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Background Frailty, defined as physical performance impairment, is a common condition in older adults and can anticipate the development of sarcopenia, a geriatric syndrome characterized by loss of muscle strength and mass. microRNAs (miRNAs) are short molecules of RNA endowed with the ability to modulate gene expression; miRNAs are present in serum and are considered potential biomarkers for several diseases. Serum concentration of miR-451a, miR-93-5p, miR-155-5p, miR-421-3p, miR-425-5p, miR-495-3p and miR-744-5p was recently shown to be altered in sarcopenic patients. Methods We verified if a particular miRNAs pattern could be detected in frailty as well by analyzing these molecules in 50 frail and 136 robust subjects. Additionally, a subgroup of these subjects (15 frail and 30 robust) underwent a 12-week program based on a multicomponent exercise protocol (VIVIFRAIL) consisting of resistance training, gait retraining, and balance training. After the program, serum miRNAs concentration was measured again, to verify whether the physical activity had an effect on their concentration. Moreover, clinical characteristics and indicators of physical performance of all subjects were compared before and after intervention to verify the effect of the VIVIFRAIL program. Results At the end of the multicomponent exercise program, Short Physical Performance Battery (SPPB) score as well right and left handgrip (p < 0.05) were significantly increased in frail subjects; right and left handgrip significantly were increased also in robust subjects (p < 0.05). Interestingly, the variation of SPPB was significantly higher in frail compared to robust subjects (p < 0.0001). Moreover, at the end of the program, in frail compared to robust subjects: miR-451a serum concentration was significantly increased (frail: 6.59 × 10 4 ; 1.12 × 10 4 –2.5 × 10 5 c/ng; robust: 2.31 × 10 4 ; 1.94 × 10 3 –2.01 × 10 5 c/ng) (p < 0.05); and 2) miR-93-5p and miR-495-3p serum concentration was reduced, whereas that of miR-155-5p was significantly increased (p < 0.05 in both cases). Serum concentration of miR-93-5p and miR-495-3p was decreased, and that of miR-155-5p was increased at the end of the program in robust subjects alone, statistical significance being reached for miR-93-5p alone (p = 0.02). Conclusion These results suggest that serum miR-451a should be investigated as a potential biomarker for frailty and show that the VIVIFRAIL multicomponent program modulates circulatory miRNAs expression, at least in older adults.

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome‐wide association study (GWAS) meta‐analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60–70 years) and Swedish TwinGene participants (n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self‐reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10−8). Many FI‐associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well‐known disease risk factors and mental health, with particular emphasis on pathways in the brain. This genome‐wide association study meta‐analysis of the frailty index (FI) in UK Biobank and TwinGene, identified 14 loci associated with the FI. Many FI‐associated loci have established associations with well‐known disease risk factors such as BMI, cardiovascular disease, smoking, HLA proteins, depression and neuroticism. However 1 was novel. Risk of frailty is influenced by many genetic factors, including well‐known disease risk factors and mental health, with particular emphasis on pathways in the brain.

ObjectiveTo optimise dementia prevention strategies, we must understand the complex relationships between lifestyle behaviours, frailty and genetics.MethodsWe explored relationships between frailty index, healthy lifestyle and polygenic risk scores (all assessed at study entry) and incident all-cause dementia as recorded on hospital admission records and death register data.ResultsThe analytical sample had a mean age of 64.1 years at baseline (SD=2.9) and 53% were women. Incident dementia was detected in 1762 participants (median follow-up time=8.0 years). High frailty was associated with increased dementia risk independently of genetic risk (HR 3.68, 95% CI 3.11 to 4.35). Frailty mediated 44% of the relationship between healthy lifestyle behaviours and dementia risk (indirect effect HR 0.95, 95% CI 0.95 to 0.96). Participants at high genetic risk and with high frailty had 5.8 times greater risk of incident dementia compared with those at low genetic risk and with low frailty (HR 5.81, 95% CI 4.01 to 8.42). Higher genetic risk was most influential in those with low frailty (HR 1.31, 95% CI 1.22 to 1.40) but not influential in those with high frailty (HR 1.09, 95% CI 0.92 to 1.28).ConclusionFrailty is strongly associated with dementia risk and affects the risk attributable to genetic factors. Frailty should be considered an important modifiable risk factor for dementia and a target for dementia prevention strategies, even among people at high genetic risk.

For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark 1 – 7 . Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK–AMPK–mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people. IL-11 is identified as a key regulator of ERK–AMPK–mTORC1 signalling, metabolism, inflammation and age-related disease and lifespan in mouse and human.

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD + -dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13 C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD + synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging. Aging is associated with increased frailty and disrupted energy homeostasis. Here, the authors show that SIRT6 overexpression extends the lifespan of male and female mice and demonstrate that SIRT6 optimizes energy homeostasis in old age, which delays frailty and preserves healthy aging.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people 1 . Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing 2 . Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples 3 , 4 . Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life. The Human Muscle Ageing Cell Atlas provides a series of integrated cellular and molecular explanations for sarcopenia and frailty development in advanced ages.

Cross-sectional studies have demonstrated strong associations between physical frailty and depression. However, the evidence from prospective studies is limited. Here, we analyze data of 352,277 participants from UK Biobank with 12.25-year follow-up. Compared with non-frail individuals, pre-frail and frail individuals have increased risk for incident depression independent of many putative confounds. Altogether, pre-frail and frail individuals account for 20.58% and 13.16% of depression cases by population attributable fraction analyses. Higher risks are observed in males and individuals younger than 65 years than their counterparts. Mendelian randomization analyses support a potential causal effect of frailty on depression. Associations are also observed between inflammatory markers, brain volumes, and incident depression. Moreover, these regional brain volumes and three inflammatory markers—C-reactive protein, neutrophils, and leukocytes—significantly mediate associations between frailty and depression. Given the scarcity of curative treatment for depression and the high disease burden, identifying potential modifiable risk factors of depression, such as frailty, is needed. Identifying modifiable risk factors that could prevent depression is important. Here, the authors show increased risks of incident depression in pre-frail and frail individuals and highlight the mediating role of brain structure and inflammation.

Background Insulin resistance (IR) is linked to an increased risk of frailty, yet it remains unclear whether the non-insulin-based IR indicators are associated with frailty trajectories and physical function decline. It aimed to examine the associations of triglyceride-glucose (TyG) index, metabolic score for insulin resistance (METS-IR), estimated glucose disposal rate (eGDR) and with long-term deficit-accumulation frailty trajectories and physical function decline. Methods Data from 6722 participants in the China Health and Retirement Longitudinal Study (CHARLS) were analyzed. Baseline TyG index, METS-IR, eGDR, along with the frailty index (FI) over nine years, were calculated. FI trajectories were assessed using group-based trajectory model (GBTM). Logistic regression models were used to analyze the associations between IR indicators with FI trajectory and frailty risk. Restricted cubic splines (RCS) models were utilized to detect potential dose-response associations. Linear mixed-effects model was used to evaluate associations with FI development speed. Age, gender, educational level, marital status, smoking status, drinking status, life satisfaction, social activity and sleep duration were adjusted. Additionally, a two-sample Mendelian randomization (MR) was performed to assess the causality of observed associations. Results Three FI trajectories including low-stable frailty, moderate-increasing frailty, and accelerated rising frailty were identified. Regarding the frail risk, each SD increment in TyG index was associated with a 16.1% increase in the risk of frailty (OR = 1.161; 95%CI: 1.092, 1.235). An inverse association was observed for eGDR with the OR (95%CI) being 0.741 (0.696, 0.788). A linear relationship was observed between baseline TyG index and frailty risk ( P nonlinear = 0.696), but nonlinear association patterns for eGDR ( P nonlinearity < 0.010) and METS-IR ( P nonlinearity < 0.010). Each SD increment of TyG index was associated with greater FI increase ( β  = 0.005 SD/y; 95%CI = 0.002, 0.008 SD/y; P  < 0.001). A similar association pattern was observed for METS-IR, and participants in the highest quartile of METS-IR showed significantly greater FI progression, with β value of 0.013 (95% CI = 0.004, 0.022). Each SD increment of eGDR was associated with a slower increase in FI ( β =-0.006 SD/y, 95% CI=-0.009, -0.003 SD/y; P  < 0.001). Participants in the highest quartile of eGDR presented a lower annual change in FI compared with participants in quartile 1 group during follow-up ( β= -0.013 SD/y, 95% CI=-0.022, -0.005 SD/y; P for trend = 0.001). Similar findings were observed for physical function decline. Findings from MR analysis showed a causal relationship between higher TyG index and increased risk of frailty ( β  = 0.214, 95% CI = 0.079, 0.349; P  = 0.002). Conclusions The non-insulin-based IR indicators, including TyG index, METS-IR and eGDR, were independently associated with the frailty progression and physical function decline. Monitoring and managing abnormal glucose metabolism should be recommended as a part of comprehensive strategies to prevent or delay the progression of frailty.

Frailty is common among individuals with chronic kidney disease (CKD), whereas its impact on incident CKD risk remains unknown. This study aimed to prospectively evaluate the association between frailty and incident CKD risk, exploring the potential modification role of genetic risk factors (GRS). A cohort of 275,442 UK Biobank participants (mean age 55.3 ± 8.1 years, 43.4% male) without CKD were included. Physical frailty was defined by Fried Frailty phenotypes (FP) and Rockwood Frailty Index (FI). New-onset CKD was identified through hospital inpatient records and death register. GRS for CKD were calculated based on 27 single-nucleotide variants. Cox proportional hazards models and Fine-Gray competing risk models were applied to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 14.1 years, 5771 incident CKD cases were documented. Cox models indicated that prefrailty and frailty were associated with an increased CKD risk, with HRs (95% CI) of 1.17 (1.10–1.24) and 1.74 (1.58–1.91) for FP, and 1.33 (1.24–1.41) and 1.87 (1.72–2.04) for FI. These associations remained significant after adjusting for competing risks. Estimated population attributable fractions of frailty for CKD were 5.6% (FP) and 9.9% (FI). A positive non-linear relationship between FI and CKD incidence was observed in women (P non-linearity < 0.001). Associations were strengthened in women and those under 60 years of age (P for interaction < 0.05). Frailty significantly interacted with genetic susceptibility (P for interaction < 0.001), with the highest CKD risk observed in participants with high genetic risk and frailty (HR, 95% CI; FI: 2.28, 1.90–2.74; FP: 1.88, 1.52–2.33). Pre-frailty and frailty associated with incident CKD, with further modulation by GRS. These findings have important implications of frailty assessment and management in CKD prevention.

BackgroundEpidemiological data have suggested that tobacco and alcohol consumption were associated with the risk of frailty and falling, but it is yet unclear whether these associations are of a causal nature. Thus, we conducted two-sample Mendelian randomisation analysis using genetic instruments to determine the causal associations of tobacco and alcohol consumption on frailty and falls.MethodsIndependent instrumental variables strongly (p<5E–09) associated with tobacco and alcohol consumption were obtained from the genome-wide association study (GWAS) and Sequencing Consortium of Alcohol and Nicotine use (up to 2 669 029 participants). Summary statistics of the frailty index (FI, N=175 226) and falling risk (N=451 179) were from the two latest published GWAS datasets on FI and falling risk.ResultsUsing the inverse-variance weighted method, our results showed that genetically determined initiation of smoking was significantly associated with an increased FI (β=0.34, 95% CI=0.29 to 0.40, p=5.48E–33) and risk of falling (OR=1.39, 95% CI=1.30 to 1.50, p=1.01E–20). In addition, the age of initiation of smoking and cigarettes consumption per day was negatively and positively associated with both FI and falls, respectively. Current smokers were prone to having a higher FI and falling risk than individuals who quit smoking. There was no significant causal association between alcohol use and the risk of frailty and falling. Similar results were obtained using other statistical approaches with good stability.ConclusionsOur findings demonstrate that tobacco use, but not alcohol drinking, significantly increases the risk of frailty and falling. Future studies are warranted to clarify the underlying physiopathological mechanisms.