Functional independence refers to the ability to perform basic activities of daily living (ADL) and instrumental activities of daily living (IADL) (1), where ADL measures the ability to perform essential activities of functional living, and IADL assesses the ability to live independently in a community (1). According to the latest China Health and Retirement Longitudinal Study, the proportion of adults aged ≥60 years requiring ADL assistance declined from 11.7% (2011) to 8.1% (2020). When defining care needs using ADL or IADL criteria, this proportion decreased from 24.5 to 17.8% during the same period (2). However, the absolute number of older adults requiring care increased due to population aging and growth (1). Potential influencing factors of disability include age, living in an aged care house or with spouse/children, low monthly income, without health insurance, tight family expenses, having stroke or malignant tumor, irregular eating habit, smoking, sedentary lifestyle, lack of physical exercise, sleeping difficulty, lack of family support, and atrial fibrillation with diabetes mellitus type 2 (3–5). Disability is strongly associated with elevated mortality risk (6, 7), reduced health-related quality of life (8, 9), and cognitive decline (10).

Metabolic syndrome (MetS), a cluster of central obesity, raised blood pressure, raised triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and elevated fasting plasma glucose (FPG), is recognized as an interesting potential risk factor for functional disability because of its potential reversibility with adequate pharmacological and health education interventions (11–13). The global prevalence of MetS is challenging to estimate because of the different criteria for its diagnosis; however, the prevalence in different countries showed an upward trend (14–16). The relationship between MetS and functional disability remains controversial; while some longitudinal studies found no association between MetS and ADL/IADL disability progression (17–19), others reported increased risks (20–23). The exact reasons for these inconsistent findings are unclear, but might depend on the diagnostic criteria of MetS, the definition of functional disability, lifestyle factors, and population characteristics. Therefore, a study on this topic in Guangxi is extremely urgent, especially in the remote ethnic minority longevity region of Southwest China.

Previous studied indicated that diabetes (24), hypertension (24, 25), low HDL-C (26, 27), TG (27), and central obesity/waist circumference (28, 29) were association with ADL disability or IADL disability. More importantly, MetS diagnosis requires ≥3 components, yet individuals may exhibit varying numbers (3–5) and distinct combinations of MetS components. Existing research has primarily focused on MetS presence or component count, with limited attention to combinations of MetS components. To date, only one study has analyzed ADL disability risks across pairs of MetS components, revealing striking disparities: individuals with hypertension combined with hyperglycemia had an almost 3-fold higher risk (hazard ratio = 3.51, 95% CI: 1.66–7.43) compared to those with dyslipidemia combined with hyperglycemia (hazard ratio = 1.32, 95% CI: 1.07–1.64) (30). No studies have explored the risks associated with different combinations of three and four MetS components with functional disability.

To address this gap, we conducted an analysis of the association between functional disability and MetS using modified Poisson regression, restricted cubic splines, subgroup analyses, and sensitive analyses based on data from Donglan County, which is one of the five counties of the Hongshuihe basin of Guangxi in China, a famous longevity area with Bama County as the center, to examine the associations of MetS status and component count with functional disability and identify high-risk combinations of MetS components affecting functional independence among adults aged ≥60 years.

The current study found that MetS was significantly associated with ADL disability risk rather than IADL disability risk. The risk of ADL disability showed a progressive increase with an increasing number of MetS components. Further analysis revealed several significant findings: (1) abdominal obesity increased the risk of ADL disability, (2) reduced HDL cholesterol decreased the risk of IADL disability, and (3) the combination of abdominal obesity, elevated blood pressure, and elevated fasting glucose increased both ADL and IADL disability risks. Our findings have brought a nuanced perspective to the fore on how individual MetS components and combinations of MetS components influence functional disability, offering important implications for public health strategies.

In present study, our results suggested that MetS was significantly associated with ADL disability but not IADL disability. This finding was in accordance with previous longitudinal and cross-sectional studies (17, 19, 38, 39). Inversely, two other studies suggested that it was significantly associated with IADL disability (22, 23). In this study, ADL disability increased with an increase in the number of MetS components, rather than IADL disability. This finding is inconsistent with those of other studies. A 7-year multicenter longitudinal study found that IADL disability increased with the number of MetS components, rather than with ADL disability (21). Another study suggested that the number of MetS components is not associated with ADL or IADL disability (23). Collectively, these differences can be explained in several ways. First, there were different definitions of MetS (definition from IDF 2005, definition from ATP III 2005, definition from JIS 2009, and so on). Second, tools of evaluating physical function were different, such as some studies adopted complete scale (Barthel index, Katz index, and physical sell-maintenance scale). Finally, the approaches to scoring for the same scale may be different (the primary approach and the modified approach). The mechanism of MetS with ADL disability might be atherogenesis induced by intravascular endothelial injury and a reduction in muscle mass. The pathogenesis of MetS involves multiple genetic and acquired entities that fall under the umbrella of chronic low-grade inflammation and insulin resistance (40). Individuals with MetS exhibit elevated levels of pro-inflammatory mediators, including adiponectin, leptin, high-sensitivity C-reactive protein (CRP), interleukin (IL)-1, IL-6, IL-8, fibrinogen, monocytic toll-like receptors 2 and 4, and tumor necrosis factor-alpha (TNF-α), compared to those without MetS (41, 42). Chronic inflammation involves a coordinated interaction between the vascular endothelium and circulating immune cells, which promotes arterial stiffening and thickening (39). These vascular changes drive atherogenesis, which may contribute to mobility impairments (e.g., walking disability) (43, 44). Furthermore, insulin and insulin-like growth factor 1 maintain muscle mass by stimulating protein synthesis and suppressing proteolysis (45, 46). Insulin resistance exacerbates muscle degradation via dysregulation of insulin and insulin-like growth factor 1 signaling. Additionally, insulin resistance activates inflammatory cascades that synergistically promote atherogenesis (47), leading to ADL disability. We also confirmed that ADL disability risk was positively associated with the number of MetS components. This association can be explained by the synergistic and additive effects of MetS components on ADL disability. Further studies are needed to understand the complex relationship between MetS components and ADL disabilities.

Our study demonstrated an inverse association between reduced HDL-C levels and IADL disability after comprehensive adjustment for potential confounders. This observed relationship may be mechanistically explained through the concept of inflammaging, a chronic low-grade inflammatory state recognized as one of the 12 hallmarks of aging (48). Inflammaging manifests through both systemic biological changes and localized pathological phenotypes, potentially mediating functional decline (49). Emerging evidence supports the role of the inflammatory pathway in functional disabilities. Elevated CRP levels have consistently been associated with IADL impairment (50). Notably, a cross-sectional study identified significant associations between inflammatory biomarkers (erythrocyte sedimentation rate, CRP, and IL-6) and IADL limitations, specifically in individuals with low HDL cholesterol concentration (51). The dualistic nature of HDL inflammatory modulation suggests a possible biological mechanism. Current research indicates that HDL particles exhibit context-dependent anti-inflammatory or pro-inflammatory properties mediated by structural modifications (including apolipoprotein composition and lipid cargo), cellular cholesterol trafficking dynamics, and signaling pathway interactions (52). Under physiological conditions, HDL demonstrates anti-inflammatory and antioxidant capacities via multiple pathways (53, 54).

However, chronic inflammatory states induce HDL dysfunction through a proposed threshold mechanism that transforms these lipoprotein complexes into pro-inflammatory mediators (52). This phenotypic conversion appears to be driven by excessive cellular cholesterol depletion, which activates the inositol-requiring enzyme 1α/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase signaling cascade (53). The subsequent induction of endoplasmic reticulum stress responses creates a pro-inflammatory feedback loop. Our findings indicate that age-related inflammation may surpass the critical threshold required to subvert the HDL-C protective function, thereby potentiating inflammatory cascades through multiple mechanisms. This pathophysiological shift could explain the paradoxical association between HDL cholesterol levels and the functional decline observed in aging populations. Additionally, the inverse relationship between reduced HDL-C and IADL disability may be due to confounding or reverse causation from cross-sectional design. Therefore, conducting longitudinal research on this topic is essential in the future.

In the current study, abdominal obesity and a combination of abdominal obesity, elevated blood pressure, and elevated fasting glucose levels were associated with ADL disability. To the best of our knowledge, this study is the first to examine the association between combinations of the three MetS components and functional disability. Our findings indicate that MetS components have pronounced synergistic or additive effects on ADL impairment. However, the exact biological mechanism remains unclear. A longitudinal study from 2011 to 2018 demonstrated that compared with middle-aged and older adults without MetS, the risk for ADL impairments was 3.51 times higher (95%CI: 1.66–7.43) for those with hypertension complicated with diabetes (30). To the best of our knowledge, this investigation represents the first systematic examination of ADL impairment risks associated with combinations of ≥3 MetS components. The longitudinal association between abdominal obesity and ADL disability incidence aligns with previous cohort studies (55, 56), whereas cross-sectional evidence further substantiates WC as a robust predictor of mobility limitations (28). The pathophysiological mechanisms linking abdominal obesity to functional decline appear to be multifactorial. Age-related changes in body composition, characterized by sarcopenic obesity and the co-occurrence of muscle mass depletion and visceral fat accumulation, create a biological substrate for functional impairment (57). Key possible mechanisms include: (1) Myosteatosis: Intramuscular lipid infiltration alters muscle architecture and contractile function (58, 59); (2) pro-inflammatory signaling: adipose tissue-driven overexpression of circulating cytokines (such as TNF-α, TNF-β, and IL-6) promotes muscle catabolism and inhibits insulin-mediated anabolic processes (60–63); (3) neuromuscular dysregulation: adipose-induced overexpression of circulating cytokines hinders the insulin-mediated repair mechanisms of motor neurons (62, 63). Longitudinal and cross-sectional analyses have demonstrated that individuals with hypertension experience greater ADL limitations than those without hypertension (24, 64–66). Moreover, a systematic review suggested that antihypertensive therapy is associated with a lower risk of ADL impairment than control therapy (67). The vascular-inflammatory axis appears central to this relationship, involving the following: (1) complement system activation and inflammasome-mediated immune cell phenotypic changes (68, 69), and (2) target organ damage via overt (stroke, myocardial infarction) and subclinical (covert stroke, sarcopenia) vascular events (70, 71). Numerous studies have shown that people with diabetes or impaired glucose tolerance have an increased risk of ADL disability compared to those without diabetes or with normal glucose tolerance (24, 70, 72, 73). An earlier meta-analysis estimating the magnitude of the association between diabetes and disability found that diabetes was associated with increased odds of difficulties with ADLs compared to no diabetes (74). The mechanisms underlying diabetes-related disabilities may be linked to skeletal muscle strength, muscle quality, and complications of diabetes. Diabetes mellitus and impaired glucose homeostasis confer a substantial risk of ADL disability through multiple pathways: (1) Systemic inflammation-induced muscle quality deterioration: Chronic hyperglycemia induces systemic inflammatory responses, promoting the development of age-related sarcopenia through sustained pro-catabolic signaling, ultimately leading to progressive mobility impairment and functional disability (75–81); (2) Imbalance of muscle protein degradation and synthesis resulting in decreased muscle mass: Insulin resistance disrupts IGF-1-mediated protein synthesis and catabolism, as insulin and insulin-like growth factor 1 are responsible not only for glucose uptake but also for maintaining muscle mass via the stimulation of muscle protein synthesis and inhibition of muscle protein breakdown (70, 82); (3) Neurological complications: The progression of diabetic neuropathy causes muscle weakness and sensorimotor deficits, which are closely associated with limitations in performing daily activities (83, 84). Taken together, healthcare providers should pay more attention to individuals with a combination of abdominal obesity, hypertension, and hyperglycemia in the MetS population, because these components may represent modifiable targets for ADL disability risk reduction.

In the present study, we found that a significant combination of abdominal obesity, elevated blood pressure, and elevated fasting glucose levels was associated with IADL disability. To the best of our knowledge, this is the first study to assess the association between this combination and IADL impairment. Our results demonstrate that the components of MetS have a significant combined impact on IADL impairment. However, the mechanisms underlying this collaboration remain unclear. Prior evidence indicates that individuals with diabetes not only suffer from IADL disability earlier than those without diabetes, but also show a higher incidence of IADL disability (72, 85, 86), a finding corroborated by meta-analytic data showing that diabetes confers 1.69-fold increased odds of IADL difficulties (74). Additionally, an earlier meta-analysis estimating the magnitude of the association between diabetes and disability showed that diabetes was associated with increased odds of difficulties with IADL compared to no diabetes. Similarly, the Atherosclerosis Risk in Communities study further substantiated this relationship, demonstrating a 1.82-fold elevated risk of IADL disability in diabetic populations (87). Mechanistically, chronic hyperglycemia may drive IADL disability through skeletal muscle degradation, as elevated glucose levels promote protein catabolism and proteolysis (79), leading to diminished muscle mass and strength, both of which are established predictors of IADL dependence (88, 89). Notably, abdominal obesity exacerbates functional decline via distinct pathways. Longitudinal analyses of 3,374 participants from the English Longitudinal Study of Aging and 1,040 subjects from the Brazilian Health Study revealed that isolated abdominal obesity accelerates IADL disability progression by 37% compared to non-abdominally obese/non-dynapenic individuals (90). Similarly, other studies have demonstrated that higher WC is associated with greater IADL disability (20, 91). This association appears to be mediated through three synergistic mechanisms: (1) visceral adipose-triggered systemic inflammation activating ubiquitin-proteasome pathways (62, 92) and (2) fatty infiltration of muscles reducing muscle strength via inflammatory and endocrine mechanisms (93, 94). Hypertension further compounds IADL limitations, as demonstrated in a cohort of 3,046 older Mexican Americans, where hypertensive individuals exhibited a 23% faster annual progression of IADL restrictions after multivariate adjustment (64). This relationship may involve mechanisms of inflammation. It is generally accepted that systemic inflammation is involved in the pathogenesis of hypertension (39). Hypertension correlates with IADL disability through the effects of inflammatory biomarkers on muscle strength and mass (50, 51). Taken together, the public health implications of this finding emphasize the importance of a comprehensive approach to IADL disability prevention. Abdominal obesity, elevated blood pressure, and elevated fasting glucose levels are modifiable risk factors, and a considerable proportion of functional disabilities may be prevented if one or two MetS components are reduced in older adults via adequate pharmacological and health education interventions.

Despite the key insights uncovered, we acknowledge the limitations of this study. First, our study was not able to establish causalities of MetS status, number of MetS components, and combinations of MetS components with functional disability, as residual confounding factors cannot be completely ruled out. Second, although the ADL/IADL information was captured using validated scales, it is still subjective and known to lead to possible measurement bias. Third, the observed interconnectedness between chronic noncommunicable diseases may not be fully considered, and the temporal order of noncommunicable disease incidence may yield a residual bias. The participants in our study resided in a remote county in the mountainous area of Guangxi, which resulted in poor access to medical and health services. Therefore, some older adults may not be aware of chronic diseases, even if they have them. Fourth, because the study sample was of more than 85% Zhuang ethnicity, whether the findings can be generalized to other ethnic groups requires further investigation. Fifth, the sample size did not allow us to conduct subgroup and interaction analyses of the associations between combinations of MetS components and functional disability. Nevertheless, despite the limitations mentioned above, our results highlight the importance of steady associations of MetS, the number of MetS components, and combinations of MetS components with ADL disability, IADL disability, and comorbid ADL-IADL disability after adjusting for different confounders and using different analysis methods, subgroup analysis, and interaction analysis.

In summary, MetS and the number of MetS components were positively correlated with ADL disability risk and comorbid ADL-IADL disability risk. Reduced HDL cholesterol levels showed a strong negative association with the risk of IADL disability. The combination of abdominal obesity, elevated blood pressure, and elevated fasting glucose levels was strongly associated with ADL disability risk, IADL disability risk, and comorbid ADL-IADL disability risk. Our findings provide potential paths for preventing or at least delaying ADL and IADL disability processes in the management of the MetS population to promote independent living for a longer and better quality of life. Further longitudinal cohort studies and interventions are needed to investigate causality and mechanisms.