Imagine telling a patient suffering from age-related (type-II) osteoporosis that a single injection of stem cells could restore their normal bone structure. This week, with a publication in Stem Cells Translational Medicine, a group of researchers from the University of Toronto and The Ottawa Hospital suggest that this scenario may not be too far away.
Osteoporosis affects over 200 million people worldwide and, unlike post-menopausal (type-I) osteoporosis, both women and men are equally susceptible to developing the age-related (type-II) form of this chronic disease. With age-related osteoporosis, the inner structure of the bone diminishes, leaving the bone thinner, less dense, and losing its function. The disease is responsible for an estimated 8.9 million fractures per year worldwide. Fractures of the hip—one of the most common breaks for those suffering from type-II osteoporosis—lead to a significant lack of mobility and, for some, can be deadly.
But how can an injection of stem cells reverse the ravages of age in the bones?
Professor William Stanford, senior author of the study, had in previous research demonstrated a causal effect between mice that developed age-related osteoporosis and low or defective mesenchymal stem cells (MSCs) in these animals.
"We reasoned that if defective MSCs are responsible for osteoporosis, transplantation of healthy MSCs should be able to prevent or treat osteoporosis," said Stanford, who is a Senior Scientist at The Ottawa Hospital and Professor at the University of Ottawa.
To test that theory, the researchers injected osteoporotic mice with MSCs from healthy mice. Stem cells are "progenitor" cells, capable of dividing and changing into all the different cell types in the body. Able to become bone cells, MSCs have a second unique feature, ideal for the development of human therapies: these stem cells can be transplanted from one person to another without the need for matching (needed for blood transfusions, for instance) and without being rejected.
After six months post-injection, a quarter of the life span of these animals, the osteoporotic bone had astonishingly given way to healthy, functional bone.
"We had hoped for a general increase in bone health," said John E. Davies, Professor at the Faculty of Dentistry and the Institute of Biomaterials & Biomedical Engineering (IBBME) at the University of Toronto, and a co-author of the study. "But the huge surprise was to find that the exquisite inner "coral-like" architecture of the bone structure of the injected animals—which is severely compromised in osteoporosis—was restored to normal."
The study could soon give rise to a whole new paradigm for treating or even indefinitely postponing the onset of osteoporosis. Currently there is only one commercially available therapy for type-II osteoporosis, a drug that maintains its effectiveness for just two years.
And, while there are no human stem cell trials looking at a systemic treatment for osteoporosis, the long-range results of the study point to the possibility that as little as one dose of stem cells might offer long-term relief.
"It's very exciting," said Dr. Jeff Kiernan, first author of the study. A graduate from IBBME who is beginning a Postdoctoral Fellowship at The Ottawa Hospital with the Centre for Transfusion Research, Kiernan pursued the research for his doctoral degree.
"We're currently conducting ancillary trials with a research group in the U.S., where elderly patients have been injected with MSCs to study various outcomes. We'll be able to look at those blood samples for biological markers of bone growth and bone reabsorption," he added.
If improvements to bone health are observed in these ancillary trials, according to Stanford, larger dedicated trials could follow within the next 5 years.
Stem cells were first discovered in the early 1960s by University of Toronto Professors James E. Till and Earnest McCulloch. UofT continues to be a world leader in stem cell research.
Source: Medical express
Provided by: University of Toronto
More information: Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis. Jeffrey Kiernan, Sally Hu, Marc D. Grynpas, John E. Davies, William L. Stanford. Stem Cells Translational Medicine. 2016;5:1–11
Will it be possible to slow the rate of human aging and extend lifespan? Maybe.
Assuming that the first metazoans had short lifespans, gene changes have already extended our lifespans dramatically. Species with tissues much like ours can live far longer than we do, suggesting that perhaps we could too. In some human families, living healthily to age ninety or older is commonplace.
With more knowledge of the genes responsible, it might be possible to design interventions to slow down aging and increase healthy lifespan.
In animals, many mutations can slow aging and extend lifespan, in some cases dramatically. Most of these life-extending mutations affect biochemical pathways that respond to nutrient, stress or energy levels. Inhibiting pathways that promote nutrient uptake or growth, or activating pathways that normally help the organism respond to stress or a shortage of energy, can extend lifespan in worms, flies and mice. Perhaps pharmaceutical techniques could be used to extend human lifespans by modifying these or other life-extension pathways.
Now, writing in eLife, Yuan Zhang of the University of Texas Southwestern (UTSW) Medical Center and co-workers report that a hormone, called fibroblast growth factor-21 (FGF-21), can extend lifespan in mice (Zhang et al., 2012). When food is withheld from an animal for 12 hours or longer, liver cells produce this hormone, which then mobilizes fat stores in the liver, and promotes the synthesis of glucose and ketones. FGF-21 also reduces basal insulin levels and increases insulin sensitivity. In addition, it suppresses further growth of the mice by preventing growth hormone from triggering the production of IGF-1 (insulin-like growth factor-1) in the liver.
Previously, a collaboration between the UTSW group and researchers at New York University School of Medicine engineered mice with levels of circulating FGF-21 that were 5–10 times higher than normal (Inagaki et al., 2008). As a consequence, these animals switched on their starvation response even though they continued to feed normally. Now Zhang et al. report that the median lifespans of these mice are increased—by 30% for male mice and 39% for female mice. One consequence of high levels of FGF-21, disruption of the growth hormone/insulin/IGF-1 pathway, is already known to extend the lifespan of mice by ~50% (Coschigano et al., 2000). This disruption is likely to be responsible for the increase in the lifespans observed by Zhang et al. Other life extension pathways they examined (the TOR, AMPK and sirtuin pathways) all appeared normal in these mice.
Because FGF-21 is a hormone, it should be possible to increase its level in humans. It is possible that this will extend lifespan, because there are already hints that inhibiting the growth hormone/IGF-1 pathway promotes human longevity. First, genetic mutations that prevent cells from responding to IGF-1 are over-represented in centenarians (Suh et al., 2008), as are other rare DNA variants that reduce the activities of other components of this pathway, including the receptor for growth hormone (Y. Suh, personal communication). Second, DNA variants in the FOXO3A gene have been linked to exceptional longevity in at least eight studies across the world. FOXO proteins switch on genes that extend lifespan when insulin/IGF-1 signalling is inhibited in animals, although we do not know how these human DNA variants affect gene function. Third, genome-wide association studies for longevity highlight this pathway (Deelen et al., 2011).
It was the ability of FGF-21 to help animals survive starvation that initially prompted Zhang and co-workers – who are based at UTSW, the Howard Hughes Medical Institute and the Salk Institute – to test its role in aging. It has been known for decades that a reduced calorie intake (caloric restriction) can increase the lifespans of rodents and other animals. When first discovered, during the Great Depression of the 1930s, caloric restriction was assumed to work simply by reducing metabolic wear and tear. However, now we know that it extends lifespan by engaging specific signalling pathways and changing patterns of gene expression.
The results of a long-running caloric restriction experiment on primates were published recently and, unexpectedly, it was found that the calorically restricted monkeys did not live any longer than control animals (Mattison et al., 2012). This finding was puzzling because caloric restriction had seemed to extend lifespan in a previous study (Colman et al., 2009). However, the monkeys in the previous study had consumed a high-glycemic index diet, and the control animals (the only group in either study with a relatively short lifespan) were allowed to eat all they wanted. The take-home message here might be that a healthy, moderate diet will provide just as much benefit as more severe food limitation. However, the differences between the outcomes of the two studies might be partly due to other factors, such as genotypic differences between the groups. Different strains of mice are now known to respond to caloric restriction in different ways: some strains even live shorter, not longer.
While caloric restriction is not fully understood, Zhang et al. show that it is unlikely to explain their results because caloric restriction does not trigger FGF-21 production. Intriguingly, however, recurrent periods of starvation, administered in the form of intermittent, every-other-day feeding, can also extend lifespan in animals. This regime does not reduce overall caloric intake, as the animals overeat when food is available, but it should trigger FGF-21 production. Moreover, in C. elegans, where the mechanism has been examined, the life extension produced by intermittent fasting appears to act by inhibiting insulin/IGF-1 signalling and activating FOXO (Honjoh et al., 2009). It would be interesting to know whether everyother-day feeding might extend the lifespans of primates.
One of the most exciting features of many long-lived worms, flies and mice is their resistance to age-related diseases such as cancer, atherosclerosis and protein-aggregation disease. Since FGF-21 activates the same longevity pathways, it is possible that this hormone might also confer resistance against disease. Unfortunately, like some other mice that are deficient in IGF-1, these long-lived mice have low bone density, so we cannot recommend injecting FGF-21 right now.
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Heart disease remains the most common cause of death and disability in our society. However, the face of this disease has evolved considerably in the decades since cardiovascular scientists began to understand the cellular and molecular mechanisms of its pathophysiology. Today, nearly 90% of patients hospitalized for a heart attack not only survive but also return to their normal activities and work within weeks, if not sooner — a vast improvement in outcome as compared with decades earlier. However, the evolution in the treatment of acute cardiovascular disease has also been paralleled by an increase in the number of patients with chronic debilitation due to heart failure. Despite advances in our understanding of the neurohormonal basis of heart failure, current therapies for heart failure are limited, and the need for additional therapies remains great. Protein homeostasis plays a role in the development of numerous disorders. Misfolded proteins are central in the pathophysiology of neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. In the past several years, misfolded proteins have been found to play a role in the pathophysiology of common human cardiac diseases such as pathologic cardiac hypertrophy and dilated and ischemic cardiomyopathies, leading to the suggestion that protein misfolding is a key contributor to the progression of heart failure. In this review, we explore the contribution of protein misfolding to the pathophysiology of cardiac disease, describing why these proteins become misfolded and how the innate systems that usually dispose of them break down. We then discuss how the knowledge obtained from studying protein misfolding in other diseases, such as Alzheimer’s disease, may aid us in understanding the pathophysiological mechanisms of cardiac diseases and developing new treatments that focus on preventing or reversing protein misfolding in the heart.
Monte S. Willis & Cam Patterson
New England Journal of Medicine, Jan 31, 2013
Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.
Dimitrije Krstic & Irene Knuesel
Nature Reviews Neurology 9, 25-34 January 2013
The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses.
Cheng A, Wan R, Yang JL, Kamimura N, Son TG, Ouyang X, Luo Y, Okun E, Mattson MP
Nature Reviews Neurology 9, 25-34 January 2013