Among 11,918 U.S. adults included in this study, we found a significant positive association between frailty and accelerated aging. When biological aging was measured using phenotypic age, higher FI was positively associated with higher phenotypic age and remained nearly consistent across partial subgroups. This study used a large, nationally representative sample and provided valuable insights into the relationship between frailty and aging in the U.S. population.
Frailty is a prevalent syndrome of old age that is strongly associated with disability, mortality, and hospitalization[14–16]. However, the underlying mechanisms of the frailty still need to be better understood[17–20]. In recent years, researchers have generally recognized the link between frailty and a wide range of diseases. A meta-analysis conducted by Yang Peng, covering 56 observational studies of 1,852,951 individuals, showed that frailty was not only associated with a significant increase in all-cause mortality (HR 2.40; 95% CI 2.17–2.65) but was also associated with a significant increase in adult-caused cardiovascular disease (HR 2.64; 95% CI 2.20–3.17), cancer (HR 1.97; 95% CI 1.50–2.57) and respiratory disease (HR 4.91; 95% CI 2.97–8.12) were strong predictors of cause-specific mortality in adults[21]. In 2011, Rockwood et al. used data from the Canadian National Population Health Survey to validate that the FI had good predictive validity across the full age range of adults[22]. Meanwhile, a Mendelian randomization analysis based on summary GWAS data suggested that the FI was causally associated with depression, Alzheimer's disease, and stroke at the genetic level[23–25]. The China Chronic Disease Prospective Study further demonstrated that the FI can effectively predict the risk of all-cause and multi-cause mortality in the population[26]. Although studies continue to support the use of epigenetic age as a proxy for biological age, such as its association [27]with frailty, Alzheimer's disease, cancer, and cardiovascular disease, some studies have failed to find an association between the epigenetic clock and frailty[27–29]. A cohort study by Maria Giulia Bacalini based on an Italian population suggests that there may not be a correlation between frailty indices and epigenetic age among older adults [30]. However, this may be influenced by small study sample sizes, inconsistent measures of frailty, differences in groups or covariates, and confounding factors such as metabolic disorders like hypertension and hyperlipidemia.
The study of frailty assessment has become a recent focus in population health. However, in academia, there still needs to be a unified definition of frailty. To address this issue, Song et al. proposed a conceptualized definition, considering frailty as an accumulative process of individual health loss in older adults, encompassing various aspects such as disease, disability measurements, and cognitive and functional decline[22]. According to this comprehensive definition, the degree of frailty in an individual is directly proportional to the accumulation of health deficits manifested in various symptoms, such as diseases and disabilities. To quantify the degree of individual frailty, the FI comes into play. This index effectively measures the proportion of unhealthy indicators among all health measurement indicators for an individual, with a range of 0 to 1, where a score of 1 indicates severe frailty and a score of 0 indicates no presence of any diseases. In previous studies, the FI has not only served as an indicator for predicting the risk of mortality but has also proven to be a good measure for health assessment, demonstrating good validity and reliability. Frailty is considered an early manifestation of aging and, simultaneously, a vital risk factor for many chronic diseases, including neurodegenerative diseases[31], metabolic syndrome[32, 33], cardiovascular diseases[34, 35]and malignant tumors[36]. Therefore, the positive correlation mechanism between frailty and biological aging is complex and extensive.
The mechanism underlying the positive correlation between weakness and physiological aging is complex and extensive. Aging itself results from various factors, including heredity and the environment. It is widely recognized that accelerating biological aging leads to more and earlier adverse consequences, while delaying biological aging helps prevent these consequences to some extent[37, 38]. Previous studies have revealed that aging characteristics are overexpressed in various tissues or samples during the processes accompanying the organism's decline. These features encompass genomic instability, epigenetic alterations, defective protein deposition, impaired mitochondrial function, cellular senescence, stem cell failure, and inflammatory states[39–41]. While these changes occur in all individuals as they age, they are particularly pronounced in the frail[42]. A meta-analysis by Bader A A et al., involving nine observational studies, concluded that frailty prevalence is higher in Middle Eastern countries[43]. Demographic studies of these countries confirm that their populations are aging rapidly, emphasizing the correlation between weakness and senescence. Interestingly, the frailty characterized by the FI is not only highly significant in older populations but also includes pathological conditions associated with accelerated biological aging in younger subject samples, even across different biological species[44–46], such as HIV/AIDS[47] and autoimmune/inflammatory diseases[48, 49]. In terms of mechanistic studies, interleukins, inflammation, carnitine, the vitamin E pathway, and disorders of mitochondrial metabolism have been identified as factors associated with the underlying mechanisms of aging and frailty[39, 50]. Previous studies have shown that down-regulation of IL-6 signaling is associated with a reduced risk of frailty[51], while IL-6 knockout inhibits the accumulation of aging-associated proteins[52]. This suggests that interleukin-6 may be one of the pathogenic mechanisms of frailty and accelerated aging. In the future, multi-omics technology development is expected to entirely reveal the developmental mechanism between weakness and aging.
Our study reveals a positive linear correlation between FI and phenotypic age acceleration in a representative sample of U.S. adults. This study is one of the most extensive investigations into these two variables' relationships. Linear and nonlinear statistical analyses provided reliable and informative results for the correlation between phenotypic age-represented senescence and frailty indices. However, it is essential to recognize some limitations of the study. First, because the study utilized a cross-sectional design, it was impossible to establish a causal relationship between FI and phenotypic age. To address this issue, it is suggested that future multi-group Mendelian randomization studies based on GWAS, transcriptomics, and proteomics be conducted further to explore the potential causal relationship between the two. This approach will provide more valuable insights. Second, considering that NHANES is based on a sample of the non-institutionalized population in the United States, the generalizability of the study results may be affected by geographic and population differences. Also, NHANES is primarily a cross-sectional study and lacks long-term follow-up data, which may limit understanding of changes in frailty indices and phenotypic age over time. Therefore, longitudinal study designs are emphasized to better understand the relationships between variables. Third, NHANES may not cover all factors that may influence FI and phenotypic age, such as genetic and lifestyle factors. These omitted variables could potentially impact study conclusions. Finally, respondents in different age groups in the NHANES sample may have other physical and social characteristics, which may confound the FI and phenotypic age analysis. Overall, it was emphasized that more prospective cohort studies and randomized controlled clinical trials are needed in the future to validate the results of the current study and to explore in depth the potential mechanisms underlying the association between FI and phenotypic age. Despite some limitations, the study provided valuable insights into the relationship between frailty and aging. Addressing these limitations, will contribute to a better understanding of this association and support the development of preventive and therapeutic strategies for diseases associated with aging.