In this study, through the use of thiol-disulfide parameters, we were able to demonstrate that older adults living with frailty had higher levels of oxidative stress. We showed that older adults living with frailty were more likely to experience geriatric syndromes, including low functionality, depressive symptoms, sarcopenia, malnutrition, poor sleep quality, and polypharmacy. The fact that just two of the complete geriatric assessment parameters—the FFI and SARC-f scores—correlated with thiol-disulfide homeostasis may mean that oxidative stress primarily impacts physical capacity. The significant correlation could not be retained with the CFS scores. In addition, we were able to detect frailty using thiol-disulfide homeostasis parameters in ROC analysis.
Frailty is a complex concept that encompasses multiple dimensions and is not limited to any certain age group. Since frailty is a reversible process, it is important to diagnose it at an early stage and prevent its progression. In this regard, many biomarkers have been examined in frailty detection to date, and most of these biomarkers are oxidative stress-related biochemicals. Besides, many circulating biomarkers, such as CRP, hemoglobin, albumin, 25-hydroxy vitamin D, and free testosterone have been associated with frailty in previous research [35]. Consistent with the literature, the present study observed a statistically significant decrease in CRP and albumin levels in the frail group.
Oxidative stress increases with advancing age and causes DNA damage; however, it may be insufficient to explain this increased oxidative stress with biological age alone. Several studies showed that plasma lipid peroxidation and protein oxidation, which are indicators of oxidative stress, are associated with frailty regardless of age [36]. In the FRAXI study, Mensah et al. showed that nitrotyrosine and 8-hydroxy-2'-deoxyguanosine, as markers of oxidative stress, were significantly higher in older adults living with frailty defined by the CFS, leading to arterial stiffness [37]. Wu et al. also found that the same biomarkers are associated with frailty defined by the FFI in the older Chinese population [38]. In another study, it was shown that oxidative stress, as determined by GSH/GSSG ratio analysis, is higher in older adults living with CFS-defined frailty. The link between DNA damage accumulation and physical frailty was also established in the same study [8]. In studies where frailty and sarcopenia were evaluated together, negative correlations were found with albumin and hemoglobin levels, while Interleukin 6 and tumor necrosis factor-alpha levels were found at higher levels when compared to robust and nonsarcopenic individuals [39]. In our study, NT and TT levels were significantly lower in the frail group. Besides, significant results were obtained in the NT, TT, D/NT, D/TT, and NT/TT parameters in the diagnosis of frailty in ROC analyses, showing that we can use these parameters in the diagnosis of physical frailty.
Dynamic thiol/disulfide homeostasis plays a crucial role in the antioxidant system of the organism. Thiols are very sensitive to oxidation due to the sulfhydryl groups in their structure. Disulfides are covalent bonds between two thiol groups and play an active role in cellular reduction and oxidation processes. In the case of oxidative stress, with the reduction of thiols to disulfides, total thiol levels decrease and disulfide levels increase. Thiol/disulfide switches play critical roles in signal transduction, thiol protection, and redox homeostasis regulation [11]. This balance has been shown to be disrupted in cases such as acute myocardial infarction, hypertension, diabetes mellitus, Alzheimer's disease, diabetic nephropathy, schizophrenia, depression, acute pulmonary embolism, nonsmall cell lung cancer, celiac disease, acute pancreatitis, and inflammatory bowel disorder, as well as familial Mediterranean fever [40–45]. To date, many approaches have been used to quantify thiol levels in order to elucidate this defense function in the organism against oxidative stress. In the method developed by Erel and Neselioglu, disulfide levels are measured as well as native thiol levels, and total thiol levels, which are the sum of native thiol and disulfide levels, are obtained [33]. In the present study, we showed that older adults living with frailty have low native thiol and total thiol levels. Besides, physical frailty scores were significantly correlated with NT and TT levels, D/NT, D/TT, and NT/TT ratios. The reason why we could not detect a significant relationship with the CFS scores may be that this scale includes parameters other than physical components. TDH parameters could be insufficient for recognizing other components of frailty.
Cognitive decline, functional dependency, malnutrition, sarcopenia, insomnia, polypharmacy, and depression accelerate the progression of frailty. The coexistence of these geriatric syndromes makes older adults more vulnerable to internal and external stressors and can lead to increased oxidative stress. The reason for the significantly lower NT and TT levels in older adults living with frailty in our study population may be that geriatric syndromes are more common in this group. Finding the most significant correlation between frailty scores and thiol-disulfide parameters, which is one of the comprehensive geriatric assessment parameters, reminded us that frailty scores are a reflection of comprehensive geriatric assessment. Besides, we found a significant correlation between SARC-f scores and native thiol and total thiol levels. It is known that oxidative stress increases with sarcopenia. However, this result may vary according to the study population and the oxidative stress biomarker examined. While studies show that the presence of sarcopenia is associated with high xanthine oxide levels in diabetic individuals, there are also studies showing that there is no significant difference in thioredoxin-1 and pentraxin-3 levels in older adults with sarcopenia when compared with non-sarcopenic older adults [46, 47]. In Özsürekçi et al.'s study, thiol–disulfide levels and disulfide total and native thiol ratios were similar between sarcopenic and non-sarcopenic older patients [48].
IMA is a marker of ischemia-induced oxidative damage. Acute myocardial ischemia, renal ischemia, diabetes mellitus, dyslipidemia, and hypertension can cause an elevation in IMA levels. Histopathological studies have also revealed that IMA levels increase in parallel with the duration of ischemia [49]. Especially in diabetic individuals, IMA can be used as an indicator of oxidative stress in cases of poor glycemic control and dyslipidemia [50]. In studies conducted with obese individuals, a high IMA level was found to be associated with oxidative damage [51]. However, in a study examining the relationship between the presence of sarcopenia and IMA levels in the geriatric population, no significant increase in IMA levels was found in the sarcopenic group. In this study, we could not find any relationship between IMA levels and physical frailty. A study with a population with a higher level of frailty may achieve significant results in the relationship between frailty status and IMA levels.
The strengths of the study include the use of two frailty scales, both physical and cumulative deficit models, comprehensive geriatric assessment of all individuals, and the evaluation of the relationship between all these results and thiol-disulfide homeostasis parameters.
The cross-sectional design can be shown as a limitation of this study. Since frailty is a continuous process, prospective studies may provide more accurate results. Repeating the study with a population with a higher level of frailty may provide more significant results. Prospective studies with different oxidative stress biomarkers may contribute to evaluating the definition, pathophysiology, and consequences of frailty. Besides, the number of participants in the study population was sufficient to determine the relationship between frailty and thiol-disulfide parameters; more participants are needed to determine the NT and TT cut-off values in the diagnosis of frailty.