More than 200 participants from North America, Europe and Asia met in post-Olympic Sochi for five days this April, as world-famous anti-aging researchers exchanged ideas at the third International Conference on Genetics of Aging and Longevity. They discussed progress and remaining obstacles, in their efforts to deepen our understanding of this complex phenomenon and develop strategies for interventions.
The central themes of the conference included (1) identification of molecular targets for lifespan-extending drugs, (2) understanding the protective genotypes of centenarians and exceptionally long-lived animal species, (3) the complex roles and interactions of genetic determinants, epigenetic regulation, metabolism, gut microbiota, lifestyle and environment in shaping the aging process, (4) developing technologies for artificial growth, cryopreservation and transplantation of organs, and (5) new technologies, including gene-editing nanoparticles and artificial chromosomes, as prospective anti-aging tools.
The doors opened on April 6, 2014, to the 3rd International conference Genetics of Aging and Longevity, organized by the Science for Life Extension Foundation in collaboration with the Institute of biology of the Komi Science Center of the Russian Academy of Sciences (RAS). Scientists from many fields of biology, medicine and informatics, and from 19 countries (Russia, U.S., Canada, Ukraine, UK, China, Kazakhstan, Belarus, Israel, The Netherlands, Germany, Poland, Israel, Italy, Estonia, Azerbaijan, Sweden, Uzbekistan, and Jordan) met in Sochi and were unified by one common goal – the ever-growing importance of understanding the mechanisms of aging, to develop ways to prevent and possibly reverse this debilitating and deadly process that underlies virtually all age-dependent diseases.
Some of the most exciting conclusions from the conference are:
Advanced methodologies for assessment of somatic mutations and DNA damage levels, metabolic profiles and biological age biomarkers have been developed and are already utilized to research the genetics and biology of aging.
Comprehensive online databases of age-related changes and genomes of long-lived animals and centenarians have been created, including some that employ artificial intelligence to extract information from literature, and are continuously expanding.
Lifespan-altering genetic alleles, processes, metabolites and gut bacterial strains are being identified and confirmed, in order to understand determinants of longevity and to create meaningful interventions.
Technologies for growth and transplantation of artificial organs, cell- and organelle-specific drug delivery, non-viral gene editing, and insertion of artificial chromosomes, are being developed, tested and improved so that they can be applied clinically.
Some potentially life-extending drugs are already available or soon will be: nicotinamide riboside, selective TORC1 inhibitors, metformin and IGF1R-blocking antibodies. Although few of these are sufficiently well studied to ensure that their benefits outweigh any negative side-effects, they offer great hope for the future.
The conference featured 50 talks, 46 posters, 4 roundtables and 2 special presentations. The roundtables were devoted to proposing and unifying theories of aging, developing personalized medicine and attracting venture capital to longevity science. The special presentations were given by sponsors of the conference – LabCures, an online funding and communication platform for life-science labs, and Atlas Biomed Group, a provider of personalized genetic testing.
Participants also signed a letter to the World Health Organization (WHO), requesting that WHO should collect and integrate data about age-related disease incidences worldwide and across the years, to support studies seeking to identify common associated risk factors.
Mikhail Batin (Science for Life Extension Foundation), Co-organizer of the Conference, summarized the conference as follows: “The best minds came together at the third International Genetics of Aging and Longevity conference in Sochi, to search for scientific methods of extending healthy human lifespan.”
Dr. Alexey Moskalev (Institute of Biology, Komi Science Center of RAS; and Moscow Institute of Physics and Technology), Co-organizer of the Conference, added “Thanks to the conference, many scientists met together, some for the first time, and learned different approaches to the study of aging, and started research collaborations for new projects. Due to unprecedented interest in the conference we are going to hold the next one in the spring of 2016.”
The conference took place in the Congress Centre of Radisson Blu Resort hotel, Sochi.
Detailed information is provided below about selected talks:
Jan Vijg (Albert Einstein College of Medicine) presented new methodologies to identify and analyze somatic mutations and epigenetic changes: single-cell whole genome sequencing as well as single-cell transcripto-genomics (SCTG). SCTG checks whether a mutation of interest is transcribed or remains silent. The number of somatic mutations, and the fraction that is silent, increases with age of mice or fruitflies.
Matt Kaeberlein (University of Washington) showed that dietary restriction could rescue near-normal lifespan in yeast with mutated mitochondrial proteins. He also showed that rapamycin increased lifespan and health in mice with defective mitochondrial complex I, a model for human Leigh syndrome, possibly through a metabolic mechanisms that alleviates accumulation of glycolytic intermediates and lactic acidosis. He proposed that depletion of NAD may underlie severe mitochondrial disease and discussed ongoing experiments to determine whether restoring NAD+ levels through nicotinamide riboside supplementation could rescue Leigh syndrome in mice. Nicotinamide riboside is currently marketed as NIAGENTM.
Vera Gorbunova (University of Rochester) showed that SIRT6, a protein extending lifespan in mice upon overexpression, serves as a guardian of the genome. SIRT6 facilitates repair of DNA breaks by mono-ADP-ribosylating and activating PARP1 . Her group also identified upstream regulator of SIRT6 and showed that SIRT6 maintains genome stability via additional mechanisms.
Alexander Maslov (Albert Einstein College of Medicine) presented the new method of DNA damage assessment using quantitative long range PCR (QLR-PCR), which showed a slight increase of DNA damage with age in the liver but not in the brain of studied animals. Another new method that allowed detection of somatic structural DNA variants (translocations, inversions, duplications) using next generation sequencing helped to show their increase in cells from liver and brain of aging mice, but not from intestine and heart.
Andrei Seluanov (University of Rochester) showed that high molecular weight (hmw) hyaluronic acid (HA) protects naked mole rat, an unusually long-lived rodent, from tumors, whereas low molecular weight HA is oncogenic. Moreover, naked mole rat ribosomes have very high translation fidelity, resulting in synthesis of high-quality proteins.
Claudio Franceschi (University of Bologna) showed that several genome-wide population studies identified APOE locus as the only one correlating with lifespan. They discovered pro-survival allele T of APOE, presence of which correlated with low blood pressure, decreased incidence of stroke and overall higher longevity. Studies also showed surprisingly beneficial effects of mutations in mitochondrial complex I, when there was not another mutation also present in complex III or V. Shotgun sequencing of gut microbiome revealed relative enrichment in Proteobacteria phylum and Escherichia and Ruminococcus genera in centenarians.
Robert J. Shmookler Reis (University of Arkansas) presented the discovery of a novel protein CRAM-1 in the aggregates formed in a nematode model of Huntington disease. Knockdown of this protein decreased aggregates, delayed paralysis and rescued chemotaxis in nematode models of both Huntington’s and Alzheimer’s diseases. CRAM-1 was shown to condense oligo-ubiquitin, potentially leading to blocks in proteasome degradation and/or autophagy.
Judith Campisi (Buck Institute for Research on Aging) presented a new transgenic mouse model to visualize and eliminate senescent cells in mice based on their elevated expression of the p16INK4a gene. She showed that senescent cells accumulate and persist after ionizing radiation or doxorubicin treatment, promote cancer metastases and mediate the adverse effects of chemotherapy. On the other hand, the transient (but not persistent) appearance of senescent cells in cutaneous wounds is required to facilitate healing through secretion of a potent growth factor.
Yousin Suh (Albert Einstein College of Medicine) showed that particular single-nucleotide polymorphism (SNP) variants in the promoter region of SIRT1 prevents binding of transcriptional activator CTCF and instead promotes binding of transcriptional repressor ZFR. This prevents upregulation of SIRT1 upon oxidative stress and increases the risk of myocardial infarction. Similarly, a longevity-associated SNP variant in the FOXO3 enhancer increases FOXO3 expression in response to oxidative stress. Also, top 25 longevity-associated genes identified by gene-based rare variant association analysis (SKAT) using target capture-seq analysis of centenarians and controls comprise mostly genes involved in DNA double-strand-break signaling and repair.
Nir Barzilai (Albert Einstein College of Medicine) showed that injection of IGF-1, but not insulin, into the brain ventricles of old rats improves peripheral insulin sensitivity through the action on IGF-1 receptor. He also highlighted the potential of using IGF-1 receptor-blocking antibodies, which do not cross blood-brain barrier, to decrease peripheral (oncogenic) but not central (neuroprotective) IGF-1 action.
David Gems (University College London) showed that in nematodes, DAF-16/FOXO activates the atypical AMP-independent AMPK subunit AAKG-4, which in turn accelerates DAF-16 activation by its direct phosphorylation and contributes to DAF-2/IGF-1R knockout-mediated longevity. Another DAF-16 target, transcription factor MDL-1, also contributes to DAF-2 KO longevity.
William Orr (Southern Methodist University) described how the redox-sensing functions of peroxiredoxins (Prx’s) in the fruitfly may play a key role in modulating the expression of key longevity gene determinants. Prx5 governs a trade-off between innate immunity and aging; its underexpression confers greater resistance to infection and its overexpression elicits reduced resistance to infection while at the same time increasing lifespan by 30% and improving resistance to oxidative stress.
Alexey Moskalev (Institute of biology of Komi Science Center of RAS; and Moscow Institute of Physics and Technology) presented the mechanisms of lifespan extension by hormesis after moderate stresses, such as ionizing radiation, revealed by using knockout Drosophila flies. The mechanisms included elimination of sensitive cells, stimulation of cellular stress responses, immune system activation and acceleration of fly growth rate. RNA sequencing showed upregulation of only 4 genes (including Sugarbabe, Tramtrack and Fat), and downregulation of 48 aging-related genes (e.g. Keap1 and Relish) after low-dose gamma irradiation.
Blanka Rogina (University of Connecticut) showed that dPGC1 mediates the Indy (transmembrane citrate transporter) mutation-induced increase in Drosophila lifespan by promoting mitochondrial biogenesis and decreasing oxidative stress. Reduced INDY levels in the midgut preserve intestinal stem cell homeostasis, resulting in maintenance of intestinal integrity.
Brian Kennedy (Buck Institute for Research on Aging) described studies to separate the efficacious effects of rapamycin from the deleterious side effects. Results indicate that the mechanisms by which the TORC1 and TORC2 complex can be inhibited differ and new compounds from Delos Pharmaceuticals were discussed that appear to reduce side effects in preclinical studies.
Michael Petrascheck (Scripps Research Inst.) presented results of a drug screen in nematodes, which identified 57 confirmed compounds with known mammalian pharmacology that increase C. elegans lifespan, 16 of which induce more than 30% extension. The main targets of these compounds are receptors for dopamine, serotonin, adrenalin, noradrenalin and hormones. Most of them (33) also increase resistance to oxidative stress.
Andrei Gudkov (Roswell Park Cancer Institute) reported that fibroblasts and tissues from lethally irradiated mice appear normal initially, but arrested cell division (at all stages of cell cycle) and showed senescent phenotypes after transfer to cell culture. This conversion of dormant senescence-prone cells (DSPC) to actual senescent cells depended on proliferation stimulus and p53 DNA-damage checkpoint. In contrast to mesenchymal cells, epithelial cells do not become DSPC.
Shay Soker (Wake Forest School of Medicine) presented recent advances in growing of organs in bioreactors. Simple organs like cornea, blood vessels and bladder are relatively easy to grow, whereas growing of complex organs like liver, kidney and pancreas requires scaffolds. Bioscaffolds can be isolated for the purpose of study by decellularisation of naturally grown organs.
Gregory Fahy (21st Century Medicine, Inc.) presented achievements and difficulties in vitrification of organs. Sophisticated cryoprotective cocktails, and protocols for tissue perfusion at high pressure prior to freezing, and rapid warming methods were developed. Nevertheless, the main problem that remains is different optimal cooling rate for different cell types and organ zones.
Paolo Macchiarini (Karolinska Institutet) presented the technology for growing non-immunogenic tracheas and other intrathoracic organs (oesophagus, lung, heart, diaphragm) and their clinical implication. Mesenchymal stem cells and mononuclear cells can be used equally well for cellularisation of biological matrices or bioartificial 3D nano materials. It was found, in humans, that G-CSF boosts in vivo cell seeding and engraftment of transplants, and erythropoietin reduces apoptosis.
Andre Watson (Ligandal Inc.) presented the proprietary nanoparticle technology aimed for cell- and organelle-specific delivery of drugs and non-viral genome editing tools, like CRISPRs or TALENs. Its effectiveness was confirmed in several in vitro and in vivo experiments.
Ksenia Yuryeva (Human Stem Cells Institute) presented emerging technologies for human artificial chromosome creation. Two approaches currently exist: top-down, in which a normal chromosome is isolated and depleted of all genes, leaving only telomere and centromere regions; and bottom-up, in which a chromosome is synthesized from scratch. Microcell-mediated chromosome transfer technology utilizes carrier cells for chromosome multiplication, then fragmentation and cell fusion to insert into the target cells of interest.
Joao Pedro de Magalhaes (University of Liverpool) presented online databases useful for aging research: Digital Aging Atlas (DAA), Human Aging Genomic Resources (HAGR) and The Naked Mole-Rat Genome Resource. He also shared some results of genome sequencing for the bowhead whale (the longest-living mammal, at >200 yr.), in particular that only 5 genes show evidence of strong, recent positive selection.
Vadim Gladyshev (Harvard Medical School) presented the results of genome and gene expression analyses across mammals. They sequenced and analyzed the genomes of long-lived subterranean mole-rats from Africa and identified candidate genes associated with longevity. In addition, genome sequencing of an exceptionally long-lived Brand’s bat from Russia revealed unique mutations in growth-hormone and IGF1 receptors. Comparative analysis of gene expression across mammals also revealed genes that associate with lifespan. These studies show how aging and control of lifespan can be understood through comparative genomics approaches.
Daniel Wuttke (University of Liverpool) presented a new open-source collaborative on-line platform aimed to decipher mechanisms of aging – Denigma. It is based on machine learning from databases, datasets or manual input, decomposition of problems into subproblems, use of ontologies, understandable by machines, machine logical reasoning, and reverse engineering of aging from data.
Daniel Promislow (University of Washington) employed a novel methodology for metabolome investigation, combining highly sensitive Orbitrap mass spectrometry with Weighted Gene Correlation Network Analysis (WGCNA) of the data to identify metabolomic modules of correlating metabolites. He showed that dietary restriction in Drosophila flies has dramatic effects not only on the levels of individual metabolites, but also on the interactions between metabolites.
Claudio Franceschi (University of Bologna) presented several biomarkers of biological age, validated in human population studies. They include blood levels of N-glycans, particularly the NGA2F/NA2F ratio, hypermethylation of ELOVL2 and FHL2 gene loci, metabolite signatures of blood and urine, and circulating mitochondrial DNA. The metabolite profile of centenarians was drastically different from that of elderly population but similar to the profile of young population. In a better-controlled experimental design, the children of centenarians were compared to age-matched controls (children of parents with unexceptional longevity).
Ancha Baranova (George Mason University) presented a new simple but robust method for determining disease or aging progression. It works by oligonucleotide array- or low-coverage NGS mRNA profiling followed by calculation of the profile distance from the norm in sample space coordinates. The method was shown to have predictive power on cancer progression.
Maria Konovalenko is a molecular biophysicist and the program coordinator for the Science for Life Extension Foundation. She earned her M.Sc. degree in Molecular Biological Physics at the Moscow Institute of Physics and Technology.
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