Center for Tissue Regeneration

Palo Alto, CA, United States

Center for Tissue Regeneration

Palo Alto, CA, United States
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What old brains need is a shot of young blood — and the younger the better. It may sound like a metaphor employed by a randy octogenarian. But new research on mice suggests it can be taken quite literally. Writing in the journal Nature, Stanford University anti-aging researchers reported Wednesday that they have found a “restorative factor for the aged hippocampus.” It’s a protein called tissue inhibitor of metalloproteinases 2, or TIMP2, that is found in the blood of young humans — and most copiously in umbilical cord blood. Harvested at the time of an infant’s birth, cord blood is a rich source of many known regenerative substances, including hematopoietic stem cells, the kind found in bone marrow. Cord blood is capable of treating more than 80 diseases, including blood cancers, inherited blood diseases such as sickle cell and thalassemia, and a range of immune deficiencies. In mice that were roughly the equivalent of 70 human years old, three injections of human cord plasma woke up a host of dormant genes in the brain. The injections also increased the flagging snap, crackle and pop of synapses in the hippocampus — a brain region that's crucial to memory. In addition, the cord blood improved the performance of aged mice as they engaged in memory and learning tasks, such as maze-running and fear-conditioning exercises. Mice who got injections of blood from humans with a median age of 22 saw some but not all of these improvements, and they were more modest. But the unlucky mice that got blood from healthy “elderly” human subjects (with a median age of 66 years) saw no improvement at all. The new study draws on a decades-old line of research called parabiosis, in which scientists lashed together the circulatory systems of young and old animals in a bid to mingle their blood and improve age-related decline in the older animal. In a pathbreaking 2014 study, a team led by the senior author of the latest research, Stanford regenerative scientist Tony Wyss-Coray, showed that many of the beneficial effects seen from parabiosis experiments — including strengthened heart and other muscle tissue — could be had with repeated injections of plasma from young animals. For the new study, Wyss-Coray’s team aimed to zero in on the precise components of blood that return an older body to youthful function — and to look for those so-called “factors” in human plasma. They focused on the hippocampus, a structure in the brain whose performance clearly suffers with age. Indeed, it is also one of the first points of attack when the brain comes under assault by diseases of age, such as Alzheimer’s. An ordinary lab mouse would mount a massive immune response to the introduction of human blood in its veins, with certain fatal result. So to begin their explorations, Wyss-Coray’s team used mice bred to be immunodeficient. Then, after identifying proteins with potential regenerative powers, the researchers isolated them and tested them in ordinary, healthy mice. So, what factor in the human cord blood was awakening the tired hippocampi of elderly mice? Solving that mystery required an exhaustive process of documenting, measuring and comparing concentrations of several proteins in the blood of mice and humans at different ages. Ultimately, the researchers began to observe that TIMP2 was especially plentiful in cord blood, but declined precipitously with age. And when they saw that treatment with TIMP2 energized production of certain cells at the heart of the hippocampus, the researchers suspected they had their regenerative elixir. When they attached chemical tracers to the TIMP2 protein and injected it into the elderly mice, they could see it take up residence in the hippocampus, and saw that it “robustly increased” the electrical signals by which cells there communicate. And the older mice demonstrated improvements in learning and memory tasks. Those behavioral improvements are hard to quantify, but amounted to a boost ranging from 30% to 50%, Wyss-Coray said. “They don’t function like a young mouse,” he said. “But they maybe get halfway in that direction.” Their improvements were especially evident in tasks involving spatial memory, an aspect of memory that suffers early in Alzheimer’s disease. TIMP2 appears to have “quite an important function,” Wyss-Coray said, and “could almost be a master regulator” of processes that are key to aging. Other researchers, he noted, have explored its role in inhibiting the growth and spread of cancer, another disease of aging. Finding that TIMP2 can alter the activity of the hippocampus as well as complex behavior in mice is a far cry from showing it can be an effective agent of neural regeneration in humans, Wyss-Coray said. But it’s an important waystation on the path to showing its potential in humans. The process of producing it in recombinant form, purifying it as a treatment, and testing it extensively in humans could take five to 10 years, he added. Wyss-Coray co-directs Stanford’s Alzheimer’s Disease Research Center and is associate director of the Center for Tissue Regeneration, Repair and Restoration at the Palo Alto (Calif.) Veterans Affairs Health Service. He co-founded a company, Alkahest, that is conducting an early clinical trial in which plasma from young donors is intravenously administered to 18 people with mild to moderate Alzheimer's disease. That trial is complete and the results are expected soon. Click here for a Spanish version of this story Why doctors are being urged to join the March for Science on Saturday What would make a computer biased? Learning a language spoken by humans

Brunet A.,Stanford University | Rando T.A.,Stanford University | Rando T.A.,Center for Tissue Regeneration
Current Opinion in Cell Biology | Year: 2017

Aging is accompanied by a decline in tissue function, regeneration, and repair. A large part of this decline is caused by the deterioration of tissue stem cell function. Understanding the mechanisms that drive stem cell aging and how to counteract them is a critical step for enhancing tissue repair and maintenance during aging. Emerging evidence indicates that epigenetic modifiers and metabolism regulators interact to impact lifespan, suggesting that this mechanism may also affect stem cell function with age. This review focuses on the interaction between chromatin and metabolism in the regulation of tissue stem cells during aging. We also discuss how these mechanisms integrate environmental stimuli such as nutrient stress to regulate stem cell function. Finally, this review examines new perspectives for regeneration, rejuvenation, and treatment of age-related decline of stem cell function. © 2017 Elsevier Ltd

Mosher K.I.,Stanford University | Andres R.H.,Stanford University | Andres R.H.,University of Bern | Fukuhara T.,Stanford University | And 9 more authors.
Nature Neuroscience | Year: 2012

We found mouse neural progenitor cells (NPCs) to have a secretory protein profile distinct from other brain cells and to modulate microglial activation, proliferation and phagocytosis. NPC-derived vascular endothelial growth factor was necessary and sufficient to exert at least some of these effects in mice. Thus, neural precursor cells may not only be shaped by microglia, but also regulate microglia functions and activity.

He Y.,Stanford University | Zhang H.,Stanford University | Yung A.,Stanford University | Villeda S.A.,Stanford University | And 9 more authors.
Nature Neuroscience | Year: 2014

The transforming growth factor-β 2 (TGF-β 2) signaling pathway serves critical functions in CNS development, but, apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β 2 signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β 2 signaling in adult neurogenesis, genetic deletion of the TGF-β 2 receptor ALK5 reduced the number, migration and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a marked increase in these aspects of neurogenesis and was associated with higher expression of c-Fos in newborn neurons and with stronger memory function. Our findings describe an unexpected role for ALK5-dependent TGF-β 2 signaling as a regulator of the late stages of adult hippocampal neurogenesis, which may have implications for changes in neurogenesis during aging and disease. © 2014 Nature America, Inc. All rights reserved.

Barzilai N.,Yeshiva University | Guarente L.,Massachusetts Institute of Technology | Kirkwood T.B.L.,Vitality | Partridge L.,Vitality | And 5 more authors.
Nature Reviews Genetics | Year: 2012

Rapidly increasing numbers of older people present many countries with growing social and economic challenges. Yet despite the far-reaching implications of ageing, its biological basis remains a topic of much debate. Recent advances in genomics have spurred research on ageing and lifespan in human populations, adding to extensive genetic studies being carried out in model organisms. But how far is ageing controlled by our genes? In this Viewpoint, six experts present their opinions and comment on future directions in ageing research. © 2012 Macmillan Publishers Limited. All rights reserved.

News Article | November 14, 2016

The idea that the blood of the young is a magical anti-aging elixir is one the most delightfully macabre themes in folklore and horror. Embodied by the real-life Hungarian countess and serial killer Elizabeth Bathory, who is rumored to have bathed in the blood of young virgins, the trope now encompasses countless vampiric characters who include youth-harvested blood in their health and beauty regimens. It has even been courted by modern day figures like entrepreneur Peter Thiel, who makes no bones about his desire to inject himself with the life-sustaining fluids of the young. As it turns out, there might be something to the idea that young blood has rejuvenating powers, and fortunately, it is not quite so nefarious as its folkloric reputation would suggest. In a newly released lecture called "Young Blood for Old Brains," Stanford University neurology professor Tony Wyss-Coray delves into the years of research he and his colleagues have poured into the curious effects of blood-sharing between mice of different ages. The entire talk, posted Thursday, is available in full. If you are squeamish, be warned: It does involve literally stitching two mice together, an experimental technique known as parabiosis. "The way we do this typically is [...] we pair a three-month-old mouse, which is equivalent to about an 20-year-old human with an 18-month-old mouse, which is equivalent to about a 65-year-old person," Wyss-Coray explains in the lecture. "We leave them together for five weeks and then ask questions regarding molecular changes, subcellular changes, cellular changes, and so forth." READ MORE: Meet Aubrey de Grey, the Researcher Who Wants to Cure Old Age Admittedly, artificially conjoining two mice of different ages together seems like some unholy mixture of blood magic and mad science, and it should come as no surprise that parabiosis has been criticized by some animal rights activists for its cruel and harmful effects on test animals. But though controversial, this experimental practice dates back 150 years, and has consistently suggested that old individuals experience health benefits from sharing blood and plasma with their younger parabiotic half. For instance, researchers have found that the brains of older mice show increased synaptic activity, neurogenesis, and plasticity, as a result of sharing a circulatory system with younger mice. The underlying mechanisms that govern these effects remain unsolved, but several teams are working towards cracking the mystery and reproducing it in humans. As the co-director of Stanford's Alzheimer's Disease Research Center and the associate director of the Center for Tissue Regeneration, Repair and Restoration, Wyss-Coray is especially interested in harnessing this hidden power of young blood to prevent neurological conditions associated with aging. To that end, he has already begun to treat human subjects with Alzheimer's disease with plasma infusions sourced from younger people. The results from those trials are expected within the next few months, according to Science. Get six of our favorite Motherboard stories every day by signing up for our newsletter.

Villeda S.A.,Stanford University | Wyss-Coray T.,Stanford University | Wyss-Coray T.,Center for Tissue Regeneration
Autoimmunity Reviews | Year: 2013

The ability of the adult brain to generate newly born neurons dramatically declines during aging, and has even been proposed to contribute, in part, to age-related cognitive impairments. While intrinsic molecular mechanisms underlying decreased neurogenesis during aging have begun to be elucidated, relatively little is still known as to the contribution of the systemic environment. Interestingly, immune signaling has quickly emerged as a key negative regulator of adult neurogenesis, and has more recently been functionally linked to the aging circulatory systemic environment. In this review we examine the role of the aging systemic environment in regulating adult neurogenesis and cognitive function. We discuss recent work from our group using the aging model of heterochronic parabiosis - in which the circulatory system of two animals is connected - to highlight the contribution of circulatory immune factors to age-related impairments in adult neurogenesis and associated cognitive processes. Finally, we propose the possibility of combating brain aging by tapping into the 'rejuvenating' potential inherent in a young circulatory systemic environment. © 2012.

Kirby E.D.,Stanford University | Kuwahara A.A.,Stanford University | Messer R.L.,Stanford University | Wyss-Coray T.,Stanford University | Wyss-Coray T.,Center for Tissue Regeneration
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The adult hippocampus hosts a population of neural stem and progenitor cells (NSPCs) that proliferates throughout the mammalian life span. To date, the new neurons derived from NSPCs have been the primary measure of their functional relevance. However, recent studies show that undifferentiated cells may shape their environment through secreted growth factors. Whether endogenous adult NSPCs secrete functionally relevant growth factors remains unclear. We show that adult hippocampal NSPCs secrete surprisingly large quantities of the essential growth factor VEGF in vitro and in vivo. This self-derived VEGF is functionally relevant for maintaining the neurogenic niche as inducible, NSPC-specific loss of VEGF results in impaired stem cell maintenance despite the presence of VEGF produced from other niche cell types. These findings reveal adult hippocampal NSPCs as an unanticipated source of an essential growth factor and imply an exciting functional role for adult brain NSPCs as secretory cells.

Mosher K.I.,Stanford University | Wyss-Coray T.,Stanford University | Wyss-Coray T.,Center for Tissue Regeneration
Biochemical Pharmacology | Year: 2014

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial "activation" and "neuroinflammation" are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

Eggel A.,University of Bern | Wyss-Coray T.,Stanford University | Wyss-Coray T.,Center for Tissue Regeneration
Swiss Medical Weekly | Year: 2014

Modern medicine wields the power to treat large numbers of diseases and injuries most of us would have died from just a hundred years ago, yet many of the most devastating diseases of our time are still untreatable. Chronic conditions of age such as cardiovascular disease, diabetes, osteoarthritis or Alzheimer's disease turn out to be of a complexity that may require transformative ideas and paradigms to understand and treat them. Parabiosis, which is characterised by a shared blood supply between two surgically connected animals, may just provide such a transformative experimental paradigm. Although forgotten and shunned now in many countries, it has contributed to major breakthroughs in tumour biology, endocrinology and transplantation research in the past century. Interestingly, recent studies from the United States and Britain are reporting stunning advances in stem cell biology and tissue regeneration using parabiosis between young and old mice, indicating a possible revival of this paradigm. We review here briefly the history of parabiosis and discuss its utility to study physiological and pathophysiological processes. We argue that parabiosis is a technique that should enjoy wider acceptance and application, and that policies should be revisited to allow its use in biomedical research.

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