We bring together the most capable and passionate scientists from a broad range of disciplines in an environment that encourages open collaboration for the purposes of identifying and changing the ways in which we age. Our science is all about increasing human healthspan and, ultimately, solving some of the biggest problems facing the world today.
C&C research team is a collective of the world top scientists in the field of aging who are sharing their methods and expertise tofind ways to help everyone lead fuller, healthier lives by ending age-related disease.
What drives the aging process? Genetics? Wear and tear? Toxic overload? At what point can we intercede? Moreover, how do particular aging mechanisms link to specific diseases? An understanding the underpinnings of the aging process are key to nearly every discovery.
Our research team is spread across six states:
The Harvard Medical lab studies the relationship between aging and the immune system. Aging is associated with defects in the adaptive immune system and with a state of chronic activation of the innate immune system (chronic inflammation).
We study how immune aging is regulated by nutrition. We have demonstrated how changes in the relative abundance of key cellular metabolites such as NAD+, acetylcoenzyme A, and the ketone body beta-hydroxybutyrate fluctuate under different nutritional conditions (obesity, calorie restriction, fasting, time-restricted feeding, ketogenic diet) and how this influences immune responses. We are working on key enzymes regulated by these metabolites. These includesirtuins (NAD+), histone acetyltransferases (acetylcoenzyme A), and histone deacetylases (HDACs).
We utilize worm, mice, and human model systems (including stem cells and iPSCs) to define how nutrients influence immune responses during aging. We are also studying how HIV infection induces a state of chronic inflammation and immune activation and how this induces accelerated aging in patients infected with HIV.
Our work on SIRT1 led us to an exciting finding that the level of nicotinamide adenine dinucleotide (NAD+), cofactor of SIRT1, declines with age. We study the mechanisms by which the NAD+ level affects DNA repair and look for therapeutic targets to improve this process. In particular, we focus on delineating the biology of NAD+-depleting and producing enzymes as direct tools to control the NAD+ level in the cells toward increased health-span and improved physiological resilience.
The discovery of longevity genes showed that it is possible to greatly slow the pace of aging and disease by manipulating just one central pathway. This raises the possibility that we can find small molecules that can treat multiple, seemingly unrelated diseases, with a single medicine. Our lab has been highly active in this area, starting with the discovery of sirtuin activating compounds (STACs) in 2003. Since then, potent activators have been discovered and some of these are now in clinical trials, producing positive results. We have active studies to understand how STACs work at the molecular and the physiological levels using cutting-edge enzymological and structural methodologies and mouse genetic models in which we can delete genes at any time throughout the lifespan of the animal, and in specific organs.
We believe chronic inflammation represents a key unifying factor underpinning the development of the chronic diseases of aging, including neurodegeneration (Parkinson’s and Alzheimer’s), cancer, type 2 diabetes, and atherosclerosis (heart attack and stroke). We are intrigued by possible connections between senescence, leaky gut, and innate immune activation. A better understanding of the mechanisms leading to the chronic inflammation associated with aging should provide novel therapeutic targets and potential interventions against human aging.
The Duke Molecular lab is focused on the role of mitochondria in health, disease, and aging. Mitochondria are subcellular structures in which nutrients are oxidized to extract their energy content in the process of oxidative phosphorylation. This energy is then distributed to the rest of the cell to drive the essential machinery of life. However, in addition to releasing energy, nutrient oxidation also produces free radicals and other reactive oxygen species. Impaired energy distribution and excessive free-radical production are thought to be among the primary drivers of aging and age-related disease.
The Duke Molecular lab has pioneered new approaches to better understand mitochondrial function and dysfunction within cells and has applied these approaches to investigate the role of mitochondrial energy metabolism in aging and disease. To investigate free-radical production, we have characterized the specific sites and regulation of mitochondrial superoxide and hydrogen peroxide generation and are studying how these sites contribute to cellular oxidative stress and damage. Using high-throughput screening, we have identified novel suppressors of radical formation that do not inhibit energy metabolism, and we are using these exciting new molecules to probe and modulate mitochondrial radical production in cell and animal models of aging and disease.
We envision treatments that would minimize the production of free radicals by mitochondria without inhibiting energy metabolism. Our lab is collaborating with others both inside and outside C&C to evaluate and mitigate the role of dysfunctional mitochondria in aging and in diseases of aging, including diabetes, cancer, hearing and vision loss, mobility, osteoporosis, heart and kidney disease, stroke, Parkinson’s, Alzheimer’s, and Huntington’s. Research has already opened up new possibilities for the control of these conditions. We aim to cut through the guesswork and establish how free radicals that impact aging and disease are generated and how they can be decreased.
Understanding how cellular metabolism interacts with the genes and pathways that regulate aging has led to many of the potential interventions now being investigated to promote healthspan. Exercise, fasting, and dietary restriction all work to promote health by activating specific cellular signaling pathways. Many of these signaling pathways involve ordinary cellular metabolites like acetyl-CoA and NAD, which have “secret” lives regulating enzymes and genes. The Stanford Medical lab focuses on an emerging signaling metabolite, the ketone body beta-hydroxybutyrate, and the roles it may have in responding to stressors and regulating healthspan.
Ketone bodies are the energy currency that allows the body’s cells to utilize fats for fuel. They are made normally in the liver from fats whenever carbohydrates are scarce, as when fasting or exercising. Ketone bodies are to fats what glucose is to carbohydrates. But beta-hydroxybutyrate has signaling activities as well, including regulating gene expression, modulating inflammation, and controlling metabolism by inhibiting enzymes, binding to proteins, and activating receptors. We have found that long-term exposure to ketone bodies using a ketogenic diet can extend the healthy lifespan of normal mice and, in particular, protect the aging brain. We seek a mechanistic understanding of how ketone bodies might work in an aging mammal to promote health, particularly in age-related memory decline and Alzheimer’s disease. Our goal is to develop targeted therapies that might enhance the resilience of older adults to diseases like Alzheimer’s and stresses like hospitalization.
The translation of geroscience into clinical practice has great potential to improve the lives of older adults. We already know that the best way to treat the complex medical problems of older adults is through the systematic, individualized geriatric medicine approach of comprehensive assessments and multidomain interventions. Interventions developed from geroscience usually act on multiple aging-related cellular pathways, like how the signaling activities of ketone bodies affect gene expression, inflammation, and metabolism. These interventions may hold great promise for treating complex geriatric syndromes like frailty, multimorbidity, and delirium that affect the health and independence of millions of older adults.
The Mayo Sirtuin lab uses advanced mass spectrometric technology to understand molecular mechanisms that underlie aging. Analyzing samples on the molecular level provides insights into protein pathways and mechanisms of disease and aging. We collaborate with all investigators at C&C as well as investigators from outside institutions. The Mayo Sirtuin lab develops and implements advanced innovative sirtuin protein analytical technologies (including quantitative proteomics, posttranslational modifications, protein dynamics and biomarker discovery) to advance basic biology and biomedical research related to aging research.
The Mayo Sirtuin lab engages in many collaborative projects and is engaged in worldwide mass spectrometric studies, as well as software development. Many different workflows are supported at our facility or can be developed together to support biological projects with innovative technologies to gain insights into molecular details in a system-wide approach. At the same time, worldwide collaborations with other proteomics and mass spectrometry laboratories keep our cutting edge workflows and our approach at the forefront of analytical technology.
Understanding what happens during aging and the development of age-related disease, and what is different in a diseased organism compared with a healthy organism, are key to developing treatments, drugs and interventions. We have focused on developing assays to discover biomarkers of aging and disease from easily accessible biofluids, such as plasma or blood from human patients. Connecting these findings with fundamental mechanisms of aging in model systems available at the C&C will drive our research forward in significant ways.
Some people live longer than others. Susceptibility to chronic disease, and many other attributes relevant for aging, also vary from one person to another. These differences are due in part to DNA sequence variants somewhere in our genome, although exactly where is still a mystery in most cases. Mice, worms, flies, and microbes can serve as powerful models for the study of the principles of genetic variation. Research in the Johns Hopkins Medical lab uses these simple organisms to understand how natural genetic changes impact longevity and health, and how they are shaped by the forces of evolution.
Sirtuins have been associated with anti-aging processes throughout the body. According to researchers at Johns Hopkins University, one of the reasons that calorie restrictive diets have been shown to increase DNA stability and life span by up to 70% in yeast, worms, and flies is because sirtuins are more active under those conditions. Sirtuins essentially act as “energy policemen” in the cell, arresting unnecessary processes in the body by removing acetyl groups from proteins involved. For example, exciting research by the Joslin Diabetes Research Center in 2005 found that increasing Sirt2 (a type of Sirtuin) levels in the cell would block the cell’s ability to undergo differentiation and store fat, demonstrating an instance of how sirtuins can decrease activities in the body. Conversely, the study also found that reducing Sirt2 would promote adiopogenesis, or fat production.
One team of Johns Hopkins Medical lab researchers is focused on differences across individuals, like strains of mice or isolates of fruit flies. We track down genetic variants that correlate with aging-relevant traits in the population, and we experimentally test their effects. Another team in the Johns Hopkins Medical lab works on radically different, long-separated species, which cannot mate to form populations. We invent new kinds of experiments to pinpoint the genes responsible for aging and stress resistance traits in these species, many of which have evolved under natural selection.
As we map the DNA sequence variants underlying differences within or between species, we often land on novel genes with no previously known function in aging or health. They lead us to molecules in humans that are of urgent interest in the field as drug targets or diagnostics. And they teach us about when and how evolution has acted to promote stress resistance and longevity in the wild.
Why do we age? Despite more than 30 years of research in the genetics of aging and a much longer history interrogating the process more generally, we still don’t know the answer to this basic question. There has been some success in manipulating the lifespan of simple laboratory organisms and, to a lesser extent, mammalian systems such as the laboratory mouse. However, true insight into the mechanisms which modulate longevity elude us at present. Otherwise we would be able to make our favorite model systems with lifespans of a few weeks live for not just a month or two but potentially decades, all while remaining youthful and healthy.
The UCLA Anti-aging lab takes a multidisciplinary geroscience approach to better understand the core mechanisms that drive aging. This includes a heavy reliance on multiple model systems, including invertebrate models, mammalian models (the laboratory mouse), human cell lines and tissues, and state-of-the-art genomic technologies that rely on heavy computational methods to better understand how cells and tissues change with age and/or pharmacological intervention.
We must constantly question our own models and data to gain genuine insights into the mechanisms that drive the degenerative changes arising from intrinsic aging processes. A key philosophy of the lab is that it is not enough to enhance healthspan through simple dietary or lifestyle interventions. We argue that such approaches merely fine-tune an organism to survive in its current environment. While worthwhile for generally improving health, such paradigms will do little to uncover the key drivers that limit lifespan. In contrast, we hope to develop novel multidisciplinary approaches in geroscience to develop therapeutics that are effective in reducing or ameliorating the cellular damage arising from endogenous aging processes. Such an approach will pay massive dividends to improve the health and longevity of a rapidly aging world.
Why is aging the largest risk for developing so many apparently disparate diseases, ranging from neurodegeneration to cancer? One answer to this question lies in the evolutionarily selected, stress-responsive state termed cellular senescence. Senescent cells cease proliferation, which prevents early life cancer. They also secrete numerous molecules that promote tissue repair and regeneration. However, because senescent cells gradually accumulate with age, they eventually cause tissue degeneration, chronic inflammation, and many age-related diseases, including, ironically, late life cancer.
The American Cancer lab studies the regulation and characteristics of cell states, with an emphasis on cellular senescence. We use simple and complex human and mouse cell cultures, intact human and mouse tissues, and mouse models to understand the molecular pathways that drive cellular senescence and other cell states. We also use genetic and pharmacological manipulations to understand how cell states cause both the degenerative diseases of aging as well as cancer and to design strategies to modulate or ameliorate their effects.
Aging is a complex, multisystem process that exacts an enormous emotional and economic toll on societies. Understanding and manipulating this process is the next big challenge in biomedical research. It is now clear that many age-related changes and pathologies are caused by cellular responses to endogenous and environmental stimuli. Understanding these responses is essential to developing safe interventions that can extend the years of healthy life in human populations.
Our bodies have amazing regenerative capacity, which is fueled by tissue-specific stem cells. This capacity declines with age, disrupting tissue maintenance. Many age-related diseases, including cancer, COPD, and sarcopenia, are likely consequence of stem cell dysfunction. Understanding how stem cells age and identifying intervention strategies to maintain stem cell function and regenerative capacity is thus likely to lead to new therapeutic approaches for maintaining our health as we age.
The Cornell Molecular lab uses the fruit fly Drosophila melanogaster as a model system to explore the basic biology of stem cell function and regeneration and to identify mechanisms of age-related stem cell dysfunction. Hypotheses emerging from this work are then tested in mammalian systems. We have identified signaling mechanisms that govern the response of stem cells to environmental stress, to nutrient conditions, and to the commensal microbiota as areas of intervention to preserve tissue health. We have also identified intervention strategies based on these findings that can extend lifespan and maintain stem cell populations in flies and mice.
Interventions that promote stem cell health are likely to provide new avenues to prolong human tissue health and to treat or prevent a wide range of age-related diseases. Coupling fundamental insight into stem cell biology to the exploration of such intervention strategies is likely to be a productive route for the identification of new and promising therapeutic approaches.
Dietary restriction (DR), the reduction in nutrient intake without malnutrition, has been well documented as a means to extend lifespan and slow age-related diseases in many systems. We and others have previously demonstrated that lifespan extension by inhibition of the TOR pathway overlaps with the effects of DR in D. melanogaster, S. cerevisiae, and C. elegans. However, other DR response mechanisms exist that remain undiscovered. The overall goal of the Imory Medical lab is to understand how an organism responds to nutrient status to influence health and disease.
We utilize worms, flies, and mice as model systems to understand how nutrients influence age-related changes in specific tissues and disease processes. We take creative approaches to develop models for various human diseases that are influenced by nutrient status using invertebrates. We study how various physiological and molecular processes, including fat metabolism, circadian clocks, advanced glycation end products, calcification, and intestinal permeability, are influenced by nutrients to impact organismal health and survival. We collaborate with multiple groups at University of California, San Francisco, and University of California, Berkeley, to undertake interdisciplinary approaches to translate our findings from multiple models to humans.
Our work has relevance to certain age-related human diseases, including diabetes, Alzheimer’s disease, kidney stone formation, intestinal diseases, and obesity. There is an ongoing debate about the limitation of lifespan as a measure of aging and the need to assess healthspan to find the most promising interventions for humans. Through functional measures of different tissue functions and disease models, we are also examining the relationship between healthspan and lifespan.
The Yale Medical lab uses multiple animal models combined with human studies to understand the mechanisms driving biological aging and to develop interventions designed to extend healthspan and lifespan. Murine disease models and stem cell culture studies are also employed to define the underlying links between aging and the onset of chronic conditions.
In yeast, large-scale genetic approaches are used to understand aging holistically in a single organism. In mammals, the lab focuses on validating conserved pathways identified using invertebrates and dissecting how those pathways interface in specific tissues with mechanisms driving aging. Finally, the lab works with drugs and small molecules that modulate aging, trying to understand their mechanisms of action and utility for human studies.
The dominant mode of health care is centered on treating diseases. When it comes to the chronic diseases of aging, which account for most of global health care costs, this strategy has yielded only incremental progress and often resulted in expensive non-curative therapies. We believe that by developing interventions that slow aging, it will be possible to extend human healthspan, delaying the onset of multiple chronic diseases and maintaining healthy function later in life.
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