Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

MitoQ supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men.

The role of mitochondrial ROS in signalling muscle adaptations to exercise training has not been explored in detail. We investigated the effect of supplementation with the mitochondria-targeted antioxidant MitoQ on a) the skeletal muscle mitochondrial and antioxidant gene transcriptional response to acute high-intensity exercise and b) skeletal muscle mitochondrial content and function following exercise training. In a randomised, double-blind, placebo-controlled, parallel design study, 23 untrained men (age: 44 ± 7 years, VO2peak: 39.6 ± 7.9 ml/kg/min) were randomised to receive either MitoQ (20 mg/d) or a placebo for 10 days before completing a bout of high-intensity interval exercise (cycle ergometer, 10 × 60 s at VO2peak workload with 75 s rest). Blood samples and vastus lateralis muscle biopsies were collected before exercise and immediately and 3 h after exercise. Participants then completed high-intensity interval training (HIIT; 3 sessions per week for 3 weeks) and another blood sample and muscle biopsy were collected. There was no effect of acute exercise or MitoQ on systemic (plasma protein carbonyls and reduced glutathione) or skeletal muscle (mtDNA damage and 4-HNE) oxidative stress biomarkers. Acute exercise-induced increases in skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) mRNA expression were augmented in the MitoQ group. Despite this, training-induced increases in skeletal muscle mitochondrial content were similar between groups. HIIT-induced increases in VO2peak and 20 km time trial performance were also similar between groups while training-induced increases in peak power achieved during the VO2peak test were augmented in the MitoQ group. These data suggest that training-induced increases in peak power are enhanced following MitoQ supplementation, which may be related to the augmentation of skeletal muscle PGC1α expression following acute exercise. However, these effects do not appear to be related to an effect of MitoQ supplementation on exercise-induced oxidative stress or training-induced mitochondrial biogenesis in skeletal muscle.

Mitochondria-targeted antioxidant supplementation does not affect muscle soreness or recovery of maximal voluntary isometric contraction force following muscle-damaging exercise in untrained men: a randomized clinical trial.

Unaccustomed exercise causes muscle damage resulting in loss of muscle function, which may be attributable to exercise-induced increases in skeletal muscle reactive oxygen species. This study examined the effect of mitochondria-targeted antioxidant supplementation on recovery of muscle function following exercise. Thirty-two untrained men received MitoQ (20 mg/day) or a placebo for 14 days before performing  300 maximal eccentric contractions of the knee extensor muscles of 1 leg. Muscle function was assessed using isokinetic dynamometry before, immediately after, and 24, 48, 72, and 168 hours after exercise. Muscle soreness was assessed using a visual analogue scale 24, 48, 72, and 168 hours after exercise. Blood samples were collected before, immediately after, and 2, 24, 48, 72, and 168 hours after exercise and urine samples were collected before and during the 48 hours after exercise. The reduction in maximal voluntary isometric contraction force and peak concentric torque following exercise was unaffected by MitoQ while recovery of peak eccentric torque was delayed in the MitoQ group. Exercise-induced increases in urine F2-isoprostanes were unaffected by MitoQ. MitoQ augmented exercise-induced increases in plasma creatine kinase levels, while plasma IL-6 was similar between groups. Muscle soreness was not affected by MitoQ. These results indicate that MitoQ does not attenuate post-exercise muscle soreness and may delay recovery of muscle function following eccentric exercise. Trial registration number: ACTRN12620001089921. Novelty: Post-exercise recovery of maximal voluntary isometric contraction force and peak concentric torque were unaffected by MitoQ. MitoQ delayed post-exercise recovery of peak eccentric torque. Post-exercise muscle soreness was unaffected by MitoQ.

Mitochondria-targeted antioxidant supplementation improves 8 km time trial performance in middle-aged trained male cyclists.

BACKGROUND: Exercise increases skeletal muscle reactive oxygen species (ROS) production, which may contribute to the onset of muscular fatigue and impair athletic performance. Mitochondria-targeted antioxidants such as MitoQ, which contains a ubiquinone moiety and is targeted to mitochondria through the addition of a lipophilic triphenylphosphonium cation, are becoming popular amongst active individuals as they are designed to accumulate within mitochondria and may provide targeted protection against exercise-induced oxidative stress. However, the effect of MitoQ supplementation on cycling performance is currently unknown. Here, we investigate whether MitoQ supplementation can improve cycling performance measured as time to complete an 8 km time trial. METHOD: In a randomized, double-blind, placebo-controlled crossover study, 19 middle-aged (age: 44 ± 4 years) recreationally trained (VO2peak: 58.5 ± 6.2 ml·kg- 1·min- 1, distance cycled per week during 6 months prior to study enrollment: 158.3 ± 58.4 km) male cyclists completed 45 min cycling at 70% VO2peak followed by an 8 km time trial after 28 days of supplementation with MitoQ (20 mg·day- 1) and a placebo. Free F2-isoprostanes were measured in plasma samples collected at rest, after 45 min cycling at 70% VO2peak and after completion of the time trial. Respiratory gases and measures of rating of perceived exertion (RPE) were also collected. RESULTS: Mean completion time for the time trial was 1.3% faster with MitoQ (12.91 ± 0.94 min) compared to placebo (13.09 ± 0.95 min, p = 0.04, 95% CI [0.05, 2.64], d = 0.2). There was no difference in RPE during the time trial between conditions (p = 0.82) despite there being a 4.4% increase in average power output during the time trial following MitoQ supplementation compared to placebo (placebo; 270 ± 51 W, MitoQ; 280 ± 53 W, p = 0.04, 95% CI [0.49, 8.22], d = 0.2). Plasma F2-isoprostanes were lower on completion of the time trial following MitoQ supplementation (35.89 ± 13.6 pg·ml- 1) compared to placebo (44.7 ± 16.9 pg·ml- 1 p = 0.03). CONCLUSION: These data suggest that MitoQ supplementation may be an effective nutritional strategy to attenuate exercise-induced increases in oxidative damage to lipids and improve cycling performance.

The effect of epidermal growth factor, insulin and transferrin on the growth-promoting properties of serum depleted by repeated culture of postimplantation rat embryos.

Homologous serum, when repeatedly used for the culture of postimplantation rat embryos, rapidly loses its capacity to support growth and development. Replenishment of the 'exhausted' serum with glucose and vitamins (MEM vitamin concentrate--Flow Laboratories) together with gentle dialysis to remove small molecular weight toxic metabolites (lactate etc) fails to restore the growth-promoting properties of the serum. This suggests that 'recycled' serum has been depleted of specific growth-promoting factors. Such serum that has been subjected to dialysis can be completely replenished by addition of 30% normal rat serum. It is therefore probable that the growth promoters are originally present at very low concentrations and become rate limiting when serum is recycled. Many growth factors and hormones fall into this category and it is likely that a considerable number are involved when serum is 'exhausted' by repeated use. When insulin, epidermal growth factor or rat transferrin are added to dialysed 'exhausted' serum each effects a partial restoration of growth of rat embryos.