ABSTRACT
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.
Subject(s)
Aging/drug effects , Biological Factors/therapeutic use , Longevity/drug effects , Prescription Drugs/therapeutic use , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Aging/genetics , Animals , Caloric Restriction/methods , Diet , Enzyme Activation , Gene Expression Regulation , Growth Hormone/antagonists & inhibitors , Growth Hormone/genetics , Growth Hormone/metabolism , Humans , Insulin-Like Growth Factor I/antagonists & inhibitors , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Longevity/genetics , Mice , Ribosomal Protein S6 Kinases/antagonists & inhibitors , Ribosomal Protein S6 Kinases/genetics , Ribosomal Protein S6 Kinases/metabolism , Signal Transduction , Sirtuins/genetics , Sirtuins/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: Irradiation results in impaired bone healing. Thus, osteosynthesis procedures are afflicted with increased failure rates. To improve osseointegration bone morphogenetic protein-2 (BMP-2) immobilized on nanocrystalline diamond (NCD)-coated implant surfaces might be 1 solution. METHODS: By 4 weeks after irradiation of pig's mandible with a dose of 60 Gy a fracture was accomplished. Osteosynthesis was performed either with titanium osteosynthesis screws or NCD-coated screws with immobilized BMP-2. Nonirradiated animals served as control. After 1, 2, 4, and 8 weeks screws were evaluated histologically. Bone biopsies were gained to extract mesenchymal stem or precursor cells (MSCs). RESULTS: MSCs after irradiation demonstrated a behavior comparable to that of unirradiated cells. Consequently, immobilized BMP-2 resulted in an initial increased bone contact ratio (p = .014) but demonstrated no sustainable effect compared with osseointegration in nonirradiated bone (p = .08). CONCLUSION: Immobilized BMP-2 demonstrates an osteoinductive effect in irradiated bone. MSCs as effector cells possess protective mechanisms to overcome the destructive effect of irradiation.
Subject(s)
Bone Morphogenetic Protein 2/pharmacology , Bone Screws , Coated Materials, Biocompatible/pharmacology , Mandible/radiation effects , Mandibular Fractures/surgery , Osseointegration/drug effects , Animals , Diamond/pharmacology , Disease Models, Animal , Fracture Fixation/instrumentation , Fracture Fixation/methods , Fracture Healing/physiology , Mandible/pathology , Mandible/surgery , Mandibular Fractures/diagnostic imaging , Radiation Dosage , Radiography , Random Allocation , Reference Values , Sensitivity and Specificity , Surface Properties , Sus scrofa , Swine , Titanium/pharmacologyABSTRACT
A major goal in the field of aging research is to identify molecular mechanisms of aging at the cellular level, which are anticipated to form the basis for the development of age-associated dysfunctions and diseases in human beings. Recent progress in research into model organisms of aging has allowed determining precise molecular mechanisms and genetic determinants of the aging process, which appear to be conserved in evolution and some of which apply to human aging as well. The consortium of the authors focuses on aging mechanisms at the cellular level, and exploits the potential of genetic analyses in lower eukaryotic model organisms for a better understanding of regulatory pathways implicated in aging processes. We have established a new database (GiSAO), which provides a unique resource for the analysis of genome-wide expression patterns as being regulated by senescence, apoptosis and oxidative stress in our model systems. This has led to the identification of candidate genes, which are being tested for their impact on lifespan regulation in yeast, the fruit fly Drosophila melanogaster and the nematode C. elegans.
