Lipid metabolites and sarcopenia-related traits: a Mendelian randomization study.

Liu J ，Wang S ，Shen Y ，Shi H ，Han L ... -  《Diabetology & Metabolic Syndrome》

Causality between urate levels with sarcopenia-related traits: a bi-directional Mendelian randomization study.

Observational studies have suggested associations between serum urate levels and sarcopenia, but the causality underlying this correlation remains uncertain. The principal objective of this study is to investigate a causal relationship of serum urate levels with sarcopenia-related traits (hand grip strength, lean mass, walking pace) using bidirectional two-sample Mendelian randomization (MR) approach. The utilization of MR methodology serves to minimize bias caused by reverse causality and confounding factors from observational studies. The summary statistics of serum urate levels were derived from a cohort consisting of 288,659 individuals participating in CKDGen study. The parameters of right-hand grip strength (N=461,089), left-hand grip strength (N=461,026), appendicular lean mass (ALM) (N=450,243), whole-body lean mass(N=454,850),right-leg fat-free mass(FFM;N=454,835),left-leg FFM(N=454,805), right-arm FFM(N=454,753),left-arm FFM(N=454,672) and walking pace (N=459,915)were sourced from the UK Biobank. MR analysis was conducted utilizing inverse variance weighted (IVW), weighted median, and MR-Egger to evaluate causality. Sensitivity analysis was performed using Cochran's Q test, MR-Egger intercept test, leave-one-out analysis and the funnel plot. IVW estimates demonstrated that serum urate levels exhibited no causal association with sarcopenia-related traits. In the inverse MR investigation, we had exclusively discerned an inverse correlation between walking pace and serum urate levels. No compelling evidence had surfaced to substantiate any association of other sarcopenia-related traits with serum urate. Supplemental MR methods consistently validated the findings obtained from the primary analysis. Sensitivity analysis demonstrated the robustness of findings. Our MR study revealed the absence of the bidirectional causal relationship between serum urate levels and sarcopenia. It is imperative to acknowledge that advanced age and an individual's health status are pivotal determinants influencing urate level and the initiation and advancement of sarcopenia. However, it is worth underscoring that these aspects remain unexamined within the purview of this study. Thus, future investigations should delve deeper into these intricate facets.

Lin Y ，Wang X ，Yao W ，Sun Y ，Zhou J ，Feng F ... -  《Frontiers in Endocrinology》

The causal relationship of depression, anxiety, and neuroticism with main indicators of sarcopenia: A Mendelian randomization study.

Observational studies have shown the relationship between sarcopenia and psychiatric disorders. However, due to the limitations of traditional research methods, the causal relationship between them has not been accurately concluded. At the same time, considering that sarcopenia is mainly manifested by low muscle strength and low muscle mass, we used Mendelian randomization (MR) analysis in this study to explore the causal relationship of anxiety, depression, and neuroticism with muscle strength and muscle mass, respectively. Genetic variants associated with depression were obtained from FinnGen Biobank (Ncase = 33,812, Ncontrol = 271,380), those associated with anxiety were from FinnGen Biobank (Ncase = 21,519, Ncontrol = 307,558), and those associated with neuroticism, including 12 items, were from a large-scale genome-wide association study (N range: 366,301-375,913). Muscle strength was represented by the hand grip strength (HGS), and muscle mass was represented by the appendicular lean mass (ALM) and the body fat percentage. The inverse-variance weighted (IVW) method was used as the primary analysis method, and the Mendelian Randomization Egger (MR-Egger) and the weighted median were used as supplementary methods to test whether the three psychological factors were causally related to these two main indicators of sarcopenia severity. Depression and neuroticism had different degrees of causal influence on muscle mass and strength, which was statistically significant. Specifically, the depression predicted by genes was significantly associated with ALM (beta = -0.043, p = 0.027), low hand grip strength (LHGS, measured for people of 60 years and older) (odds ratio (OR) = 1.129 (1.019-1.251), p = 0.019), right HGS (beta = -0.050, p = 0.001), left HGS (beta = -0.06, p = 0.001), and body fat percentage (beta = 0.035, p = 0.0138). The neuroticism predicted by genes was significantly associated with ALM (beta = -0.073, p = 0.034), LHGS (OR = 1.222 (1.085-1.377), p = 0.001), right HGS (beta = -0.058, p = 0.000), left HGS (beta = -0.080, p < 0.000), and body fat percentage (beta = 0.063, p = 0.008). However, anxiety was only significantly associated with LHGS (OR = 1.215 (1.008-1.465), p = 0.041) but not significantly associated with ALM (beta = 0.033, p = 0.313), right HGS (beta = -0.008, p = 0.678), left HGS (beta = 0.007, p = 0.712), or body fat percentage (beta = 0.022, p = 0.559). This study supported the causal association of depression and neuroticism with muscle strength and mass, which are the two main indicators of sarcopenia. At the same time, there was no sufficient evidence for the causal relationship between anxiety and muscle strength or mass. The results of this study pointed to the need to intervene in the mental health of the elderly to prevent sarcopenia or reduce its severity.

Zhang Y ，Song Y ，Miao Y ，Liu Y ，Han D ... -  《-》

Metabolome-Wide Mendelian Randomization Assessing the Causal Relationship Between Blood Metabolites and Sarcopenia-Related Traits.

Sarcopenia is among the most common musculoskeletal illnesses, yet its underlying biochemical mechanisms remain incompletely understood. In this study, we used Mendelian randomization (MR) to investigate the causal relationship between the genetically determined blood metabolites and sarcopenia, with the overall objective of identifying likely molecular pathways for sarcopenia. We used 2-sample MR to investigate the effects of blood metabolites on sarcopenia-related traits. 452 metabolites were exposure, and 3 sarcopenia-related traits as the outcomes: handgrip strength, appendicular lean mass, and walking pace. The inverse-variance weighted (IVW) causal estimates were determined. For sensitivity analysis, methods such as MR-Egger regression, the weighted median, the weighted mode, and the heterogeneity test were used. Additionally, for complementation, we performed replication, meta-analysis, and metabolic pathway analyses. Candidate biomarkers were defined by meeting one of the following criteria: (1) significant metabolites are defined as pIVW < pBonferroni [1.11 × 10-4 (.05/452)]; (2) strong metabolites are defined as 4 MR methods p < .05; and (3) suggestive metabolites are defined as passing sensitivity analysis. Three metabolites (creatine, 1-arachidonoylglycerophosphocholine, and pentadecanoate [15:0]) with significant causality, 3 metabolites (glycine, 1-arachidonoylglycerophosphocholine, and epiandrosterone sulfate) with strong causality, and 25 metabolites (including leucylleucin, pyruvic acid, etc.) with suggestive causality were associated with sarcopenia-related traits. After further replication analyses and meta-analysis, these metabolites maintained substantial effects on sarcopenia-related traits. We additionally identified 14 important sarcopenia-related trait metabolic pathways. By combining metabolomics with genomics, these candidate metabolites and metabolic pathways identified in our study may provide new clues regarding the mechanisms underlying sarcopenia.

Chen S ，Dong Y ，Aiheti N ，Wang J ，Yan S ，Kuribanjiang K ，Li H ，Peng X ，Wupuer A ，Li Y ，Yang L ，Zhao J ... -  《-》

Mapping the causal associations of cytokines with sarcopenia and aging traits: Evidence from bidirectional Mendelian randomization.

Cytokines and growth factors may serve as a bridge in studying the causal relationships between inflammaging and sarcopenia due to their roles in inflammaging. In this study, we aim to explore the causal association of cytokines with sarcopenia and aging traits and further identify the significant inflammation factors. Bidirectional Mendelian randomization (MR) analysis was used to identify the causality. Forty-one kinds of circulation cytokines and growth factors were set as exposures, and the data were from a summary genome-wide association study (GWAS) containing three cohorts with 8293 healthy participants of European ancestry from 1983 to 2011. Hand grip strength, adjusted appendicular lean mass (AALM), usual walking pace, moderate-to-vigorous physical activity (MVPA) levels, able to walk or cycle unaided for 10 min (AWCU10) and telomere length were selected as outcomes. Data for outcomes were obtained from meta-GWAS and the UK Biobank, and sample sizes ranged from 69 537 to 472 174. Low hand grip strength was defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and Foundation for the National Institutes of Health (FNIH) cut-off points, respectively. Other outcome traits were defined and measured according to the UK Biobank and raw cohorts' criteria. We set two significance thresholds for single nucleotide polymorphisms (SNPs) associated with exposures to obtain adequate SNPs (5 × 10-6 and 5 × 10-8). Inverse-variance weighted, MR-Egger and weighted median were employed to estimate the causality. Twenty-seven factors were identified to relate to sarcopenia and aging traits causally, and most were associated with only one outcome trait. IL16 (interleukin-16), CTACK (cutaneous T-cell attracting chemokine), MIP1b (macrophage inflammatory protein 1b) and PDGFbb (platelet-derived growth factor BB) were proven to relate causally to at least one sarcopenia and aging trait in both analyses with two significance thresholds. IL16 was causally associated with hand grip strength (0.977 [0.956-0.998] for EWGSOP and 0.933 [0.874-0.996] for FNIH), AALM (0.991 [0.984, 0.998]), MVPA (0.997 [0.995-1.000]) and AWCU10 (1.008 [1.003-1.013]). CTACK was proven to relate causally to hand grip strength (1.013 [1.007-1.019] for EWGSOP and 1.090 [1.041-1.142] for FNIH), AWCU10 (0.990 [0.986-0.994]) and telomere length (0.998 [0.983-0.994]). The results indicated that MIP1b has a causal effect on hand grip strength (1.032 [1.001-1.063] for EWGSOP), AWCU10 (0.994 [0.988-1.000] and 0.993 [0.988-0.998]) and telomere length (1.006 [1.000-1.012]). PDGFbb may causally relate to AALM (1.016 [1.001-1.030]) and telomere length (1.011 [1.007-1.015]). Reserve MR analyses also proved their unidirectional causal effects. Twenty-seven factors were causally related to sarcopenia and aging traits, and the causal effects of IL16, CTACK, MIP1b and PDGFbb were proven in both analyses with two significance thresholds.

Liu M ，Fu X ，Yu D ，Li M ，Pan Y ，Yang C ，Sun G ... -  《-》