Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10⁻¹⁷), arthritis (GDF5p = 4 × 10⁻¹³), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Age-related losses of lean mass and shifts to central adiposity are related to functional decline and may predict mortality and/or explain part of the risk of weight loss. To determine how mortality risk is related to shifts in body composition, changes should be considered in the context of overall weight change. Five-year changes in body composition were assessed with computed tomography (cm²) and dual x-ray absorptiometry (kg) in 869 men and 934 women initially aged 70–79 years. All-cause mortality was monitored for up to 12 years (2002–2003 to September 30, 2014), and risk was assessed using sex-specific Cox models. Both men and women lost weight, visceral fat area, thigh muscle area, lean mass, and fat mass (all p < .01) but gained intermuscular thigh fat area (p < .01). There were 995 deaths. After adjustment for total weight change, demographics, and chronic disease, losing thigh muscle area was associated with higher mortality in both men (1.21, 1.08–1.35) and women (1.18, 1.01–1.37, per 9.0cm²) and was especially strong in normal weight (body mass index < 25kg/m²) individuals and those losing weight. Losing intermuscular thigh fat was protective against mortality only in normal weight (0.66, 0.51–0.86) and weight stable men (0.79, 0.66–0.95, per 3.2cm²). Changes in visceral fat area were not associated with mortality. Older adults with greater loss of thigh muscle than expected for overall weight change had a higher mortality risk compared to those with relative thigh muscle preservation, suggesting that conservation of muscle mass is important for survival in old age.

Purpose. Evaluate the effects of weight loss on muscle mass and area, muscle fat infiltration, strength, and their association with physical function.Methods. Thirty-six overweight to moderately obese, sedentary older adults were randomized into either a physical activity plus weight loss (PA+WL) or physical activity plus successful aging health education (PA+SA) program. Measurements included body composition by dual-energy X-ray absorptiometry, computerized tomography, knee extensor strength, and short physical performance battery (SPPB).Results. At 6 months, PA+WL lost greater thigh fat and muscle area compared to PA+SA. PA+WL lost 12.4% strength; PA+SA lost 1.0%. Muscle fat infiltration decreased significantly in PA+WL and PA+SA. Thigh fat area decreased 6-fold in comparison to lean area in PA+WL. Change in total SPPB score was strongly inversely correlated with change in fat but not with change in lean or strength.Conclusion. Weight loss resulted in additional improvements in function over exercise alone, primarily due to loss of body fat.

Fatigability increases while the capacity for mitochondrial energy production tends to decrease significantly with age. Thus, diminished mitochondrial function may contribute to higher levels of fatigability in older adults. The relationship between fatigability and skeletal muscle mitochondrial function was examined in 30 participants aged 78.5 ± 5.0 years (47% female, 93% white), with a body mass index of 25.9 ± 2.7 kg/m ² and usual gait-speed of 1.2 ± 0.2 m/s. Fatigability was defined using rating of perceived exertion (6–20 point Borg scale) after a 5-minute treadmill walk at 0.72 m/s. Phosphocreatine recovery in the quadriceps was measured using ³¹ P magnetic resonance spectroscopy and images of the quadriceps were captured to calculate quadriceps volume. ATPmax (mM ATP/s) and oxidative capacity of the quadriceps (ATPmax·Quadriceps volume) were calculated. Peak aerobic capacity (VO ₂ peak) was measured using a modified Balke protocol. ATPmax·Quadriceps volume was associated with VO ₂ peak and was 162.61mM ATP·mL/s lower ( p = .03) in those with high (rating of perceived exertion ≥10) versus low (rating of perceived exertion ≤9) fatigability. Participants with high fatigability required a significantly higher proportion of VO ₂ peak to walk at 0.72 m/s compared with those with low fatigability (58.7 ± 19.4% vs 44.9 ± 13.2%, p < .05). After adjustment for age and sex, higher ATPmax was associated with lower odds of having high fatigability (odds ratio: 0.34, 95% CI: 0.11–1.01, p = .05). Lower capacity for oxidative phosphorylation in the quadriceps, perhaps by contributing to lower VO ₂ peak, is associated with higher fatigability in older adults.