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Introduction: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia., Methods: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures., Results: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019)., Conclusion: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shrestha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia., Methods: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial., Results: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone., Conclusion: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bashir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study., Methods: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables., Results: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo., Conclusion: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rossios et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Dietary protein supplementation combined with resistance exercise (RE) may counteract declines in muscle strength, mass, and function (sarcopenia), but the role of whole foods rich in protein, such as milk, is less well understood. In the MIlkMAN study, we aimed to examine the feasibility and acceptability of milk+RE as an intervention for muscle function in community-dwelling older adults, and provide exploratory pilot data for future substantive research in population at risk of sarcopenia., Methods: In a parallel groups design, 30 older adults (71.7±3.6 years; 12 women) were randomised into three groups: WM (whole milk 3.6% fat)+RE, SM (skimmed milk 0.3% fat)+RE, and C (isocaloric carbohydrate drink)+RE. RE was performed twice-weekly over 6 weeks in a community gym, followed by the consumption of 500 ml of milk (~20 g protein) or carbohydrate drink immediately after exercise and a further 500 ml at home within the following 4-5 hours. The feasibility and acceptability of the study was determined by calculating recruitment and attendance rates, compliance with the intervention, rating participants' experiences, and recording adverse health events., Results: The response rate was 49% (out of 400 invitations sent), and the recruitment rate was 73.2% (30 participants recruited out of 41 screened for eligibility). Twenty-nine participants completed the intervention-an attendance rate of 97.1%; 89.7% rated their experience as 'excellent'/very good'. Compliance with taking the drinks was 97.1% (WM), 98.3% (SM), and 95.0% (C); 93.1% rated their drink intake as 'easy'/'very easy' with no adverse effects. Collection of exploratory pilot data to inform future trials was successful. Mean change in grip strength, 5-chair rises, and gait speed were 0.9±3.4 kg, 1.8±2.2 s, 0.1±0.1 m/s, respectively with no differences between the groups., Conclusions: This community-based milk+RE intervention was feasible and acceptable to older adults. The study successfully collected pilot data for future substantive research., Competing Interests: The authors have declared that no competing interests exist.

Background: Higher physical activity (PA) has been linked to better health and functioning. Trajectories of PA and associated factors have been studied in older adults aged ≥65, but less is known about influences on PA change in the very old (aged ≥85)., Objective: To investigate factors associated with self-reported PA and PA change over time in very old adults., Methods: 845 participants in the Newcastle 85+ Study were followed for health and functioning at 1.5-, 3-, and 5-year follow-up (wave 2 to 4). PA scores (range 0-18) and PA levels (low (PA scores 0-1), medium (2-6) and high (7-18)) were determined using a purpose-designed PA questionnaire. We used linear mixed models (LMM) to investigate factors associated with 5-year change in PA scores., Results: Overall, men had higher mean PA scores than women (up to 2.27 points). The highest proportion of participants (42-48%) had medium levels of PA across the waves. Although most experienced decline-stability in moderate and increases in high PA levels were also observed. The fully adjusted LMM revealed a curvilinear annual decline in PA scores of 0.52 (0.13) (β (SE), p<0.001), which decelerated by 0.07 (0.02) points (p<0.01) over time. The factors associated with low PA scores at baseline were female gender, higher waist-hip ratio, and no alcohol intake. Better self-rated and cognitive health and having fewer diseases were associated with higher PA scores. None were associated with the rate of change in PA over time., Conclusion: We observed a curvilinear trend and deceleration in PA scores decline in the very old. Men and those in better health and who drank alcohol were more physically active at baseline. None of the factors were associated with the rate of PA decline. Investigating those who maintain or increase levels of PA may inform interventions for at risk groups with PA decline., Competing Interests: The Newcastle 85+ Study has been partially funded by the Unilever Corporate Research. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Weak grip strength (GS) is a key component of sarcopenia and frailty and a powerful predictor of mortality, morbidity and disability. Despite increasing interest in understanding GS across the lifespan, little is known about GS decline in the very old (aged ≥85). We examined trajectories of GS in very old adults and identified the determinants., Methods: GS (kg) was measured four times over 5 years in 319 men and 526 women participating in the Newcastle 85+ Study. A weak GS sub-cohort was identified as having strength of ≤27 kg (men), and ≤16 kg (women) at baseline and follow-up. Mixed models were used to establish trajectories of GS and associated factors in all participants, men and women, and in those with weak GS., Results: Men's mean grip strength was 24.42 (SD = 6.77) kg, and women's 13.23 (4.42) kg (p<0.001) at baseline, with mean absolute change of -5.27 (4.90) kg and -3.14 (3.41), respectively (p<0.001) by 5-year follow-up. In the time-only mixed model, men experienced linear annual decline in GS of -1.13 (0.8) kg (β (SE), p<0.001), whilst women's decline although slower, accelerated by -0.06 (0.02) kg (p = 0.01) over time. In the saturated model, higher baseline physical activity, height, fat-free mass, better self-rated health, and not having arthritis in hand(s) were associated with stronger GS initially in both sexes. Annual GS decline in men and participants with weak GS who were highly physically active was slower by 0.95 and 0.52 kg, respectively compared with inactive counterparts., Conclusion: Grip strength decline in the very old followed linear (men) and curvilinear (women) trends. High levels of physical activity were protective of GS loss in men (but not in women) and in those with weak GS. Thus maintaining muscle strength in later life is important to reduce the morbidity and mortality in the very old., Competing Interests: We have the following interest: The Newcastle 85+ Study was partly funded by Unilever Corporate Research. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Background: Healthy diet has been associated with better muscle strength and physical performance in cross-sectional studies of older adults but the effect of dietary patterns (DP) on subsequent decline, particularly in the very old (aged 85+), has not been determined., Objective: We investigated the association between previously established DP and decline in muscle strength and physical performance in the very old., Design: 791 participants (61.8% women) from the Newcastle 85+ Study were followed-up for change in hand grip strength (HGS) and Timed Up-and Go (TUG) test over 5 years (four waves 1.5 years apart). Mixed models were used to determine the effects of DP on muscle strength and physical performance in the entire cohort and separately by sex., Results: Previously we have established three DP that varied in intake of red meats, potato, gravy and butter and differed with key health and social factors. HGS declined linearly by 1.59 kgF in men and 1.08 kgF in women (both p<0.001), and TUG slowed by 0.13 log10-transformed seconds (log10-s) in men and 0.11 log10-s in women per wave after adjusting for important covariates (both p<0.001), and also showed a nonlinear change (p<0.001). Men in DP1 ('High Red Meat') had worse overall HGS (β = -1.70, p = 0.05), but men in DP3 ('High Butter') had a steeper decline (β = -0.63, p = 0.05) than men in DP2 ('Low Meat'). Men in DP1 and women in DP3 also had overall slower TUG than those in DP2 (β = 0.08, p = 0.001 and β = 0.06, p = 0.01, respectively), but similar rate of decline after adjusting for sociodemographic, lifestyle, health, and functioning factors. The results for HGS and TUG were not affected by participants' cognitive status., Conclusions: DP high in red meats, potato and gravy (DP1), or butter (DP3) may adversely affect muscle strength and physical performance in later life, independently of important covariates and cognitive status.

Introduction: Epidemiological studies have shown that weaker grip strength in later life is associated with disability, morbidity, and mortality. Grip strength is a key component of the sarcopenia and frailty phenotypes and yet it is unclear how individual measurements should be interpreted. Our objective was to produce cross-sectional centile values for grip strength across the life course. A secondary objective was to examine the impact of different aspects of measurement protocol., Methods: We combined 60,803 observations from 49,964 participants (26,687 female) of 12 general population studies in Great Britain. We produced centile curves for ages 4 to 90 and investigated the prevalence of weak grip, defined as strength at least 2.5 SDs below the gender-specific peak mean. We carried out a series of sensitivity analyses to assess the impact of dynamometer type and measurement position (seated or standing)., Results: Our results suggested three overall periods: an increase to peak in early adult life, maintenance through to midlife, and decline from midlife onwards. Males were on average stronger than females from adolescence onwards: males' peak median grip was 51 kg between ages 29 and 39, compared to 31 kg in females between ages 26 and 42. Weak grip strength, defined as strength at least 2.5 SDs below the gender-specific peak mean, increased sharply with age, reaching a prevalence of 23% in males and 27% in females by age 80. Sensitivity analyses suggested our findings were robust to differences in dynamometer type and measurement position., Conclusion: This is the first study to provide normative data for grip strength across the life course. These centile values have the potential to inform the clinical assessment of grip strength which is recognised as an important part of the identification of people with sarcopenia and frailty.

Background: Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance., Methods: Using data from four UK adult cohorts (ages 53-80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2)., Results: Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p =0.08) after further adjustment., Conclusions: Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Background: Low muscle mass and function have been associated with poorer indicators of physical capability in older people, which are in-turn associated with increased mortality rates. The growth hormone/insulin-like growth factor (GH/IGF) axis is involved in muscle function and genetic variants in genes in the axis may influence measures of physical capability., Methods: As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women from seven UK cohorts aged between 52 and 90 years old were genotyped for six polymorphisms: rs35767 (IGF1), rs7127900 (IGF2), rs2854744 (IGFBP3), rs2943641 (IRS1), rs2665802 (GH1) and the exon-3 deletion of GHR. The polymorphisms have previously been robustly associated with age-related traits or are potentially functional. Meta-analysis was used to pool within-study genotypic effects of the associations between the polymorphisms and four measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance., Results: Few important associations were observed among the several tests. We found evidence that rs2665802 in GH1 was associated with inability to balance for 5 s (pooled odds ratio per minor allele = 0.90, 95% CI: 0.82-0.98, p-value = 0.01, n = 10,748), after adjusting for age and sex. We found no evidence for other associations between the polymorphisms and physical capability traits., Conclusion: Our findings do not provide evidence for a substantial influence of these common polymorphisms in the GH/IGF axis on objectively measured physical capability levels in older adults.

Background: Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood., Methods and Findings: Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations., Conclusions: Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.