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Article ; Online: Combining a High Dose of Metformin With the SIRT1 Activator, SRT1720, Reduces Life Span in Aged Mice Fed a High-Fat Diet.

Palliyaguru, Dushani L / Minor, Robin K / Mitchell, Sarah J / Palacios, Hector H / Licata, Jordan J / Ward, Theresa M / Abulwerdi, Gelareh / Elliott, Peter / Westphal, Christoph / Ellis, James L / Sinclair, David A / Price, Nathan L / Bernier, Michel / de Cabo, Rafael

The journals of gerontology. Series A, Biological sciences and medical sciences

2020 Volume 75, Issue 11, Page(s) 2037–2041

Abstract: SRT1720, a sirtuin1-activator, and metformin (MET), an antidiabetic drug, confer health and life-span benefits when administered individually. It is unclear whether combination of the two compounds could lead to additional benefits. Groups of 56-week-old ...

Abstract	SRT1720, a sirtuin1-activator, and metformin (MET), an antidiabetic drug, confer health and life-span benefits when administered individually. It is unclear whether combination of the two compounds could lead to additional benefits. Groups of 56-week-old C57BL/6J male mice were fed a high-fat diet (HFD) alone or supplemented with either SRT1720 (2 g/kg food), a high dose of MET (1% wt/wt food), or a combination of both. Animals were monitored for survival, body weight, food consumption, body composition, and rotarod performance. Mice treated with MET alone did not have improved longevity, and life span was dramatically reduced by combination of MET with SRT1720. Although all groups of animals were consuming similar amounts of food, mice on MET or MET + SRT1720 showed a sharp reduction in body weight. SRT1720 + MET mice also had lower percent body fat combined with better performance on the rotarod compared to controls. These data suggest that co-treatment of SRT1720 with MET is detrimental to survival at the doses used and, therefore, risk-benefits of combining life-span-extending drugs especially in older populations needs to be systematically evaluated.
MeSH term(s)	Animals ; Body Composition ; Body Weight ; Diet, High-Fat ; Heterocyclic Compounds, 4 or More Rings/administration & dosage ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Longevity/drug effects ; Male ; Metformin/administration & dosage ; Metformin/pharmacology ; Mice ; Mice, Inbred C57BL ; Models, Animal ; Sirtuin 1
Chemical Substances	Heterocyclic Compounds, 4 or More Rings ; SRT1720 ; Metformin (9100L32L2N) ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2020-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glaa148
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Article: Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction.

Minor, Robin K / Chang, Joy W / de Cabo, Rafael

Molecular and cellular endocrinology

2008 Volume 299, Issue 1, Page(s) 79–88

Abstract: Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and ... ...

Abstract	Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important faculties like cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR's beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. Neuropeptide Y (NPY), a neurotransmitter in the front line of the arcuate response to low energy availability, is the primary hunger signal affected by CR and therefore may be a critical mechanism for lifespan extension.
MeSH term(s)	Aging/physiology ; Animals ; Arcuate Nucleus of Hypothalamus/physiology ; Caloric Restriction ; Humans ; Hunger/physiology ; Longevity/physiology ; Models, Biological ; Neuropeptide Y/physiology
Chemical Substances	Neuropeptide Y
Language	English
Publishing date	2008-11-11
Publishing country	Ireland
Document type	Journal Article ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2008.10.044
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Zs.A 1127: Show issues

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Article ; Online: Are sirtuins viable targets for improving healthspan and lifespan?

Baur, Joseph A / Ungvari, Zoltan / Minor, Robin K / Le Couteur, David G / de Cabo, Rafael

Nature reviews. Drug discovery

2012 Volume 11, Issue 6, Page(s) 443–461

Abstract: Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well ... ...

Abstract	Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1.
MeSH term(s)	Aging/physiology ; Animals ; Biotransformation/physiology ; Caloric Restriction ; Geriatrics ; Health ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Life Expectancy ; Mammals ; Resveratrol ; Sirtuin 1/metabolism ; Sirtuin 1/physiology ; Sirtuin 3/physiology ; Sirtuins/drug effects ; Sirtuins/physiology ; Stilbenes/pharmacology
Chemical Substances	Heterocyclic Compounds, 4 or More Rings ; SRT1720 ; Stilbenes ; SIRT1 protein, human (EC 3.5.1.-) ; SIRT3 protein, human (EC 3.5.1.-) ; SIRT6 protein, human (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Sirtuin 3 (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-) ; Resveratrol (Q369O8926L)
Language	English
Publishing date	2012-06-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/nrd3738
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Zs.A 5564: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dietary interventions to extend life span and health span based on calorie restriction.

Minor, Robin K / Allard, Joanne S / Younts, Caitlin M / Ward, Theresa M / de Cabo, Rafael

The journals of gerontology. Series A, Biological sciences and medical sciences

2010 Volume 65, Issue 7, Page(s) 695–703

Abstract: The societal impact of obesity, diabetes, and other metabolic disorders continues to rise despite increasing evidence of their negative long-term consequences on health span, longevity, and aging. Unfortunately, dietary management and exercise frequently ...

Abstract	The societal impact of obesity, diabetes, and other metabolic disorders continues to rise despite increasing evidence of their negative long-term consequences on health span, longevity, and aging. Unfortunately, dietary management and exercise frequently fail as remedies, underscoring the need for the development of alternative interventions to successfully treat metabolic disorders and enhance life span and health span. Using calorie restriction (CR)-which is well known to improve both health and longevity in controlled studies-as their benchmark, gerontologists are coming closer to identifying dietary and pharmacological therapies that may be applicable to aging humans. This review covers some of the more promising interventions targeted to affect pathways implicated in the aging process as well as variations on classical CR that may be better suited to human adaptation.
MeSH term(s)	Aging/physiology ; Animals ; Antioxidants/pharmacology ; Caloric Restriction ; Glucose/metabolism ; Health ; Humans ; Insulin/physiology ; Intracellular Signaling Peptides and Proteins/physiology ; Longevity/physiology ; Protein-Serine-Threonine Kinases/physiology ; Sirtuins/physiology ; TOR Serine-Threonine Kinases
Chemical Substances	Antioxidants ; Insulin ; Intracellular Signaling Peptides and Proteins ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Sirtuins (EC 3.5.1.-) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2010-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glq042
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Article: Copy number analysis of NIPBL in a cohort of 510 patients reveals rare copy number variants and a mosaic deletion.

Cheng, Yu-Wei / Tan, Christopher A / Minor, Agata / Arndt, Kelly / Wysinger, Latrice / Grange, Dorothy K / Kozel, Beth A / Robin, Nathaniel H / Waggoner, Darrel / Fitzpatrick, Carrie / Das, Soma / Del Gaudio, Daniela

Molecular genetics & genomic medicine

2013 Volume 2, Issue 2, Page(s) 115–123

Abstract: Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by growth retardation, intellectual disability, upper limb abnormalities, hirsutism, and characteristic facial features. In this study we explored the occurrence of ... ...

Abstract	Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by growth retardation, intellectual disability, upper limb abnormalities, hirsutism, and characteristic facial features. In this study we explored the occurrence of intragenic NIPBL copy number variations (CNVs) in a cohort of 510 NIPBL sequence-negative patients with suspected CdLS. Copy number analysis was performed by custom exon-targeted oligonucleotide array-comparative genomic hybridization and/or MLPA. Whole-genome SNP array was used to further characterize rearrangements extending beyond the NIPBL gene. We identified NIPBL CNVs in 13 patients (2.5%) including one intragenic duplication and a deletion in mosaic state. Breakpoint sequences in two patients provided further evidence of a microhomology-mediated replicative mechanism as a potential predominant contributor to CNVs in NIPBL. Patients for whom clinical information was available share classical CdLS features including craniofacial and limb defects. Our experience in studying the frequency of NIBPL CNVs in the largest series of patients to date widens the mutational spectrum of NIPBL and emphasizes the clinical utility of performing NIPBL deletion/duplication analysis in patients with CdLS.
Language	English
Publishing date	2013-11-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2734884-2
ISSN	2324-9269
ISSN	2324-9269
DOI	10.1002/mgg3.48
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Article ; Online: The arcuate nucleus and neuropeptide Y contribute to the antitumorigenic effect of calorie restriction.

Minor, Robin K / López, Miguel / Younts, Caitlin M / Jones, Bruce / Pearson, Kevin J / Anson, Robert Michael / Diéguez, Carlos / de Cabo, Rafael

Aging cell

2011 Volume 10, Issue 3, Page(s) 483–492

Abstract: Calorie restriction (CR) is known to have profound effects on tumor incidence. A typical consequence of CR is hunger, and we hypothesized that the neuroendocrine response to CR might in part mediate CR's antitumor effects. We tested CR under appetite ... ...

Abstract	Calorie restriction (CR) is known to have profound effects on tumor incidence. A typical consequence of CR is hunger, and we hypothesized that the neuroendocrine response to CR might in part mediate CR's antitumor effects. We tested CR under appetite suppression using two models: neuropeptide Y (NPY) knockout mice and monosodium glutamate-injected mice. While CR was protective in control mice challenged with a two-stage skin carcinogenesis model, papilloma development was neither delayed nor reduced by CR in the monosodium glutamate-treated and NPY knockout mice. Adiponectin levels were also not increased by CR in the appetite-suppressed mice. We propose that some of CR's beneficial effects cannot be separated from those imposed on appetite, and that NPY neurons in the arcuate nucleus of the hypothalamus are involved in the translation of reduced intake to downstream physiological and functional benefits.
MeSH term(s)	9,10-Dimethyl-1,2-benzanthracene/adverse effects ; Animals ; Appetite/drug effects ; Appetite/physiology ; Arcuate Nucleus of Hypothalamus/cytology ; Arcuate Nucleus of Hypothalamus/drug effects ; Arcuate Nucleus of Hypothalamus/physiology ; Caloric Restriction ; Female ; Hunger/drug effects ; Hunger/physiology ; Male ; Mice ; Mice, Knockout ; Neoplasms, Experimental/chemically induced ; Neurons/cytology ; Neurons/drug effects ; Neurons/metabolism ; Neuropeptide Y/deficiency ; Neuropeptide Y/genetics ; Papilloma ; RNA, Messenger/analysis ; Skin Neoplasms/chemically induced ; Sodium Glutamate/pharmacology ; Tetradecanoylphorbol Acetate/adverse effects
Chemical Substances	Neuropeptide Y ; RNA, Messenger ; 9,10-Dimethyl-1,2-benzanthracene (57-97-6) ; Tetradecanoylphorbol Acetate (NI40JAQ945) ; Sodium Glutamate (W81N5U6R6U)
Language	English
Publishing date	2011-04-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2113083-8
ISSN	1474-9726 ; 1474-9718
ISSN (online)	1474-9726
ISSN	1474-9718
DOI	10.1111/j.1474-9726.2011.00693.x
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Article: Calorie restriction alters physical performance but not cognition in two models of altered neuroendocrine signaling.

Minor, Robin K / Villarreal, Julissa / McGraw, Michael / Percival, Susan S / Ingram, Donald K / de Cabo, Rafael

Behavioural brain research

2008 Volume 189, Issue 1, Page(s) 202–211

Abstract: A major neuroendocrinological effect of calorie restriction (CR) is induction of neuropeptide Y (NPY) in the arcuate nucleus (ARC). Aside from its appetite-stimulating effects, NPY is thought to be involved in the modulation of behavioral processes ... ...

Abstract	A major neuroendocrinological effect of calorie restriction (CR) is induction of neuropeptide Y (NPY) in the arcuate nucleus (ARC). Aside from its appetite-stimulating effects, NPY is thought to be involved in the modulation of behavioral processes including anxiety and learning and memory. In the present study physical fitness, anxiety, and learning/memory-related tasks were assessed in mice lacking NPY or a functional ARC after dietary manipulation by CR. Physical fitness was improved by CR when measured by inclined screen and rotarod, and this diet effect was not affected by NPY or ARC status. As has been observed previously, the NPY knockout mice displayed heightened anxiety in an open field. This phenotype was not fully recapitulated in the ARC-lesioned model. CR affected neither total locomotor activity in the open field nor thigmotaxic behavior in these models. Neither NPY nor CR had a significant effect on Morris water maze performance; however, ARC-damaged mice were unable to learn the task, and this deficit was not corrected by CR. We conclude that despite established effects of CR on ARC signaling, our results suggest a mechanistic separation between the two where behavior is concerned.
MeSH term(s)	Adiposity/physiology ; Analysis of Variance ; Animals ; Arcuate Nucleus of Hypothalamus/metabolism ; Caloric Restriction ; Exploratory Behavior/physiology ; Female ; Male ; Maze Learning/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity/physiology ; Neuropeptide Y/genetics ; Neuropeptide Y/metabolism ; Nutritional Status/physiology ; Physical Conditioning, Animal/physiology
Chemical Substances	Neuropeptide Y
Language	English
Publishing date	2008-05-16
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	449927-x
ISSN	1872-7549 ; 0166-4328
ISSN (online)	1872-7549
ISSN	0166-4328
DOI	10.1016/j.bbr.2007.12.030
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Zs.A 1599: Show issues

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Article ; Online: The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet.

Mitchell, Sarah J / Martin-Montalvo, Alejandro / Mercken, Evi M / Palacios, Hector H / Ward, Theresa M / Abulwerdi, Gelareh / Minor, Robin K / Vlasuk, George P / Ellis, James L / Sinclair, David A / Dawson, John / Allison, David B / Zhang, Yongqing / Becker, Kevin G / Bernier, Michel / de Cabo, Rafael

Cell reports

2014 Volume 6, Issue 5, Page(s) 836–843

Abstract: The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, improves metabolism and ... ...

Abstract	The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of proinflammatory gene expression in both liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered the phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice.
MeSH term(s)	Animals ; Diet ; Heterocyclic Compounds, 4 or More Rings/metabolism ; Longevity ; Male ; Mice ; Mice, Inbred C57BL ; Sirtuin 1/genetics ; Sirtuin 1/metabolism ; Survival Analysis ; Transcriptome
Chemical Substances	Heterocyclic Compounds, 4 or More Rings ; SRT1720 ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2014-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2014.01.031
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Article ; Online: Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy.

Scheibye-Knudsen, Morten / Ramamoorthy, Mahesh / Sykora, Peter / Maynard, Scott / Lin, Ping-Chang / Minor, Robin K / Wilson, David M / Cooper, Marcus / Spencer, Richard / de Cabo, Rafael / Croteau, Deborah L / Bohr, Vilhelm A

The Journal of experimental medicine

2012 Volume 209, Issue 4, Page(s) 855–869

Abstract: Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. 80% of the cases are caused by mutations in the CS complementation group B (CSB) gene known to be involved in DNA ... ...

Abstract	Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. 80% of the cases are caused by mutations in the CS complementation group B (CSB) gene known to be involved in DNA repair and transcription. Recent evidence indicates that CSB is present in mitochondria, where it associates with mitochondrial DNA (mtDNA). We report an increase in metabolism in the CSB(m/m) mouse model and CSB-deficient cells. Mitochondrial content is increased in CSB-deficient cells, whereas autophagy is down-regulated, presumably as a result of defects in the recruitment of P62 and mitochondrial ubiquitination. CSB-deficient cells show increased free radical production and an accumulation of damaged mitochondria. Accordingly, treatment with the autophagic stimulators lithium chloride or rapamycin reverses the bioenergetic phenotype of CSB-deficient cells. Our data imply that CSB acts as an mtDNA damage sensor, inducing mitochondrial autophagy in response to stress, and that pharmacological modulators of autophagy are potential treatment options for this accelerated aging phenotype.
MeSH term(s)	Animals ; Autophagy ; Calcium/metabolism ; Cells, Cultured ; DNA Helicases/physiology ; DNA Repair Enzymes/physiology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Poly-ADP-Ribose Binding Proteins ; Reactive Oxygen Species/metabolism
Chemical Substances	Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Poly-ADP-Ribose Binding Proteins ; Reactive Oxygen Species ; DNA Helicases (EC 3.6.4.-) ; ERCC6 protein, human (EC 3.6.4.12) ; DNA Repair Enzymes (EC 6.5.1.-) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2012-04-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20111721
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Article: Bioenergetics of aging and calorie restriction.

Hunt, Nicole D / Hyun, Dong-Hoon / Allard, Joanne S / Minor, Robin K / Mattson, Mark P / Ingram, Donald K / de Cabo, Rafael

Ageing research reviews

2006 Volume 5, Issue 2, Page(s) 125–143

Abstract: Aging is a physiological process that involves a multi-factorial set of deleterious changes. These alterations are caused by an exponential increase in damage to macromolecules. This process is likely due to the cumulative effects of oxidative stress ... ...

Abstract	Aging is a physiological process that involves a multi-factorial set of deleterious changes. These alterations are caused by an exponential increase in damage to macromolecules. This process is likely due to the cumulative effects of oxidative stress over time. One area of ongoing research in gerontology has focused on determining why there is an age-dependent decrease in cellular bioenergetics. The aim of this review is to summarize the recent findings on the effects of aging and calorie restriction on energy metabolism. The effect of calorie restriction on age-associated changes in bioenergetic parameters will be examined.
MeSH term(s)	Aging/physiology ; Animals ; Caloric Restriction ; Energy Metabolism/physiology ; Humans ; Mitochondria/physiology ; Models, Biological
Language	English
Publishing date	2006-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	2075672-0
ISSN	1872-9649 ; 1568-1637
ISSN (online)	1872-9649
ISSN	1568-1637
DOI	10.1016/j.arr.2006.03.006
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Zs.A 5579: Show issues

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