In the present study, plasma BDNF levels were significantly lower in individuals with frailty than in those without among community-dwelling older adults. We also found that plasma BNDF was significantly associated with frailty, regardless of the presence of dementia or depression. Interestingly, the association between plasma BDNF and frailty remained even after exclusion of the effects of dementia, depression, and metabolic disorders, including stroke, diabetes, CVD, and osteoporosis.
BDNF plays a crucial role in the development and functioning of the central nervous system. It is well established that dysfunction of BDNF has been involved in the progression of multiple neurological diseases and psychiatric disorders such as Alzheimer’s disease, stroke, and depression5–8. BDNF interacts with receptor tyrosine kinase TrkB and activates downstream intracellular signaling pathways: mainly the phosphatidylinositol 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathways30, Furthermore, BDNF is an important modulator of inflammation and has an antioxidant effect with enhancing sestrin2 expression through NF-κB-dependent pathway in rat cortical neurons31. Through the regulation of the activity of certain transcription factors, BNDF promotes neuronal differentiation, survival, and regeneration. Thus, potential therapeutic benefits of BDNF has been studied widely in Alzheimer's disease, stroke, and depression30. Down-regulation of BDNF results in neuronal susceptibility to oxidative stress and dysfunction induced by neurotoxic amyloid-β in Alzheimer’s disease11. Circulating BDNF derives from both central and peripheral sources3,4, because BDNF can cross the blood brain barrier in both directions32. Many investigations have been conducted on the value of blood BDNF as a biomarker of dementia, depression, and stroke5–8. Consistent with previous studies, we confirmed that plasma BDNF was associated with the presence of dementia and depression in this nationwide multicenter study.
BDNF and TrkB signaling in hypothalamus has a role for feeding behavior and energy homeostasis33,34. BDNF heterozygous mice exhibited abnormalities in eating behavior or locomotor activity and developed hyperplasia and obesity in early adulthood35. Additionally, BDNF administration had beneficial effects on glucose metabolism and insulin sensitivity in db/db mice and obese diabetic mice, but these effects of BDNF were not solely dependent on food intake36,37. In humans, individuals with type 2 diabetes showed low circulating levels of BDNF, and low plasma BDNF was associated with the severity of insulin resistance9. In their study, cerebral output of BDNF was abrogated during hyperglycemic clamp conditions, leading to decreased plasma BDNF levels. Another cohort study also showed that low levels of BDNF is an independent risk factor for diabetes and obesity29,38. On the other hand, diabetic patients older than 65 years were more likely to have higher prevalence of frailty than nondiabetic individuals39,40. In the present study, the association between BDNF and frailty persisted even after excluding individuals with diabetes.
Furthermore, BDNF is a contraction-induced muscle cell-derived protein that can increase lipid oxidation in skeletal muscle though AMPK activation13. Exercise is capable of increasing BDNF in various brain regions as well as circulating BDNF levels16. Recently, it has been reported that lower blood BDNF levels are associated with skeletal muscle strength and physical performance, but not with muscle mass, in patients with heart failure17 and patients with hemodialysis18. Although loss of muscle mass and function in elderly can precede frailty, few studies were conducted on the association between plasma BDNF concentrations and frailty. Plasma BDNF levels were decreased with frailty determined by Fried Frailty Phenotype in elderly women16. In addition, plasma BDNF levels were associated with frailty defined according to a Japanese version of CHS criteria in hemodialysis patients18. However, their studies only included 48 Brazilian women or 20 Japanese patients with chronic renal failure, respectively, and did not evaluate the influence of cardiometabolic variables as well as the impact of associated chronic disorders, such as dementia, depression, stroke, diabetes, CVD, and osteoporosis. In the present study, we observed that plasm BDNF levels were significantly lower in participants with frailty. Furthermore, the presence of frailty was significantly associated with plasma BDNF levels even after extensive adjustment for confounding factors, including age and neurodegenerative diseases. Circulating levels of BDNF has been shown to decline with increasing age22. In sensitivity analyses after excluding dementia, depression, and insulin resistance-related metabolic diseases, which is closely related to BDNF, the association was maintained.
Our study has some limitations. Due to the intrinsic limitations of the cross-sectional study design, we could not determine the existence of a causal relationship between plasma BDNF and frailty. Decline in BDNF levels is accompanied by loss of muscle strength and physical performance caused by a decrease in physical activity and ageing, and as a result, it is thought to contribute to the development of frailty. Further studies are needed on the underlying mechanisms by which BDNF and TkrB signaling play a role in the development of frailty. Another limitation of the present study is that our study was limited to Korean men and women. Thus, it is difficult to apply our study results to different ethnic groups. Nevertheless, this study benefitted from using a nationally representative multicenter sample of community-dwelling elderly Korean adults from KFACS cohort database. Furthermore, multivariate analyses after adjusting for various confounding factors and extensive sensitivity analyses demonstrated consistent results, which may support the robustness of the present findings.