Fibroblasts from long‐lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress

Wang, Min; Miller, Richard A.

doi:10.1111/j.1474-9726.2012.00833.x

Cited by 48 publications

(37 citation statements)

References 46 publications

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“…Conversely, long-lived Snell/Dwarf mice show increased basal activation of the NFE2L2 pathway, suggesting that IIS and the antioxidant response cooperate to influence longevity (Leiser and Miller 2010). In fact, Snell/Dwarf mice-derived fibroblasts show lower levels of mTORC1 activity and enhanced autophagy in response to stress (Wang and Miller 2012). Similarly, we and others show that prolonged reduction of mTORC1 signaling increases autophagy and delays cellular senescence (Demidenko et al 2009;Lerner et al 2013;Cao et al 2011).…”

Section: P62/sqstm1: a Novel Aging Genesupporting

confidence: 57%

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p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

122

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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Section: P62/sqstm1: a Novel Aging Genesupporting

confidence: 57%

“…Autophagy in particular can degrade damaged proteins, protein aggregates, and damaged organelles that accumulate during aging and in age-related pathologies (Mizushima et al 2008) and is elicited by ageextending interventions and in long-lived mutants (Hansen et al 2008;Tóth et al 2008;Wang and Miller 2012;Alvers et al 2009). …”

mentioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

122

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“…Furthermore, autophagy seems to be upregulated in CR mice, and to mediate some of the beneficial effects of a CR diet on the heart, liver, and kidneys (52)(53)(54). Cells from long-lived Snell dwarf mice also show evidence of increased autophagy (55). Cardiomyocytes isolated from aged mice have lower autophagy and exhibit defects in calcium handling, both of which are corrected by exposure to rapamycin ex vivo (56).…”

Section: Potential Mechanisms Of Life Span Extension By Rapamycinmentioning

confidence: 99%

Rapalogs and mTOR inhibitors as anti-aging therapeutics

Lamming

Ye²,

Sabatini³

et al. 2013

J. Clin. Invest.

464

382

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Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling.

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“…Similar studies were performed on other long-lived dwarf mice (Ames, GHR KO) and revealed increased resistance against UV, H 2 O 2 and paraquat (Salmon et al, 2005). More recently it has been shown skin-derived fibroblasts from both Snell and GHR KO have diminished phosphorylation of mTOR, S6K and 4EBP1 after amino acid deprivation (in GHR KO and Snell fibroblasts), H 2 O 2 (Snell fibroblasts), and paraquat (Snell fibroblasts), consistent with the higher levels of autophagy in these cells following a stress stimulus (Wang & Miller, 2012) Additionally it has been suggested that stress resistance might be dependent on developmental changes (hormonedependent) that occur during the first few months after birth since no differences were observed in fibroblasts derived from neonates of dwarf mice and littermate controls (Salmon et al, 2005).…”

Section: Stress Resistance: Ability To Deal With Rosmentioning

confidence: 53%

“…Although stress resistance has been extensively studied in skin-derived fibroblasts from Ames, Snell and GHR KO mice (Wang & Miller, 2012;Murakami et al, 2003;Salmon et al, 2005) there is a lack of free radical scavenging reported in vivo in GHR KO liver and kidney with conflicting results from the same lab (Hauck et al, 2002;Al-Regaiey, 2013). This may be attributed to different genetic background of mice and the age group used between the two studies.…”

Section: Reductions In Gh-mediated Stat5 and Resistance Against Stressmentioning

confidence: 99%

The growth hormone receptor mediated oncogenesis

Chhabra¹

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Growth hormone (GH) is a major regulator of postnatal growth, cellular proliferation and differentiation, as well as of metabolism. All actions of GH are mediated via its cognate Growth Hormone Receptor (GHR). It is now clear that the role of GH extends well beyond the conventional notions of longitudinal growth and childhood development. A substantial body of evidence supports a role for the GH/IGF-1 axis in cancer incidence and progression in animals and humans and because of widespread clinical application of GH, there has been considerable interest in the mechanism of activation of its receptor. It was originally thought that GH initiated its actions by sequentially binding two GHR monomers, resulting in receptor dimerisation and initiation of intracellular signalling cascades, including Jak/STAT and MAPK pathways. However, recent evidence by our group and others has indicated that the GHR is constitutively dimerised, and that dimerisation alone is not sufficient for GHR activation.To this end the main objective of this thesis was to evaluate the role of GH-mediated signalling via its GHR in mediating oncogenesis. We have taken a multi-disciplinary approach by first determining how the GHR is activated via its transmembrane domain (TMD) and the nature of its interaction with Src family of tyrosine kinase (Lyn). We have determined the basis of the contrasting actions of autocrine GH from independent publications and sought to evaluate the effect of various constitutively active GHR constructs in cancer promotion in vitro and in vivo by establishing a tissue-specific delivery system (TVA system) for introducing multiple genes in a spatial and temporally controlled manner. We have provided the molecular basis of increased cancer susceptibility of the first reported GHR variant from two independent epidemiological studies. Finally, we have evaluated cancer resistance and anti-aging pathways in various GHR knockin and knockout mice models.In order to determine the role of GHR transmembrane domain (TMD) and upper juxtamembrane domain (JMD) in signalling, cysteine-scanning mutagenesis was employed with truncated and full length receptors in a thiol-free background. Using these GHR constructs and sequentially substituting residues along the GHR JMD and TMD with cysteine we observed a ligandindependent spontaneous dimerisation pattern of upper JMD and TMD residues with evidence for a 'tilt and twist' movement for this region of GHR during activation. By using Cu-o-phenanthroline we were able to show that GHR activation could occur following disulfide bond formation at the upper TMD boundary resulting in constitutive activation. Finally we were able to conclude that GHR activation requires the JMD residues to come in close proximity which results in separation of iii the lower TMD residues and activation. Another outcome of this study was the generation of the first full-length constitutively active receptor.GHR has been shown to activate numerous pathways and one such pathway involves Src Family Kinase (SFK),...

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Fibroblasts from long‐lived mutant mice exhibit increased autophagy and lower TOR activity after nutrient deprivation or oxidative stress

Cited by 48 publications

References 46 publications

p62/SQSTM1 at the interface of aging, autophagy, and disease

p62/SQSTM1 at the interface of aging, autophagy, and disease

Rapalogs and mTOR inhibitors as anti-aging therapeutics

The growth hormone receptor mediated oncogenesis

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