Buck Institute for Research on Aging

Autophagy, which declines with age, may hold more mysteries than researchers previously suspected. Scientists have now uncovered possible novel functions for various autophagy genes, which may control different forms of disposal including misfolded proteins -- and ultimately affect aging. Autophagy, which declines with age, may hold more mysteries than researchers previously suspected. In the January 4th issue of Nature Aging, it was noted that scientists from the Buck Institute, Sanford Burnham Prebys and Rutgers University have uncovered possible novel functions for various autophagy genes, which may control different forms of disposal including misfolded proteins -- and ultimately affect aging. "While this is very basic research, this work is a reminder that it is critical for us to understand whether we have the whole story about the different genes that have been related to aging or age-related diseases," said Professor Malene Hansen, Ph.D., Buck's chief scientific officer, who is also the study's co-senior author. "If the mechanism we found is conserved in other organisms, we speculate that it may play a broader role in aging than has been previously appreciated and may provide a method to improve life span." These new observations provide another perspective to what was traditionally thought to be occurring during autophagy. Autophagy is a cellular "housekeeping" process that promotes health by recycling or disposing of damaged DNA and RNA and other cellular components in a multi-step degradative process. It has been shown to be a key player in preventing aging and diseases of aging, including cancer, cardiovascular disease, diabetes and neurodegeneration. Notably, research has shown that autophagy genes are responsible for prolonged life span in a variety of long-lived organisms. The classical explanation of how autophagy works is that the cellular "garbage" to be dealt with is sequestered in a membrane-surrounded vesicle, and ultimately delivered to lysosomes for degradation. However, Hansen, who has studied the role of autophagy in aging for most of her career, was intrigued by an accumulation of evidence that indicated that this was not the only process in which autophagy genes can function. "There had been this growing notion over the last few years that genes in the early steps of autophagy were 'moonlighting' in processes outside of this classical lysosomal degradation," she said. Additionally, while it is known that multiple autophagy genes are required for the increased life span, the tissue-specific roles of specific autophagy genes are not well defined. To comprehensively investigate the role that autophagy genes play in neurons -- a key cell type for neurodegenerative diseases -- the team analyzed Caenorhabditis elegans, a tiny worm that is frequently used to model the genetics of aging and which has a very well-studied nervous system. The researchers specifically inhibited autophagy genes functioning at each step of the process in the neurons of the animals, and found that neuronal inhibition of early-acting, but not late-acting, autophagy genes, extended life span. These initial observations were made in Dr. Hansen's lab at Sanford Burnham Prebys in La Jolla, California, before she moved to the Buck Institute in 2021. An unexpected aspect was that this life span extension was accompanied by a reduction in aggregated protein in the neurons (an increase is associated with Huntington's disease, for example), and an increase in the formation of so-called exophers. These giant vesicles extruded from neurons were identified in 2017 by Dr. Monica Driscoll, a collaborator and professor at Rutgers University. "Exophers are thought to be essentially another cellular garbage disposal method, a mega-bag of trash," said Dr. Caroline Kumsta, co-senior author and assistant professor at SBP. "When there is either too much trash accumulating in neurons, or when the normal 'in-house' garbage disposal system is broken, the cellular waste is then being thrown out in these exophers." Interestingly, worms that formed exophers had reduced protein aggregation and lived significantly longer. This finding suggests a link between this process of this massive disposal event to overall health, said Kumsta. The team found that this process was dependent on a protein called ATG-16.2. The study identified several new functions for the autophagy protein ATG-16.2, including in exopher formation and life span determination, which led the team to speculate that this protein plays a nontraditional and unexpected role in the aging process. If this same mechanism is operating in other organisms, it may provide a method of manipulating autophagy genes to improve neuronal health and increase life span. "But first we have to learn more -- especially how ATG-16.2 is regulated and whether it is relevant in a broader sense, in other tissues and other species," Hansen said. The Hansen and Kumsta teams are planning on following up with a number of longevity models, including nematodes, mammalian cell cultures, human blood and mice. "Learning if there are multiple functions around autophagy genes like ATG-16.2 is going to be super important in developing potential therapies," Kumsta said. "It is currently very basic biology, but that is where we are in terms of knowing what those genes do." The traditional explanation that aging and autophagy are linked because of lysosomal degradation may need to expand to include additional pathways, which would have to be targeted differently to address the diseases and the problems that are associated with that. "It will be important to know either way," Hansen said. "The implications of such additional functions may hold a potential paradigm shift."

Having healthy mitochondria, the organelles that produce energy in all our cells, usually portends a long healthy life whether in humans or in C. elegans, a tiny, short-lived nematode worm often used to study the aging process.  Researchers have identified a new drug-like molecule that keeps mitochondria healthy via mitophagy, a process that removes and recycles damaged mitochondria in multicellular organisms. The compound, dubbed MIC, is a natural compound that extended lifespan in C. elegans, ameliorated pathology in neurodegenerative disease models of C. elegans, and improved mitochondrial function in mouse muscle cells. Having healthy mitochondria, the organelles that produce energy in all our cells, usually portends a long healthy life whether in humans or in C. elegans, a tiny, short-lived nematode worm often used to study the aging process. Researchers at the Buck Institute have identified a new drug-like molecule that keeps mitochondria healthy via mitophagy, a process that removes and recycles damaged mitochondria in multicellular organisms. The compound, dubbed MIC, is a natural compound that extended lifespan in C. elegans, ameliorated pathology in neurodegenerative disease models of C. elegans, and improved mitochondrial function in mouse muscle cells. Results are published in the November 13, 2023, edition of Nature Aging. The impact of mitochondrial dysfunction in age-related disease Defective mitophagy is implicated in many age-related diseases. It's tied to neurodegenerative disorders such as Parkinson's and Alzheimer's; it plays a role in cardiovascular diseases including heart failure; it influences metabolic disorders including obesity and type 2 diabetes; it is implicated in muscle wasting and sarcopenia and has a complex relationship with cancer progression. Even though interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold great promise for addressing these conditions, not one treatment has been approved for human use despite advances in the field. What's MIC? MIC (Mitophagy-Inducing Compound) is a coumarin, which are naturally bioactive compounds that have anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties (among others) as well as being an antioxidant with neuroprotective effects. Coumarin is found in many plants and is found in high concentrations in certain types of cinnamon, which is one of the most frequent sources for human exposure to the substance. A new mechanism of action in mitophagy The project started in a mouse model of Parkinson's disease where researchers in the laboratory of Julie Andersen, PhD, a senior author of the paper, were looking at known enhancers of mitophagy, including rapamycin. "Co-author Shankar Chinta, PhD, started screening natural compounds in neuronal cells and MIC came up as a major hit," she said. "Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB." In an effort spearheaded by Andersen and research scientist Manish Chamoli, PhD, lead author of the study, researchers found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is the intracellular recycling process whereby cells clean up damaged proteins; it derives its abilities from the lysosome. Researchers found that MIC robustly increased the lifespan of C. elegans while also preventing mitochondrial dysfunction in mammalian cells. "This paper helps support the overall notion of TFEB being a key autophagy regulator that extends lifespan, "said Buck professor and Chief Scientific Officer Malene Hansen, PhD, who collaborated on the paper. She added, "Mitophagy is a selective and very significant form of autophagy. The field has recognized TFEB as a player when it comes to quality control in mitochondria. This study provides a possible translational route to induce mitophagy in a TFEB-dependent fashion." A link to the brain/gut connection Mechanistically MIC works upstream of TFEB by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12 (in worms)/FXR (in humans), which in turn induces mitophagy and extends lifespan. FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, where it acts to regulate levels of TFEB as part of a feed-fast cycle, but recently TFEB was shown to also be present in brain neurons. This provided Andersen with the clue needed to piece together MIC's potential mechanism of action in the latter. "This study provides another piece of the puzzle when it comes to understanding the brain/gut connection in terms of health and disease," said Andersen. FXR is regulated by bile salts which are formed in the gut microbiome. "The gut microbiome impacts the body's use of bile acids. Aging impacts our microbiome," said Chamoli. "If levels of bile acids aren't correct it hinders mitophagy. That's how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration," he said, noting that experiments are underway to explore neuronal FXR as a therapeutic target for Alzheimer's disease as part of a jointly funded grant shared by the Andersen and Lithgow labs. MIC as a general geroprotective therapeutic "There's a bottleneck in efforts to develop potential therapeutics in the field of geroscience, and the bottleneck is that we don't have enough molecules in the pipeline," said Gordon Lithgow, PhD, Buck Professor and Vice President of Academic Affairs and senior co-author. "MIC is a great candidate to bring forward given its therapeutic effect across multiple models and the fact that it is a naturally occurring molecule." Chamoli highlighted the direct links between mitophagy and aging, suggesting that drugs enhancing this process could offer treatment well beyond neurodegeneration or muscle wasting. He added, "All these possibilities can be explored at the Buck where the research environment supports such endeavors."

The Buck Institute and Phenome Health Announce Major Strategic Partnership NOVATO, Calif., Sept. 27, 2023 /PRNewswire/ -- The Buck Institute for Research on Aging and Phenome Health are joining forces in the quest to understand the biology of aging. Phenome Health, a Seattle-based nonprofit research organization led by CEO Lee Hood, MD, PhD, uses a data-driven approach to health and disease that integrates diverse types of biological big data. The new Center for Phenomic Health at the Buck will be co-led by Dr. Hood, who joins the Buck as Chief Innovation Officer and Distinguished Professor, and Eric Verdin, MD, Buck President and CEO. Dr. Hood is a world-renowned scientist whose technology (automated DNA sequencing) paved the way for the Human Genome Project. He is a member of the National Academy of Sciences, the National Academy of Engineering, and the National Academy of Medicine. Of the more than 6,000 scientists worldwide who belong to one or more of these academies, Dr. Hood is one of only 20 people elected to all three. Dr. Hood has co-founded 17 biotech companies and the Institute of Systems Biology. His many national and international awards include the Lasker Prize, the Kyoto Prize, and the National Medal of Science. His most recent book, coauthored with long-time collaborator Dr. Nathan Price, is titled The Age of Scientific Wellness: Why the Future of Medicine is Personalized, Predictive, Data-Rich, and in Your Hands. Dr. Hood will continue to run his laboratory at the Institute for Systems Biology which he co-founded in 2000. "I am delighted to welcome Dr. Hood to the Buck family as our Chief Innovation Officer and Distinguished Professor. The opportunity to form a Center with Lee Hood and his Phenome Health team will be transformational for the Buck," said Dr. Verdin. "We believe combining the novel computational and human characterization engine of Phenome Health with the Buck's expertise in geroscience, the biology of aging, has the power to redefine how we age and treat—or prevent altogether—the chronic diseases of aging." Phenome Health's platform combines whole-genome sequencing with phenomic data, including social determinants of health, electronic health records, self-tracking data from wearables and self-assessments, cognitive and psychiatric brain assessments, and clinical samples of the blood, saliva, and microbiome. Using next-generation AI, the team integrates these data to understand the biology of aging, its associated diseases and interventions targeting the aging process. The Center will be the nexus for these two distinguished research partners to advance healthspan for everyone. "I could not be more delighted to enter into this partnership with the Buck," said Dr. Hood. "The Center is uniquely positioned to translate data into understanding healthy aging, ushering in scientific wellness and ultimately extending each individual's healthspan." About Phenome Health: Phenome Health is a nonprofit research organization committed to delivering scientific innovation and enacting social change. By taking a data-driven approach to better understanding human health and biology, Phenome Health tackles some of the biggest challenges facing medicine and healthcare today aimed at increasing longevity, detecting disease, and optimizing wellness and prevention. It has assembled an ecosystem of partners and resources to employ a powerful approach to personalized population health. Phenome Health boasts a unique team of biotechnology, health, clinical, psychology, and computational technology experts across the United States. About the Buck Institute: The Buck's success will ultimately change healthcare. The Buck Institute for Research on Aging aims to end the threat of age-related diseases for this and future generations by bringing together the most capable and passionate scientists from a broad range of disciplines to identify and impede the ways in which we age. An independent, nonprofit institution, its goal is to increase human healthspan, or the healthy years of life. Globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious chronic diseases including Alzheimer's, Parkinson's, cancer, macular degeneration, atherosclerosis (heart attack and stroke), and type 2 diabetes, the Buck wants to help people live better longer. SOURCE Buck Institute For Research On Aging