Interventions to Slow Aging in Humans: Are We Ready?

The workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF‐I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro‐longevity effects and ability of these interventions to prevent or delay multiple age‐related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.

[1]  B. Kristal,et al.  Preoperative dietary restriction reduces intimal hyperplasia and protects from ischemia-reperfusion injury. , 2016, Journal of vascular surgery.

[2]  A. Nakai Heat Shock Factor , 2016, Springer Japan.

[3]  James M. Flegal,et al.  Nordihydroguaiaretic Acid Extends the Lifespan of Drosophila and Mice, Increases Mortality-Related Tumors and Hemorrhagic Diathesis, and Alters Energy Homeostasis in Mice , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[4]  S. Ghavami,et al.  Induction of Autophagy: Role of Endoplasmic Reticulum Stress and Unfolded Protein Response , 2015 .

[5]  H. Hausenblas,et al.  Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. , 2015, Molecular nutrition & food research.

[6]  V. Longo,et al.  Protein and amino acid restriction, aging and disease: from yeast to humans , 2014, Trends in Endocrinology & Metabolism.

[7]  D. Gems What is an anti-aging treatment? , 2014, Experimental Gerontology.

[8]  J. Kopchick,et al.  Growth hormone signaling is necessary for lifespan extension by dietary methionine , 2014, Aging cell.

[9]  T. Illig,et al.  Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice , 2014, Nature Communications.

[10]  A. Schambach,et al.  A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage , 2014 .

[11]  S. McKnight,et al.  P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage , 2014, Cell.

[12]  G. Bray,et al.  FGF21 is an endocrine signal of protein restriction. , 2014, The Journal of clinical investigation.

[13]  Weiquan Li,et al.  ATF4 activity: a common feature shared by many kinds of slow-aging mice , 2014, Aging cell.

[14]  B. Manning,et al.  The TSC complex is required for the benefits of dietary protein restriction on stress resistance in vivo. , 2014, Cell reports.

[15]  A. Freedman,et al.  Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: a review of the literature , 2014, Expert opinion on drug safety.

[16]  C. Franceschi,et al.  New advances in CMV and immunosenescence , 2014, Experimental Gerontology.

[17]  Laura C. Greaves,et al.  Chronic inflammation induces telomere dysfunction and accelerates ageing in mice , 2014, Nature Communications.

[18]  N. Ruderman,et al.  AMPK activation: a therapeutic target for type 2 diabetes? , 2014, Diabetes, metabolic syndrome and obesity : targets and therapy.

[19]  T. Dorff,et al.  Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. , 2014, Cell stem cell.

[20]  C. Franceschi,et al.  Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[21]  Michael J. MacDonald,et al.  Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase , 2014, Nature.

[22]  F. Johnson,et al.  Methionine Restriction Activates the Retrograde Response and Confers Both Stress Tolerance and Lifespan Extension to Yeast, Mouse and Human Cells , 2014, PloS one.

[23]  C. Franceschi,et al.  Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for “inflamm‐aging” , 2014, European journal of immunology.

[24]  Fabio Demontis,et al.  GDF11/Myostatin and aging , 2014, Aging.

[25]  B. Kennedy,et al.  Drugs that modulate aging: the promising yet difficult path ahead. , 2014, Translational research : the journal of laboratory and clinical medicine.

[26]  G. Kroemer,et al.  Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification , 2014, PLoS genetics.

[27]  Reinhard Guthke,et al.  D-Glucosamine supplementation extends life span of nematodes and of ageing mice , 2014, Nature Communications.

[28]  V. Gladyshev,et al.  Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino acid status , 2014, Nature Communications.

[29]  P. Chanson,et al.  Expert consensus document: A consensus on the medical treatment of acromegaly , 2014, Nature Reviews Endocrinology.

[30]  R. Weindruch,et al.  Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys , 2014, Nature Communications.

[31]  D. Sinclair,et al.  Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38: Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome. Diabetes 2013;62:1084–1093 , 2014, Diabetes.

[32]  A. Antebi,et al.  Hexosamine Pathway Metabolites Enhance Protein Quality Control and Prolong Life , 2014, Cell.

[33]  A. Criollo,et al.  Spliced X-Box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway , 2014, Cell.

[34]  P. Cohen,et al.  Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity , 2014, Aging cell.

[35]  C. López-Otín,et al.  Regulation of autophagy by cytosolic acetyl-coenzyme A. , 2014, Molecular cell.

[36]  M. Levine,et al.  Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. , 2014, Cell metabolism.

[37]  G. Juhász,et al.  Nucleocytosolic Depletion of the Energy Metabolite Acetyl-Coenzyme A Stimulates Autophagy and Prolongs Lifespan , 2014, Cell metabolism.

[38]  Richard G Melvin,et al.  The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. , 2014, Cell metabolism.

[39]  D. Sinclair,et al.  Small molecule SIRT1 activators for the treatment of aging and age-related diseases. , 2014, Trends in pharmacological sciences.

[40]  K. Rudolph,et al.  Impact of genomic damage and ageing on stem cell function , 2014, Nature Cell Biology.

[41]  Z. D. Sharp,et al.  Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction , 2014, Aging cell.

[42]  Mark P Mattson,et al.  Fasting: molecular mechanisms and clinical applications. , 2014, Cell metabolism.

[43]  Min Wei,et al.  Serine- and Threonine/Valine-Dependent Activation of PDK and Tor Orthologs Converge on Sch9 to Promote Aging , 2014, PLoS genetics.

[44]  C. Franceschi,et al.  Reprint of: A parallel randomized trial on the effect of a healthful diet on inflammageing and its consequences in European elderly people: Design of the NU-AGE dietary intervention study , 2013, Mechanisms of Ageing and Development.

[45]  M. Mattson Interventions that improve body and brain bioenergetics for Parkinson's disease risk reduction and therapy. , 2014, Journal of Parkinson's disease.

[46]  B. Winblad,et al.  Long-term metformin usage and cognitive function among older adults with diabetes. , 2014, Journal of Alzheimer's disease : JAD.

[47]  D. Sinclair,et al.  Small molecule SIRT 1 activators for the treatment of aging and age-related diseases , 2014 .

[48]  E. Feskens,et al.  A parallel randomized trial on the effect of a healthful diet on inflammageing and its consequences in European elderly people: Design of the NU-AGE dietary intervention study , 2013, Mechanisms of Ageing and Development.

[49]  E. Mercken,et al.  Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging , 2013, Cell.

[50]  J. Geschwind,et al.  Tumor glycolysis as a target for cancer therapy: progress and prospects , 2013, Molecular Cancer.

[51]  N. Neretti,et al.  Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues , 2013, Aging.

[52]  Seung-Jae V. Lee,et al.  Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF‐1 signaling pathways in C. elegans , 2013, Aging cell.

[53]  R. Vessella,et al.  Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer , 2013, Oncotarget.

[54]  Dejian Huang,et al.  Independent and Additive Effects of Glutamic Acid and Methionine on Yeast Longevity , 2013, PloS one.

[55]  N. Neretti,et al.  Death by transposition – the enemy within? , 2013, BioEssays : news and reviews in molecular, cellular and developmental biology.

[56]  S. Anton,et al.  Fasting or caloric restriction for Healthy Aging , 2013, Experimental Gerontology.

[57]  L. Ferrucci,et al.  Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. , 2013, Cell metabolism.

[58]  D. Ingram,et al.  Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. , 2013, Cell metabolism.

[59]  R. de Cabo,et al.  Resveratrol Prevents β-Cell Dedifferentiation in Nonhuman Primates Given a High-Fat/High-Sugar Diet , 2013, Diabetes.

[60]  Erik D Herzog,et al.  Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. , 2013, Cell metabolism.

[61]  C. Franceschi,et al.  MicroRNAs linking inflamm-aging, cellular senescence and cancer , 2013, Ageing Research Reviews.

[62]  E. Mercken,et al.  Metformin improves healthspan and lifespan in mice , 2013, Nature Communications.

[63]  G. Rena,et al.  Molecular mechanism of action of metformin: old or new insights? , 2013, Diabetologia.

[64]  C. Conover Role of PAPP-A in aging and age-related disease , 2013, Experimental Gerontology.

[65]  David Carling,et al.  AMPK, insulin resistance, and the metabolic syndrome. , 2013, The Journal of clinical investigation.

[66]  E. Cava,et al.  Will calorie restriction work in humans? , 2013, Aging.

[67]  Fei Li,et al.  Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. , 2013, Biochemical and biophysical research communications.

[68]  G. Shadel,et al.  Epigenetic silencing mediates mitochondria stress-induced longevity. , 2013, Cell metabolism.

[69]  D. Newby,et al.  Cardiovascular Effects of a Novel SIRT1 Activator, SRT2104, in Otherwise Healthy Cigarette Smokers , 2013, Journal of the American Heart Association.

[70]  L. Tsai,et al.  A Dietary Regimen of Caloric Restriction or Pharmacological Activation of SIRT1 to Delay the Onset of Neurodegeneration , 2013, The Journal of Neuroscience.

[71]  Sang Gyun Kim,et al.  Nutrient regulation of the mTOR Complex 1 signaling pathway , 2013, Molecules and cells.

[72]  P. Cohen,et al.  Protein restriction cycles reduce IGF‐1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer's disease mouse model , 2013, Aging cell.

[73]  Sara Hillenmeyer,et al.  Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements , 2013, Aging cell.

[74]  C. Franceschi,et al.  Oxidative stress and the ageing endocrine system , 2013, Nature Reviews Endocrinology.

[75]  David Weinkove,et al.  Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism , 2013, Cell.

[76]  D. Sinclair,et al.  Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38 , 2013, Diabetes.

[77]  C. Franceschi,et al.  N-glycomic biomarkers of biological aging and longevity: A link with inflammaging , 2013, Ageing Research Reviews.

[78]  Lan Ye,et al.  Rapalogs and mTOR inhibitors as anti-aging therapeutics. , 2013, The Journal of clinical investigation.

[79]  J. Campisi,et al.  Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. , 2013, The Journal of clinical investigation.

[80]  H. Jäckle,et al.  A Histone Mutant Reproduces the Phenotype Caused by Loss of Histone-Modifying Factor Polycomb , 2013, Science.

[81]  A. Bracher,et al.  Large FK506-Binding Proteins Shape the Pharmacology of Rapamycin , 2013, Molecular and Cellular Biology.

[82]  P. Rabinovitch,et al.  mTOR is a key modulator of ageing and age-related disease , 2013, Nature.

[83]  C. Franceschi,et al.  Inflamm-ageing , 2013, Current opinion in clinical nutrition and metabolic care.

[84]  J. Mitchell,et al.  Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. , 2013, The Biochemical journal.

[85]  E. Nevo,et al.  High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat , 2013 .

[86]  R. de Cabo,et al.  Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[87]  James M. Flegal,et al.  β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice , 2013, AGE.

[88]  C. Scrideli,et al.  Tetra-O-methyl nordihydroguaiaretic acid, an inhibitor of Sp1-mediated survivin transcription, induces apoptosis and acts synergistically with chemo-radiotherapy in glioblastoma cells , 2013, Investigational New Drugs.

[89]  K. Schechtman,et al.  Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. , 2012, Cell metabolism.

[90]  S. Bojesen,et al.  Statin use and reduced cancer-related mortality. , 2012, The New England journal of medicine.

[91]  M. Fenech,et al.  A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. , 2012, Cancer treatment reviews.

[92]  David B. Allison,et al.  Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study , 2012, Nature.

[93]  Karen Ocorr,et al.  Statin Treatment Increases Lifespan and Improves Cardiac Health in Drosophila by Decreasing Specific Protein Prenylation , 2012, PloS one.

[94]  J. Auwerx,et al.  The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. , 2012, Cell metabolism.

[95]  Matthew J. Crowley,et al.  Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treatment of ischemic heart disease: Future research needs prioritization. , 2012, American heart journal.

[96]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[97]  Christos G Mihos,et al.  The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: a comprehensive review. , 2012, Journal of cancer research and therapeutics.

[98]  Dudley Lamming,et al.  Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity , 2012, Science.

[99]  M. Buchfelder,et al.  Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. , 2012, The Journal of clinical endocrinology and metabolism.

[100]  Pedro Mejia,et al.  Surgical Stress Resistance Induced by Single Amino Acid Deprivation Requires Gcn2 in Mice , 2012, Science Translational Medicine.

[101]  K. Ellison,et al.  Optimising the Use of β-Adrenoceptor Antagonists in Coronary Artery Disease , 2012, Drugs.

[102]  M. Speicher,et al.  Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction , 2011, Nature Cell Biology.

[103]  J. Couzin-Frankel Genetics. Aging genes: the sirtuin story unravels. , 2011, Science.

[104]  J. Auwerx,et al.  Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. , 2011, Cell metabolism.

[105]  R. Bloomer,et al.  Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings , 2011, Nutrition journal.

[106]  S. Imai,et al.  Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. , 2011, Cell metabolism.

[107]  E. Mercken,et al.  SRT1720 improves survival and healthspan of obese mice , 2011, Scientific reports.

[108]  Kenneth S Boockvar,et al.  Recent trends in chronic disease, impairment and disability among older adults in the United States , 2011, BMC geriatrics.

[109]  H. Hausenblas,et al.  Resveratrol and health--a comprehensive review of human clinical trials. , 2011, Molecular nutrition & food research.

[110]  J. Boeke,et al.  Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition , 2011, BMC Biochemistry.

[111]  J. Cuzick,et al.  The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women , 2011, International Journal of Obesity.

[112]  A. Brenner,et al.  Common toxicities of mammalian target of rapamycin inhibitors , 2011, Targeted Oncology.

[113]  Z. Laron,et al.  Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. , 2011, European journal of endocrinology.

[114]  P. Bénit,et al.  Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome , 2011, The Journal of cell biology.

[115]  Federica Madia,et al.  Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans , 2011, Science Translational Medicine.

[116]  P. Dandona,et al.  A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. , 2011, The Journal of clinical endocrinology and metabolism.

[117]  Donald K. Ingram,et al.  Glycolytic inhibition as a strategy for developing calorie restriction mimetics , 2011, Experimental Gerontology.

[118]  M. Hansen,et al.  A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in -1 , 2011 .

[119]  V. Anisimov Metformin for aging and cancer prevention , 2010, Aging.

[120]  S. Vatner,et al.  Modulation of β-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5 , 2010, Heart Failure Reviews.

[121]  S. Spindler Caloric restriction: From soup to nuts , 2010, Ageing Research Reviews.

[122]  P. Brigidi,et al.  Through Ageing, and Beyond: Gut Microbiota and Inflammatory Status in Seniors and Centenarians , 2010, PloS one.

[123]  P. Lin,et al.  Molecular mechanisms and clinical applications of nordihydroguaiaretic acid (NDGA) and its derivatives: an update. , 2010, Medical science monitor : international medical journal of experimental and clinical research.

[124]  Linda Partridge,et al.  Extending Healthy Life Span—From Yeast to Humans , 2010, Science.

[125]  Heidi Ledford Ageing: Much ado about ageing , 2010, Nature.

[126]  D. Allison,et al.  Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats. , 2010, Toxicology and applied pharmacology.

[127]  Anil Wipat,et al.  Feedback between p21 and reactive oxygen production is necessary for cell senescence , 2010, Molecular systems biology.

[128]  J. Campisi,et al.  The senescence-associated secretory phenotype: the dark side of tumor suppression. , 2010, Annual review of pathology.

[129]  B. Hoogwerf Renin-angiotensin system blockade and cardiovascular and renal protection. , 2010, The American journal of cardiology.

[130]  Zheng Yang,et al.  BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR , 2009, Molecular Cancer Therapeutics.

[131]  T. Dorff,et al.  Fasting and cancer treatment in humans: A case series report , 2009, Aging.

[132]  Frank Sinner,et al.  Induction of autophagy by spermidine promotes longevity , 2009, Nature Cell Biology.

[133]  J. Vaupel,et al.  Ageing populations: the challenges ahead , 2009, The Lancet.

[134]  J. Lambert,et al.  Synthesis, characterization, and anti-melanoma activity of tetra-O-substituted analogs of nordihydroguaiaretic acid. , 2009, Bioorganic & medicinal chemistry letters.

[135]  F. Konishi,et al.  Long-term oral polyamine intake increases blood polyamine concentrations. , 2009, Journal of nutritional science and vitaminology.

[136]  Marco Pahor,et al.  Rapamycin fed late in life extends lifespan in genetically heterogeneous mice , 2009, Nature.

[137]  A. Gradman Evolving understanding of the renin-angiotensin-aldosterone system: pathophysiology and targets for therapeutic intervention. , 2009, American heart journal.

[138]  A. Shilatifard,et al.  Histone H4 lysine-16 acetylation regulates cellular lifespan , 2009, Nature.

[139]  A. Bartke,et al.  Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[140]  D. Yellon,et al.  Statins and cardioprotection--more than just lipid lowering? , 2009, Pharmacology & therapeutics.

[141]  V. Longo Linking sirtuins, IGF-I signaling, and starvation , 2009, Experimental Gerontology.

[142]  G. Ruvkun,et al.  Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. , 2009, Genes & development.

[143]  Christian Sell,et al.  Life-span extension : , 2009 .

[144]  C. Allis,et al.  PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. , 2008, Mutation research.

[145]  Kenneth L. Hensley,et al.  Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice , 2008, Aging cell.

[146]  M. Manns,et al.  Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease , 2008, Proceedings of the National Academy of Sciences.

[147]  Leonid Peshkin,et al.  Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. , 2008, Cell metabolism.

[148]  H. Madhani,et al.  Genomewide Screen for Negative Regulators of Sirtuin Activity in Saccharomyces cerevisiae Reveals 40 Loci and Links to Metabolism , 2008, Genetics.

[149]  D. Leahy,et al.  Functionally significant insulin-like growth factor I receptor mutations in centenarians , 2008, Proceedings of the National Academy of Sciences.

[150]  M. Driscoll,et al.  A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans , 2008, PLoS genetics.

[151]  Chao Cheng,et al.  Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9 , 2007, PLoS genetics.

[152]  T. Kunkel,et al.  Exonuclease-1 Deletion Impairs DNA Damage Signaling and Prolongs Lifespan of Telomere-Dysfunctional Mice , 2007, Cell.

[153]  A. Trumpp,et al.  Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment , 2007, Nature Medicine.

[154]  C. Allis,et al.  Epigenetics: A Landscape Takes Shape , 2007, Cell.

[155]  Z. Laron,et al.  Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. , 2007, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[156]  G. Castellani,et al.  Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans , 2007, Mechanisms of Ageing and Development.

[157]  H. J. Frank About the authors , 2021, Gov. Inf. Q..

[158]  Hong Jiang,et al.  Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation , 2006, Nature Genetics.

[159]  P. Puigserver,et al.  Resveratrol improves health and survival of mice on a high-calorie diet , 2006, Nature.

[160]  Joseph A. Baur,et al.  Therapeutic potential of resveratrol: the in vivo evidence , 2006, Nature Reviews Drug Discovery.

[161]  D. Sabatini,et al.  Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. , 2006, Molecular cell.

[162]  A. Michalsen,et al.  Mediterranean diet or extended fasting's influence on changing the intestinal microflora, immunoglobulin A secretion and clinical outcome in patients with rheumatoid arthritis and fibromyalgia: an observational study , 2005, BMC complementary and alternative medicine.

[163]  F. Hofmann,et al.  The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes Small Cell Lung Cancer Cell Lines to the Effects of Chemotherapy , 2005, Clinical Cancer Research.

[164]  K. Ellison,et al.  Optimising the use of beta-adrenoceptor antagonists in coronary artery disease. , 2005, Drugs.

[165]  Corby K. Martin,et al.  Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. , 2005, The American journal of clinical nutrition.

[166]  P. Redman,et al.  Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer , 2004, Aging cell.

[167]  M. Prentki,et al.  Amp kinase and malonyl-coa: Targets for therapy of the metabolic syndrome , 2004, Nature Reviews Drug Discovery.

[168]  Pierre Corvol,et al.  82 – Peptidyl-dipeptidase A/angiotensin I-converting enzyme , 2004 .

[169]  Tibor Vellai,et al.  Genetics: Influence of TOR kinase on lifespan in C. elegans , 2003, Nature.

[170]  Phuong Chung,et al.  Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan , 2003, Nature.

[171]  D. Hall,et al.  Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans , 2003, Science.

[172]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[173]  J. Kopchick,et al.  Growth hormone receptor antagonists. , 2002, Minerva endocrinologica.

[174]  E. C. Stevens,et al.  Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. , 2002, Endocrine reviews.

[175]  J. Zierath,et al.  5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice , 2002, Diabetologia.

[176]  J. A. Scarlett,et al.  Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist , 2001, The Lancet.

[177]  C. Franceschi,et al.  Inflamm‐aging: An Evolutionary Perspective on Immunosenescence , 2000 .

[178]  M. S. Tewart,et al.  Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. , 2000 .

[179]  L. Guarente,et al.  Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase , 2000, Nature.

[180]  M. Bristow β-Adrenergic Receptor Blockade in Chronic Heart Failure , 2000 .

[181]  J. A. Scarlett,et al.  Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. , 2000, The New England journal of medicine.

[182]  M. Bristow beta-adrenergic receptor blockade in chronic heart failure. , 2000, Circulation.

[183]  R. Holman,et al.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) , 1998, The Lancet.

[184]  Tatsuya Hayashi,et al.  Evidence for 5′AMP-Activated Protein Kinase Mediation of the Effect of Muscle Contraction on Glucose Transport , 1998, Diabetes.

[185]  T. Wagner,et al.  A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[186]  N. Barzilai,et al.  Increased Hexosamine Availability Similarly Impairs the Action of Insulin and IGF-1 on Glucose Disposal , 1996, Diabetes.

[187]  P Corvol,et al.  Peptidyl dipeptidase A: angiotensin I-converting enzyme. , 1995, Methods in enzymology.

[188]  A. Meijer,et al.  Regulation of autophagy , 1995 .

[189]  Paul Tempst,et al.  RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs , 1994, Cell.

[190]  Stuart L. Schreiber,et al.  A mammalian protein targeted by G1-arresting rapamycin–receptor complex , 1994, Nature.

[191]  C. Kenyon,et al.  A C. elegans mutant that lives twice as long as wild type , 1993, Nature.

[192]  V. Tyler,et al.  The Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies , 1981 .

[193]  D. C. Fletcher,et al.  Inhibition of mitochondrial electron transport by nor-dihydroguaiaretic acid (NDGA). , 1970, Biochemical pharmacology.