A Purkinje neuron in the cerebellum of a mouse. After a bone marrow transplant, two donor-derived cells were found in the brain of the recipient mouse

James Weimann from Weimann JM, Johansson CB, Trejo A, & Blau HM, (2003). Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nature Cell Biology 5, 959-966.


Regardless of the source of stem cells, there are problems that must be solved to turn them into agents for healing damage in tissues.
- Stuart A. Lipton

Stem Cells

So much sturm und drang has been spent on whether to create new embryonic stems cells for research – vs. “reprogramming” adult stem cells to seek the same ends – that the real promise of stem cell research remains submerged in controversy.*

Clear answers are not yet in on which approach is best. Still, most observers would agree that doing both kinds of experiments is essential. Much is being learned from adult stem cell research that might be applied to cultured embryos, and vice versa.

One of the golden goals of such work is to someday be able to safely replace damaged or ill tissues, or even whole organs. So, do you start with adult stem cells that are already programmed to make a certain cell type, such as renal tissue? Or do you go all the way back to square one, using embryonic stem cells – even totipotent cells – to generate younger, highly specific tissue types that can be used therapeutically? Is it faster and easier to start from scratch? Or might cells that are already “halfway there,” already committed to a certain cell lineage, be a better starting place? Also, might adult stem cells be less immunogenic, less likely to be rejected, when re-implanted into their original, familiar host?

Research hasn’t provided many satisfying answers yet. But the picture may soon change dramatically since federal regulations in the U.S. started being modified to allow creation of new embryonic stem cell lines for research. This change is likely to greatly speed up the pace of experimentation, as will the flow of federal money meant to spur embryonic stem cell work.

The politically motivated restrictions imposed upon researchers limiting research to only use a few already-established embryonic cell lines, plus prohibiting federal funding for most embryonic stem cell research – severely hampered U.S. stem cell experimentation, inadvertently allowing research teams in the United Kingdom, Korea, Japan and elsewhere gain a strong head-start in this new biotechnical industry. Fortunately, some states such as California responded by setting up stem cell research programs of their own – free of federal restrictions hoping to help keep U.S.-based researchers competitive.

In any case, the latest stem cell results coming from The Ellison Medical Foundation scholars show that stem cells of either type – embryonic or adult – are dependent on vital information gleaned from their surroundings. Stem cells, like all other cells, need to know who they are, where they came from and who their neighbors are. In other words, each cell lives in a particular niche, and it’s the flow of “positional” information – via growth factors and other signaling molecules from neighbors, that tells stem cells what they should be doing, even whether to live or die. So science’s important task now is to decode, understand and manipulate all this inter-cellular signaling.

*During the period from the years 2000 through 2008 there were no U.S. federal guidelines for stem cell research. To address this much needed guidance, The Ellison Medical Foundation provided major funding for stem cell guideline development by The National Academy of Sciences and the subsequent formation and operation of The National Academies’ Human Embryonic Stem Cell Research Advisory Committee. The formation of the committee is a result of a recommendation from the EMF supported report on “Guidelines for Human Embryonic Stem Cell Research.” The committee will meet 2 to 3 times a year to monitor and review scientific stem cell research and to produce periodic updates and revisions to the “Guidelines” as needed.

 

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 Telomeres on metaphase chromosomes in normal human fibroblasts, visualized using digital fluorescence microscopy.

 From the laboratory of Drs. Jerry W. Shay and Woodring E. Wright.


We must better understand the function of the telomeric complexes in balancing cell proliferation and tissue renewal against the risk of cancer

- Emmanuel Skordalakes

Telomeres

For almost half a century bioscientists have known there’s a strong natural barrier that prevents immortality – most of the time. An intriguing, important clue came from Leonard Hayflick, decades ago when he was at Stanford University. Hayflick determined that cells growing in culture can only keep dividing through about 50 doublings before they fall into senescence and stop growing. That also seems to be true in vivo.

An important part of this genetic timing mechanism seems to be the telomere, a DNA-based structure that decorates the tip ends of each chromosome. Research has shown that each time a somatic cell divides all of its telomeres lose a little bit of length. They keep getting shorter until they get so small they shut down cell division, inducing cell senescence. There seem to be several reasons for this. First, if a cell can’t become immortal, it can’t become cancerous. Second, telomere shortening serves as a clock, a timing mechanism that tells a cell how old it is. And third, telomeres contribute to genome stability by keeping chromosomes from being scrambled.

But there’s also an enzyme called telomerase, which rebuilds telomeres in stem cells, allowing them to keep on dividing indefinitely for the sake of reproduction and wound repair. And telomerase is also “turned on,” perhaps accidentally, in cancer cells, which exploit immortality – with lethal results.

Thus research into telomeres, telomerase, their relationships, activities and impacts is one of the hottest areas of biomedical research, being important in aging, cancer, and genome science. The Ellison Medical Foundation is a major contributor to this effort.

 

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A microarray of genes involved in replicative senescence. Red represents increased expression of a gene in senescent cells compared to early passage proliferating cells; green represents decreased expression.

Laboratory of Dr. Stanley N. Cohen, Stanford University


Cells that were once vital and capable of dividing repeatedly to supply healthy new tissues lose that ability.


Replicative Senescence

Among all the biomedical riddles almost everyone would like to overcome, there’s the enigma of aging. We spend years struggling to grow up, enduring teenage angst, learning a trade, raising a family, coping with parenthood, only to reach the Golden Years burdened with declining energy, chronic ailments, failing vision, and finally dark oblivion. For this reason, improving end of life health has to be a major objective of gerontological research.

We humans, of course, are not alone. Nature has arranged life to emphasize successful reproduction, not successful aging. Discovering how and why we age is the challenge for basic biomedical research.

What’s clear is that for some reason, or various reasons, a phenomenon called replicative senescence occurs along with advancing age. Cells that were once vital and capable of dividing repeatedly to supply healthy new tissues lose that ability. They go into senescence (as if asleep), remaining alive but no longer rebuilding their assigned body parts. How and why this happens – and how to restart cellular growth – are under intense study.

There’s also strong focus on telomeres, the end-caps on chromosomes that keep the double helix from unraveling, and naked chromosome tips from binding to each other. And there’s the fascinating p53 gene – the guardian of the genome – which sits in every cell ready to repair damaged DNA, or if that fails, kill its host cell to prevent unrestrained growth from becoming cancer. Paradoxically, p53 – while it’s guarding the genome – also seems to play some unexplained role in premature aging.

Most anxiously awaited, of course, are useful treatments that lessen or eliminate the chronic diseases that make old age such a chore. Parkinson’s disease, Alzheimer’s disease and other neurodegenerative disorders – and the big one, cancer – are all on the list of major research targets that are linked to aging.

 

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Different species age at vastly different rates. Even among members of a given species, the rate of aging can be modified dramatically by changes in a single gene.

Genes that control the rate of aging have been uncovered by studies of many different species including: birds, rodents (especially mice), humans, yeast, the nematode worm Caenorhabditis elegans, and the fruit fly Drosophila melanosgaster.


Our ultimate goal is not simply to extend life but to extend the disease-free period of our lives. In fact, calorie-restricted animals not only live longer but they also remain relatively free of the common ailments of old age, including osteoporosis and cancer.
David A. Sinclair

Genes and Aging

THE SEARCH FOR GENES that extend lifespan and control important aspects of aging has been one of the most active areas of aging research. With a blossoming of new resources and technologies, including the Human Genome Project, RNA interference, and high throughput screening, researchers have identified scores of genes that appear to extend lifespan in the laboratory organisms that serve as models of human aging — yeast, nematodes, fruit flies and mice. But knowing that particular genes influence lifespan doesn't necessarily tell us how those genes produce their effects. Increasingly, researchers have sought to figure out the biochemical pathways that lead to longer, healthier life and to understand the interplay between longevity genes, other genes, hormones and environmental factors, such as caloric restriction, which have been linked to lifespan extension in several species. One theme emerging from the work is how highly conserved some aging-related functions are throughout evolutionary history, from yeast to human. Another is that studies of genes that influence lifespan may provide important clues to preventing characteristic illnesses of age, such as cancer and Alzheimer's disease, and to alleviating the physical and mental degeneration that so often makes a torment of old age. Some Ellison Medical Foundation Scholars already have played a major role in uncovering genetic influences on aging, helping to create a new field of knowledge in the process. The Ellison Medical Foundation continues to fund a full range of research, from yeast to human populations, in this centrally important biological arena.

 

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A cell and its mitochondria

Douglas C. Wallace


We believe that mitochondrial DNA damage is a major factor in aging, and that the cause of damage is the mitochondria generating oxygen radicals, which then attack their mitochondrial DNA

—Douglas Wallace

Mitochondria and Aging

Although it was a research subject sorely neglected for decades, the intriguing interplay of nuclear DNA, mitochondrial DNA and the flow of energy is now getting intense study worldwide, and the results may soon be stunning.

Importantly, such studies seem to offer key insights into the problems associated with aging, including rapid-aging disorders such as Werner syndrome, plus the aging-associated diseases that include cancer and diabetes.

From the perspective of aging, DNA damage more and more seems to reflect the accumulating harm being done to the enzymes and enzyme systems involved in sensing and regulating the energy supply. Because of oxidative damage done by reactive oxygen species, and by sloppy DNA repair, the evidence suggests the slow-down known as aging results from individual cells losing the ability to do their assigned jobs. Heart muscle cells pump less vigorously, communication among brain cells falters, and other organs show the signs of deterioration.

New Scholar Vera Gorbunova, at the University of Rochester, for example, is pursing the evidence that point mutations and erroneous chromosomal rearrangements that accumulate with age take a toll as error-correcting mechanisms become less effective with age.

She suspects that “in aging cells, the machinery for double-strand break repair becomes error-prone.” So research in this area may increasingly inform science about fundamental aspects of the aging process, and maybe even suggest corrective measures.

In contrast, Marion Schmidt is researching the other end of the equation, looking at the increase in mitochondrial dysfunction that goes along with aging. In work at the Albert Einstein College of Medicine of Yeshiva University, Schmidt and colleagues are focusing on a universally-conserved proteasome activator, Blm10, which appears to be essential for normal mitochondrial homeostasis.

In another approach, Kevin D. Mills, at The Jackson Laboratory, has focused his Ellison-supported research on the natural world, setting up to study several strains of well-characterized mice that are essentially normal. “I propose to investigate the connection between DNA damage and ‘natural’ variations in aging,” Mills said. To do that, he and his colleagues are studying 32 lines of genetically-defined young, middle-aged and old mice. It’s a rich resource that should allow them to follow any genetic factors involved in natural DNA repair, and try to learn how the errors may impact the aging process, as well as the diseases related to aging.

Also, because declining energy seems to be deeply involved in the aging process, Tina M. Iverson – at Vanderbilt University – is examining the delicate balance that exists between getting enough energy and avoiding the damage done by energy production in the mitochondria.

Thus Iverson’s team is looking into the molecular basis for the formation of ROS (reactive oxygen species) that are known to damage the DNA, proteins and membranes inside living cells. The goal, of course, is to identify novel treatments that will improve the aging process, helping people live longer and healthier lives.

These multiple avenues of research are all pulling in the same direction to help eliminate the debilitating chronic diseases that can often accompany old age. 

See also: DNA Damage and Repair

 

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Glutamate receptors (pink spots) concentrate at sites of synaptic contact on a hippocampal neuron dendrite. Changes in the abundance of these receptors alter synaptic transmission in the aged brain.

Michael Ehlers, Duke University


Our work should provide important information on why older individuals are so vulnerable to neurodegenerative diseases. And we’ll try to define the therapeutic targets that are most important for older patient populations.
- Mel B. Feany

Aging of the Nervous System

Although it wasn’t realized for generations, it’s now clear that the living body is always working on the wiring. That has long been established fact, of course, for the peripheral nervous system, which runs our fingers, toes, tongue and arms. For the sake of survival in the face of peril, quick and effective repairs are needed in the extremities, where injury is common. So the peripheral nervous system has evolved great ability to maintain continuity, ready to grow new cells and redo the wiring to circumvent any damage that results from injury.

But the central nervous system, meaning the brain and spinal cord, is different, and medical wisdom held that no new brain cells, neurons, are made after early childhood. In other words, what you got was all you’ll get.

Now that’s clearly not true. Modern research has demonstrated that the brain also contains stem cells, a supply of immature cells that can be called on to grow, differentiate and become new neurons. This shows that the brain does have some “plasticity,” that the capacity exists to repair some kinds of damage.

But it’s also clear that major brain repairs don’t happen often. There seems to be no natural repair that restores the spinal cord after injury. Nor is major loss of certain brain cells repaired, such as the losses that lead to Alzheimer’s disease and Parkinson’s disease. Even when neural stem cells are present, somehow they fail to make adequate repairs.

So that’s where the clarity ends, at least for now. Much has yet to be learned.

Fortunately, the tools that are being focused on neurobiology are improving dramatically. Active MRI allows researchers to observe the brain while it’s thinking, or responding to various stimuli. New approaches to microscopy, precision laser ablation of individual cells and capillaries, and genetic engineering of model organisms are opening new vistas for exploring the brain and how it works.

So right now, ever more powerful and precise research methods are being applied to animals such as soil worms, fruit flies and mice, in which researchers can study nerve connections, neurotransmitter chemicals, genetic alterations, and stem cell responses. Where the brain was once a black box we were trying to influence with magic, a few viewing ports have been created where scientists are taking a peek.

Still, a major barrier that’s been hard to penetrate is the brain’s tremendous complexity.  It’s hard to find a window that reveals much about the billions of neurons, plus glial cells and others, that make up the brain. Also, each of these billions of neurons makes multiple connections to others at the complex junctures called synapses. And within the brain the synapse maps are constantly being revised and rearranged as the cells make new connections and break others. How this occurs, why it occurs and what can go wrong are all questions that are being asked, but are difficult to answer. Hidden within all the complexity, of course, is the learning process, several different types of memory, and the roots of neurodegenerative diseases that often occur with aging.

But there is reason for optimism. The pace of research is accelerating. The new tools of biotechnology are extraordinarily precise and powerful. And the people doing the work are asking good questions, getting interesting answers, and making steady progress.

 

 

 

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When paraquat, which induces oxidative stress, is added to mouse fibroblasts in culture, CMA-active lysosomes are seen to move toward the perinuclear area. Similar activation was seen during nutritional stress.

Ana Maria Cuervo, Reprinted from Molecular Biology of the Cell (Mol. Biol. Cell 2004 15:4829-40; published online before print as 10.1091/mbc.E04-06-0477) with the permission of The American Society for Cell Biology


And as vital cells die, say, in the brain, the impact may show up gradually as Alzheimer's disease, Parkinsonism, or other chronic, age-related disorders.


Response Systems

The constant and intense push and pull exerted by hormones, growth factors, kinases and other signaling molecules makes it clear that evolution has used all the tricks in the book to control life – both normal and abnormal.

It’s also clear the biosystems that Nature has produced are not infallible, that they sometimes make mistakes, act badly, generally run down and slow down with advancing age. Although the common admonition is to age gracefully, sometimes we can’t, even though the body has complex defense mechanisms that help keep decay at bay – at least until the time of reproduction is past.

Of course, simply growing up is an enormously complex enterprise for any organism. Genes, cells and organs must work in exquisite concert to build tissues in just the right places, at just the right times. Not too big, not too small. Not too active, not too quiet.

Built-in response systems also activate when we’re sick or injured, for example, or when responding to the mating call. Hormones rage in response to stimuli. Immune cells signal among themselves to arm for combat at the first hint of infection. And blood platelets remain on guard, ready to respond by clogging up any breaches in the body’s exterior armor.

But aging is another story. The oxidative damage done by normal energy production inexorably causes DNA damage, harms membranes and even limits the lifespan of some cells. And as vital cells die, say, in the brain, the impact may show up gradually as Alzheimer’s disease, Parkinsonism, or other chronic, age-related disorders.

In efforts to learn how aging impacts various systems – and perhaps how to protect them –­ The Ellison Medical Foundation is supporting pioneering work by dozens of leading bioscientists engaged in fundamental studies of aging and its interplay with time.

Alfred L. Goldberg, for instance, is studying protein degradation that must occur if the cell’s protein-folding machinery makes errors. Accumulation of abnormal proteins poses a hazard to health, so Goldberg’s laboratory at the Harvard Medical School is looking into the details of how the ubiquitin-proteosome pathway gets rid of faulty proteins, and hoping to learn how it may relate to aging.

Peter G. Schultz, at the Scripps Research Institute, in La Jolla, Calif., is studying the molecules that respond by up-regulating the antioxidant response element. And Ao-Lin Hsu, at the University of Michigan, is working on heat shock factors and how they seem to play some role in controlling longevity.

As a result of these and other research projects, much is being learned about biological response systems. But the findings so far also make it very clear there’s still a lot to be learned.  One ultimate goal is to first understand, and then begin gaining control of, the aging process, to see if there’s any way to slow it down, or at least retard the onset of  chronic disabilities that are so strongly associated with aging.

 

 

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The nucleus of a dermal fibroblast obtained from a Hutchinson Gilford Progeria patient expressing the G608G mutation in nuclear lamin A. This shows the presence of nuclear blebs and lobules that are hallmarks of the disease. Differential Interference contrast with DNA in blue (DAPI stained) and lamin A in red (anti-lamin A) as seen by confocal microscopy. Other slides show the same type of cell as seen in first slide. These are confocal immunofluorescence micrographs of a progeria nucleus. Lamin A, green and chromatin, blue.


Accelerated aging

The deep and difficult problem of aging is intimately linked to the cell nucleus, certainly, but what the linkages are and how they work still stands as an abiding enigma.

What has emerged in recent years, however, is a basket of data about proteins called lamins which, when mutated, seem to play a role – or roles – in the dreadful rapid aging disorder called progeria.

As discovered by Robert Goldman, at Northwestern University in Chicago, the family of lamin proteins is involved in building and probably maintaining a mesh-like network of fibers, the nuclear lamina, that apparently serves as structural scaffolding inside the cell nucleus. Goldman has shown that if this system is disrupted, or made imperfectly, the typical symptoms of advanced aging begin showing up in infants as early as six months of age.

These symptoms include signs of aged skin, loss of subcutaneous fat, abnormal tooth development and loss, joint stiffness and severe circulatory problems. These unfortunate children typically die by age 13, usually as a result of heart attack or stroke.

It is suspected, Goldman said, that the lamina is so important because it serves as a critical platform where the machinery that assembles life’s command molecules – DNA and RNA – can do its work. That offers one potential explanation why the defects typical of progeria strike in so many ways in so many organ systems.

Similarly, Stephen Young, at UCLA, is experimenting with lamins via transgenic mice, looking at a protein-modifying process called farnesylation. Young and his colleagues are trying to assess how farnesylation may be related to causing a dire form of progeria called Hutchinson-Gilford progeria syndrome (HGPS). The Goldman team is also working on this same very rare form of progeria.

Both teams are hoping that data gathered from their work with HGPS will offer clues to how normal aging occurs, but far more gradually, in the elderly human population, as well as hints about how to slow or even reverse the fundamental aging process.

 

 

 

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(Aging and cancer)

(no summary content available)

 

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(Aging of the Cardiovascular system)

(no summary content available)

 

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THERE WERE NO FRICKIN RESULTS

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