numbers above 20% from 85 to 89 years-old and above 30% in 90 years and older (Corneliusson et al., Reference Corneliusson, Gustafson and Olofsson2024). Epidemiological studies have identified several predictors of LLD, including the paucity of leisure and intellectual activities, scarcity of social activities, poor physical health, unhealthy lifestyle, and negative views on ageing (Read et al., Reference Read, Sharpe, Modini and Dear2017; Maier et al., Reference Maier, Riedel-Heller, Pabst and Luppa2021; Belvederi Murri et al., Reference Belvederi Murri, Cattelani, Chesani, Palumbo, Triolo and Alexopoulos2022). While a complex interplay among biological, psychological, and social factors plays a role in LLD, the increase of prevalence rates with rising age may be explained by ageing-related factors such as a higher proportion of females, more physical disability, higher cognitive impairment, lower socioeconomic status, and stay in hospital and nursing homes (Luppa et al., Reference Luppa, Sikorski, Luck, Ehreke, Konnopka, Wiese, Weyerer, König and Riedel-Heller2012; Cheung & Mui, Reference Cheung and Mui2023).
The negative association between LLD and quality of life has been confirmed by cross-sectional and longitudinal epidemiological studies (Sivertsen et al., Reference Sivertsen, Bjørkløf, Engedal, Selbæk and Helvik2015). Depressive disorders in the elderly also present a reciprocal interaction with frailty, a geriatric syndrome conceptualised as a clinical state of poor health in which there is an increased vulnerability to functional dependency and/or mortality when exposed to stressors (Soysal et al., Reference Soysal, Veronese, Thompson, Kahl, Fernandes, Prina, Solmi, Schofield, Koyanagi, Tseng, Lin, Chu, Cosco, Cesari, Carvalho and Stubbs2017; Zou et al., Reference Zou, Yu, Wang, Ding and Chen2023; Kim & Rockwood, Reference Kim and Rockwood2024). Accordingly, LLD is associated with 1.34 increased risk of all-cause mortality, and 1.31 cardiovascular mortality in elderly people (Wei et al., Reference Wei, Hou, Zhang, Xu, Xie, Chandrasekar, Ying and Goodman2019). There is also strong association between depression and dementia. However, the nature of this association, i.e. whether depression is a risk factor, a prodrome or a consequence of a neurodegenerative disease progressing with dementia, remains debateable (Byers & Yaffe, Reference Byers and Yaffe2011; Antonio L. Teixeira et al., Reference Teixeira, Gregg, Gentry, Gujral, Rapp, Oberlin, Ajilore, Weisenbach and Patrick2025a).
LLD is a complex and multifaceted condition. The cellular and molecular mechanisms underlying LDD pathophysiology remain to be clearly determined (Xia et al., Reference Xia, Chen, Shao, Chen, Zhu, Zhao, Luo, Yang and Wu2023). The traditional monoamine neurotransmitter hypothesis fails to explain the onset and progression of LLD, as partly reflected on the limited benefits of antidepressants for its treatment (Tedeschini et al., Reference Tedeschini, Levkovitz, Iovieno, Ameral, Nelson and Papakostas2011; Alexopoulos, Reference Alexopoulos2019; Patrick et al., Reference Patrick, Dickinson, Gentry, Kim, Oberlin, Park, Principe, Teixeira and Weisenbach2024a; de Miranda et al., Reference de Miranda, C B Toscano, Venna, Graeff and Teixeira2025). Therefore, exploring new pathophysiological hypotheses and therapeutic approaches for LLD is highly needed (Xia et al., Reference Xia, Chen, Shao, Chen, Zhu, Zhao, Luo, Yang and Wu2023). Growing evidence has supported the link between ageing-related inflammation and LLD (Diniz et al., Reference Diniz, Reynolds, Sibille, Lin, Tseng, Lotrich, Aizenstein and Butters2017; Charlton et al., Reference Charlton, Lamar, Zhang, Ren, Ajilore, Pandey and Kumar2018; Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018; Dias et al., Reference Dias, Teixeira, Diniz, Vieira, Viana and Barbosa2024). Unravelling the relationship between inflammation and LLD could lead to novel diagnostic and prognostic biomarkers and new treatments based on immune and/or anti-inflammatory strategies for this disabling condition.
The objective of this manuscript is to review the physiopathology of LLD highlighting the role played by increased inflammation and the related opportunities to define biomarkers and therapeutic targets.
The physiopathology of late-life depression
The three major biological hypotheses proposed to explain depression in older adults are 1) the “inflammatory hypothesis”, which suggests that LLD can be driven by ageing-related increase in inflammation; 2) the “vascular hypothesis”, which implicates vascular-related white matter lesions in the development of LLD; and 3) the “degenerative hypothesis”, which suggests that an emerging depression in an older adult can be the prodrome of a neurodegenerative disease. These hypotheses are not mutually exclusive and highlight the pivotal role of inflammation in LLD. While inflammation constitutes the basis of the “inflammatory hypothesis” of LLD, inflammatory mechanisms and pathways have been implicated in the development of neurodegenerative and microvascular (white matter) changes, as discussed below.
Immune dysfunction in late-life depression
There are several lines of evidence supporting the association between mood disorders, especially MDD, and immune dysfunction toward a pro-inflammatory profile (Colpo et al., Reference Colpo, Leboyer, Dantzer, Trivedi and Teixeira2018; Bauer & Teixeira, Reference Bauer and Teixeira2019; Brunoni et al., Reference Brunoni, Supasitthumrong, Teixeira, Vieira, Gattaz, Benseñor, Lotufo, Lafer, Berk, Carvalho and Maes2020; Osimo et al., Reference Osimo, Pillinger, Rodriguez, Khandaker, Pariante and Howes2020; Islam et al., Reference Islam, Sohan, Daria, Masud, Ahmed, Roy and Shahriar2023). (Bauer and Teixeira, Reference Bauer and Teixeira2019) The most robust evidence comes from studies describing increased circulating levels of inflammatory markers in depression across the lifespan (Colpo et al., Reference Colpo, Leboyer, Dantzer, Trivedi and Teixeira2018; Brunoni et al., Reference Brunoni, Supasitthumrong, Teixeira, Vieira, Gattaz, Benseñor, Lotufo, Lafer, Berk, Carvalho and Maes2020). High levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumour necrosis factor (TNF-α), among other inflammatory mediators, have been reported in patients with depression (Haapakoski et al., Reference Haapakoski, Mathieu, Ebmeier, Alenius and Kivimäki2015; Osimo et al., Reference Osimo, Pillinger, Rodriguez, Khandaker, Pariante and Howes2020; Islam et al., Reference Islam, Sohan, Daria, Masud, Ahmed, Roy and Shahriar2023). The most recent meta-analysis including a total of 2,708 participants, being 1,366 MDD drug-naïve patients and 1,342 controls, reported increased peripheral levels of TNF-α but not IL-6 and CRP (Islam et al., Reference Islam, Sohan, Daria, Masud, Ahmed, Roy and Shahriar2023), pointing out to the heterogeneity of results, possibly related to the intrinsic heterogeneity of MDD and confounding factors (e.g., physical comorbidities, lifestyle parameters). While not present in all patients with depression, at least a subgroup will exhibit this low-grade systemic inflammation (Teixeira et al., Reference Teixeira, Martins, Berk and Bauer2022). Interestingly enough, pharmacological treatment with antidepressants can decrease the circulating levels of inflammatory markers like IL-6, TNF-α, and CCL2 in depressed patients (Köhler et al., Reference Köhler, Freitas, Stubbs, Maes, Solmi, Veronese, de Andrade, Morris, Fernandes, Brunoni, Herrmann, Raison, Miller, Lanctôt and Carvalho2018; Wang et al., Reference Wang, Wang, Liu, Qiao, Baldwin and Hou2019). In this scenario, it is tempting to speculate whether there is an ‘inflammation-related subtype’ of depression with a specific pattern of therapeutic response. However, discrimination between atypical versus melancholic and moderate versus severe forms of depression does not seem possible based on inflammatory biomarkers (Veltman et al., Reference Veltman, Lamers, Comijs, Stek, van der Mast and Rhebergen2018). In parallel with peripheral changes, neuroinflammation or an enhanced inflammatory profile in the central nervous system (CNS) is observed in patients with depression. For instance, MDD has been associated with high levels of IL-6, IL-8 and TNF-α in the cerebrospinal fluid (CSF) and increased TNF-α, monocytes chemoattractant protein 1 (MCP-1/CCL2) and toll like receptor 3 and 4 expression in post-mortem brain specimens (Torres-Platas et al., Reference Torres-Platas, Cruceanu, Chen, Turecki and Mechawar2014; Enache et al., Reference Enache, Pariante and Mondelli2019; Pandey et al., Reference Pandey, Rizavi, Bhaumik and Ren2019; Wang et al., Reference Wang, Wang, Liu, Qiao, Baldwin and Hou2019).
LLD has been associated with higher peripheral levels of inflammatory mediators/molecules, such as IL-6 (Dentino et al., Reference Dentino, Pieper, Rao, Currie, Harris, Blazer and Cohen1999; Bremmer et al., Reference Bremmer, Beekman, Deeg, Penninx, Dik, Hack and Hoogendijk2008; Charlton et al., Reference Charlton, Lamar, Zhang, Ren, Ajilore, Pandey and Kumar2018; Nie et al., Reference Nie, Fang, Chen, Aidina, Qiu, Zhao, Liu, Sun, Li, Zhong, Li and Li2021; Lozupone et al., Reference Lozupone, Castellana, Sardone, Berardino, Mollica, Zupo, De Pergola, Griseta, Stallone, La Montagna, Dibello, Seripa, Daniele, Altamura, Solfrizzi, Bellomo and Panza2023; Dias et al., Reference Dias, Teixeira, Diniz, Vieira, Viana and Barbosa2024), sTNFR2 (Diniz et al., Reference Diniz, Teixeira, Talib, Mendonça, Gattaz and Forlenza2010), GDF-15 (Teunissen et al., Reference Teunissen, Durieux-Lu, Blankenstein, Oude Voshaar and Comijs2016), IL-1β (Thomas et al., Reference Thomas, Davis, Morris, Jackson, Harrison and O’Brien2005; Charlton et al., Reference Charlton, Lamar, Zhang, Ren, Ajilore, Pandey and Kumar2018; Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018) compared to non-depressed older adults. One important issue when studying LLD is that ageing itself has been associated with increased systemic inflammation, a phenomenon termed ‘inflammaging’. Franceschi and coworkers (2018) proposed that the physiological and unavoidable inflammatory tone increases over time and can become highly detrimental with ageing. Accordingly, all major age-related diseases would be derived from a basic ageing mechanism dependent on inflammation as the major player (Franceschi et al., Reference Franceschi, Garagnani, Parini, Giuliani and Santoro2018). Another relevant question is whether the pro-inflammatory profiles differ between EOD versus LOD. Most studies focused on LDD without discriminating EOD versus LOD (Diniz et al., Reference Diniz, Lin, Sibille, Tseng, Lotrich, Aizenstein, Reynolds and Butters2016; Teunissen et al., Reference Teunissen, Durieux-Lu, Blankenstein, Oude Voshaar and Comijs2016; Saraykar et al., Reference Saraykar, Cao, Barroso, Pereira, Bertola, Nicolau, Ferreira, Dias, Vieira, Teixeira, Silva and Diniz2018) or were not capable to observe meaningful differences between EOD and LOD (Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018; Rozing et al., Reference Rozing, Veerhuis, Westendorp, Eikelenboom, Stek, Marijnissen, Oude Voshaar, Comijs and van Exel2019; Lozupone et al., Reference Lozupone, Castellana, Sardone, Berardino, Mollica, Zupo, De Pergola, Griseta, Stallone, La Montagna, Dibello, Seripa, Daniele, Altamura, Solfrizzi, Bellomo and Panza2023). Interestingly, patients with LLD exhibit a negative correlation between serum levels of TNF-α and hippocampal volume and cognitive performance (processing speed), suggesting that peripheral inflammation may also contribute to LLD-related CNS dysfunction (Ho et al., Reference Ho, Hsiao, Lin, Wu and Wu2024).
Further discussion on the immune basis of LLD appears in section 3. Fig. 1 shows potential immune/inflammatory processes that may underlie LLD onset and progression.
Figure 1. Potential immune/Inflammatory processes underlying late life depression pathogenesis. Ageing-related chronic low-grade inflammation (inflammaging) contributes to blood brain barrier (BBB) increased permeability and peripheral immune cells infiltration in the central nervous system resulting in senescent microglial activation, and neuroinflammation. Microglial activation and systemic inflammation also result in reduction of brain neurotrophic factor (BDNF) levels, all of which ultimately leading to pathological protein aggregation and neuronal death. These inflammatory events may underlie late life depression pathophysiology. Furthermore, older adults frequently present metabolic disorders, which contribute to the accumulation of endogenous metabolites including cholesterol crystals, urate crystals and lipotoxic ceramides that can activate the NOD-, LRR-, and Pyrin domain-containing protein 3 (NLRP3) inflammasome. The activation of NLRP3 inflammasome promote the release of inflammatory cytokines interleukin-IL (IL1-β) and IL-18, and, hence, a cascade of pro-inflammatory events that may also contribute to late life depression onset and progression. IL-6- Interleukin-6; TNF-α - tumour necrosis factor alpha. Created in BioRender.
The vascular component of late-life depression
The vascular depression hypothesis proposes that cerebrovascular diseases, mainly small vessel ischaemic disease, may predispose, precipitate, and/or perpetuate depressive symptoms in late life. Aizenstein and coworkers (2016) proposed criteria for depression due to a vascular component, also called ‘vascular depression’: (i) depression occurring in an elderly person; (ii) absence of family history of depression; (iii) clinical symptoms marked by loss of energy, impaired motivation, anhedonia, subjective feelings of sadness, limited insight; (iv) cognitive dysfunction characterised by impaired executive function, processing speed and visuospatial skills; (v) presence of meaningful cerebrovascular risk factors; (vi) neuroimaging data confirming cerebrovascular disease; (vii) evidence of vascular pathology in elderly subjects with or without cognitive impairment (Aizenstein et al., Reference Aizenstein, Baskys, Boldrini, Butters, Diniz, Jaiswal, Jellinger, Kruglov, Meshandin, Mijajlovic, Niklewski, Pospos, Raju, Richter, Steffens, Taylor and Tene2016). While approximately one third of patients develop depression after a stroke (Ozkan et al., Reference Ozkan, Ambler, Esmail, Banerjee, Simister and Werring2025), the concept of ‘vascular depression’ encompasses a broader group of patients with no history of transient ischaemic attack (TIA) or stroke or TIA but established cardiovascular risk factors for cerebrovascular disease and white matter changes indicative of small vessel disease. Importantly, ‘vascular depression’ is usually associated with LOD (Empana et al., Reference Empana, Boutouyrie, Lemogne, Jouven and van Sloten2021). However, white matter changes are one of the most frequent neuroimaging findings in adults with depression, indicating that microvascular changes are not restricted to LOD and can be associated with depression earlier in life (Wang et al., Reference Wang, Leonards, Sterzer and Ebinger2014).
Several pathogenic factors have been implicated in ‘vascular depression’, such as hemodynamic changes, neurovascular pathology, disorders of the glutamatergic system, mitochondrial dysfunction, lipid dysmetabolism, deficits of neurotrophic factors, and pro-inflammatory changes (Empana et al., Reference Empana, Boutouyrie, Lemogne, Jouven and van Sloten2021; Jellinger, 2021, 2022). Cerebrovascular risk factors, like diabetes and obesity, may promote a chronic pro-inflammatory profile. This enhanced peripheral inflammation may cause endothelial dysfunction and subsequent blood-brain barrier (BBB) disruption and microglia activation (Antonio L. Teixeira et al., Reference Teixeira, Scholl and Bauer2025b). Activated microglia can produce a series of cytokines in the CNS, contributing to further changes in the endothelial cells and BBB, also affecting the function of neural circuits with the development of behavioural and cognitive symptoms (Mayer & Fischer, Reference Mayer and Fischer2024).
Late-life depression and neurodegeneration
There is a bidirectional relationship between depression and neurodegenerative diseases. While depression can be seen as a well-established risk factor for dementia, including Alzheimer’s disease (AD) and vascular dementia, it is also frequently comorbid with these conditions (Antonio Lucio Teixeira et al., Reference Teixeira, de Erausquin and Olvera2025). Moreover, LLD and AD share clinical (e.g., cognitive symptoms) and neurobiological (e.g., decreased hippocampus volume) features (Antonio L. Teixeira et al., Reference Teixeira, Gregg, Gentry, Gujral, Rapp, Oberlin, Ajilore, Weisenbach and Patrick2025a). Different models have been proposed to explain the bidirectional association between depression and AD, the prototype of neurodegenerative disease. More specifically, it has been postulated that EOD, especially with persistent or severe symptoms, should be regarded as a risk factor for AD, whereas LOD is a prodrome of AD (Huang et al., Reference Huang, Gan, Yang, Cheng and Yu2024).
From a mechanistic perspective, in addition to shared genetic liabilities, depression could contribute to the pathological aggregation of peptides, especially amyloid beta (Harrington et al., Reference Harrington, Lim, Gould and Maruff2015). More likely, depression contributes to an inflammatory milieu in the CNS, influencing brain structure and function through the generation of toxic oxidative stress products, damage to neural and glial cells, and increased BBB permeability (Hayley et al., Reference Hayley, Hakim and Albert2021). The combination of increased levels of inflammatory cytokines both locally and systemically with BBB permeability can lead to CNS immune activation and further lesion, perpetuating a damage cycle that can eventually progress to dementia. Antidepressant treatment of LLD can improve cognition, raising the possibility of prevention and/or attenuation of neurodegenerative changes (Ainsworth et al., Reference Ainsworth, Marawi, Maslej, Blumberger, McAndrews, Perivolaris, Pollock, Rajji and Mulsant2024). Theoretically, this antidepressant effect could be mediated through anti-inflammatory mechanisms (Bajaj and Mahesh, Reference Bajaj and Mahesh2024) . Neuroprotective effects were reported in APP/ PS1 transgenic mice, a model of AD, treated with antidepressants such as fluoxetine, a SSRIs (Huang et al., Reference Huang, Liang, Chen, Xu, Chai and Xing2018; Zhou et al., Reference Zhou, Chao, Zhang, Jiang, Zhang, Fan, Wu, Dou and Tang2019). Fluoxetine-related neuroprotection in AD seems to be, at least in part, mediated by the inhibition of the NF-κB/TLR4/NLRP3 signalling pathways and resultant release of pro-inflammatory cytokines like IL-1β and TNF-α (Bougea et al., Reference Bougea, Angelopoulou, Vasilopoulos, Gourzis and Papageorgiou2024).
Immunopsychiatry of LLD: the convergence of depression- and age-related inflammatory changes
The ageing immune system (immunosenescence) refers to remodelling humoral and cellular changes implicated in the development of most (if not all) age-related diseases. Ageing affects both innate and adaptive immune responses, ultimately contributing to a systemic chronic low-grade inflammatory state or ‘inflammaging’ (Cisneros et al., Reference Cisneros, García-Aguirre, Unzueta, Arrieta-Cruz, González-Morales, Domínguez-Larrieta, Tamez-González, Leyva-Gómez and Magaña2022). Among others, age-related immune changes include thymic involution, decreased number of T and B lymphocytes, blunted antibody memory responses, impaired phagocytic functions and antigen presentation, as well as increased levels of inflammatory mediators (Thomas et al., Reference Thomas, Wang and Su2020; Teissier et al., Reference Teissier, Boulanger and Cox2022). ‘Inflammaging’ in the context of immunosenescence have been implicated in several pathological conditions, including neurodegenerative diseases and mood disorders (Fig. 2) (Barbé-Tuana et al., Reference Barbé-Tuana, Funchal, Schmitz, Maurmann and Bauer2020; Antonio L. Teixeira et al., Reference Teixeira, Scholl and Bauer2025b).
Figure 2. Age-related immune changes (immunosenescence) and systemic chronic low-grade inflammatory state or ‘inflammaging’. The ageing immune system is characterised, among others, by senescence of haematopoietic stem cells (HSCs) leading to an increased number of myeloid cells and decreased T and B lymphocytes, blunted antibody memory responses, impaired phagocytic and autophagy functions and antigen presentation, as well as increased levels of inflammatory mediators like interleukin-IL (IL1-β) and tumour necrosis factor alpha (TNF-α). ‘Inflammaging’ in the context of immunosenescence have been implicated in the development and progression of neuropsychiatric disorders and cognitive dysfunctions. IL-4- Interleukin-4; IL-5- Interleukin-5; IL-6- Interleukin-6; IFN-γ- interferon gamma. Created in BioRender.
Although hypothalamic-pituitary-adrenal axis dysfunction, vascular risk factors, and deficits in neurotransmitter signalling have been implicated in the pathogenesis of depression, including LLD, its neurobiological basis remains unclear. Over the past two decades, immune/inflammatory processes have also been associated with depression pathogenesis in pre-clinical and clinical studies (Köhler et al., Reference Köhler, Freitas, Stubbs, Maes, Solmi, Veronese, de Andrade, Morris, Fernandes, Brunoni, Herrmann, Raison, Miller, Lanctôt and Carvalho2018; Yin et al., Reference Yin, Zhang, Li, Tang, Zheng, Ma, Chen, Lei, Xiong, Guo, Li and Xie2023). For instance, systemic or central administration of lipopolysaccharide (LPS), a potent inductor of immune response, have been widely employed as a model of depressive-like behaviours in rodents (Yin et al., Reference Yin, Zhang, Li, Tang, Zheng, Ma, Chen, Lei, Xiong, Guo, Li and Xie2023). In clinical settings, a meta-analysis of 82 case-control studies reported increased circulating levels of the inflammatory cytokines TNF-α and IL-6 in patients diagnosed with MDD compared to healthy controls (Köhler et al., Reference Köhler, Freitas, Stubbs, Maes, Solmi, Veronese, de Andrade, Morris, Fernandes, Brunoni, Herrmann, Raison, Miller, Lanctôt and Carvalho2018). Cytokines play a pivotal role in the regulation of inflammatory response and have been implicated in intercellular communication, such as glia-neuron interaction, and neuronal activity (Barbosa et al., Reference Barbosa, Bauer, Machado-Vieira and Teixeira2014; Suchting et al., Reference Suchting, Razouq, Jose, Silva, Wardle, Soares, Teixeira and Selvaraj2023). As for depression in adults, cytokines have been associated with LLD onset and progression.
Cross-sectional studies have reported increased levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 in the serum of patients with LLD (Penninx et al., Reference Penninx, Kritchevsky, Yaffe, Newman, Simonsick, Rubin, Ferrucci, Harris and Pahor2003; Tiemeier et al., Reference Tiemeier, Hofman, van Tuijl, Kiliaan, Meijer and Breteler2003; Thomas et al., Reference Thomas, Davis, Morris, Jackson, Harrison and O’Brien2005; Bremmer et al., Reference Bremmer, Beekman, Deeg, Penninx, Dik, Hack and Hoogendijk2008). Similar findings were observed in longitudinal studies (Stewart et al., Reference Stewart, Rand, Muldoon and Kamarck2009; Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018). A two-year follow-up study with 521 Korean individuals aged ≥65 years showed a significant association between higher serum levels of IL-1β and IL-8 and LLD at baseline, independent of confounding variables like sex, cognitive performance, disability, lifestyle, and vascular risk factors. Both LLD at baseline and incident on follow-up were significantly associated with increased levels of IL-1β, IL-6, and IL8 at follow-up (Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018). Interestingly, increased inflammatory cytokine levels at baseline did not predict incident LLD, suggesting that cytokine changes could be secondary to the development of depression but not their main driver (Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018). A six-year longitudinal community study also showed that baseline IL-6 levels did not predict depressive symptoms on follow-up in a cohort of 263 healthy older adults (Stewart et al., Reference Stewart, Rand, Muldoon and Kamarck2009). Conversely, the Sydney Memory and Aging study reported that two-year incident depressive symptoms were associated with increased IL-18 levels at baseline in non-depressed and non-demented elderly participants aged 70 – 90 years (Baune et al., Reference Baune, Smith, Reppermund, Air, Samaras, Lux, Brodaty, Sachdev and Trollor2012). Furthermore, higher levels of IL-1 receptor antagonist (IL-1ra) at baseline were capable of predicting the development of LLD over a six-year follow-up (Milaneschi et al., Reference Milaneschi, Corsi, Penninx, Bandinelli, Guralnik and Ferrucci2009). Differences in the questionnaires and scales for evaluating depression, immunoassays for assessing biomarkers, age range of patients, and time-points of interviews may have contributed to the discrepancies found in these studies. Therefore, it remains to be defined whether elevated levels of inflammatory cytokines precede LLD onset (Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018), cytokines increase as a response to LLD, or both can coexist, reflecting the intrinsic heterogeneity of LLD. Further prospective studies are warranted to clarify this issue.
IL-6, known to be increased in ageing (Martínez-Cengotitabengoa et al., Reference Martínez-Cengotitabengoa, Carrascón, O’Brien, Díaz-Gutiérrez, Bermúdez-Ampudia, Sanada, Arrasate and González-Pinto2016), MDD and LDD (Kim et al., Reference Kim, Stewart, Kim, Kang, Bae, Kim, Shin and Yoon2018), is the primary cytokine responsible for inducing the hepatic synthesis and release of acute phase proteins (APPs) such as CRP, pre-albumin, and albumin (Bode et al., Reference Bode, Albrecht, Häussinger, Heinrich and Schaper2012). Among these APPs, CRP has been the most extensively investigated as an inflammatory marker in LLD. The Atherosclerosis Risk in Communities (ARIC) Study conducted a 21-year longitudinal study with 4,614 participants and demonstrated that individuals who maintained elevated plasma levels of CRP over the study period had greater depression symptoms as older adults (Sonsin-Diaz et al., Reference Sonsin-Diaz, Gottesman, Fracica, Walston, Windham, Knopman and Walker2020). This observation supports the concept that sustained chronic (or repeated) inflammation for years or decades may contribute to the development of depression later in life (Sonsin-Diaz et al., Reference Sonsin-Diaz, Gottesman, Fracica, Walston, Windham, Knopman and Walker2020). In this line, the Netherlands Study of Depression in Older Persons (NESDO) showed that, after adjustment for demographics, health indicators, and medication use, higher plasma levels of CRP were associated with LOD but not EOD, suggesting a distinct etiopathogenetic profile depending on depression onset (Rozing et al., Reference Rozing, Veerhuis, Westendorp, Eikelenboom, Stek, Marijnissen, Oude Voshaar, Comijs and van Exel2019). Prospective, large cohort studies with older participants also revealed that inflammatory dysregulation, including elevated CRP and IL-6 levels, alongside age-related metabolic changes (e.g., high triglycerides and glucose levels and lower levels of HDL cholesterol) were associated with more severe depression and worse clinical prognosis (de la Torre-Luque et al., Reference de la Torre-Luque, Ayuso-Mateos, Sanchez-Carro, de la Fuente and Lopez-Garcia2019; Kokkeler et al., Reference Kokkeler, Marijnissen, Wardenaar, Rhebergen, van den Brink, van der Mast and Oude Voshaar2022). Finally, a study assessing 22 senescence-associated secretory phenotype (SASP)-related proteins in the plasma of 111 older adults found that patients with LLD had significantly higher SASP index compared to non-depressed controls, after controlling for age, sex, medical comorbidities, and cognitive performance (Diniz et al., Reference Diniz, Reynolds, Sibille, Lin, Tseng, Lotrich, Aizenstein and Butters2017). Altogether, these results indicate the unequivocal association between LLD and a low-grade systemic inflammation.
In addition to systemic alterations, peripheral immunosenescence may cause microglial activation and neuroinflammation, which in turn may contribute to LLD (Ishizuka et al., Reference Ishizuka, Nagata, Nakagawa and Takahashi2024). Senescent/dystrophic microglia and increased inflammatory mediators such as TNF-α, IL-1β, and IL-6 have been detected in the aged brain (Streit et al., Reference Streit, Sammons, Kuhns and Sparks2004; Wong, Reference Wong2013; Ishizuka et al., Reference Ishizuka, Nagata, Nakagawa and Takahashi2024). Studies using positron emission tomography (PET) imaging have shown increased [11C]PK11195 binding in the anterior cingulate cortex and hippocampus of individuals with MDD (Holmes et al., Reference Holmes, Hinz, Conen, Gregory, Matthews, Anton-Rodriguez, Gerhard and Talbot2018) and LLD (Su et al., Reference Su, Faluyi, Hong, Fryer, Mak, Gabel, Hayes, Soteriades, Williams, Arnold, Passamonti, Rodríguez, Surendranathan, Bevan-Jones, Coles, Aigbirhio, Rowe and O’Brien2016). As [11C]PK11195 is a radioligand that binds to the translocator protein (TSPO), a receptor expressed on activated microglia, these neuroimaging findings corroborate neuropathological data connecting neuroinflammation and depression. Particularly in LLD, microglial reactivity was associated with increased peripheral levels of CRP, supporting the link between ageing-related systemic and brain inflammation in LLD (Su et al., Reference Su, Faluyi, Hong, Fryer, Mak, Gabel, Hayes, Soteriades, Williams, Arnold, Passamonti, Rodríguez, Surendranathan, Bevan-Jones, Coles, Aigbirhio, Rowe and O’Brien2016). Furthermore, microglial activation and neuroinflammation have been implicated in decreasing BDNF signalling during ageing (Wu et al., Reference Wu, Pan, Tsai, Chiang, Huang, Mo and Kuo2020). Lower serum and CSF levels of BDNF have been associated with LLD and worse clinical outcomes (Diniz et al., Reference Diniz, Teixeira, Machado-Vieira, Talib, Radanovic, Gattaz and Forlenza2014; Woods et al., Reference Woods, Babicz, Shahani, Colpo, Morgan and Teixeira2021). Upon binding to high-affinity tropomyosin-associated kinase family (Trk) receptors, BDNF play critical roles in synaptic plasticity and neuronal growth, survival and differentiation (Xia et al., Reference Xia, Chen, Shao, Chen, Zhu, Zhao, Luo, Yang and Wu2023). Pharmacological and non-pharmacological approaches, including physical exercise and diet, that have the potential to enhance systemic and brain BDNF levels in older individuals are promising therapeutic strategies for LLD (Azevedo et al., Reference Azevedo, Pereira, Silva Santos, Rocha, Teixeira, Christo, Santos and Scalzo2022; Pereira et al., Reference Pereira, de Queiroz, Miranda, Rocha, Felício, Mateo, Favero, Coelho, Jesus-Moraleida, Gomes Pereira, Teixeira and Máximo Pereira2013).
Another immune/inflammatory pathway that may underlie LLD onset and progression is the NOD-, LRR-, and Pyrin domain-containing protein 3 (NLRP3) inflammasome, composed of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 (de Miranda et al., Reference de Miranda, de Brito Toscano, O’Connor and Teixeira2024). NLRP3 inflammasome drives innate immune responses through the release of the inflammatory cytokines IL-1β and IL-18, with the former being consistently implicated in MDD and LLD (Xia et al., Reference Xia, Chen, Shao, Chen, Zhu, Zhao, Luo, Yang and Wu2023; Ishizuka et al., Reference Ishizuka, Nagata, Nakagawa and Takahashi2024). Metabolic diseases, including obesity and insulin resistance/diabetes, are common during ageing and have a reciprocal interaction with LLD (Martins et al., Reference Martins, Braga Tibães, Berk and Teixeira2022; Dias et al., Reference Dias, Teixeira, Diniz, Vieira, Viana and Barbosa2024). The pathological accumulation of endogenous metabolites, such as reactive oxygen species, cholesterol crystals, urate crystals and lipotoxic ceramides, can activate the NLRP3 inflammasome, leading to the release of cytokines and, hence, a cascade of pro-inflammatory events (Stienstra et al., Reference Stienstra, van Diepen, Tack, Zaki, van de Veerdonk, Perera, Neale, Hooiveld, Hijmans, Vroegrijk, van den Berg, Romijn, Rensen, Joosten, Netea and Kanneganti2011; Grant and Dixit, Reference Grant and Dixit2013; Lee et al., Reference Lee, Kim, Kim, Shong, Ku and Jo2013; Youm et al., Reference Youm, Grant, McCabe, Albarado, Nguyen, Ravussin, Pistell, Newman, Carter, Laque, Münzberg, Rosen, Ingram, Salbaum and Dixit2013; Xia et al., Reference Xia, Chen, Shao, Chen, Zhu, Zhao, Luo, Yang and Wu2023). The combination of metabolic diseases and inflammation has been associated with severe depressive symptoms in older individuals (de la Torre-Luque et al., Reference de la Torre-Luque, Ayuso-Mateos, Sanchez-Carro, de la Fuente and Lopez-Garcia2019; Kokkeler et al., Reference Kokkeler, Marijnissen, Wardenaar, Rhebergen, van den Brink, van der Mast and Oude Voshaar2022). Conversely, antidepressant treatments inhibited NLRP3 inflammasome in MDD, as observed by decreased serum levels of IL-1β and IL-18 and decrease of NLRP3 and IL-1β (p17) protein expression. Monitoring NLRP3 inflammasome components may have clinical value in drug selection and regulating the NLRP3/ASC/caspase-1/IL-1β/IL-18 pathway might be a promise therapeutic target for the development of novel antidepressant drugs (Alcocer-Gómez et al., Reference Alcocer-Gómez, Casas-Barquero, Williams, Romero-Guillena, Cañadas-Lozano, Bullón, Sánchez-Alcazar, Navarro-Pando and Cordero2017; Xia et al., Reference Xia, Chen, Shao, Chen, Zhu, Zhao, Luo, Yang and Wu2023; de Miranda et al., Reference de Miranda, de Brito Toscano, O’Connor and Teixeira2024). Large population clinical studies addressing the potential link between NLRP3 inflammasome and LLD may lead to a deeper understanding of LLD neurobiological basis, better stratification of patients, and improvement of treatment outcomes.
As the body ages, haematopoietic stem cells (HSCs) tend to differentiate into myeloid cells, limiting the maturation of lymphoid progenitors of T and B cells. During ageing, there is an increased recruitment of inflammatory monocytes into the brain (Martin et al., Reference Martin, Boucher, Fontaine and Delarasse2017). Interestingly, the age-related cognitive decline was associated with increased MCP-1/CCL2 levels, a chemokine involved with monocyte recruitment (Bettcher et al., Reference Bettcher, Neuhaus, Wynn, Elahi, Casaletto, Saloner, Fitch, Karydas and Kramer2019), and higher levels of this chemokine were observed in LLD (Bocharova et al., Reference Bocharova, Borza, Watne, Engedal, O’Brien, Selbæk, Idland, Hodsoll, Young and Aarsland2025). In addition, brains of depressed suicides show significantly more infiltrated monocytes than healthy controls (Torres-Platas et al., Reference Torres-Platas, Cruceanu, Chen, Turecki and Mechawar2014). The inflammatory profile of recruited monocytes into the brain may contribute to mood and cognitive changes observed in depression through activation of microglia, neurochemical changes (reduced monoamines and increased glutamate), and reduced brain neuroplasticity.
The aged-related inflammatory environment also contributes to immunosenescence of neutrophils, leading to cell metabolism dysregulation and increased neutrophils apoptosis (Dubey et al., Reference Dubey, Nagarkoti, Awasthi, Singh, Chandra, Kumaravelu, Barthwal and Dikshit2016). In MDD patients, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and monocyte to lymphocyte ratio are elevated (Demir et al., Reference Demir, Atli, Bulut, İbiloğlu, Güneş, Kaya, Demirpençe and Sır2015; Demircan et al., Reference Demircan, Gözel, Kılınç, Ulu and Atmaca2016; Bulut et al., Reference Bulut, Yorguner and Çarkaxhiu Bulut2021) and may hold clinical value as low-cost and easily accessible inflammatory markers of MDD development and progression (Kayhan et al., Reference Kayhan, Gündüz, Ersoy, Kandeğer and Annagür2017; Wei et al., Reference Wei, Hou, Zhang, Xu, Xie, Chandrasekar, Ying and Goodman2019). However, their clinical potential in LLD remains to be further explored.
In addition to myeloid cells, aged circulating lymphocytes may also contribute to physiopathology of LLD. Human ageing and mood disorders lead to the expansion of senescent T cells (ex., CD28null T cells), associated with poor immune responses and cognitive impairment (Bauer and Teixeira, Reference Bauer and Teixeira2019). These aged T cells are defined as senescent and display various cytotoxic and inflammatory properties, which may contribute to inflammaging by secreting large amounts of pro-inflammatory cytokines interferon (IFN)-γ, TNF-α, IL-1β, and IL-6 upon stimulation. The underlying mechanism by which senescent T cells modulate cognition is largely unknown, but there is preliminary evidence suggesting that senescent effector memory T cells can activate microglia (Ritzel et al., Reference Ritzel, Crapser, Patel, Verma, Grenier, Chauhan, Jellison and McCullough2016). Patients with depression or LLD had leukocytes with shortened telomeres than age-matched controls, especially those with a more severe depressive episode (Mendes-Silva et al., Reference Mendes-Silva, Vieira, Xavier, Barroso, Bertola, Martins, Brietzke, Belangero and Diniz2021). These changes support the notion that neuropsychiatric disorders are characterised by premature ageing. Although there is a lack of information regarding the role of aged T cells in LLD, one study reported the accumulation of peripheral senescent T cells (CD57+CD28null) in older hip fracture patients who developed depressive symptoms (Duggal et al., Reference Duggal, Upton, Phillips, Hampson and Lord2014).
Taken together these studies provided compelling evidence of the involvement of immunosenescence and inflammaging in the pathophysiology of LLD (Table 1), supporting the concept that targeting ageing-associated immune/inflammatory changes might be a promising therapeutic approach for LLD.
Table 1. Clinical evidence of inflammatory markers in late life depression
aMCI- amnestic mild cognitive impairment, BDNF- Brain-Derived Neurotrophic Factor; CBA- cytometric bead array; CRP- C-reactive protein; CCL-2-CC chemokine ligand 2; CCL-4-CC chemokine ligand 4; ELISA - enzyme-linked immunosorbant assay; EOD- early-onset depression; FABP-liver - fatty acid binding protein – liver; GDF-15-Growth Differentiation Factor-15; IL-1β - interleukin (IL)-1beta, IL-1ra -IL-1 receptor antagonist (ra); IL-4- interleukin (IL)-4; IL-6- interleukin (IL)-6; IL-10- interleukin (IL)-10; IL-17a- interleukin (IL)-17a; IL-18- interleukin (IL)-18; Interferon-gamma (IFN-γ); LLD- late life depression; MDD- major depressive disorder; MCI- mild cognitive impairment; NCD - non cognitive decline; NGAL-neutrophil gelatinase-associated lipocalin; PAI-1 -plasminogen activator inhibitor-1; PET -positron emission tomography imaging; sVCAM-1- serum vascular adhesion molecule-1; TNF-α- tumour necrosis factor-alpha;, TSPO- translocator protein.
Therapeutic opportunities in LLD: focus on inflammation
The DSM-5 criteria for depression are the same for younger and older adults. However, a patient with LLD tends to have more physical complaints such as fatigue, pain, multiple unexplained medical symptoms rather than a depressed mood and related subjective (e.g., sadness) symptoms (Hegeman et al., Reference Hegeman, Kok, van der Mast and Giltay2012). Despite these clinical and potential pathophysiological differences, the treatment of depression in older patients is also similar to the one applied to younger patients. The main treatments are depression-specific psychotherapies, like cognitive-behavioural and interpersonal therapies, and antidepressants. However, a significant proportion of patients with LLD have treatment-resistant depression (Steffens, Reference Steffens2024; 87). The mechanisms underlying this phenomenon are not clear (de Miranda et al., Reference de Miranda, C B Toscano, Venna, Graeff and Teixeira2025), but seem to involve clinical (e.g., presence of multiple physical comorbidities) and neurobiological mechanisms. As discussed above, LLD has significant associations with cerebrovascular burden, neurodegenerative changes and exacerbated inflammatory profile. In this context, inflammation-related biomarkers and targets could help the identification, categorisation, and management of LLD.
But what are the sources or causes of this inflammatory profile in LLD? Increasing evidence suggests that ageing and illness-related changes in neuroendocrine function with dysregulation of the hypothalamic-pituitary-adrenal axis, diet/microbiota (e.g., western diet pattern), unhealthy behaviours (e.g., physical inactivity, smoking, social isolation), and ‘wear and tear’ of physiological systems driven by comorbidities are important drivers of inflammation (Bauer & Teixeira, Reference Bauer and Teixeira2019; Teixeira et al., Reference Teixeira, Martins, Berk and Bauer2022). Therefore, addressing diet, physical inactivity, use of drugs and optimal management of physical comorbidities can be relevant strategies to prevent and/or minimise the severity of LLD (Martins et al., 2021, 2022; Pearce et al., Reference Pearce, Garcia, Abbas, Strain, Schuch, Golubic, Kelly, Khan, Utukuri, Laird, Mok, Smith, Tainio, Brage and Woodcock2022; Barbosa et al., Reference Barbosa, Miranda, Berk and Teixeira2025). For instance, the Mediterranean diet, usually characterised by a higher intake of fruits, vegetables, whole grains, and good quality sources of protein (e.g., fish) and diets with lower ‘Diet Inflammatory Index’ have been associated with lower incidence of depression (Lassale et al., Reference Lassale, Batty, Baghdadli, Jacka, Sánchez-Villegas, Kivimäki and Akbaraly2019). Moreover, microbiota-targeted interventions, such as symbiotics, prebiotics, and probiotics, seem to attenuate depression, at least in part, through inflammation-related mechanisms (Barbosa et al., Reference Barbosa, Miranda, Berk and Teixeira2025). One caveat is related to the fact that most of the available evidence in the field of nutrition psychiatry has been obtained in adult populations, and studies involving older adults and LLD are still scarce.
In addition to their effects on neurotransmitter systems, influencing the levels of monoamines and the expression of related receptors, antidepressants also have immunomodulatory actions (Tomaz et al., Reference Tomaz, Chaves Filho, Cordeiro, Jucá, Soares, Barroso, Cristino, Jiang, Teixeira, de Lucena and Macedo2020). A recent meta-analysis including 839 patients confirmed that selective serotonin reuptake inhibitors (SSRIs) significantly reduce the circulating levels of IL-6 and TNF-α in patients with depression (Patel et al., Reference Patel, Varma and Ganguly2024). While this decrease may be an indirect effect of depression improvement, SSRIs can directly influence immune cells number (decreasing their proliferative activity and increasing their apoptosis) and function (Szałach et al., Reference Szałach, Lisowska and Cubała2019). It is therefore tempting to speculate that the therapeutic effects of antidepressants are partly mediated by their immunomodulatory/anti-inflammatory actions. This hypothesis is supported by studies showing that anti-inflammatory and immunomodulatory strategies, including non-steroidal anti-inflammatory and anti-cytokine antibodies, can improve depressive symptoms (Colpo et al., Reference Colpo, Leboyer, Dantzer, Trivedi and Teixeira2018; Köhler et al., Reference Köhler, Freitas, Stubbs, Maes, Solmi, Veronese, de Andrade, Morris, Fernandes, Brunoni, Herrmann, Raison, Miller, Lanctôt and Carvalho2018). However, in contrast with studies carried out in adult populations, clinical trials with celecoxib (Fields et al., Reference Fields, Drye, Vaidya and Lyketsos2012), naproxen (Fields et al., Reference Fields, Drye, Vaidya and Lyketsos2012), and aspirin (Berk et al., Reference Berk, Agustini, Woods, Nelson, Shah, Reid, Storey, Fitzgerald, Lockery, Wolfe, Mohebbi, Dodd, Murray, Stocks, Fitzgerald, Mazza and McNeil2021) in LLD failed to demonstrate benefit of anti-inflammatory strategies. These data strengthen the view that LLD must be seen as a condition with unique pathophysiological mechanisms and, thus, a particular therapeutic response profile, not necessarily as an extension of adult depression. It is possible that inflammation-related biomarkers can help to define subtypes of LLD. Although previous attempts to differentiate clinical subtypes of depression in adults (e.g., atypical versus melancholic) based on inflammatory biomarkers have failed (Veltman et al., Reference Veltman, Lamers, Comijs, Stek, van der Mast and Rhebergen2018), this hypothesis must be thoroughly considered in LLD where other biological players (e.g. neurodegeneration) play pivotal roles.
It is worth mentioning that neuromodulation methods, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and vagus nerve stimulation, have shown promising results in the elderly population with depression (Steffens, Reference Steffens2024). Interestingly, it has been proposed that the observed therapeutic effects are partly mediated through immune/inflammatory mechanisms (Kranaster et al., Reference Kranaster, Hoyer, Aksay, Bumb, Müller, Zill, Schwarz and Sartorius2018; Belge et al., Reference Belge, Van Diermen, Sabbe, Moens, Morrens, Coppens, de Timary, Constant, Vansteelandt, Sienaert and Schrijvers2021; Goerigk et al., Reference Goerigk, Cretaz, Sampaio-Junior, Vieira, Gattaz, Klein, Lafer, Teixeira, Carvalho, Lotufo, Benseñor, Bühner, Padberg and Brunoni2021). For instance, Zhao et al. (Reference Zhao, Li, Tian, Zhu and Zhao2019) reported that a course of TMS for five times a week for four weeks significantly decreased the severity of depression symptoms in parallel with increase in BDNF levels, and decrease in IL-1β and TNF-α levels in patients with treatment-resistant LLD (Zhao et al., Reference Zhao, Li, Tian, Zhu and Zhao2019). The evidence is less clear for ECT as cytokine levels and CRP were similar between remitters and non-remitters patients with LLD submitted to ECT (Carlier et al., 2019, 2022).
Conclusion
LLD has unique clinical and biological features compared to depression in other periods of life. The recognition of its intrinsic pathophysiological heterogeneity, comprising multiple psychosocial and biological pathways, is an important step toward its proper management. Inflammatory mechanisms seem to play pivotal roles in LLD development and progression, directly influencing neural circuits subserving depressive symptoms and indirectly influencing other pathways, such as vascular and neurodegenerative ones. While the pathogenesis of the low-grade inflammation in LLD is still unclear, it is potentiated by the senescence of immune cells (that tend to assume a proinflammatory profile with ageing) and the burden of physical comorbidities (e.g., cardiovascular and metabolic diseases). These inflammatory mechanisms can be targeted and, if downregulated, can help to mitigate and/or prevent LLD. In this context, immune-based strategies may play a therapeutic role for LLD. Large-sample, randomised, double-blind clinical studies focusing on anti-inflammatory treatment for geriatric depression is urgent needed to deepen our understanding of the efficacy and safety of these therapies for LLD.
Supplementary material
For supplementary material/s referred to in this article, please visit https://doi.org/10.1017/neu.2025.10019
Author contribution
All authors contributed to the conceptualisation, writing, and review of the manuscript.
Financial support
This paper was not funded.
Competing interests
The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.
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