Neurofilament light chain (NfL) is a critical structural component of the neuronal cytoskeleton, essential for maintaining axonal integrity and function (Bridel et al., 2019; Koini et al., 2021). Under normal conditions, blood NfL levels remain low due to tight homeostatic regulation (Hviid et al., 2022). However, axonal damage or degeneration leads to the release of NfL proteins into the cerebrospinal fluid and subsequently into the bloodstream (Dietmann et al., 2023; Kölliker Frers et al., 2022). Elevated serum NfL (sNfL) levels have emerged as a valuable biomarker for various neurodegenerative diseases, including multiple sclerosis (Bittner et al., 2021), Alzheimer’s Disease (Novobilský et al., 2023), and acute hepatic porphyrias (Sgobbi et al., 2024). These elevated levels reflect the extent of axonal damage and disease progression, correlating with disease severity (Disanto et al., 2017; Preische et al., 2019). Recent studies have highlighted the impact of elevated NfL levels on cognitive function, emphasizing its significance as a biomarker for cognitive impairment (He et al., 2021; Liu et al., 2024; Wheelock et al., 2023). Additionally, NfL levels have been found to mediate the connection between depressive symptoms and cognitive function in older adults (Xu et al., 2024).

Frailty, a geriatric syndrome characterized by decreased physiological reserve and increased vulnerability to stressors, has become a significant health concern in aging populations (Collard et al., 2012). This multidimensional condition is associated with adverse health outcomes, including falls, hospitalization, disability, and mortality (Ji et al., 2024; Ning et al., 2024). Frailty is intricately linked to cognitive impairment and depression in older adults. Studies have shown that frail individuals are at a higher risk of experiencing neuropsychiatric symptoms, especially in the context of Alzheimer’s disease and mild cognitive impairment (Chi et al., 2024). Cognitive decline, depressive symptoms, and functional disability are significantly correlated with frailty, indicating a strong association between these factors (Chi et al., 2024; Monteiro and Borges, 2023). Cognitive frailty, a combination of physical frailty and cognitive impairment, is considered a risk factor for late-life depression, emphasizing the bidirectional relationship between frailty and depression (Panza et al., 2023). Older adults with cognitive frailty are more susceptible to depression, with somatic symptoms being prevalent, highlighting the importance of recognizing and addressing mental health issues in this population (Panza et al., 2023).

The relationship between frailty and serum neurofilament light chain levels may also be influenced by renal function, as measured by glomerular filtration rate (GFR). Impaired renal function can lead to altered levels of circulating biomarkers, including sNfL (Akamine et al., 2020; Polymeris et al., 2022), potentially complicating the interpretation of cognitive and physical health assessments. As kidney function declines, the clearance of various neurotoxic substances may be affected (Lim et al., 2021; Pieniazek et al., 2021), which could exacerbate both neurodegenerative processes and frailty. Thus, understanding the role of GFR in the association between frailty and sNfL levels is essential for elucidating the shared biological mechanisms underlying these conditions.

Identifying the relationship between frailty, sNfL, and renal function may facilitate a better understanding of their complex interplay. However, the precise nature of these associations and the factors influencing them remain to be fully elucidated. Despite the potential significance of these interrelationships, there is a paucity of research directly examining the association between frailty, sNfL levels, and renal function. Addressing these knowledge gaps is crucial for advancing our understanding of frailty pathophysiology and improving risk stratification and management strategies.

To address this research gap, we conducted an analysis utilizing data from the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. Our study aims to explore the association between frailty and sNfL levels in a population representative of the United States, while also investigating the mediating role of estimated glomerular filtration rate (eGFR) in this relationship. This approach may uncover new insights into the complex relationship between frailty, neurodegeneration, and cognitive health in aging populations.

This study aimed to investigate the association between frailty and sNfL levels in a representative U.S. population and to explore the mediating role of eGFR in this relationship. Our findings reveal several important insights into the complex interplay between frailty, neuronal damage, and kidney function. First, we observed a significant positive association between frailty and sNfL levels in our study population. The prevalence of pre-frailty and frailty was considerable, at 45.39 and 11.60%, respectively. Importantly, although the restricted cubic spline (RCS) model allows for the assessment of non-linear relationships, our analysis revealed an approximately linear association between frailty scores and sNfL levels across the observed range, as indicated by the RCS analysis (P for non-linearity = 0.0519). Frail individuals exhibited significantly higher sNfL levels compared to non-frail participants, even after adjusting for potential confounders. We also observed a negative association between eGFR and sNfL levels. Notably, eGFR was found to mediate the relationship between frailty and sNfL levels, accounting for 12.52% of the total effect.

The concept of frailty as an accelerated aging process is well-supported by numerous studies demonstrating its association with various markers of biological aging (Kuiper et al., 2023; Mitchell et al., 2023; Sepúlveda et al., 2022). A study conducted by Bountziouka et al. (2022) found that frailty was significantly associated with shorter telomere length, supporting the link between frailty and accelerated cellular aging. Phyo et al. (2024) found that frailty was associated with multiple epigenetic age acceleration indicators, including the DunedinPACE and GrimAge, further confirming the close relationship between frailty and biological aging. Neurodegeneration, characterized by the progressive loss of structure or function of neurons, is increasingly recognized as a critical element in the development and progression of frailty (Gómez-Gómez and Zapico, 2019; Ward et al., 2022). Evidence suggests that frail individuals exhibit higher rates of cognitive decline and are at an increased risk of developing neurodegenerative conditions (Cao et al., 2023; Li C. et al., 2023; Robertson et al., 2013). Kulmala et al. (2014) demonstrated frailty is strongly associated with cognitive impairment and clinically diagnosed dementia among persons aged 76 and older. Li R. et al. (2023) demonstrated in a longitudinal study that severe frailty was significantly associated with the subsequent decline in cognitive function. In the five identified frailty trajectories, participants with mild frailty and frailty were all significantly associated with the subsequent cognition decline in the elderly (Li R. et al., 2023). Neuroimaging studies have provided further evidence of the neurobiological underpinnings of this relationship. Du et al. demonstrated that white matter hyperintensities (WMHs) mediate the association between frailty and cognitive impairment in moyamoya disease (MMD) (Du et al., 2024). These findings revealed a complex interplay between frailty and neurodegeneration. Neurofilament light chain has emerged as a robust biomarker for neurodegeneration due to its sensitivity to neuronal damage and its ability to reflect disease severity and progression (Gaetani et al., 2019; Lu et al., 2015). Elevated sNfL levels have been correlated with cognitive impairment and brain atrophy in conditions like Alzheimer’s disease (Lehmann et al., 2023; Xiong et al., 2021). These findings suggest that sNfL could potentially serve as a biomarker for neurodegenerative processes underlying frailty.

Previous studies have reported associations between elevated sNfL levels and frailty-related conditions. Capo et al. found that NfL levels increased significantly with age, particularly in men, and were associated with decreased muscle function, including grip strength, walking speed, and chair test performance (Capo et al., 2023). Ladang et al. (2023) reported that NfL was associated with performance tests and was an independent predictor of severe sarcopenia. In this study, we demonstrated a clear association between frailty and sNfL levels in a large, representative sample across a wide age range. Our study builds on these findings by establishing a linear relationship between frailty score and sNfL levels, suggesting that neuronal damage may increase progressively with frailty severity. Subgroup analyses revealed potential sex-specific and age-dependent mechanisms linking frailty and neuronal damage, with stronger associations observed in males and older age groups. Significant associations in specific socioeconomic subgroups (e.g., those with higher education levels or lower family income) highlight the complex interplay between social determinants of health, frailty, and neurological integrity.

The negative association between eGFR and sNfL levels is consistent with previous research indicating that impaired kidney function contributes to increased sNfL levels, possibly due to reduced clearance of neurofilament proteins (Koini et al., 2021; Dittrich et al., 2023; Tang et al., 2022). Our results revealed a consistent and statistically significant negative association between eGFR (as a continuous variable) and sNfL levels across all adjusted models. However, when examining eGFR as a categorical variable (<60 vs. ≥60 mL/min/1.73m²), a positive association with sNfL levels was observed for participants with lower eGFR, although this relationship did not reach statistical significance in the fully adjusted models. This may be due to the relatively small number of participants with eGFR <60 mL/min/1.73m² associated with the study population. The mediating role of eGFR in the frailty-sNfL relationship suggests that kidney function significantly influences the relationship between frailty and neuronal damage. Impaired kidney function, which is common in frail individuals, may exacerbate neuronal damage by several mechanisms: Firstly, reduced kidney function may lead to the accumulation of neurotoxic metabolites, contributing to neuronal damage and elevated sNfL levels (Stanciu et al., 2020). Secondly, both frailty and kidney dysfunction are associated with chronic inflammation and oxidative stress, which may synergistically promote neuronal injury (Ebert et al., 2021; Gill et al., 2024). Lastly, shared risk factors and pathophysiological pathways between frailty, kidney disease, and neurodegeneration may underlie these complex relationships (Shen et al., 2017).

Our findings have significant clinical implications. The association between frailty and elevated sNfL levels suggests that sNfL could serve as a potential biomarker for frailty-related neuronal damage. This may have important applications in early detection and monitoring of frailty, particularly in identifying individuals at higher risk of frailty-associated neurological decline. The mediating role of eGFR underscores the importance of considering kidney function in frailty assessment and management strategies. One of the strengths of our study is the large, representative sample from the U.S. population, which enhances the generalizability of our findings. Additionally, the comprehensive assessment of frailty using a 49-item frailty index provides a robust measure of frailty status. However, limitations include the cross-sectional design, which precludes establishing causality, and potential confounding factors despite adjustments in our models. The use of self-reported data for some variables may introduce recall bias.

Future research should include longitudinal studies to investigate the predictive value of sNfL for frailty progression and associated outcomes. Mechanistic studies exploring the biological pathways linking frailty, kidney function, and neuronal damage are warranted. Clinical trials evaluating interventions targeting the frailty-sNfL-eGFR relationship could provide valuable insights for frailty prevention and management strategies.

This study demonstrates a significant association between frailty and elevated sNfL levels in a representative U.S. population, with eGFR partially mediating this relationship. These findings advance our understanding of the complex interplay between frailty, neuronal damage, and kidney function in aging populations. By highlighting sNfL as a potential biomarker for frailty-related neuronal damage and emphasizing the role of kidney function, this study opens new avenues for research and clinical practice in aging neuroscience. These insights may lead to improved strategies for early detection, monitoring, and management of frailty, potentially mitigating its impact on neurological health and overall well-being in aging populations.