Abstract
The age-dependent declines of skeletal muscle and cognitive functions often coexist in elderly subjects. The underlying pathophysiological mechanisms share common features of mitochondrial dysfunction, which plays a central role in the development of overt sarcopenia and/or dementia. Dietary supplementation with formulations of essential and branched-chain amino acids (EAA-BCAA) is a promising preventive strategy because it can preserve mitochondrial biogenesis and function. The senescence-accelerated mouse prone 8 (SAMP8) is considered an accurate model of age-related muscular and cognitive alterations. Hence, we aimed to investigate the progression of mitochondrial dysfunctions during muscular and cognitive aging of SAMP8 mice and to study the effects of a novel EAA-BCAA-based metabolic modulator on these changes. We evaluated body condition, motor endurance, and working memory of SAMP8 mice at 5, 9, 12, and 15 months of age. Parallel changes in protein levels of mitochondrial respiratory chain subunits, regulators of mitochondrial biogenesis and dynamics, and the antioxidant response, as well as respiratory complex activities, were measured in the quadriceps femoris and the hippocampus. The same variables were assessed in 12-month-old SAMP8 mice that had received dietary supplementation with the novel EAA-BCAA formulation, containing tricarboxylic acid cycle intermediates and co-factors (PD-0E7, 1.5 mg/kg/body weight/day in drinking water) for 3 months. Contrary to untreated mice, which had a significant molecular and phenotypic impairment, PD-0E7-treated mice showed preserved healthy body condition, muscle weight to body weight ratio, motor endurance, and working memory at 12 months of age. The PD-0E7 mixture increased the protein levels and the enzymatic activities of mitochondrial complex I, II, and IV and the expression of proliferator-activated receptor γ coactivator-1α, optic atrophy protein 1, and nuclear factor, erythroid 2 like 2 in muscles and hippocampi. The mitochondrial amyloid-β-degrading pitrilysin metallopeptidase 1 was upregulated, while amyloid precursor protein was reduced in the hippocampi of PD-0E7 treated mice. In conclusion, we show that a dietary supplement tailored to boost mitochondrial respiration preserves skeletal muscle and hippocampal mitochondrial quality control and health. When administered at the early onset of age-related physical and cognitive decline, this novel metabolic inducer counteracts the deleterious effects of precocious aging in both domains.
Highlights
Aging is a natural multifactorial process characterized by a gradual decrease in physiological functions, resulting in reduced resistance to stress, high vulnerability to diseases, and increased probability of death
We have previously demonstrated that a specific mixture of essential amino acids (EAAs) enriched in branched-chain amino acids (BCAA-enriched mixture, BCAAem) activated the eNOS/ mTORC1/proliferator-activated receptor g coactivator-1a (PGC-1a) cascade in middle-aged mice, so preserving cardiac and skeletal muscle mitochondrial biogenesis, enhancing physical endurance and increasing average lifespan (D’Antona et al, 2010)
Western blot analysis on total homogenates of quadriceps femoris showed that the amount of phosphorylated p70 S6 kinase 1 (S6K1) was significantly augmented in the PD-0E7-treated group compared to unsupplemented controls (Figure 5C), demonstrating the activation of the mTORC1/S6K1 pathway (Ma and Blenis, 2009), as we reported previously with the in vivo administration of the BCAAem formula (D’Antona et al, 2010)
Summary
Aging is a natural multifactorial process characterized by a gradual decrease in physiological functions, resulting in reduced resistance to stress, high vulnerability to diseases, and increased probability of death. Sarcopenia, recently recognized as a disease by the World Health Organization (Anker et al, 2016), is an age-associated loss of skeletal muscle mass and function, leading to reduced physical performance (Cruz-Jentoft and Sayer, 2019). It is independently associated with comorbidities, including cognitive impairment (Hsu et al, 2014). Sarcopenia is recognized as a core feature of frailty syndrome (Cruz-Jentoft and Sayer, 2019), a condition of decreased physiological reserve mostly affecting the skeletal muscle and the brain, besides other organs and systems, and leading to increased vulnerability to adverse health outcomes (Clegg et al, 2013). It would be useful to investigate the shared pathophysiological mechanism(s) of physical and cognitive decline as potential target(s) for preventive or therapeutic interventions
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