The global rise in mortality among the elderly is driven not only by pandemics like COVID-19 but also by age-related diseases. In developed nations, aging is frequently linked to lifestyle factors such as poor diet and lack of physical activity, which increase the risk of obesity, muscle mass loss, and high blood pressure. These factors, in turn, cause biochemical changes including insulin resistance, impaired carbohydrate metabolism, dyslipidemia, and dysproteinemia. Over time, these unfavorable biochemical phenomena, including increased inflammation and oxidative stress, accumulate, leading to clinical dysfunction and premature death. Metabolic syndrome, characterized by insulin resistance, hyperglycemia, hyperlipidemia, and often hypertension and cardiovascular disease, is a significant clinical manifestation of these processes. The increasing elderly population fuels a rise in metabolic syndrome cases. Furthermore, frailty syndrome, a multisystem geriatric syndrome, develops in the context of deteriorating bio-psycho-social factors associated with aging, including multiple illnesses, social isolation, and financial concerns. Existing literature typically treats metabolic syndrome and frailty syndrome separately, despite overlapping pathomechanisms. This review aims to highlight the interrelationships between inflammation, oxidative stress, and metabolic pathways in the development of both frailty and metabolic syndromes in older adults.

The authors reviewed articles from PubMed and Google Scholar databases (initially n=93,682), focusing on human studies of elderly populations (≥65 years old) published between 2002 and 2022. The search terms included "oxidative stress and/or inflammation", and "frailty and/or metabolic syndrome". The final selection included systematic reviews, meta-analyses, qualitative and quantitative studies, and opinion pieces relevant to the study's aims. The review synthesizes these findings to describe the role of oxidative stress and inflammation in the pathogenesis of frailty and metabolic syndromes.

The study employed a narrative review methodology. The authors searched PubMed and Google Scholar databases for relevant articles using specific keywords related to oxidative stress, inflammation, frailty, and metabolic syndrome. Initial searches yielded a large number of results (n=93,682). The authors applied several filters, including restricting the search to human studies and studies focusing on the elderly population (≥65 years old). This filtering process significantly reduced the number of articles (n=14,246). Further refinement was conducted by manually checking for missing articles and selecting studies published between 2002 and 2022. The selected articles included systematic reviews, meta-analyses, qualitative studies, quantitative studies, and opinion pieces. The authors performed a narrative synthesis of the selected literature to explore the association between oxidative stress, inflammation, and the development of frailty and metabolic syndromes.

The review highlights several key findings concerning the interplay between oxidative stress, inflammation, and the development of frailty and metabolic syndrome in older individuals. Theories of aging, such as the free radical theory and inflammaging, are discussed in the context of these conditions. Regarding metabolic syndrome, increased oxidative stress (evidenced by markers like malondialdehyde) and inflammation are linked to DNA damage and impaired glucose metabolism. Studies demonstrate decreased activity of antioxidant enzymes (superoxide dismutase, glutathione peroxidase) and increased pro-inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-α) in individuals with metabolic syndrome. Lifestyle interventions, including antioxidant-rich diets and exercise (such as tai chi), show promise in improving oxidative stress and inflammatory markers. In frailty syndrome, oxidative stress and inflammation contribute through various pathways. Markers like urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (RNA oxidation), shortened telomere length, and increased levels of TNF-α, oxidized glutathione, and MDA are associated with frailty. Similarly, elevated inflammatory markers (CRP, IL-6, IL-8, TNF-α) are strongly linked to frailty. Gut dysbiosis, characterized by alterations in the gut microbiota composition and metabolites, is implicated in both oxidative stress and inflammation in frail individuals. Dietary interventions and exercise demonstrate beneficial effects on frailty by improving antioxidant capacity, muscle mass, and strength, and reducing inflammation. The findings suggest a considerable overlap in the pathophysiology of metabolic syndrome and frailty, characterized by shared mechanisms involving oxidative stress and inflammation, suggesting these syndromes are two sides of the same coin.

The review's findings strongly suggest that inflammation and oxidative stress are central to the pathogenesis of both frailty and metabolic syndromes in older adults. The shared pathophysiological mechanisms highlight the potential for interventions targeting these processes to positively affect both conditions. Lifestyle interventions such as improved diet, regular physical activity, and possibly improved sleep hygiene, show promise for preventing or mitigating the severity of both syndromes. The close relationship between these two conditions indicates a need for integrated approaches to prevention and treatment. The results emphasize the importance of considering the synergistic effects of inflammation and oxidative stress in developing comprehensive interventions to improve the health and longevity of the elderly population.

Both frailty and metabolic syndrome contribute significantly to reduced quality of life, increased healthcare utilization, and mortality in older adults. This review demonstrates a significant overlap in their underlying pathophysiology, largely involving inflammation and oxidative stress. The ‘syndemic’ nature of these conditions warrants integrated prevention strategies encompassing primary (lifestyle modifications such as diet, exercise and sleep hygiene), secondary (early detection and management), and tertiary (managing existing conditions to reduce complications) levels. Future research should prioritize developing and evaluating interventions targeting both inflammation and oxidative stress to improve the health and survival of elderly individuals.

As a narrative review, this study is subject to the inherent limitations of this methodology. The authors relied on existing literature, which may be influenced by publication bias and variations in study designs and methodologies. The review did not exhaustively analyze all aspects of frailty and metabolic syndromes, nor did it delve deeply into specific treatment strategies beyond lifestyle interventions.