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  • The AMPK and sirtuins sense low energy


    The AMPK and sirtuins sense low energy states through detection of higher AMP and NAD+ levels. AMPK leads to restoration of the energy balance through catabolic responses including proteolysis, fatty PTK0796 oxidation, and inhibition of cell growth and proliferation [133]. AMPK has been reported to inhibit mTOR signaling [134], and has synergistic effects to calorie restriction [135] extending the health span and lifespan. PTK0796 Sirtuins have been reported to regulate the aging process and are essential for the calorie restriction induced longevity in S. cerevisiae, C. elegans, D. melanogaster and mice [118,136]. AMPK has been reported to be involved in differential expression of proteins in metabolic pathways through regulation of coactivators and transcription factors including C. elegans' DAF-16 and the human homologue FoxO3 [137,138]. Genomewide expression profiling and functional analysis revealed a link between CEP-1/p53 and CEH-23 suggesting their role downstream of AAK2 and the AMPK catalytic subunit homologue in C. elegans, in promoting stress resistance and longevity [139]. An antioxidant, chicoric acid, stimulated activation of AMPK pathways extends lifespan in C. elegans. Tissue specific upregulation of AMPK catalytic subunit, including neuronal-specific or intestinal, also increases lifespan in Drosophila [140]. A heterozygous mutation in AMP biosynthetic enzymes causing the increased AMP/ATP and ADP/ATP ratios, and transgenic overexpression of AMPK in the fly's fat body or muscle increased the lifespan, while RNAi-mediated AMPK knockdown in these tissues decreased the lifespan in Drosophila [141]. A decline in AMPK activation has been observed in different tissues with age in rats [142]. In mice, AMPK is involved in inhibition of TOR activity either directly through phosphorylation of the Raptor subunit, or indirectly through phosphorylation of an upstream kinase, tuberous sclerosis protein 2 (TSC2) [143,144]. Another target of AMPK phosphorylation includes the FOXO family of transcription factors, which is involved in lifespan extension through reduced insulin/insulin-like growth factor (IGF) signaling [145]. The beta-adrenergic system consists of β1 and β2 receptors that are found in the heart, lung, and peripheral tissues [146]. The activation of any of the two receptors causes positive inotropic and chronotropic responses, cardiac myocyte growth, and cardiac toxicity. Transgenic mice overexpressing β-adrenergic receptor 2 (β2AR) showed increased incidence of death resulting from cardiomyopathy and heart failure as early as 8.5 months with maximum age of 15 months [147]. Adenylyl cyclases (AC) are membrane bound enzyme that catalyze the synthesis of cAMP from ATP and play a vital role in β-adrenergic signaling. The cardiac tissue-specific overexpression of AC6 resulted in restoring myocyte AC function, improved heart function, increased cAMP generation, and abrogated myocardial hypertrophy leading to increased lifespan in the mice with cardiomyopathy background [148]. AC5-KO mice showed increased protection against oxidative stress, apoptosis, and osteoporosis, leading to longevity through the activation of the Raf/MEK/ERK signaling pathway [149]. Moreover, overexpression of mammalian ERK2 extended lifespan and improved resistance against heat shock and oxidative stress in budding yeast [149]. Pharmacological inhibition of β1AR through βAR blockers, metoprolol or nebivolol, resulted in the extension of lifespan in Drosophila and mice [150]. Recently, β2AR inhibition was reported to diminish the age-related accumulation of hepatic triglyceride, increased body weight and improved glucose tolerance in mice [151]. Consistent with the reports from animal models, our previous study provided the clues of involvement of β-adrenergic system in longevity, which was evident from genotyping and Single Nucleotide Polymorphism (SNP) association study in Han Chinese Population and backed by transfection studies using HEK293A cells [152]. β2AR has been reported to be associated with gender dependent human longevity supporting the well documented sexual dimorphism exhibited by longevity, as two SNPs (rs1042718 and rs1042719) of β2AR coding gene ADRB2 and their haplotypes leading to the reduced translation efficiency of ADRB2 were reportedly associated with longevity in men [110,152]. Together these results provided the evidence of the conservation of β-adrenergic system across the species, its involvement in promoting longevity, and suggest βAR suppression as a therapeutic intervention for lifespan and health span extension (Fig. 2).