Frailty is defined as a state of increased vulnerability to stressors, at the core of which is a decline in physiological reserves or decompensation of multiple organ systems, leading to an increased risk of adverse outcomes (1–3). Frailty is related not only to advanced age, but also to chronic diseases and infections. Accumulating evidence has indicated that people living with HIV (PLWH) experience a higher prevalence of frailty compared to non-HIV-infected people (4–6). A cross-sectional study of 2028 women conducted in the United States of America indicated that the prevalence of frailty in PLWH was 17.3%, which is significantly higher than that in non-HIV-infected individuals (10.0%) (7). One prospective cohort study in the Netherlands utilized the Fried frailty phenotype score to assess the prevalence of frailty in 521 HIV-infected and 513 non-HIV-infected individuals, and observed that the prevalence of frailty in HIV-infected individuals was 10.6% and the prevalence of pre-frailty was 50.7%, which were significantly higher than prevalence rates in non-HIV-infected individuals (2.7% and 36.3%) (8). A cross-sectional study in Brazil assessed the prevalence of frailty and quality of life in 201 HIV-infected patients aged ≥50 years and observed that the prevalence of frailty in HIV-infected patients was 19.4% and the prevalence of pre-frailty was 49.3% (9); a similar study assessing patients in Canada observed that the prevalence of frailty in HIV-infected patients aged ≥50 years was 14% (10).

The underlying mechanisms which result in frailty has been investigated in the non-HIV-infected population. Previous studies have revealed that impaired intestinal permeability (11, 12) and the translocation of gut microbiota and products (13, 14) may possibly lead to an overall frail state over time. In 2017, Buford and colleagues confirmed that serum concentrations of zonulin and high-mobility group box protein (HMGB1) were 22% (p=0.005) and 16% (p=0.010) higher in older adults compared to young adults (15). Four years later, Xiong et al., further demonstrated that higher concentrations of zonulin and HMGB1 were associated with frailty in older adults (16). A systematic review which included ten case-control studies and one cohort study observed that frail older adults had significantly increased levels of serum zonulin, pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α), HMGB-1, interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL1-ra), and macrophage inflammatory protein beta (MIP-1β)] than healthy controls (17). A study by Kühn indicated that oral intestinal alkaline phosphatase (IAP) supplementation may regulate the intestinal barrier and further counteract the chronic inflammatory state which leads to frailty (18). The preceding studies indicate that intestinal barrier damage is one of the key underlying mechanisms leading to frailty in non-HIV-infected older populations.

It has been previously shown that HIV infection damages and disrupts the intestinal barrier, and that intestinal barrier damage may be associated with microbial translocation (19, 20), local and systemic inflammation, and the development of non-acquired immune deficiency syndrome (AIDS)-related comorbidities (21). However, there is a paucity of direct research evidence which demonstrates the putative association between intestinal barrier damage and frailty in PLWH. The present study measured representative hematological biomarkers of intestinal barrier damage, microbial translocation, and systemic inflammation in aging PLWH (aPLWH) with or without frailty, aiming to ascertain whether intestinal barrier damage may or may not contribute to a higher prevalence of frailty in aPLWH, and to potentially reveal mechanisms which underlie the development of frailty in aging.

In a review published in 2018, Di Sabatino et al., discussed the correlation between intestinal barrier function and frailty in the general population, and proposed the hypothesis that preservation of gut permeability and maintenance of gut microbiota composition might reduce the susceptibility to develop, or even prevent frailty-related changes (28). Several past reviews have illustrated the intricate relationship between frailty and gut anomalies. Chen et al., for example, have observed that in frail individuals, the most significant change in the gut microbiota is a decrease in the microbial (alpha) diversity of the gut microbiome (13). Picca et al., also observed that frail patients have decreased gut microbiota abundance and changes to serum concentrations of some cytokines (29). Although previous studies have reported that gut microbiota alterations in PLWH are associated with frailty, no past studies have definitively demonstrated the association between gut barrier damage/dysfunction and frailty. Our study has observed that in frail/pre-frail PLWH, the levels of gut damage biomarkers (Reg-3α and I-FABP) are higher than in non-frail participants, and even after adjusting for confounding factors, levels of I-FABP in blood remain significantly different between the two groups. Meanwhile, LPS and sCD14 levels in serum/plasma were observed to correlate with the Freid Phenotype Score. Plasma biomarkers related to intestinal barrier damage (including I-FABP and, REG3α) as well as biomarkers of microbial translocation [such as lipopolysaccharide (LPS), (1,3)-β-D-glucan (BDG), and sCD14] have been shown, in previous studies conducted by our team, to be relevant in assessing intestinal barrier function in HIV-infected individuals (30). The present study reveals the correlation between the preceding biomarkers and frailty, suggesting that a possible mechanism for the emergence of frailty in older HIV-infected individuals may be related to damage or dysfunction of the intestinal barrier.

Most often, frailty is mentioned in conjunction with inflammation, and there has been shown to be an undeniable relationship between them (31, 32). Some studies have suggested that gut biomarkers may trigger a significant immune response during HIV infection (33), causing the synthesis and release of pro-inflammatory cytokines such as IL-8 and IL-6 into the circulation (30). A systematic review by Rashidah et al., observed that frail older adults produce increased pro-inflammatory cytokines (IL-6) when compared to healthy controls (17). The present study observed both the positive correlation between inflammatory cytokines (IP-10) and frailty in aPLWH, and also between inflammatory cytokines (IL-6, IL-8 and IP-10) and biomarkers of intestinal barrier damage (as shown in Figure 2 ). In light of this, we have hypothesized that in aPLWH, the impaired intestinal barrier promotes hyper-activation of the mucosal immune system, and thus, the production of pro-inflammatory cytokines (34), which consequently fosters the emergence and development of frailty.

Although the present study found different distributions of inflammatory cytokines between case and control groups, the detected levels of IL-6 and IL-8 were lower than those in other studies. In research involving HIV-infected patients, IL-6 in plasma of PLWH prior to ART initiation (median: 2.7 pg/mL; IQR: 0.9–40.6 pg/mL) was higher than those without HIV infection (median: 1.5 pg/mL; IQR: 0.5–11.3 pg/mL), subsequently decreasing to levels lower than those of HIV-negative participants after viral suppression (median: 1.2 pg/mL; IQR:0.3–4.0 pg/mL) (35). In a study from Brazil, IL-8 levels measured in HIV-negative participants (median: 3.2 pg/mL; IQR: 2.29–4.96pg/mL) were lower than those in PLWH (median: 5.13 pg/mL; IQR: 4.26–6.48 pg/mL), although no statistically significant difference was noted between the groups (27). Given the naturally low expression of IL-6 and IL-8 in PLWH, it is important to consider potential influences from sample cryostorage and freeze-thaw cycles (36, 37), as well as anticoagulants (36–38). These factors may have contributed to values approaching zero for both IL-6 and IL-8 in this study, as illustrated in Table 2 .

Frailty is multidimensional and complex, and some studies have classified frailty into physical frailty, psychological frailty, cognitive frailty, and social frailty according to the relevant prevailing characteristics in an afflicted patient (39, 40). In this study, the frailty assessment that we have employed primarily focuses on physical frailty, as it is frequently associated with poorer survival outcomes (41) and because the Fried frailty phenotype score utilized herein effectively evaluates the frailty status related to physical health, having been widely applied and validated in the relevant literature. Social frailty includes difficulties in understanding and communication, and difficulties in social participation and social support, and it has been reported that in the general population the incidence of social frailty is approximately 20% (42). The present study observed that in aPLWH, the incidence of social frailty [difficulties in understanding and communication (30%), and difficulties in social participation (80.7%) and social support (29.3%)] is higher than that in the general population. Also, the incidence of stress (30%), depression (41.4%) and anxiety (52.1%) is higher than that in the general older population (14%) (43). This suggests that HIV infection may exacerbate the degree of comorbid social and psychological disorders, and may well be induced by the shame, stigma, and social ostracization associated with HIV infection, and poor self-acceptance of the individual’s diagnosis after HIV infection (44–46).

The intestinal barrier is influenced by a multitude of factors, including stress and anxiety. Past research has demonstrated that chronic psychological stress and anxiety may lead to increased intestinal permeability and trigger inflammatory responses, thereby adversely impacting intestinal health. These factors may be particularly pronounced in PLWH, as mental health conditions can significantly affect the immune systems and overall well-being of these patients (47–49). In the present study, we observed a higher prevalence of anxiety, stress, and depression within the frail population; however, this difference was eliminated following multivariable statistical adjustment. Future studies must carefully consider the roles that stress and anxiety may play when investigating potential causal relationships between intestinal barrier damage and frailty.

Frailty in PLWH is also associated with prevailing HIV viral loads and CD4+ T-cell counts (which represents severity of HIV infection) (32), and our results in the present study concur with this, indicating that uncontrolled HIV replication and impaired immune function may increase the risk of development of frailty. Nadir CD4+ T-cell counts between the two groups of participants also showed a statistically significant difference, suggesting that the severity of HIV infection may also influence the development of the frailty.

We acknowledge that our study has several limitations. Firstly, the sample size is relatively small and has been derived from a single hospital, and this may impact the statistical power and reliability of the results of our study. Also, as this was a preliminary study, the inclusion and exclusion criteria were not prohibitively strict. To obtain more accurate results which focus specifically on the relationship between intestinal barrier damage and frailty, it would have been beneficial to mitigate certain confounding factors, such as the duration of HIV infection, HIV RNA viral loads, and CD4+ T-cell counts. Appropriate control of these factors may more lucidly explain the association between frailty and intestinal barrier damage. Some samples used for the present study were stored for an extended period, potentially resulting in protein degradation, which renders the low-expressing biomarkers used for this study undetectable, and leading to potential effects related to statistical correlations utilized in this study. As the present study is a retrospective case control study, we inevitably expect some recall bias, and thus prospective cohort studies in this specific field of research are required to validate our findings.

In conclusion, frailty may be considered as a comprehensive, intuitive clinical syndrome for aging persons which may potentially lead to higher hospitalization risk and substantial additional healthcare costs (50, 51). The present study indicates that the inflammation induced by intestinal barrier damage that is observed in HIV-infected individuals is likely to contribute to frailty in older PLWH. Our observations in this study may possibly contribute to the development of novel interventional options for the mitigation of manifestations of frailty, to further extend the lifespans of aPLWH, and to improve the overall quality of life of individuals with HIV infection.