Inflammation and Oxidative Stress in Frailty and Metabolic Syndromes-Two Sides of the Same Coin

The paper addresses rising mortality and morbidity in older adults, highlighting how aging-related lifestyle and metabolic changes promote insulin resistance, hyperglycemia, dyslipidemia, and cardiovascular disease. It posits that frailty and metabolic syndrome, traditionally studied separately, share key biological underpinnings—particularly chronic low-grade inflammation and oxidative stress—and may represent two manifestations of the same pathophysiological continuum. The review’s objective is to synthesize evidence on inflammation and oxidative stress markers and their interplay with metabolic pathways in the development of both frailty and metabolic syndrome among older individuals.

The review synthesizes theories of aging (programmed vs. damage/accumulation), emphasizing the free radical theory, mitochondrial ROS production, caloric restriction, immunosenescence, inflammaging, and the concept of “oxinflammation” as a cross-talk between oxidative stress and inflammation. It integrates evidence on endocrine changes with age (glucocorticoids, sex steroids, GH/IGF-1), their roles in muscle function, oxidative stress protection, and frailty risk. The literature on metabolic syndrome covers oxidative stress biomarkers (e.g., MDA, protein carbonyls), antioxidant systems (SOD, GPx, GSH), inflammatory markers (CRP, IL-6, TNF-α), DNA damage, gut microbiota influences, and PGC-1α regulation. For frailty, the review compiles data on oxidative damage (MDA, 4-HNE adducts), telomere shortening, altered antioxidant capacity, systemic inflammatory markers (CRP, IL-6, IL-8, TNF-α), coagulation/fibrinolysis markers, proteomic signatures, and gut dysbiosis. It also summarizes intervention studies on diet, antioxidants, and exercise relevant to both syndromes.

This is a narrative review. The authors searched PubMed and Google Scholar for full-text human studies in older adults (≥65 years) from 2002 to end of 2022 using terms: “oxidative stress and/or inflammation” and “frailty and/or metabolic syndrome.” Initial hits were n=93,682, narrowed to human research (n=87,669) and elderly (n=14,246) via filters, with additional manual searches. Eligible sources included systematic reviews, meta-analyses, qualitative and quantitative studies, and opinion pieces. Findings were synthesized narratively focusing on oxidative stress and/or inflammation markers and their roles in the pathomechanisms of frailty and/or metabolic syndromes in elderly individuals.

- Shared biology: Both metabolic syndrome and frailty are characterized by chronic low-grade inflammation and increased oxidative stress that drive insulin resistance, sarcopenia, and multiple organ/system dysregulation. - Metabolic syndrome markers: Elevated oxidative stress (e.g., increased MDA and protein carbonyls) and reduced antioxidant enzyme activities (SOD, GPx, GSH) are frequently observed. Waist circumference is a strong predictor of oxidant–antioxidant imbalance, even after age and gender adjustment. Lower SOD activity correlates with metabolic syndrome components and may independently predict metabolic syndrome. DNA damage (e.g., comet tail length, micronucleus frequency) is increased in metabolic syndrome. Gut microbiota influence adipose inflammation and fibrosis (e.g., via TLR4), and PGC-1α modulates antioxidant gene expression and inflammation. - Frailty markers: Frail older adults show higher inflammatory markers (CRP, IL-6, IL-8, TNF-α) and oxidative stress indices (MDA, GSSG, 4-HNE adducts), altered total antioxidant capacity, and leukocyte abnormalities. Telomere length tends to be shorter with oxidative stress; associations vary by study. Urinary oxidative nucleoside markers (e.g., 8-oxo-7,8-dihydroguanosine) associate with frailty. Proteomic profiles differentiate robust versus frail individuals, highlighting proteins in growth, inflammation, and coagulation pathways. - Cross-syndrome links: Increasing cardiometabolic disorders raises frailty risk by up to about 30% in cohort data. Sedentary lifestyle, short sleep, and poor diet exacerbate inflammatory load and oxidative stress. - Interventions: Antioxidant-rich diet for 4 weeks in elderly with metabolic syndrome reduces oxidized LDL and lipid peroxidation and improves central obesity, dyslipidemia, hypertension, and arterial stiffness. Tai chi (5 days/week for 6 months) increases total antioxidant status in sedentary older adults with metabolic syndrome. Exercise plus nano-curcumin increases total antioxidant capacity and lowers MDA, TNF-α, IL-6, and hs-CRP while increasing IL-10 and BDNF in elderly women with metabolic syndrome. Higher dietary total antioxidant capacity and protein intake associate with lower frailty prevalence, whereas higher saturated fat intake associates with greater frailty and mortality.

The compiled evidence supports the central hypothesis that oxidative stress and inflammation are convergent mechanisms driving both metabolic and frailty syndromes in older adults. Insulin resistance links metabolic dysregulation to sarcopenia and functional decline, while immunosenescence and inflammaging amplify ROS production and deplete antioxidant defenses, creating a vicious cycle. Biomarkers including MDA, protein carbonyls, SOD/GPx/GSH, CRP, IL-6, IL-8, TNF-α, and coagulation markers collectively characterize frail and metabolically unhealthy elderly populations. The involvement of gut dysbiosis and endocrine alterations (e.g., IGF-1 decline) further underscores the multisystem nature. These findings advocate for integrated prevention and management strategies targeting inflammation and oxidative stress through lifestyle modifications (dietary antioxidants, protein adequacy, physical activity, sleep hygiene) and potentially pharmacologic approaches to improve resilience, reduce morbidity, and delay progression of both syndromes.

Frailty and metabolic syndrome share key pathophysiological processes—chronic low-grade inflammation and oxidative stress—representing two sides of the same coin. Multiple biomarkers and omics signatures corroborate their overlap and clinical interdependence. Given the aging population, integrated prevention strategies across primary, secondary, and tertiary levels are needed, emphasizing diet quality, antioxidant and protein intake, physical activity, and sleep hygiene. While some interventions improve biomarkers, muscle outcomes, and cardiometabolic profiles, effects on mortality are mixed. Future research should prioritize mechanistic studies, multi-level interventions (including pharmacological strategies), standardized biomarker panels, and longitudinal trials to clarify causality and optimize prevention and treatment of the syndemia of frailty and metabolic syndrome.

As a narrative review, the synthesis is subject to selection and publication biases and does not provide pooled effect estimates. The heterogeneous populations, study designs, and biomarker assays across included studies limit direct comparability and causal inference. The search was limited to full-text human studies in older adults (≥65 years) from 2002–2022, potentially omitting relevant data. Medication strategies were not explored in detail. Some cited interventions showed limited effects on hard outcomes (e.g., mortality), underscoring uncertainty regarding clinical impact despite biomarker improvements.