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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
Site: motherboard.vice.com

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.


Hunt K.J.,Stanford University | Barr C.R.,Stanford University | Lindsey D.P.,Center for Tissue Regeneration | Chou L.B.,Stanford University
Foot and Ankle International | Year: 2012

Background: First metatarsophalangeal (MTP) arthrodesis using dorsal plate fixation is a common procedure for painful conditions of the great toe. Locked plates have become increasingly common for arthrodesis procedures in the foot, including the hallux MTP joint. The biomechanical advantages and disadvantages of these plates are currently unknown. The purpose of this study was to compare locked and nonlocked plates used for first MTP fusion for strength and stiffness. Materials and Methods: The first ray of nine matched pairs of fresh-frozen cadaveric feet underwent dissection, preparation with cup-and-cone reamers, and fixation of the MTP joint with a compression screw and either a nonlocked or locked stainless steel dorsal plate. Each specimen was loaded in a cantilever fashion to 90 N at a rate of 3 Hz for a total of 250,000 cycles. The amount of plantar MTP gap was recorded using a calibrated extensometer. Load-to-failure testing was performed for all specimens that endured the entire cyclical loading. Stiffness was calculated from the final loadto- failure test. Results: The locked plate group demonstrated significantly less plantar gapping during fatigue endurance testing from cycle 10,000 through 250,000 (p < .05). Mean stiffness was significantly greater in the locked plate group compared with the nonlocked plate group (p = .02). There was no significant difference in load to failure between the two groups (p = .27). Conclusion: Compared with nonlocked plates, locked hallux MTP arthrodesis plates exhibited significantly less plantar gapping after 10,000 cycles of fatigue endurance testing and significantly greater stiffness in load-to-failure testing. Clinical Relevance: As the use of locked plate technology is becoming increasingly common for applications in the foot, a thorough understanding of the biomechanical characteristics of these implants may help optimize their indications and clinical use. Copyright © 2012 by the American Orthopaedic Foot & Ankle Society.


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.


O'Brien C.E.,Stanford University | O'Brien C.E.,Center for Tissue Regeneration | Wyss-Coray T.,Stanford University | Wyss-Coray T.,Center for Tissue Regeneration
Journal of Neuroimmune Pharmacology | Year: 2014

Beclin 1 has a well-established role in regulating autophagy, a cellular degradation pathway. Although the yeast ortholog of beclin 1 (Atg6/Vps30) was discovered to also regulate vacuolar protein sorting nearly 30 years ago, the varied functions of beclin 1 in mammalian cells are only beginning to be sorted out. We recently described a role for beclin 1 in regulating recycling of phagocytic receptors in microglia, a function analogous to that of its yeast ortholog. Microglia lacking beclin 1 have a reduced phagocytic capacity, which impairs clearance of amyloid β (Aβ) in a mouse model of Alzheimer's Disease (AD). Here we summarize these findings and discuss the implications for beclin 1-regulated receptor recycling in neurodegenerative disease. © 2014 Springer Science+Business Media.


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.


Czirr E.,Stanford University | Czirr E.,Center for Tissue Regeneration | Wyss-Coray T.,Stanford University | Wyss-Coray T.,Center for Tissue Regeneration
Journal of Clinical Investigation | Year: 2012

While immune responses in neurodegeneration were regarded as little more than a curiosity a decade ago, they are now increasingly moving toward center stage. Factors driving this movement include the recognition that most of the relevant immune molecules are produced within the brain, that microglia are proficient immune cells shaping neuronal circuitry and fate, and that systemic immune responses affect brain function. We will review this complex field from the perspective of neurons, extra-neuronal brain cells, and the systemic environment and highlight the possibility that cell intrinsic innate immune molecules in neurons may function in neurodegenerative processes.


Kerchner G.A.,Stanford University | Berdnik D.,Stanford University | Shen J.C.,Stanford University | Bernstein J.D.,Stanford University | And 5 more authors.
Neurology | Year: 2014

Objectives: Using high-resolution structural MRI, we endeavored to study the relationships among APOE e4, hippocampal subfield and stratal anatomy, and episodic memory. Methods: Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE e4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment. Results: We found a selective, dose-dependent association of APOE e4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the e4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE e4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE e4 allele to its phenotypic effects on memory. Conclusions: The APOE e4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.

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