Category Archives: Buck Institute for Research on Aging

Interview with Dr. Sushmita Roy: Predicting Cell-Type Specific Mammalian Regulatory Networks

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
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Interview with Dr. Sushmita Roy: Predicting Cell-Type Specific Mammalian Regulatory Networks

Research Background

Dr. Sushmita Roy

Sushmita Roy is an Assistant Professor in the Biostatistics and Medical Informatics Department at the University of Wisconsin, Madison.  She received her B.S. in Computer Engineering at the University of Pune, India. She received her Ph.D. in Computer Science in 2009 from the University of New Mexico and did a post-doctorate at the Broad Institute of MIT and Harvard. She is a recipient of the 2014 Alfred P. Sloan Foundation Fellowship and an NSF CAREER award.

It’s not just genes that make us who we are. The way that genes are regulated and turned on or off (also called epigenetics), rather than the DNA sequence of the genes themselves, is also very important. Dr. Roy’s lab focuses on the development and application of statistical computational methods to identify the gene regulation networks which drive cellular functions by integrating different types of genome-wide datasets. In her seminar at the Buck Institute, she first explained why mammalian gene regulation is complex:

  • There are thousands of transcription factors with unknown binding specificity
  • Gene expression is regulated by the interplay of transcription factors and chromatin (chromatin is the combination or complex of DNA and proteins that make up the contents of the nucleus of a cell)
  • Regulatory DNA elements are not necessarily next to the gene
  • 3D organization of the genome also plays a role in gene expression.

She also introduced three projects from her lab:

  • Gene regulatory network which controls host response to different strains of influenza infections
  • Examining chromatin state model to help identify epigenetic barriers in cellular reprogramming
  • Predicting target genes of candidate enhancers (regulatory sequence elements).

SAGE sat down with Dr. Roy to ask a few more questions…


Q: Could you summarize your research to the general public using non-scientific words?

SR: I am interested in understanding how cells know what to do when. So basically more complicated organisms have different types of cells, and each cell has different types of functions. One of the ways that cells are able to do a particular specialized function is by expressing the right type of genes or the right set of genes. I am interested in developing computational methods to try to understand the molecular circuitry of cells that determine what genes must be expressed when and where. Specifically, we want to know: what is the underlying gene network in a particular cell type? How does the network change between different cell types or different environmental conditions?

Q: Can you tell us a little more about how chromatin state plays a role in gene expression?

SR: When I say the chromatin state, I mean that you should think of DNA as not just a string of letters. DNA is wrapped around histone proteins, and this is how the DNA is packaged inside the nucleus of a cell. These histones get modified bio-chemically, which in turn influences the accessibility of the associated DNA to other important proteins that activate genes (e.g. transcription factor proteins). In particular, some modifications make the DNA more conducive to activate expression while some modifications make the DNA less open and conducive to expression. Expression of a gene in turn is controlled by the set of transcription factors that are bound to the gene’s promoter. We are still figuring out the interplay between chromatin state and transcription factors. As more datasets from multiple cell types become available, we hope to get a better understanding of the relative importance of chromatin state, chromatin modifying enzymes and transcription factors in specifying gene expression levels.

One would expect that when chromatin state changes, the associated gene expression levels also change. However we see that this is only partially true.

Q: What is the main challenge in your field right now? We know that the machine learning model involves using known data to make predictions of the unknown. Can you use your model to predict?

SR: A major challenge in the network community is the lack of good gold standards of a “correct” regulatory network that is large enough to get realistic estimates of how a method for network reconstruction works. Interpretation of results is also a challenge, again, due to the large number of unknowns. We can use our models to predict expression in a new condition provided we can measure the activity of some of the components of the network. The big picture would be to try to predict how a cell behaves in new perturbation – something that you’ve not measured.

Q: Which research project is the one you’re most excited about right now?

SR: All three of them are very exciting projects that ask pieces of a bigger question of building a predictive model of a cell’s expression profile. I’m very interested in delving deeper into the chromatin state and its connection to mRNA levels. That link is not very well understood, and I want to have a bigger picture of what it is. You can think of chromatin modifying enzymes also as potential regulators. I want to try to understand the connections among these different chromatin modifications and how that affects the structure and function of a regulatory network driving a particular process or a particular phenotype. That certainly is something that I want to spend more time on and understand more. Ultimately, I would like to gain a better understanding of transcriptional regulation as a function of the chromatin state, transcription factor occupancy, signaling networks and the organization of the genome and how network change impacts complex phenotypes.

Q: Are you planning to conduct studies that collaborate with aging research groups?

SR: Certainly if there is an area where I can add my expertise to. I would be certainly enthusiastic about working on aging, which I think is a very important problem. It would be very interesting to study the connection between diet and aging as well as aging and different diseases. So if approaches like mine can be used to try to address such problems, I would be enthusiastic to collaborate.

Q: Can you give postdocs advice for how to succeed in an academic career?

SR: You have to figure out what you want to do, what’s exciting to you and let that drive you. You need to ask yourself if you like research and if you’re driven by it. It’s also important to acquire skills that enable one to collaborate with a diverse set of scientists from different disciplines including from computational and biological areas.

I think having a good postdoc experience is also important. For me, my experience was great because I was working on what I wanted to do, and I was fortunate enough to meet people who were willing to support me. I am originally from India, and I was fortunate to have the opportunity to pursue higher education in the US. I always wanted to do something in medicine and biology, but I was a computer engineer. I really wanted to come back to biology, and I was fortunate to meet my PhD mentors in New Mexico to support my interdisciplinary focus of computer science and biology.   For my postdoc at the Broad Institute, I dived deeper into computational biology, and I was surrounded by computational scientists as well as experimentalists who were working in close collaboration with the computational scientists to address important questions in biology. That was a very useful and nurturing experience for me.

Q: As an international research scientist, what kind of difficulties or challenges have you faced, and how did you overcome them?

SR: When I came here, I came with uncertainties about funding, so that was bit of a worry initially. Making sure I had some way to support my education was important and once that was taken care of, I really enjoyed being here. I was also fortunate to have great advisors to support my PhD efforts. Overall, I’ve been around people who’ve been very supportive and encouraging mentors. I think I am pretty fortunate in having these kinds of people to help me understand how to be a scientist and researcher.

Q: What is the academic environment in India?

SR: It’s getting better but it’s not nearly as great as it is over here. There are some institutes with new PIs over there with a lot of energy, who have funded labs doing great work. But in general, we don’t have the resources and the infrastructure like the US. India is behind, but it’s getting better and better. Certainly having more funding and more support would help things to improve. The government is supporting, but I think there needs to be more.

For more on Dr. Roy’s work, check out the Roy lab website.

The Evolution of Science Teaching

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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The Evolution of Science Teaching

A generation ago, before the Internet (when floppy disks really were floppy), science in middle and high school typically consisted of memorizing lots of rules, names and numbers. In many ways, it was a bit like history class: you learned all the facts, but didn’t question how those “facts” became “facts.” Sometimes experiments were demonstrated to show us these “facts”, but how often were we actually asked to design or analyze the experiments? Instead, these demonstrations were more akin to a magic show: meant to illicit awe, but not always able to produce understanding. This method wasn’t necessarily wrong, and in fact in the context of those times it was appropriate. The only place to find science facts was in a large, heavy book, which was not the most convenient object to fit in your back pocket.

But times have changed, and in today’s world of ever increasing smartphone use and the ability to Google any fact instantaneously, the need for rote memorization is decreasing, giving teachers the opportunity to focus more on the underlying methods of how science “facts and theory” become accepted knowledge.

The STEAM project featured Buck Scientists teaching local teachers about inquiry-based science teaching.

Science teachers are at the forefront of this change in scientific teaching methods. Recently, The Buck Institute partnered with Marin and Sonoma County middle school teachers in a program called STEAM Engine to help enhance this new method of teaching call “inquiry based” science.

In simple terms, “inquiry based” science teaching is a method that encourages children to analyze and fully understand the experimental method and apply this knowledge to designing their own experiments. This understanding is the main foundation on which all scientific knowledge is based. Normally this type of teaching strategy isn’t regularly employed until college or perhaps even graduate school, after years of tedious memorization of species names and balancing chemical equations. Some memorization is still useful (knowing that NaCl is table salt), but with this need drastically reduced, teachers have been asking younger students to explore the “why” and the “how” behind scientific concepts and experiments.

“Why” and “how” are the two questions that most professional scientists spend their lives asking and answering. It’s also important to ask these same questions of younger children to enhance their critical thinking skills. These exercises will benefit them and set them apart if they choose to pursue a scientific career as they enter college and graduate school. Additionally, “why and how” are often the questions that create that first “spark” of knowledge. This method will help engage not just children who have an ability to memorize facts, but also those who can think abstractly and critically, skills which are quite valuable when planning future experiments.

Postdoc Jihyun Kim explains cellular differentiation with legos.

In an effort to help ignite and inspire our local middle school teachers the Buck Institute hosted a week of inquiry-based “scientists inspire the teachers” workshop called STEAM Engine, funded by a generous gift from Dayton and Sheri Coles. At this workshop, Buck Institute scientists shared their research expertise with several Marin and Sonoma County middle school teachers. The presentations focused on the brain and the nervous system.

In addition to these presentations, there were hands on activities designed to encourage inquiry-based science teaching. Some of these activities included a cell differentiation game, building a functioning neuron, and a chemical sensory experiment. The cell differentiation game was designed to help students understand the specific molecular signals and pathways that occur in cells that are maturing/differentiating into cell types of different tissues. The second experiment involved building neurons from common craft materials, which taught teachers about the form and function of an important cell type in the brain. Finally, the chemical sensory experiment was hypothesis driven, and asked if C. elegans (lab worms) would respond to certain chemical stimuli through movement. All of these activities had multiple “correct” results and encouraged creative and critical thinking.

The STEAM Engine event was organized by the Bucks own Clare Peters-Libeu, Beth Kradepohl (Marin County Office of Education), and hosted in the learning center by Julie Mangada. The response from the teachers was overwhelmingly positive with many stating that they now had a better understanding of the current research being done at the Buck and of how scientists worked on a daily basis. The teachers were very excited to take what they learned back to their classrooms and design lesson plans around this new information.

Marin and Sonoma County teachers learning how to assemble neurons.

It will be enlightening to see how students respond to inquiry-based teaching during the school year. As science teaching continues to evolve, collaborations between teachers and scientists could greatly enhance the public education system and benefit all involved, especially students. Scientists will learn how to better communicate their research and inspire the next generation of scientists. With inquiry based science, the fear of failed experiments could be dramatically decreased leading to more students feeling excited and confident about science, and ultimately boosting the numbers of potential scientists.

In Marin and Sonoma County our future scientists will now receive critical science training as early as middle school. This change will be very exciting, and the results are sure to be positive and fascinating!

The Adult Stem Cell Revolution: How Regenerative Medicine Rediscovered Old Science

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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The Adult Stem Cell Revolution: How Regenerative Medicine Rediscovered Old Science

If you’ve read this blog on a regular basis, you’ll note that we have brought up the topic of “adult stem cells” when discussing aging or regeneration (see our blog on how stem cells age). This is because a lot of current research focuses on how adult stem cells maintain health and proper functioning of our tissues and organs. But knowledge of adult stem cells and their importance to aging wasn’t appreciated until fairly recently.

stem-cell-hemopoietic

So why the current interest in stem cells? After all, stem cells have been well known to developmental biologists and medical scientists for over 100 years, since early embryos are basically made entirely of stem cells. The notion of stem cells playing an important role in adults is slightly more recent. As early as the 1850s, German physician Rudolf Virchow proposed that cancer arises from embryonic-like cells, and further work by Julius Cohnheim showed that these “embryonic remnants” were still present in adult tissue. By the 1930s, medical pathologists began to understand that adult stem cells (bone marrow “hematopoietic stem cells”, HSCs) formed the basis for our continually regenerating blood supply and immune system. By the 1960s, scientists had discovered that these stem cells had a wider use than expected, even being able to produceskin and bone cell types. But for a long time, stem cells were really only discussed among hematologists and other scientists who study blood.

Stem cells circa 1905

Why then did it take until the 2000s for people to start getting excited about stem cells, particularly adult stem cells? Well, it turns out that there were a few hurdles, some having to do with understanding and some having to do with technical difficulties.

1) “Mitotic” vs “Post-mitotic” tissues

First, most regeneration within the body doesn’t happen directly via stem cells but rather through mitosis (cellular division), and many tissues in our body are not capable of this. Your skin and gut lining are examples of tissues that continually regenerate by mitosis of existing adult cells; hence they are referred to as “mitotic” tissues. Your muscles (including your heart) and brain are examples of tissues that don’t continually regenerate by mitosis; they’re “post-mitotic”. As such, it’s a common misinterpretation that the brain and muscle *don’t* regenerate—you see a lot of internet commentary even today saying that “the number of muscle cells one is born with is all they will ever have” (the same misinterpretation also happens regarding the brain). While scientists know better, the fact that *most* regeneration doesn’t occur directly via stem cells probably led to ignoring their contribution.

2) Difficulty of detecting stem cells and their “daughter cells”

Stem cells are rare and sometimes difficult to detect in tissues, and it’s also difficult to detect new cells (“daughter cells”) that arise from them. A major advancement in this area came in 2005 by scientists at the Karolinska Institute. They discovered that naturally occurring radioactive isotopes like carbon-14 (14C, which dramatically built up in the earth after nuclear testing, and has since gradually decreased by decay after nuclear testing bans) could be used to determine the “birth date” of different tissues in our body. By measuring the levels of 14C in different tissues, researchers could determine how recently new cells were produced (newer tissues have less 14C, older tissues have more). These studies allowed scientists to see that, for example, rib muscle cells in 30-year olds had an average age of 15 years—suggesting that either the post-mitotic muscle cells divide (less likely) or that stem cells were adding new muscle cells to the mix (more likely). These results fit in with earlier studies using DNA labeling in mice to show that “new” cells appear in many different tissues throughout a mouse’s lifetime.

At about the same time, improved techniques allowed detection of adult stem cells in many different “post-mitotic” tissues (muscle, fat, liver, joints, brain) in the late 1990s/2000s, including some that were not believed to regenerate at all (heart). These stem cells were capable of producing the full range of cell types found in the each tissue and were very long-lived, which are the main criteria for considering a cell type a “stem cell”.

3) Evidence of use and replacement of stem cells

Lastly, if adult stem cells really are playing an important role in tissue regeneration, we should see evidence of their being used, replicated, and replaced by the body. Evidence for this came with a series of studies in the early 2000s showing that patients who underwent bone marrow transplants and organ transplants developed “new” cells thatappeared to “colonize” organs and develop into replacement tissue cells. Because receiving a bone marrow or organ transplant causes a patient to have two different types of DNA, scientists were able to detect new cells with “foreign” DNA in the patient’s organs as evidence this colonization was going on.

The result of discoveries of type (2) and (3) was that, by the mid-2000s, scientists realized that stem cells are present in virtually all tissues and can regenerate or repair them in certain situations. The fact that stem cells are present and seem to contribute to even “post-mitotic” tissues like muscle (heart and skeletal muscle) and brain suggests that they may be especially important for preventing age-related damage to these tissues. The exciting research that remains to be done is determining how to stimulate them to do so, and how to maintain their health throughout a lifetime.

Geroscience Course: Cellular Senescence and Aging

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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Geroscience Course: Cellular Senescence and Aging

The process of aging is accompanied by numerous degenerative phenotypes. Muscles and bone break down, brain cells die, and overall physical ability deteriorates. One exception to this common trend of age-related degeneration is cancer, which results from a population of cells that survive through uncontrollable and unregulated proliferation.

Cells frequently enter the senescent stage when typical age-related phenomena, such as DNA damage, occur. (Nature Publishing Group)

If most tissue functions decline with age, how can one of deadliest age-related diseases (cancer) arise from cells that are too active? The work of Dr. Judy Campisi at the Buck Institute has found a potential link between these phenomena. Many age-related traits result from replicative senescence (also called cellular senescencefor more, see our blog on this topic), a process in which cells stop growing and dividing in response to stress. This process occurs as a safe guard to prevent the spread of aged or damaged DNA during mitosis (cell division). It was previously believed that senescent cells serve no purpose, but it’s now known that senescent cells secrete a number of pro-inflammatory cytokines, proteases, and growth factors that may contribute to the aging process. This phenotype is referred to as the senescence-associated secretory phenotype or SASP.

SASP is now under great scrutiny and scientists are avidly trying to determine its role and effects on surrounding tissues.SASP has been shown to induce cancer cell growth, thus providing a link between cellular decline and cancer with age. Knowing this connection, a key question is whether SASP-induced cancer formation can be prevented? Since senescence is a naturally occuring event, it can be inferred that it arose evolutionarily to serve a beneficial purpose. The pro-inflammatory cytokines and growth factors secreted by senescent cells heavily suggest a role in regenerating damaged tissue. Recent findings suggest that an early SASP factor, platelet-derived growth factor AA (PDGF-AA), is responsible for wound healing, and that the absence of this factor prevents healing. This raises a significant challenge for cancer research, SASP plays opposing roles: it has the essential function of inducing cell proliferation during wound healing, but it can also induce aging and death through the promotion of cancer tumor growth.

After senescence, cells secrete a number of factors that can contribute to cancer and aging. (Journal of Cell Biology)

A number of approaches have been used to prevent the negative effects of SASP. DNA damage response proteins can induce SASP, and inactivating DNA repair mechanisms can potentially prevent SASP. The obvious problem with this strategy is that the DNA damage response is a critical component of cellular maintenance. Another approach is to eliminate senescent cells in various tissues. Interestingly, ablating senescent cells in mice does not affect lifespan but delays onset of age-associated diseases.

At the Buck Institute, Dr. Judy Campisi’s lab utilizes transgenic mouse and in vitro human cell models to identify and selectively clear senescent cells. The goal of her work is to answer questions about the benefits and drawbacks of senescent cell clearance. Dr. Campisi is also interested in understanding the molecular signals that regulate and inhibit SASP expression. A recently published study from the Campisi lab (see our interview of first author Remi Martin-Laberge) determined that suppression of MTOR activity through rapamycin treatment suppresses particular SASP-associated cytokine levels, especially IL1A. IL1A suppression hinders NF-κB activity, which is largely responsible for maintaining cell survival and inducing pro-inflammatory signals (including those found in SASP). This finding suggests that it’s possible to hinder SASP selectively. Additionally, the expression of particular microRNAs such as miR-146a and 146b is elevated in senescent cells. It is thought that these microRNAs might be part of a negative feedback loop to suppress the production of SASP factors such as Interleukins 6 and 8, and thus ectopic expression of these microRNAs can inhibit SASP signals.

Despite their benefits, cellular senescence and SASP clearly contribute to the aging process and cancer. Targeted approaches that eliminate senescent cells or SASP under specific circumstances appear to be the best possible method for preventing SASP-induced aging and disease without hindering the necessary wound healing effects that SASP also regulates. There is still much to be understood about cellular senescence and its purpose, however. Understanding how it occurs and the factors that regulate this process are paramount in revealing key mechanisms that contribute to aging and the onset of age-related diseases.

“The Worm Conference”: from the bonds of many droplets, a mighty river roars…

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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by | Jul 15, 2015 | Aging, News and Events Original Article Here

“What do you like about studying C. elegans?”

celegansconfThis was the question posed to attendees (myself included) by long-time scientists/entertainers Morris Maduro and Curtis Loer at the Genetics Society of America (GSA)’s 20th Annual Worm Conference hosted at UCLA this past June. Out of all the worm conferences around the nation each year, this is the only one referred to simply as “THE Worm Meeting.”

The emcees of the ever-popular, conference-ending variety show (the Worm Show) asked attendees of the conference what they enjoyed the most. By far the most popular answer was “the community.” One couldn’t help but feel caught up in something big and cohesive, held intact by the youthful stringiness of the field: most of the pioneers are still alive and kicking with webs of prodigy scientists succeeding and spreading the worm gospel.

This year the organizers overtly recognized the history of our biomedical research niche in which C. elegans nematodes are used as a model organism (see our SAGE blog on how C. elegans models are used to study aging). The genesis ofCaenorhabditis in research dates to ideas put forth by Sydney Brenner in 1963 in a letter to Max Perutz. The idea took off and led to major breakthroughs in genetics, molecular science, and pharmacokinetics in the 1970s.

Caenorhabditis elegans, Dr. Garrison's preferred model organism for studying neuropeptide activities. (Image source Wikimedia)

I’m relatively new to worm research, with previous experience as a technical writer, wildlife biologist, and nonprofit development officer. After working in administration and development at the Buck Institute for 6 years, I got an offer I could not refuse: to work in the lab of Dr. Gordon Lithgow. I jumped at the chance, and am now a technician on a consortium project between the Lithgow lab and the labs of Monica Driscoll (Rutgers) and Patrick Phillips (Univ. of Oregon). We are using worms to screen healthspan-enhancing compounds and to develop controlled methods for broad experimental reproducibility.

Stepping from the microcosm of our lab into the macrocosm of Worm People was like emerging from a thin trickle into the rush of a whitewater rapid. I was blown away by the energy, community, and mutual affection of worm folks. Names on journal pages became faces with eureka stories, friendly jibes, and advice for newer researchers – names like Nobel laureates Marty Chalfie (co-developer of GFP techniques) and Craig Mello (co-developer of RNAi technology).

It wasn’t long after I arrived that I started to hear the hive buzz among the thousand-plus audience members during the plenary talks in the beautiful Royce Hall on UCLA’s main campus. It sounded like a collective call-to-action: “One of us! One of us!”

The conference ran for five days with large plenary talks interspersed with breakout discussions on diverse subjects (physiology, neurology, cell development, gene regulation, etc.) I stuck mainly to sessions on stress, aging, and worm tracking and image capture. Keeping an eye on worms and their activity is a lot easier when one doesn’t have to look at them through a scope and poke them with a sharp wire to see if they are alive. On my project (the Caenorhabditis Intervention Testing Program or CITP), we use modified scanners and image-analysis software to assess worms on a touch-free system over their entire post-reproductive lifespan. This so-called “Lifespan Machine” was developed by Nick Stroustrup in the Fontana lab at Harvard Medical School. I heard his presentation on the technology and enjoyed learning about other competing platforms.

CITP worms on the Lifespan Machine

It’s impossible to describe the whole elephant – to capture the enormity of the hundreds of posters, talks, and conversations of the Worm Conference. So here are a few snapshot moments that stand out from my experience:

  • Meeting several of my collaborators from other institutions face-to-face for the first time and really liking them as people. I prefer face-to-face contact. It’s way better than busy, tweaky conference calls and nuts-and-bolts emails.
  • Hearing inspirational talks from the aforementioned Nobel laureates, especially Craig Mello. He really got me when he used the Hubble Ultra Deep Field image as a metaphor for the value of looking ever deeper into areas of inquiry that may seem “picked-over” or absent of interest. In that image taken of a tiny slice of dark sky devoid of visible stars, Hubble imaged something like 10,000 galaxies.
  • Realizing that I could learn something from every talk, no matter how unfamiliar the subject matter seemed to be.
  • Getting locked in my dorm bathroom at 4:30 in the morning. Luckily for me, the guy in the room on the other side of the shared bathroom was a worm scientist studying sleep (ha!) and wasn’t too cross when I had to pound on his door to get help. So we sat in his room – both in our jammies – and chatted about worms until help came to let me into my room. I never saw him again.
  • Seeing former colleagues from the Buck, like Di Chen (Kapahi lab) and Pedro Rodrigues (Lithgow lab) who have gone on to other labs.
  • Learning about the recent discovery of C. elegans’ so-called “sister species” – Species 32 – by Gavin Woodruff in Okinawa. Species 34 lives on living figs visited by a certain species of fig wasp, unlike most Caenorhabditis which prefer rotting fruit in compost or on top of soil. Gavin was working at FFPRI at Tsukuba but now works with CITP collaborator Patrick Phillips.
  • Seeing this amazing “rainbow cloud” during a break between sessions. While the Rainbow image seemed especially poignant in light of the recent Supreme Court decision on gay marriage since gay is something normal now a days and there are adult sites such as https://www.gayporn.wiki exclusively for this people, I think that it also reflects the many voices, talents, and experiences of the river of Worm People.Outside Royce Hall, UCLA.

I’m definitely looking forward to the next Worm Conference!

Stem cells get old too…

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After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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Stem cell basics and applications.

embryonic_stem_cells_large

When a scientist is asked to describe stem cells, words that come to mind include: pluripotent, self-renewal, and regeneration.Embryonic stem cells harbor all three of these traits. They are derived from early stage embryos and are capable of differentiating into any type of cell in the human body (this is what scientists refer to as “pluripotency”). Researchers are able to grow them in culture dishes for long periods of time because of their ability to divide and produce more copies of themselves (also known as the ability to “self-renew”). They are valuable tools and many labs use embryonic stem cells to model and understand human development and various human diseases.

Stem cells are also well known for their ability to regenerate tissues. Humans aren’t lizards, and they can’t regrow entire body parts or organs (with the exception of the amazing regenerative capacity of the human liver). However, adult stem cells present in specific tissues, such as the bone marrow (hematopoietic stem cells), brain (neural stem cells), and heart (cardiac stem cells), play very important roles in maintaining tissue homeostasis and function by replacing the existing cells that die off over time. Adult stem cells are a more mature version of embryonic stem cells, meaning that the differentiated cell types they produce are specific to the tissue that the stem cells inhabit.

Adult stem cells (also known as somatic stem cells) are located in different tissues and organs all over the body.

In cases of injury or disease, adult stem cells in affected tissues can divide and differentiate to repopulate certain cell types and repair or restore function. Thus, scientists and clinicians have turned to adult stem cells as promising candidates for regenerative applications to treat diseases of aging and traumatic injury. Bone marrow transplants, which contain hematopoietic stem cells, are a classic example. Doctors use healthy bone marrow to reconstitute a sick patient’s immune system and to treat patients with blood cancers and other genetic or immune disorders. More recently, transplants of other adult stem cell types are being explored as potential treatments for traumatic conditions such as spinal cord injury.

 

 

When stem cells get old…

But what happens to adult stem cells as a person ages? Can they always maintain their regenerative capacity? The answer is no. As mentioned previously, adult stem cells maintain tissue homeostasis and differentiate into the cell types that make up the tissue in which they reside, however these processes become less efficient over time. Adult stem cell dysfunction caused by aging has been reported in many organ systems including the heart, muscle, and bone marrow. Some adult stem cell populations like neural stem cells in the brain and melanocyte stem cells in hair follicles actually decline with age. Both adult adult stem cell dysfunction and a decline in number translate to a reduced regenerative response to tissue or age-related damage.

Let’s take a closer look at a few of the culprits that make stem cells grow old.

  • DNA damage occurs in aging stem cells over time because of factors present inside and outside of the cells and because of exposure to genotoxic stress (chemical factors that cause genetic mutations). The machinery that repairs DNA in older stem cells does not function as precisely, and this can cause genomic instability, cell death, or even cancer if a person is really unlucky.
  • Cellular senescence is a term that refers to cells that have entered a state where they can no longer proliferate and divide. Senescence occurs in older stem cells because of elevated cellular stress. Senescent stem cells are bad news because they secrete factors that can cause inflammation and stem cell dysfunction, which further exacerbates symptoms of aging and disease.
  • Mitochondrial dysfunction. Mitochondria are the batteries that power our cells (think of the energizer bunny: mitochondria keeps our cells going and going…). Mitochondria have their own genome, and in aging stem cells, mitochondrial DNA can be damaged, which impairs mitochondrial function and consequently, adult stem cell function.

Of course there are many other factors that cause adult stem cell aging (see scientific figure below), but for the sake of not getting to technical, we will leave these other causes for future blog posts.

Mechanisms that cause aging in adult stem cells. (Oh et al, 2014)

 

Can we rejuvenate aging stem cells?

So how do we solve the problem of aging stem cells? One obvious approach is to rejuvenate adult stem cells by preventing DNA damage, cellular senescence, and mitochondrial dysfunction. Another strategy is to transplant healthy adult stem cells from a donor into a patient with disease or damaged tissue.

Fountain of Youth by Lucas Cranach the Elder

However, the issue with adult stem cell transplantation is that the environment (called the niche) into which you transplant healthy stem cells may contain toxic factors (caused by disease or damage) that will kill off the newly transplanted stem cells or impair their function. Thus, a better approach would be to fix or reverse aging phenotypes in the surviving stem cells and other mature cells in that niche, and then transplant healthy donor stem cells into a rejuvenated, healthy environment.

One last thing to consider as one addresses the aging adult stem cell issue is when to intervene therapeutically. Trying to restore adult stem cell function in already diseased or older tissue might not be as effective as preventing damage from accumulating in the same stem cells earlier in life. Prevention of stem cell aging would be a promising strategy to fight aging itself, but that would require the ability to predict or diagnose disease onset in healthy people, which is a huge and complicated endeavor.

Final words on stem cell aging and human health.

Aging stem cells and their impact on aging-related diseases and injury repair are issues that still need to be addressed. In general though, scientists and the general public view stem cells as a promising therapeutic option for treating or curing patients with unmet medical needs. Clinical trials using human stem cell transplantations are already underway for the treatment of spinal cord injury and age-related macular degeneration.

While everyone is eagerly waiting to see the results of these clinical trials, in the mean time, scientists should remember that they can use the tools that already exist in the human body. If we find a way to reset the clock on aging adult stem cells in humans, we will have a new and powerful strategy for preventing disease, repairing tissue damage, and prolonging lifespan.clock


For more information on stem cell aging and rejuvenation, check out these reviews:

Stem Cell Clinical Trials

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The Parkinsonian Brain: Cellular Senescence and Neurodegeneration

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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Parkinson’s Disease (PD) is the second most common age-related neurological disorder in the US. Many genetic factors that contribute to an increased risk of developing PD have been identified over the years. These include mutations in the α-synuclein and Parkin genes. Additionally, epidemiology studies show increased risk of PD after exposure to pesticides and organic pollutants, as well as heavy metals. However, recent research shows that aging is a major player in the development of PD.

Handwriting by a PD patient shows abnormal characteristics and micrographia. (Wikimedia)

Key clinical features of PD are impairments in motor activities including difficulty initiating voluntary movement, loss of facial expression (masked faces), and smaller handwriting (micrographia). Other non-motor symptoms include sleep disturbance, depression, and cognitive decline.

The motor issues present in PD patients are primarily caused by loss of dopaminergic neurons in the substantia nigra (SN) of the brain, which is a key regulator of motor movement and reward-seeking behavior. As a result, the most widely available PD treatments focus on replacing the neurotransmitter dopamine, which is produced by dopamingergic neurons, in various ways.

In the Parkinsonian brain, dopaminergic neurons in the substantia nigra degenerate, resulting in reduced release of the dopamine neurotransmitter. (Credit: Delilah R. Cohn)

These treatments do not halt disease progression, since dopaminergic neurons continue to degenerate even with these treatments. Instead, they only treat the symptoms of PD and make everyday life more manageable for PD patients. For example, L-DOPA is a precursor to dopamine that can be administered to patients to increase the level of dopamine synthesis. (A Nobel Prize was given to Arvid Carlsson in 2000 for showing that administration of L-DOPA reduces Parkinsonian symptoms in animal models of PD).

Other treatments include forms of pseudo-dopamine, which activate dopaminergic receptors (pramipexole, ropinirole) and drugs that inhibit dopamine breakdown (MAO inhibitors). Since the effects of these drugs are temporary, patients need to take them frequently and in increasing doses with age. So rather than replacing the lost dopamine, a better approach to treating PD would be to replace the lost dopaminergic neurons.

Our brains possess the capability to replace lost cells through a process called neurogenesis, or the formation of new neurons. Exercise and growth factors such as fibroblast growth factor 2 (FGF2) enhance neurogenesis in the brain. A logical treatment for PD would be to stimulate neurogenesis to replace lost dopaminergic neurons. However, it turns out that the ability of the brain to produce new neurons is reduced both with age and in people who have a mutant version of α-synuclein (a major genetic risk factor for PD).

This reduced capacity for neurogenesis extends to stem cell transplants in PD patients. Many groups have reported thathealthy transplanted stem cells in PD patient brains show pathological characteristics over time. Thus it seems that there is something about the environment in the brain that causes healthy cells to develop the neurodegenerative characteristics of PD.

Here at the Buck Institute, the Andersen and Campisi labs have found that cellular senescence may play a large role in the pathological neurodegeneration of PD. Cellular senescence is an anti-cancer mechanism intended to irreversibly prevent cell division when a cell is exposed to stress. Senescent cells show distinct biological markers, such as secretion of inflammatory compounds (ie. IL-1α, IL-6, IL-8) in a phenomenon also referred to as Senescence Associated Secretory Phenotype (SASP).

Senescent astrocytes are labeled blue by uptake of beta-galactosidase. (Wikimedia)

Data from the Andersen and Campisi labs suggest that cellular senescence in astrocytes may alter the brain environment to promote disease progression and inhibit neurogenesis. Astrocytes show increased levels of SASP factors, and manipulations that reduce cellular senescence also reduce Parkinsonian phenotypes in mouse models. Since cellular senescence is associated with age, astrocyte senescence may explain the age-dependency of PD onset. The Andersen and Campisi labs are currently searching for potential treatments that can inhibit cellular senescence in the brain, thereby halting the progress of PD.

While the field of cellular senescence is relatively young in the larger field of neurobiology, it is becoming more evident that cellular senescence is key to explaining age-related disorders. Cellular senescence in the brain may prove to be one of the underlying factors common to multiple age-related neurodegenerative diseases, which would make it an important therapeutic target to pursue.

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Interview with Buck Professor Dr. Henri Jasper: Stem cells and aging, lessons from Drosophila

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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Research Background

Dr. Heinrich (Henri) Jasper is a German-American biologist and Professor at the Buck Institute. He received his BS in biochemistry from the University of Tübingen, Germany. He was also a research student at the Max Planck Institutes of Biochemistry and Neurobiology in Munich, Germany. In 2002, he received a PhD in Biology ‘summa cum laude’ from the University of Heidelberg, Germany. After receiving his PhD, Dr. Jasper moved to the University of Rochester Medical Center, first as a researcher in the department of biomedical genetics, then as a tenured research professor at the department of biology. He has been at the Buck Institute since the summer of 2012.

Dr. Jasper’s lab is interested in regulatory mechanisms that control stress tolerance, metabolism and aging. Current projects ongoing in his lab focus on the control of tissue regeneration, metabolic homeostasis, and cell death by insulin and stress signaling pathways. Most of these studies are being conducted inDrosophila melanogaster (fruit fly), taking advantage of the wide range of genetic, molecular, and genomic techniques available for this model organism. During his research seminar at the Buck Institute, Dr. Jasper summarized his lab’s projects, which fall under three main topics.

  • The interaction between the stress signaling pathway and insulin signaling, and its control on metabolic homeostasis and lifespan.
  • The development of the fly retina as a model system in which to assess the regulation of cell survival and cell death decisions. Also using this model to identify molecular and cellular mechanisms governing tissue recovery after genotoxic stress.
  • The study of stem cells in the fruit fly midgut epithelium to address how stress and aging influence the ability of these stem cells to self-renew, and whether optimizing stem cell activity can influence the aging process.

SAGE sat down with Dr. Jasper to ask a few more questions…


What is the big picture of your current research and how does it relate to aging research?

HJ: There are two aspects. One is what I started with, which is the metabolic homeostasis question. We study how the stress system impacts insulin and the metabolism of the animal. It is of course a fundamental problem not just in aging but also in diabetic patients. You need to understand how obesity results in insulin resistance and a decline in metabolic function. It has been shown that the stress signals, particular the signal called JNK, is actually causing the insulin resistance and obesity. In the aging field, we know that there is an age related insulin resistance and a decline of metabolic function as well. By reducing insulin signaling activity in invertebrates, such as the worm and fly, you can extend lifespan. In the mouse model, it is more complex because there is tissue specificity. Suppressing insulin signaling can be bad because you could end up with diabetes. But insulin signaling can also be beneficial, for example, in adipose tissue. When you knock down insulin receptors in adipose tissue, you end up extending lifespan in mice. The second aspect is stem cell function. We are asking fundamentally how aging impacts the regenerative capacity. We know that the decline of regenerative capacity is actually an anti-cancer mechanism. So there is a balance between maintaining regeneration and preventing cancer, and this is what we are trying to figure out. We are trying to improve the regenerative capacity but prevent dysplasia and cancer.

What is the project that you are most excited about right now in your lab?

HJ: The reason that we have so many projects is because I tend to get excited about many different things. So it is hard for me to choose. At this particular point, I am quite excited about the calcium oscillation. Because we developed a new tool, which allows us to look at what is going on in live tissue. And it gives us insight directly into stem cell biology. We can look at the activity when the animal is alive. The level of detail we can go to is amazing. That is what I am excited about in that project. And other projects that I discussed are also exciting, such as understanding hemostasis more globally in order to understand how commensal bacteria impact the gut activity and lifespan. This is where I am right now. But who knows, maybe next week I will be interested in somethings else [laughs].

We know that there are a lot of interventions that can regulate aging in animal models. Do you really believe any? If you have to choose one intervention to apply on yourself, what would you choose?

HJ: I think the dietary restriction is the most likely way to impact lifespan. But it’s also probably the hardest thing to do [laughing while eating potato chips]. I wouldn’t want to do it for sure. You also have to look at those things from the perspective of the quality of life. You’re not going to have a lot of fun on dietary restriction. So to me, it’s not worth it. Instead, we should understand the mechanism of calorie restriction and find out an intervention based on that mechanism to extend the quality of life without any negative effects. I believe that is really the challenge. For other interventions, I do think improving our commensal microbiome is going to have an impact. We have no idea how that would work. But I think there is a promising opportunity there. Another thing that I believe in is to improve the ability of the system to respond to challenges that will have an impact on aging. I do believe that when we are young, our bodies can respond to challenges like stress, damage etc. very effectively. I think this is a critical thing that we need to address. And one of the most promising answers would be regeneration.

After you got your PhD from Germany you directly became a faculty without doing a postdoc. How did that happen?

HJ: Things can happen right [laughs]? I did my PhD at the University of Heidelberg in Germany. This university is really one of best places to do life science in Europe. I was involved in a lot of developmental biology, and that was the best place to do it. My advisor was recruited to the University of Rochester, where we continued to some of the work. People in the University of Rochester were really excited about what we were doing. After I finished my PhD, I was looking around for a postdoc, and they really wanted me to stay. They first gave me a Research Assistant Professorship and then gave me tenure track. But I am not sure I would recommend this career path. Because normally you are allowed to apply for grants and get funded, but in reality you would hardly ever get funded. It’s because you are not ready to be independent as a Research Assistant Professor. So that would be a challenge. It was ok for me because I had learned to write grants at that point, and I was very lucky to work with outstanding graduate students at the time to publish good papers. And doing a postdoc in a big lab is not a bad thing: you learn to network, and you get to know new people, techniques, and the environment. It would help you develop your own research.

How is conducting research in Germany different or similar to academic research in the US?

HJ: The reason I stayed in the US is because I think the academic environment in the US is more dynamic due to the funding environment. It’s so challenging to get funded. It’s always a challenging environment that rewards you for being creative, efficient and productive. I feel like in Europe it matters more who you know than what you do. Never-the-less, Germany right now is a good place for research because they have invested in science quite heavily over the past 20 years. And the funding environment is great compared to the US. They have done a good job trying to break open the heretical system that I talked about. Now it’s very easy to become independent early on and less related to your mentor. Germany actually adopted a lot of great practices from the US. So the environment there is very good right now. Sometimes their funding environment is very tempting.

Why did you choose to study the fly?

HJ: I started working on developmental biology when I was an undergraduate student. I was at the Max Planck Institute for Developmental Biology in Tübingen. The director there was Nüsslein-Volhard, who is a Nobel Prize winning scientist. She did a big fly screening in the mid-80s where they identified basically every single gene that is required for early development. And when you looked at that work, pretty much everything we know, such as growth factors and singling pathways, ultimately were discovered and characterized in the fly. And it was all done in the early 90s. When I was an undergraduate student, I was working close to that but I wasn’t working on flies. I was working on frogs (xenopus), which is another classic developmental model. The problem with frogs was that it is very difficult to study genetics in frogs, because they have a lot of redundancy in their genome; there were no tools available. I was doing transcriptome analyses in the frog at the very early stage. I identified a lot of genes that were very interesting, and then I got stuck. I couldn’t do a knock out and I couldn’t do an over-expression. And next door, people were working on flies and they had mutants and could rescue these mutants. The ability to manipulate the system in the fly is so much better. So I decided to go to a fly lab for my PhD research. Once you understand what you can do in the fly, it’s very hard to go back. We have started to do mouse work now. I have to say that it is interesting, but it takes forever.

How do you manage so many people in your lab?

HJ: The exciting thing about coming to the Buck was that I was able to get a lot of independent and self-motivated postdocs. They are all very excited about what they are doing, and they have their own ideas. So all I need to do now is try to help them, either by helping them to narrow the focus of their work, or by helping them write papers or apply for fellowships. At this point, it‘s not a hard job for me anymore, because they are the ones that are driving the projects, and I am just there to support them. I already have 8 postdocs and 3 graduate students, and I don’t think I will go much more than this. I would say that maybe 15 people are the maximum for me. I like to meet with everyone once a week for half an hour for a one-on-one meeting.

How do you help your postdocs get jobs in academia or industry?

HJ: I help them as much as I can. But sometimes, it’s hard to give good advice. I can share my connections and network, and I know when there are job postings. But to advise someone to be successful in the current environment is hard. A lot of things depend on luck right now. But I always share my experiences and try to explain what I think would be good steps for each postdoc.

What do you do for fun? I know you like bike riding. Anything else?

HJ: I don’t like biking at all! I am from the northern part of Germany where biking is the way to go to work. I always do that, and it’s a good work out. Biking to the Buck is very hard because of the hill. It is terrible! I do bike maybe twice a week. I play soccer for fun. We play soccer on Wednesday every week at the Buck. The other fun is pretty standard: I go to the wine country, and to the beach. That is another reason to come work here.

For more on Dr. Jasper’s research check out the Jasper Lab Website.

Watch Dr. David Perlmutter and Dr. Dale Bredesen discuss the brain-gut-microbiome connection

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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Dr Perlmutter

Gut health has proven to be critical for healthy brain function. Learn how the gut microbiome influences the brain in this provocative YouTube video from last Thursday’s inspiring conversation between Dr. David Perlmutter and Buck ProfessorDr. Dale Bredesen.

Dr. Bredesen says Dr. Perlmutter’s new book, “Brain Maker: The Power of Gut Microbes to Heal and Protect Your Brain—for Life“, explains how nurturing gut health can enhance brain function. “Thanks in large part to a dramatic new understanding of the brain-gut-microbiome connection, there’s new hope for the treatment of autism to Alzheimer’s to multiple sclerosis. David Perlmutter is a leader in this burgeoning field. His book is a landmark contribution.”

More on the Speakers

Board-Certified Neurologist Dr. David Perlmutter received his M.D. from the University of Miami School of Medicine. He is a recipient of the Linus Pauling Award for his innovative approaches to neurological disorders, Clinician of the Year Award from the National Nutritional Foods Association, and Humanitarian of the Year award from the American College of Nutrition.Dr. Perlmutter has been interviewed on 20/20, Larry King Live, CNN, Fox News, The Today Show, Oprah, and CBS.

Dr. Dale Bredesen was the Buck Institute’s founding President and CEO and is an internationally recognized expert on Alzheimer’s disease. Dr. Bredesen’s ground-breaking discoveries have led to a recent clinical trial as well as evidence for memory loss reversal associated with Alzheimer’s disease using lifestyle modifications. He earned his M.D. from Duke University Medical Center and served as Chief Resident in Neurology at UCSF before joining Nobel laureate Stanley Prusiner’s lab at UCSF as an NIH Postdoctoral Fellow. He has held faculty positions at UCSF, UCLA and UC San Diego.

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100 and Counting: More Facts on Centenarians

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Undergraduate at The University of Southern Indiana + More Years Less Tears + Your NeXt Computer
After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.
Jonathon Fulkerson
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SAGE recently featured an article on Centenarians that described how the world’s 100+ population is steadily expanding due to advances in healthcare and technology that are extending lifespans. In writing that article, I found myself looking at various sources from universities, longevity associations, and scientific publications. There is a massive amount of data out there on centenarians as both scientists and the general public are becoming more interested in understanding why some people and not others live an entire century.

I tried my best to summarize the main facts on centenarians and what we know about the genetic and environmental components that promote longevity. However, in our current era where social media and visual content are the most effective means for communicating with others, we have decided to include more visuals in our blogs to make our content easier to understand and more fun to read!

So to start, we are featuring an infographic titled “100 and Counting”. This is a comprehensive summary of important facts on Centenarians both in the UK and around the world. This infographic was produced on behalf of ThyssenKrupp Encasa.

Enjoy!