Frailty is recognized as a medical condition, with its initial definition attributed to Fried et al. (1), characterizing it as “a heightened vulnerability to homeostatic disruption following a stressful event.” As the global population ages, the prevalence of frailty is on the rise, positioning it as a growing health concern worldwide. Beyond impacting the quality of life, frailty is linked to higher mortality, increased hospital admissions, a heightened risk of falls, and the demand for prolonged care (2). This makes its prevention and management crucial for public health.

Fatigue, defined as a symptom associated with the weakening or depletion of a person’s physical and/or mental resources, constitutes a fundamental component of frailty (3–5). Often overlooked, fatigue is a non-motor symptom of Parkinson’s disease (PD). While James Parkinson identified fatigue in patients with the disease as far back as 1817, it was only in 1993 that researchers pinpointed fatigue as a concurrent condition in PD, marking it as a distinct non-motor symptom (6, 7). This symptom is among the most debilitating for those with PD (8). Remarkably, fatigue is prevalent in over half of PD (9), with studies indicating its occurrence in 33 to 70% of cases (9). This fatigue can appear early in Parkinson’s progression, even before the onset of motor symptoms, significantly affecting patients’ quality of life (10). Furthermore, while cross-sectional studies have established the high prevalence of frailty in PD patients, recent longitudinal investigations have uncovered a significant association between frailty and incident PD. This relationship persists independently of sociodemographic characteristics, lifestyle factors, multiple comorbidities, and genetic predisposition (11). The widespread nature of fatigue/frailty in Parkinson’s underscores the imperative for comprehensive research.

With the rise in global life expectancy, aging-related chronic diseases are also on the increase (12). Two predominant topics in aging research are frailty and oxidative stress (13). The latter emerges from the overproduction of reactive oxygen species (ROS) and an imbalance within the antioxidant system (12). This skewness can result in cellular damage, hastening the aging process and leading to cell death (12). Recent research indicates a strong link between frailty and oxidative stress (13, 14). Such stress can particularly impair muscle cells, causing diminished muscle function - a hallmark of frailty (15, 16). Moreover, oxidative stress ties in with inflammation, further influencing the development of frailty (17). A deeper grasp of these interactions could pave the way for novel strategies to address frailty, improving elderly health and life quality. As a result, diets high in antioxidants show promise in countering frailty and safeguarding the nervous system. The Composite Dietary Antioxidant Index (CDAI) provides a comprehensive evaluation of an individual’s intake of dietary antioxidants. It encompasses a mix of dietary antioxidants, including vitamins A, C, E, selenium, zinc, and carotenoids (18), and was crafted due to its cumulative anti-inflammatory actions against markers like TNF-α and IL-1β. The CDAI is not only tied to several health outcomes such as depression, overall mortality, and colorectal cancer but also acts as a vital metric for analyzing the link between antioxidant dietary consumption and overall health (15). Yet, research has not yet delved into how dietary antioxidant intake affects frailty, especially among PD sufferers.

Using a nationally representative NHANES cohort, we investigated the correlations of the dietary antioxidant index (CDAI) and its components with frailty status in the general population and PD patients. We hypothesized that higher antioxidant intakes would be associated with lower frailty risk. Additionally, we employed restricted cubic splines (RCS) to flexibly model potential nonlinear dose–response patterns, informing individualized intake recommendations. Findings from this study will help elucidate the role of dietary antioxidants in frailty etiology and provide evidence to guide nutritional guidance for managing frailty.

In this large, nationally representative study, we found novel evidence that higher CDAI and its component antioxidants are associated with lower likelihood of frailty in the general US population aged 40 years and older. Several antioxidants including vitamins A, C, E, selenium and carotenoids exhibited nonlinear J-shaped correlations with frailty risk, highlighting potential optimal intake levels. These findings persisted after adjusting for various sociodemographic, lifestyle, and health factors. Notably, these associations were weaker and less consistent among PD patients, suggesting potential disease-specific differences in the role of dietary antioxidants in frailty etiology and management. The antioxidant-frailty associations were notably attenuated and less consistent in this patient population, suggesting that the complex pathophysiology of PD may modulate the impact of dietary antioxidants on frailty. These differential findings underscore the need for a nuanced, disease-specific approach to understanding the role of dietary antioxidants in frailty etiology and management, particularly in the context of neurodegenerative conditions like PD.

Our analyses revealed different patterns of antioxidant-frailty associations between the general population and PD patients. In the general population, higher CDAI was consistently associated with lower frailty prevalence. All studied antioxidants (vitamins A, C, E, zinc, selenium, and carotenoids) showed protective effects against frailty. However, among PD patients, the CDAI-frailty association was notably weaker, with only vitamins C and E, selenium, and carotenoids showing protective effects. The dose–response patterns also differed between populations. In the general population, several antioxidants showed J-shaped relationships with frailty risk, suggesting optimal intake ranges. In contrast, PD patients showed simpler relationships, with only vitamin C and zinc demonstrating nonlinear associations. These distinct patterns suggest that dietary antioxidants may work differently in PD patients compared to the general population, highlighting the need for disease-specific approaches to nutritional intervention.

Previous studies have suggested a potential link between frailty and oxidative stress. Oxidative stress results from an imbalance between reactive oxygen species and antioxidants, leading to cellular damage. This imbalance may contribute to the pathophysiology underlying frailty in the elderly. Some researchers propose that oxidative stress-induced damage could be an early event in the development of frailty, as it may lead to the multiple alterations seen in frail individuals (30, 31). Furthermore, oxidative stress has been implicated as a key mechanism in neurodegenerative diseases like Alzheimer’s disease and PD (13), suggesting it may significantly impact the progression of frailty symptoms. Epidemiological studies reveal an association between physical frailty and cognitive decline, with mitochondrial dysfunction and oxidative stress as potential common denominators (32, 33). Given the role of oxidative stress in neurodegenerative diseases, antioxidant supplementation may help ameliorate cognitive impairment and thereby an important component of frailty (34). Further research is warranted to elucidate the relationship between oxidative stress, frailty, and neurodegenerative disease. Antioxidant therapy may provide a potential avenue for prevention or treatment of frailty, particularly the cognitive aspects, in aging populations.

Handgrip strength serves as a valuable diagnostic tool for assessing frailty. Prior investigations have consistently demonstrated a strong positive correlation between handgrip strength and the CDAI. Notably, the intake of antioxidant nutrients such as vitamin E, selenium, and zinc has been linked to enhanced handgrip strength among men, while for women, improved handgrip strength is specifically associated with zinc intake (15). An in-depth exploration of dietary status and frailty among elderly Koreans revealed that elevated consumption of vitamin D, vitamin C, and folate holds the potential to mitigate frailty and diminish the risk of malnutrition in the aging population (35). Similar findings have been replicated in various cross-sectional studies (36). Furthermore, a separate cross-sectional study unveiled that individuals with robust health exhibit higher levels of blood carotenoids in comparison to frail or pre-frail counterparts. This underscores the potential utility of carotenoid concentrations as a blood biomarker for assessing frailty (37). In the context of a prospective Australian study, it was established that inadequate intake of antioxidants, particularly vitamin E, significantly correlates with frailty in elderly men. The investigation also indicated that supplementation with low-dose antioxidants could be a promising strategy for preventing frailty (38). Our study undertook a comprehensive analysis of the collective impacts of these dietary antioxidants and identified a positive relationship between heightened total antioxidant intake and reduced frailty. Furthermore, we observed that insufficient intake of selenium and zinc corresponded to an increased risk of frailty. Some research has indicated that diminished serum selenium levels are linked to reduced muscle mass in elderly women (39), as well as diminished handgrip strength among older females (40). The deficiency of zinc may impair antioxidant functionality, potentially contributing to muscle loss and frailty. However, the relationship between zinc and frailty requires further substantiation through additional evidence (41). Within our study, increased intake of zinc and carotenoids was associated with reduced frailty, while other antioxidants, including vitamins A, C, and E, as well as selenium, demonstrated efficacy in alleviating frailty only when consumed below specific threshold levels.

Degeneration of dopaminergic neurons is the core pathology in Parkinson’s disease, and oxidative stress is a major contributing factor to this neurodegeneration (42). Deficiencies in some antioxidant vitamins have been shown to associate with increased PD risk, and may even contribute to PD onset and progression, such as carotenoids, vitamin A, and vitamin C (43–45). Previous studies show vitamin A intake can effectively protect dopaminergic neurons and improve motor impairment in PD rat models in vitro (46). However, contradictory results exist, as supplementing vitamin A may also promote oxidative stress, increase α-synuclein phosphorylation, elevate oxidative stress levels, and facilitate neuronal death (47). Some cohort studies have struggled to elucidate correlations between vitamin A and PD risk, indicating the role of vitamin A in neuroprotection remains unclear (48, 49). Our study found vitamin A exhibited a possible U-shaped relationship with PD frailty improvement, though not statistically significant. Vitamin E deficiency may lead to dopaminergic neuron degeneration (44), and dietary vitamin E intake associates with reduced PD risk (50). Similarly, dietary zinc intake correlates with decreased PD risk (51). Basic research has confirmed selenium as a protective factor for PD. For example, sodium selenite can dose-dependently reverse the decrease in dopamine and metabolites induced by MPTP (52). A selenium-deficient diet can enhance methamphetamine-induced tyrosine hydroxylase-like immunoreactivity in the substantia nigra, reduce dopamine and metabolites, exacerbate loss of dopaminergic neurons, while a selenium-rich diet can significantly mitigate methamphetamine neurotoxicity in dopaminergic neurons (53). Although various dietary antioxidants demonstrate neuroprotective effects in PD, no studies have examined associations between dietary antioxidants and PD frailty. Our results show increased dietary zinc and carotenoid intakes associate with reduced frailty risk in a dose-dependent manner. Additionally, total dietary antioxidant intake may correlate with improved PD frailty.

In summary, for the general population, our findings suggest that adopting a diet rich in these key antioxidant nutrients may help prevent or manage frailty. This could involve increasing consumption of fruits, vegetables, nuts, seeds, and other antioxidant-dense foods. In contrast, the associations between dietary antioxidants and frailty were weaker and less consistent among PD patients. This suggests that the management of frailty in PD may require a more nuanced, disease-specific approach that goes beyond just optimizing antioxidant intake. Personalized nutritional strategies combined with other therapeutic approaches may be most beneficial for this patient population.

This study has several notable strengths. Firstly, the large, nationally representative NHANES dataset allowed analysis of over 21,000 adults to provide robust insights into antioxidant-frailty associations in the general United States population. Furthermore, the availability of detailed dietary data enabled construction of the composite Dietary Antioxidant Index as well as investigation of individual antioxidant components. Other strengths include adjustment for a comprehensive set of confounders, measurement of frailty using a validated scale, and novel use of flexible nonlinear methods to uncover potential optimal intake levels.

Despite these strengths, our study has several limitations that warrant consideration. First, the cross-sectional design precludes causal inferences about the relationship between dietary antioxidants and frailty. Although we adjusted for numerous potential confounders, residual confounding by unmeasured factors such as physical activity, sleep quality, and medication use cannot be ruled out. Second, dietary intake was assessed using 24-h recalls, which may not capture long-term or usual intake patterns and are susceptible to recall bias. However, the use of trained interviewers and standardized protocols in NHANES helps mitigate these issues. Third, while the frailty index is a validated measure of overall health status, it may not fully capture all dimensions of frailty. Future studies using more specific frailty scales are needed to confirm our findings. Fourth, the relatively small sample size of PD patients may have limited statistical power to detect associations in this subgroup, especially for the rarer antioxidant nutrients. Finally, the lack of longitudinal follow-up data precluded assessment of temporal relationships and changes in frailty status over time. Prospective cohort studies with repeated measures of diet and frailty are needed to better understand the long-term effects of dietary antioxidants on frailty risk and progression.

In conclusion, this is the first study elucidating the link between dietary total antioxidant intake and frailty risk, while also revealing differences between the general and PD populations. This large nationally representative study provides novel evidence linking higher dietary antioxidant intake to lower frailty risk in the general US population aged 40 and older. We found significant inverse associations between the CDAI and several individual antioxidant nutrients, including vitamins A, C, E, selenium, and carotenoids, with frailty prevalence. Notably, these associations were weaker and less consistent among PD patients, suggesting potential disease-specific differences in the role of dietary antioxidants in frailty etiology and management.