Adenosine Nucleotide Biosynthesis and AMPK Regulate Adult Life Span and Mediate the Longevity Benefit of Caloric Restriction in Flies

Stenesen, Drew; Suh, Jae Myoung; Seo, Jin Ho; Yu, Kweon; Lee, Kyu-Sun; Kim, Jong Seok; Min, Kyung Jin; Graff, Jonathan M.

doi:10.1016/j.cmet.2012.12.006

Cited by 169 publications

(173 citation statements)

References 56 publications

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“…The relationship between AMPK and cellular senescence/aging has been suggested (Stenesen et al ., 2013; Ido et al ., 2015), and the role of AMPK in aging prevention is generally attributed to its effects on the activation of Sirt1 and FoxO1 (Wang et al ., 2011; Yun et al ., 2014), as well as the suppression of mTOR (Salminen & Kaarniranta, 2012). However, in the level of cellular aging, contradictory findings exist (Lee et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

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AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

et al. 2016

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Summary AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress‐induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated. Importantly, AMPK activation prevented hydrogen peroxide‐induced impairment of the autophagic flux in senescent cells, evidenced by the decreased p62 degradation, GFP‐RFP‐LC3 cancellation, and activity of lysosomal hydrolases. We also found that AMPK activation restored the NAD + levels in the senescent cells via a mechanism involving mostly the salvage pathway for NAD + synthesis. In addition, the mechanistic relationship of autophagic flux and NAD + synthesis and the involvement of mTOR and Sirt1 activities were assessed. In summary, our results suggest that AMPK prevents oxidative stress‐induced senescence by improving autophagic flux and NAD + homeostasis. This study provides a new insight for exploring the mechanisms of aging, autophagy and NAD + homeostasis, and it is also valuable in the development of innovative strategies to combat aging.

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Section: Discussionmentioning

confidence: 99%

“…The role of AMPK in preventing aging/senescence has been suggested in many studies (Apfeld et al ., 2003; Stenesen et al ., 2013; Ido et al ., 2015). AMPK signaling also activates autophagy.…”

Section: Introductionmentioning

confidence: 99%

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

et al. 2016

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“…UAS- AMPK and UAS-AMPKRNAi (v106200) lines have been described 46,47 . UAS-AMPKRNAi line (TRiP #25931, Bloomington Stock Center) produced similar phenotypes to UAS-AMPKRNAi (v106200) and was used for most experiments.…”

Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

219

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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“…They could vary the ADP/ATP content, and in that fashion set energy-state response via regulating AMPK signalling [54][55][56]. This AMP-activated kinase is a sensor that has effects in Drosophila [57,58], which provides a link between lifespan and caloric restriction [59].…”

Section: Discussionmentioning

confidence: 99%

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

Talbert¹,

Barnett²,

Hoff³

et al. 2015

Proc. R. Soc. B.

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There is a connection between nutrient inputs, energy-sensing pathways, lifespan variation and aging. Despite the role of metabolic enzymes in energy homeostasis and their metabolites as nutrient signals, little is known about how their gene expression impacts lifespan. In this report, we use P-element mutagenesis in Drosophila to study the effect on lifespan of reductions in expression of seven central metabolic enzymes, and contrast the effects on normal diet and dietary restriction. The major observation is that for five of seven genes, the reduction of gene expression extends lifespan on one or both diets. Two genes are involved in redox balance, and we observe that lower activity genotypes significantly extend lifespan. The hexokinases also show extension of lifespan with reduced gene activity. Since both affect the ATP/ADP ratio, this connects with the role of AMP-activated protein kinase as an energy sensor in regulating lifespan and mediating caloric restriction. These genes possess significant expression variation in natural populations, and our experimental genotypes span this level of natural activity variation. Our studies link the readout of energy state with the perturbation of the genes of central metabolism and demonstrate their effect on lifespan.

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Adenosine Nucleotide Biosynthesis and AMPK Regulate Adult Life Span and Mediate the Longevity Benefit of Caloric Restriction in Flies

Cited by 169 publications

References 56 publications

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

An obligatory role for neurotensin in high-fat-diet-induced obesity

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

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Adenosine Nucleotide Biosynthesis and AMPK Regulate Adult Life Span and Mediate the Longevity Benefit of Caloric Restriction in Flies

Cited by 169 publications

References 56 publications

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

An obligatory role for neurotensin in high-fat-diet-induced obesity

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

Contact Info

Product

Resources

About

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD ⁺ elevation