Fight Aging! Newsletter, April 17th 2017

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Cellular Reprogramming Approach Reverses Parkinson's Symptoms in a Mouse Model
  • A Certain Irrationality Still Pervades Much of the Aging Research Community
  • Mice Raised in a Germ-Free Environment Exhibit Less Age-Related Inflammation and Longer Average Lifespans
  • Use of the CD9 Cell Surface Receptor to Target Senescent Cells
  • Evidence for Cellular Senescence to Contribute to Osteoporosis
  • Latest Headlines from Fight Aging!
    • Hair Greying Correlates with Heart Disease Risk
    • Promising Results from an Early Trial of a Stem Cell Heart Patch
    • The Dual Nature of Reactive Oxygen Species in Aging
    • Heart Assist Devices Restore Normal Function in Some Heart Failure Patients
    • Declining BubR1 Contributes to Age-Related Loss of Neurogenesis
    • Reviewing the Aging of Microglia
    • An Interview with João Pedro de Magalhães
    • Tomatidine as a Mitophagy Enhancer
    • MicroRNA-210 Stabilizes Atherosclerotic Plaques
    • Similarities Between Alzheimer's Disease and Parkinson's Disease

Cellular Reprogramming Approach Reverses Parkinson's Symptoms in a Mouse Model

The prospect of replacing lost neurons is one of the major themes of research into Parkinson's disease. The most evident symptoms of this neurodegenerative condition, the tremors and loss of control, are caused by the progressive loss of a small but critical population of dopamine-generating neurons in the brain. This is actually a problem that occurs to all of us to some degree as we age, but Parkinson's patients have either a genetic or environmental vulnerability that makes them less resistant to the underlying processes that drive damage and cell death. As is the case for most neurodegenerative conditions, once you move past the proximate cause of dying cells, the list of mechanisms involved at lower levels in the chain of cause and effect starts to include all of the usual suspects: mitochondrial function; cellular maintenance processes; accumulations of misfolded proteins and other forms of metabolic waste; and so forth.

With the blossoming of the stem cell research community over the past twenty years, replacing lost neurons and their contribution to the functioning of the brain has seemed like a possible short-cut past the difficult question of why exactly it is that these particular neurons are dying. That it is in fact a short cut may or may not be the case, however. Certainly, the root causes of Parkinson's disease are still operating even following a hypothetical safe and reliable replacement of neurons, and it is an open question as to how long they will take to chew through those replacement neurons. Further, actually replacing dopamine-generating neurons safely and reliably has turned out to be a more challenging process than hoped. This is often the case in any field of medical research - even the goals that are easy to explain and visualize, and enjoy widespread support, are long roads. Still, the materials below note one of a number of promising results in neuron replacement that have arrived in recent years. The researchers used cellular reprogramming methods to generate patient-matched neurons from existing support cells in the brain, and went on to show positive results in mice engineered to exhibit Parkinson's symptoms.

Mighty morphed brain cells cure Parkinson's in mice, but human trials still far off

Mice that walk straight and fluidly don't usually make scientists exult, but these did: The lab rodents all had a mouse version of Parkinson's disease and only weeks before had barely been able to lurch and shuffle around their cages. Using a trick from stem cell science, researchers managed to restore the kind of brain cells whose death causes Parkinson's. And the mice walked almost normally. The same technique turned human brain cells, growing in a lab dish, into the dopamine-producing neurons that are AWOL in Parkinson's. Success in lab mice and human cells is many difficult steps away from success in patients. The study nevertheless injected new life into a promising approach to Parkinson's that has suffered setback after setback - replacing the dopamine neurons that are lost in the disease, crippling movement and eventually impairing mental function.

There is no cure for Parkinson's. Drugs that enable the brain to make dopamine help only somewhat, often causing movement abnormalities called dyskinesia as well as other side effects. Rather than replacing the missing dopamine, scientists tried to replace dopamine neurons - but not in the way that researchers have been trying since the late 1980s. In that approach, scientists obtained tissue containing dopamine neurons from first-trimester aborted fetuses and implanted it into patients' brains. Instead, several labs have used stem cells to produce dopamine neurons in dishes. Transplanted into the brains of lab rats with Parkinson's, the neurons reduced rigidity, tremor, and other symptoms. Human studies are expected to begin in the US and Japan this year or next.

Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model

Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGFβ, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability.

In a mouse model of Parkinson's disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.

A Certain Irrationality Still Pervades Much of the Aging Research Community

Imagine for a moment that the inhabitants of a town beside a river are hampered by their inability to get across the river. They have been talking about getting across the river for so long, and without any meaningful progress towards that goal, that it has become a polarized topic by now. Most people won't mention crossing the river these days because it has become the subject of tall tales and ridicule. The town is growing, however, and now it has a concrete works and enough revenue to order all the rest of the materials needed for a bridge. Accordingly, a bridge faction arises, but is almost immediately set upon by another, larger faction who think that a better use for the concrete and the funding would be a nice viewing platform overlooking the river, and a road leading up to it. Wouldn't that be a benefit to the town, and safely certain in comparison to actually having to set up pilings and cranes and all the rest of what might be needed to build a bridge? Both of these factions amount to only a handful of people in total, however, and are largely ignored by the rest of the town, whose support they need in order to move ahead.

This sketch is somewhat akin to the situation we find ourselves in when it comes to biotechnology and aging. The people who want to take credible paths to human rejuvenation, bringing aging under medical control, now that such a goal is possible given the technology to hand, are a minority in comparison to the people who want to do no more than slightly slow down aging. The difference in the potential benefits produced by these two courses of action is night and day: one does very little, the other is a road to agelessness and an end to all age-related disease. The difference in cost is likely minimal in the grand scheme of things. Yet the majority of that part of the aging research community interested treating aging as a medical condition are following the objectively far worse path, rather than the objectively far better path. Meanwhile, the majority of the public pays no attention and has little to no interest in the topic - despite the fact that this is, quite literally, a matter of life and death.

Thus, there are two battles of importance when it comes to advocacy for the treatment of aging. The first is to create widespread public support for longer, healthier lives and the research needed to achieve that goal. We currently live in a world in which most people are all for cancer research and heart disease therapies, but opposed to or disinterested in research that targets aging, the root cause of those conditions. Progress at the large scale requires greater public support for this cause than presently exists. The second battle is to ensure that the right projects are funded: comprehensive rejuvenation, not a slight slowing of aging. Bringing an end to aging, not just tweaking it a little. Both goals are equally possible, but at present the better of the two has far less support and funding. That this second battle is still being fought, and needs to be fought if we are going to see significant progress in our lifetimes, is why articles like the one quoted below appear every so often - though not as often as they should.

Fear of Life Extension

In about the year 2000, a commandment came down from the very heights of the Geriatric Olympus: "Thou Shalt Not Study Life Extension. Nay, nor shall thou speak wistfully of such a prospect. For it is written that life extension scares the bejesus out of the gods of policy." The fear haunting policy makers is that medical progress will result in longer lives without better health - the specter of millions of empty shells in wheelchairs populating ever-expanding nursing homes. Ever since this commandment, the ruling concept has been "quality, not quantity." We don't want to live longer - just better.

This concept ignores two realities: firstly, that we do want to live longer; secondly, that at a population level, it is impossible to live longer without living better. Conversely, living better means living longer. At one level, these realities are too obvious to require explanation. However, policy gods work at the level of abstract concepts, and strange things can happen when abstractions are substituted for actual experience.

We do want to live longer. As any clinician knows, those with serious chronic illnesses not only cling to life but for the most part enjoy it and are grateful for the opportunity. Even in places with easy access to un-messy and legally sanctioned suicide, there are not that many takers. And it is virtually impossible to separate quality from quantity in human life. Measures that reduce disease also increase longevity, and vice versa. There are rare examples where quality and quantity might diverge - perhaps chemotherapy and radiation for glioblastoma multiforme is one - but I challenge clinicians to come up with common examples. Aggressive end of life care does not increase quantity. Palliative care does not shorten life and in some trials even extends it.

Thirty years ago, there were serious articles by various experts about how the (then) continued increase in life expectancy would lead to an epidemic of Alzheimer's and thence to a need for more nursing homes, more wheelchairs, more of everything unpleasant and costly. But that was silly. People live longer because they are healthier, not because some magic pill or machine keeps decrepit, barely functioning organisms alive. Yet the commandment outlawing enthusiasm for life extension requires researchers to start their publications with statements about wanting only to improve quality, not quantity of life.

Mice Raised in a Germ-Free Environment Exhibit Less Age-Related Inflammation and Longer Average Lifespans

The research I'll point out here is an interesting data point to add to what is known of the impact of a life-long exposure to pathogens on aging and longevity. Researchers raised mice in a germ-free environment, and found that they did not suffer anywhere near the same age-related increase in inflammation, and the average life span increased. You might compare it with another recent study in which germ-free mice developed less metabolic waste in brain tissues over a lifetime. The research here focused on the interaction between gut microbiota and the immune system over the course of aging, a topic that has been explored to an increasing degree in recent years. The influence of the microbial populations of the gut on long-term health appears to be of around the same order of magnitude as that of other prominent environmental factors, such as level of exercise, though no-one has yet demonstrated as large an effect as that of calorie restriction via manipulation of gut microbes.

The high level summary is simple to outline, but the picture is a complicated one under the hood. Even given just the three broad categories of (a) immune cells, (b) gut microbes, and (c) pathogens - a dramatic oversimplification of the real picture - we can still argue about the direction of causation. Does exposure to pathogens cause malfunctions in the immune system, that in turn leads to changes in the gut microbe populations, that in turn feed back to cause further immune issues and other problems in intestinal function? Or are direct effects of pathogens on gut microbes more important? Or are other bodily systems involved in a significant way? There is much work yet to be accomplished in this part of the field. Further, the usual caveats apply here despite promising supporting evidence from other parts of the field: mice are not people, and the interactions with pathogens that are important over a mouse life span are unlikely to be the same as those that are most important over a human life span.

That said, there is a good deal of evidence for the aging of the immune system over a normal human life span to be accelerated by exposure to persistent pathogens like cytomegalovirus. An ever increasing fraction of immune cells are dedicated, uselessly, to this class of invader, while other activities are neglected. The immune system malfunctions in ways that promote ever greater inflammation, but with ever less of the usual benefits in terms of increased beneficial immune activity. Transient inflammation in younger people is useful, a necessary part of the way in which the immune system functions. Chronic inflammation in the old, on the other hand, is essentially a form of damage that contributes to the progression of many age-related diseases. Further, we can look at recent human history to see the effects of reduced exposure to infectious pathogens on long-term health and average lifespans. Older people in a given age group today are considerably less physically aged than was the case for that age group a century ago. Further again, there is a fair amount of research in shorter-lived species to suggest that declining intestinal function is an important component of degenerative aging. In flies, for example, it might be the most important component, though in mammals that is probably not the case. That decline is linked, separately, to immune function and the microbes of the gut.

More than a 'gut feeling' on cause of age-associated inflammation

Gut microbes cause age-associated inflammation and premature death in mice. The research shows that imbalances in the composition of gut microbes in older mice cause the intestines to become leaky, releasing bacterial products that trigger inflammation, impair immune function and reduce lifespan. Humans with high levels of inflammatory molecules are more likely to be frail, hospitalized, and less independent. They are also more susceptible to infections, chronic conditions such as dementia and cardiovascular disease and death. Up until now, the cause of the relationship between the composition of gut microbes and inflammation and poor health in the elderly has not been determined.

"To date, the only things you can do to reduce your age-associated inflammation are to eat a healthy diet, exercise and manage any chronic inflammatory conditions to the best of your ability. We hope that in the future we will be able use drugs or pre- or probiotics to increase the barrier function of the gut to keep the microbes in their place and reduce age-associated inflammation and all the bad things that come with it."

In contrast to conventionally raised mice, germ-free mice did not show age-related increases in inflammation and a higher proportion of them lived to a ripe old age. Age is associated with an increase in levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF), in the bloodstream and tissues. It was found that germ-free mice did not have increased TNF with age. In addition, TNF-deficient mice that did not develop age-associated inflammation or conventional mice that were treated with an anti-TNF drug approved for humans had reduced age-related changes in the microbiome. "We assume that if we reduce inflammation, we improve immune function. If we improve immune function, we maintain the ability to farm a healthy gut microbiota, but we don't know for sure yet. We also believe that targeting age-associated inflammation will improve immune health and we are investigating repurposing drugs that are already on the market and developing novel strategies or therapeutics to this effect."

Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction

Levels of inflammatory mediators in circulation are known to increase with age, but the underlying cause of this age-associated inflammation is debated. We find that, when maintained under germ-free conditions, mice do not display an age-related increase in circulating pro-inflammatory cytokine levels. A higher proportion of germ-free mice live to 600 days than their conventional counterparts, and macrophages derived from aged germ-free mice maintain anti-microbial activity.

Co-housing germ-free mice with old, but not young, conventionally raised mice increases pro-inflammatory cytokines in the blood. In tumor necrosis factor (TNF)-deficient mice, which are protected from age-associated inflammation, age-related microbiota changes are not observed. Furthermore, age-associated microbiota changes can be reversed by reducing TNF using anti-TNF therapy. These data suggest that aging-associated microbiota promote inflammation and that reversing these age-related microbiota changes represents a potential strategy for reducing age-associated inflammation and the accompanying morbidity.

Although manipulation of the microbiota may improve health in the elderly, until now it has not been clear whether microbial dysbiosis is a driver of immune dysfunction. For example, it has been demonstrated that gut microbial composition correlates with levels of circulating cytokines and markers of health in the elderly and that intestinal permeability and systemic inflammation increase in old mice, but not whether the microbiota drive these changes. Our data demonstrate that microbial dysbiosis occurs with age, even in minimal microbiota, and these changes are sufficient to promote age-associated inflammation, although we have not determined whether this is due to enrichment of specific species, changes in microbe-microbe interactions, alterations in the functional capacity of the aging microbiota (e.g., changes in short-chain fatty acid production), or loss of compartmentalization of the microbiota as is found in Drosophila.

Although there were significant changes in the composition of the microbiota with anti-TNF treatment, we have not yet identified which members of the microbial community alter barrier function with age. Further experiments will need to be performed to determine if it is the loss of beneficial members of the microbial community, overgrowth of harmful members, or a shift in metabolism that contributes to this phenomenon.

Use of the CD9 Cell Surface Receptor to Target Senescent Cells

As ever more researchers turn their attention to cellular senescence as a cause of aging and age-related disease, more potential approaches to selectively targeting these unwanted cells are emerging. In the paper I'll point out here, the cell surface receptor CD9 is used to target nanoparticles carrying a therapeutic payload into senescent cells. The researchers chose to use rapamycin as the drug payload, as for one it doesn't matter too greatly if it gets into other cells, and secondly there is a fairly active line of research involving mTOR and its influence over the behavior of senescent cells. Rapamycin, as you'll recall, inhibits mTOR, but has some unpleasant side-effects that make it a poor option for a therapeutic. Targeting via nanoparticles in this way greatly lowers the provided dose; it is a way to deliver potentially harmful drugs in order to obtain a narrow set of benefits while minimizing the unwanted side-effects.

For my money, the best use of targeting mechanisms in the case of senescent cells is to deliver cell-killing mechanisms rather than the sort of cell-adjusting mechanisms used here, but when killing cells the targeting method has to have a very high degree of discrimination. To my knowledge, no-one has made it all that far down that road yet. The present approaches to destroying senescent cells, those under active development and heading towards the clinic, don't even try to deliver their therapeutic agents selectively to senescent cells. They are applied to all cells and target senescence in the sense of preferentially activating inside senescent cells. Some are more effective in that discrimination than others, but the basic concept certainly works. So it is interesting to see a group working on the more traditional method of steering delivery via cell surface markers, in order to place the therapeutic into the target cell population only, or at least to the greatest degree possible. A few years back, I had predicted that this would be the sort of technology first used to destroy senescent cells, and was completely incorrect on that front.

Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles

Cellular senescence refers to a state of irreversible growth arrest and altered function of normal somatic cells after a finite number of divisions. Senescent cells are characterized by a flattened shape, senescence-associated β-galactosidase (SA-β-gal) activity, and hypersecretion of cytokines, chemokines, and proteases, the senescence-associated secretory phenotype (SASP). Senescence partly depends on mechanistic target of rapamycin (mTOR) signaling that mainly regulates tumor suppressor pathways p53/p21 and Rb/p16, and leads to disease development/progression through tissue function impairment. In addition, progressive inability of the immune system to destroy senescent cells during aging results in the accumulation of "death-resistant" cells that accelerate aging and disease development by altering neighboring cell behavior, lowering the pool of mitotic-competent cells, degrading the cellular matrix, and stimulating cancer. Diverse age-related diseases result from cellular senescence progression. Therefore, strategies for the prevention, treatment, or removal of senescent cells are of prime interest for clinical applications.

A recently reported proof-of-concept demonstrated the use of capped mesoporous silica nanoparticles for targeted cargo delivery inside senescent cells mediated by β-galactosidase activity. However, it fails to justify cell-specific uptake of these nanosystems to senescent cells following intravenous or subcutaneous delivery. A mechanism driven approach for specific interaction and uptake of nanoparticles by senescent cells has thus become a challenging necessity. Hence, we proposed a proof-of-concept regarding delivery of rapamycin (Rapa) loaded calcium carbonate (CaCO3) nanoparticles with CD9 receptor mediated targeting, in addition to utilization of β-galactosidase activity, in senescent cells.

Rapamycin (Rapa), an mTOR inhibitor, was found to prevent replicative senescence in rat embryonic fibroblasts by affecting the p53/p21 pathway. In addition, several studies have indicated the beneficial effects of Rapa for life span extension in aging models. More importantly, CD9 - a glycoprotein receptor of the tetraspanin family that regulates cellular activity, development, growth, and motility - is overexpressed in senescent cells and thus, can potentially be used in targeted drug delivery. Although contradictory reports on CD9 receptors in different cancer cells suggest either enhancement or inhibition of growth and motility functions, implying cell type-specific activity, senescent cells are closely related to cancer development. Our study is the first report for the utilization of CD9 receptors in targeting drug-loaded nanoparticles to senescent cells and can be a stepping stone for further research in the field of targeted therapy to senescent cells.

In our study, CD9 monoclonal antibody-conjugated lactose-wrapped calcium carbonate nanoparticles loaded with rapamycin (CD9-Lac/CaCO3/Rapa) were prepared for targeted rapamycin delivery to senescent cells. The nanoparticles exhibited an appropriate particle size (~130 nm) with high drug-loading capacity (~20%). In vitro drug release was enhanced in the presence of β-galactosidase suggesting potential cargo drug delivery to the senescent cells. Furthermore, CD9-Lac/CaCO3/Rapa exhibited high uptake and anti-senescence effects (reduced β-galactosidase and p53/p21/CD9/cyclin D1 expression, reduced population doubling time, enhanced cell proliferation and migration, and prevention of cell cycle arrest) in old human dermal fibroblasts. Importantly, CD9-Lac/CaCO3/Rapa significantly improved the proliferation capability of old cells along with significant reductions in senescence-associated secretory phenotypes (IL-6 and IL-1β). Altogether, our findings suggest the potential applicability of CD9-Lac/CaCO3/Rapa in targeted treatment of senescence.

Evidence for Cellular Senescence to Contribute to Osteoporosis

Today I noticed a recent paper in which the researchers tested a senolytic drug in the course of working on mechanisms relevant to the development of osteoporosis. Once they realized that cellular senescence might be involved in the development of osteoporosis, they put the drug to work in order to clear out senescent cells and see if that improved the picture. This is something we'll be seeing a lot more of in future research papers, whether in cell cultures or in animal models, and it certainly makes a great deal of difference to the quality of the evidence produced by a study. When researchers can address a specific cause of aging in a narrowly targeted way, rather than simply observing it, then it becomes a great deal easier to (a) show that the mechanism is in fact causing age-related disease, and (b) map the size of its effect.

The weakening of bone known as osteoporosis affects every older individual. It is, at root, an imbalance between the constantly ongoing activities of bone creation and absorption: too few osteoblasts creating bone and too many osteoclasts removing it. Any therapy that can reliably and safely tilt back the balance of activity towards creation should be helpful, but none of the approaches to date address the root causes. Instead, as is usually the case in modern medicine, researchers focus on proximate causes, trying to force cellular behavior back towards a more youthful pattern of activity without addressing the reasons why that pattern has changed. This is usually going to be hard to do well - as is any attempt to keep a damaged engine running without fixing the damage - which is why most present treatments for most age-related diseases are marginal at best.

Senescent cells accumulate with age, a lingering tiny minority of all such cells, the few that manage to evade destruction via programmed cell death or the immune system. They might be few in number, but those numbers grow over time and they cause great harm. These cells behave badly, generating signals that spur chronic inflammation, destructively remodel the extracellular matrix, and change the behavior of nearby cells for the worse as well. This adds up to produce failing organ function and disruption of vital processes such as tissue regeneration. Researchers have shown that removing senescent cells can fairly rapidly remove their malign influence as well, to some degree restoring tissue function and to some degree turning back the clock on measures of aging. Linking osteoporosis to increased numbers of senescent cells offers the hope of a better class of therapy for this condition, one that will arrive in clinics within the next few years. Numerous research groups and companies are presently involved in producing the means to selectively destroy these unwanted, harmful cells.

DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age

Old age is, by far, the most important risk factor for the development of osteoporosis. In bone biopsies from elderly men and women, the age-related loss of both cancellous and cortical bone is associated with decreased mean wall thickness - the histomorphometric hallmark of decreased bone formation. Loss of bone mass in aged rodents is associated with a decline in the number of osteoblasts, the cells responsible for the synthesis and mineralization of the bone matrix. Because osteoblasts are postmitotic cells with a short lifespan, they need to be constantly replaced with new ones. Osteoblasts arise from progenitors of mesenchymal origin, which express the transcription factors Runx2 and Osterix1 (Osx1).

The decline in the regenerative capacity of most tissues with old age has led to the idea that aging is due, at least in part, to increased cell senescence causing the loss of functional adult stem/progenitor cells. Cellular senescence is a process in which cells stop dividing and initiate a gene expression pattern known as the senescence-associated secretory phenotype (SASP). Several stimuli associated with aging promote senescence. Because the number of senescent cells increases in multiple tissues with aging, it has been widely assumed that senescence contributes to aging. Importantly, ablation of senescent cells using genetically modified mice prolongs lifespan and delays age-related pathologies in naturally aged mice or progeria models. We have recently shown that senescent cells induced by normal aging or ionizing radiation (IR) can be eliminated by administration of ABT263, a drug that kills senescent cells selectively; and clearance of senescent cells rejuvenates aged tissue stem and progenitor cells.

In both humans and rodents, the reduced osteoblast number in the aging skeleton has been attributed to changes in bone marrow-derived mesenchymal progenitors, including a decrease in the number of mesenchymal stem cells, defective proliferation/differentiation of progenitor cells, increased apoptosis, or increased senescence. However, it remains unclear whether the number of senescent osteoblast progenitors increases with old age. Moreover, the contribution of the decline in osteoblast progenitor number to the decrease in bone formation with age remains unknown because of the lack of methods to specifically identify and isolate mesenchymal progenitors. Therefore, the molecular mechanisms responsible for the decline in osteoblast number have remained elusive. To overcome these limitations, we generated a mouse model in which osteoblast progenitors are labeled with a red fluorescent protein (TdRFP) to facilitate their isolation by fluorescence-activated cell sorting (FACS) and examination of the effects of aging in freshly isolated cells. We present evidence that the decline in bone formation with age can be accounted for by a decrease in the number of osteoprogenitors due to DNA damage-induced cell senescence.

We report that the number of TdRFP-Osx1 cells, freshly isolated from the bone marrow, declines by more than 50% between 6 and 24 months of age in both female and male mice. Moreover, TdRFP-Osx1 cells from old mice exhibited markers of DNA damage and senescence. Bone marrow stromal cells from old mice also exhibited elevated expression of SASP genes, including several pro-osteoclastogenic cytokines, and increased capacity to support osteoclast formation. These changes were greatly attenuated by the senolytic drug ABT263. Together, these findings suggest that the decline in bone mass with age is the result of intrinsic defects in osteoprogenitor cells, leading to decreased osteoblast numbers and increased support of osteoclast formation.

Latest Headlines from Fight Aging!

Hair Greying Correlates with Heart Disease Risk

Since aging is a global phenomenon in the body, an accumulation of a small number of forms of root cause molecular damage that produce many more secondary and later consequences, it should be expected to find strong correlations between observed measures of aging. Chance and lifestyle gives some people a larger amount of root cause damage, and that means they have greater degrees of all of the related secondary and later consequences. Better assessments of the correlations between those consequences do not necessarily tell us anything new.

Grey hair has been linked with an increased risk of heart disease in men. "Ageing is an unavoidable coronary risk factor and is associated with dermatological signs that could signal increased risk. More research is needed on cutaneous signs of risk that would enable us to intervene earlier in the cardiovascular disease process." Atherosclerosis and hair greying share similar mechanisms such as impaired DNA repair, oxidative stress, inflammation, hormonal changes and senescence of functional cells. This study assessed the prevalence of grey hair in patients with coronary artery disease and whether it was an independent risk marker of disease.

This was a prospective, observational study which included 545 adult men who underwent multi-slice computed tomography (CT) coronary angiography for suspected coronary artery disease. Patients were divided into subgroups according to the presence or absence of coronary artery disease, and the amount of grey/white hair. The amount of grey hair was graded using the hair whitening score: 1 = pure black hair, 2 = black more than white, 3 = black equals white, 4 = white more than black, and 5 = pure white. Each patients' grade was determined by two independent observers. Data was collected on traditional cardiovascular risk factors including hypertension, diabetes, smoking, dyslipidaemia, and family history of coronary artery disease.

The researchers found that a high hair whitening score (grade 3 or more) was associated with increased risk of coronary artery disease independent of chronological age and established cardiovascular risk factors. Patients with coronary artery disease had a statistically significant higher hair whitening score and higher coronary artery calcification than those without coronary artery disease. In multivariate regression analysis, age, hair whitening score, hypertension and dyslipidaemia were independent predictors of the presence of atherosclerotic coronary artery disease. Only age was an independent predictor of hair whitening. "Our findings suggest that, irrespective of chronological age, hair greying indicates biological age and could be a warning sign of increased cardiovascular risk."

Promising Results from an Early Trial of a Stem Cell Heart Patch

Heart patches are one manifestation of the tissue engineering approach to regenerative medicine. Cells delivered to the patient are usually combined with a biodegradable scaffold material that provides support to help the cells survive and undertake beneficial signaling actions. A heart patch is some amount of this combined material applied to the exterior of the heart, in some cases simply by injection since the scaffold can be made to be a viscous fluid. The researchers here claim better results by abandoning the scaffolds, however, and implanting thin sheets of engineered cells. This paper reports on the results of an early human trial:

Heart failure, caused primarily by ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), is life-threatening even with excellent treatment. We developed a cell-sheet implantation method that can heal severely damaged myocardium through cytokine paracrine effects, as evidenced by several experiments using infarction or DCM models in both large and small animals. Cell-sheet implants are reported to offer better functional recovery than needle-injection methods, mainly by cytokine paracrine effects despite poor cell survival. Based on these findings from preclinical work, we previously conducted a First-in-Man Clinical Trial using cell-sheet implants. In the present study, we introduced cell-sheet implants to treat cardiomyopathy patients in a Phase I clinical trial to determine the safety, feasibility, and potential effectiveness of cell-sheet implants as a sole therapy.

Fifteen ischemic cardiomyopathy patients and 12 patients with dilated cardiomyopathy, who were in New York Heart Association functional class II or III and had been treated with the maximum medical and/or interventional therapies available, were enrolled. Scaffold-free cell sheets derived from autologous muscle were transplanted over the left ventricle free wall via left thoracotomy, without additional interventional treatments. There were no procedure-related major complications during follow-up. The majority of the ischemic cardiomyopathy patients showed marked symptomatic improvement in New York Heart Association classification and the Six-Minute Walk Test with significant reduction of serum brain natriuretic peptide level, pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress after transplantation instead of limited efficacy in dilated cardiomyopathy patients.

This Phase I study found cell-sheet transplantation as a sole therapy to be a feasible treatment for cardiomyopathy. The promising results in the safety and functional recovery seen in this study warrant further clinical follow-up and larger studies to confirm the therapeutic efficacy of autologous skeletal stem-cell sheets for severe congestive heart failure.

The Dual Nature of Reactive Oxygen Species in Aging

Reactive oxygen species (ROS) are largely generated in the mitochondria of the cell, a side-effect of the energetic processes taking place there to power cellular operations. ROS cause damage that must be repaired by reacting with molecular machinery in the cell, and that stress on the cell increases with age, and features prominently in most discussions of aging. ROS also play an important role as signals, however, triggering important processes related as cellular maintenance. That exercise is beneficial, for example, depends upon an increase in ROS production, and a number of ways of increasing life span in laboratory species incorporate some degree of increased ROS generation.

Historically, mitochondrial ROS (mtROS) production and oxidative damage have been associated with aging and age-related diseases. In fact, the age-related increase in ROS has been viewed as a cause of the aging process while mitochondrial dysfunction is considered a hallmark of aging, as a consequence of ROS accumulation. However, pioneering work in Caenorhabiditis elegans has shown that mutations in genes encoding subunits of the electron transport chain (ETC) or genes required for biosynthesis of ubiquinone extend lifespan despite reducing mitochondrial function. The lifespan extension conferred by many of these alterations is ROS dependent, as reduction of ROS abolishes this effect. Moreover, chemical inhibition of glycolysis or exposure to metabolic poisons that block respiratory complex I (CI) or complex III (CIII) also prolong lifespan in C. elegans in a ROS-dependent manner. Various studies have shown that ROS act as secondary messengers in many cellular pathways, including those which protect against or repair damage. ROS-dependent activation of these protective pathways may explain their positive effect on lifespan. The confusion over the apparent dual nature of ROS may, in part, be due to a lack of resolution as without focused genetic or biochemical models it is impossible to determine the site from which ROS originate.

A promising path to resolving ROS production in vivo is the use of alternative respiratory enzymes, absent from mammals and flies, to modulate ROS generation at specific sites of the ETC. The alternative oxidase (AOX) of Ciona intestinalis is a cyanide-resistant terminal oxidase able to reduce oxygen to water with electrons from reduced ubiquinone (CoQ), thus bypassing CIII and complex IV (CIV). NDI1 is an alternative NADH dehydrogenase found in plants and fungi, which is present on the matrix-face of the mitochondrial inner membrane where it is able to oxidize NADH and reduce ubiquinone, effectively bypassing CI. Our group and others have demonstrated that allotopic expression of NDI1 in Drosophila melanogaster can extend lifespan under a variety of conditions and rescue developmental lethality in flies with an RNAi-mediated decrease in CI levels.

To determine the role of increased ROS production in regulating longevity, we utilized allotopic expression of NDI1 and AOX, along with Drosophila genetic tools to regulate ROS production from specific sites in the ETC. We show that NDI1 over-reduces the CoQ pool and increases ROS via reverse electron transport (RET) through CI. Importantly, restoration of CoQ redox state via NDI1 expression rescued mitochondrial function and longevity in two distinct models of mitochondrial dysfunction. We show that mitochondrial ROS production increases with age and that un-detoxified ROS can be detrimental to Drosophila lifespan, while increasing ROS production specifically from reduced CoQ, possibly via RET, acts as a signal to maintain mitochondrial function (notably CI) and extend lifespan. It is possible that an intact CI is required for lifespan extension in fruit flies, as metformin, which increases lifespan by blocking CI and increasing ROS in worms, fails to do so in fruit flies. If the mechanism we describe here is conserved in mammals, manipulation of the redox state of CoQ may be a strategy for the extension of both mean and maximum lifespan and the road to new therapeutic interventions for aging and age-related diseases.

Heart Assist Devices Restore Normal Function in Some Heart Failure Patients

The heart is one of the least regenerative organs in the body. Given that, it is interesting to see that in some heart failure patients, the use of mechanical devices to assist heart function gives the heart a chance to somewhat restore itself. The underlying mechanisms have yet to be explored, but it is always possible that the effect might be recreated without the use of devices if better understood.

A study has shown that nearly 40% of severe heart failure patients initially fitted with a mechanical heart which was later removed go on to fully recover. As we face a shortage of donated hearts for transplant, the study authors are calling for the devices to be considered as a tool which can allow patients to restore their health. The research examined the effect of mechanical heart pumps, known as left ventricular assist devices (LVAD). The devices are used to support patients with severe heart failure while they wait for a heart transplant. Surgeons implant the battery operated, mechanical pump which helps the main pumping chamber of the heart - the left ventricle - to push blood around the body. LVADs are used for patients who have reached the end stage of heart failure.

Researchers report that LVAD combined with medication can fully restore heart function in patients. "We talk about these devices as a bridge-to-transplant, something which can keep a patient alive until a heart is available for transplantation. However, we knew that sometimes patients recover to such an extent that they no longer need a heart transplant. For the first time, what we have shown is that heart function is restored in some patients - to the extent that they are just like someone healthy who has never had heart disease. In effect, these devices can be a bridge to full recovery in some patients."

In the clinical trial, 58 men with heart failure were tested for their heart fitness levels. Of the men, 16 were fitted with an LVAD and then had it removed due to the extent of their recovery. Furthermore 18 still had an LVAD and 24 patients were waiting for a heart transplant. On average, a patient had a device fitted for 396 days before it was removed, though it varied from 22 days to 638 days. The participants were compared with 97 healthy men who had no known heart disease. All were tested on a treadmill with a face mask to monitor their oxygen utilisation and heart pumping capability. The authors report that 38% of people who recover enough to allow the device to be removed demonstrated a heart function which was equivalent to that of a healthy individual of the same age. "Our ongoing and future research is aiming to identify the markers of early heart recovery while patients are fitted with a device. These markers will inform clinical care teams to make right decisions about which patient respond well to device and when to consider potential removal or disconnection of the device while ensuring heart failure will not occur again in the future."

Declining BubR1 Contributes to Age-Related Loss of Neurogenesis

The brain generates new cells to replace those lost to injury and age, but only to a very modest degree - nowhere near enough to compensate for the damage that accumulates over a life span. Further, the processes of neurogenesis, the birth and integration of new neurons, decline with age. There is some interest in finding ways to spur greater neurogenesis, as the basis for therapies or enhancement technologies, and here researchers investigate a possible proximate cause of the age-related reduction in the pace at which new neurons are created in brain tissue.

The hippocampus is one neurogenic niche where new neurons arising from neural stem cells (NSCs) are constantly generated throughout life in a process called adult hippocampal neurogenesis. Deficits in this process are observed with aging and are believed to underlie age-related cognitive deficits. However, the molecular identity governing such deficits is not fully understood. A mitotic checkpoint kinase, BubR1, has emerged as a key factor in age-related pathology and lifespan. Whether BubR1 also regulates age-related changes in hippocampal neurogenesis is unknown. Notably, BubR1 is expressed in the postnatal mouse dentate gyrus and is relatively higher in the subgranular zone (SGZ) than the dentate granule layer. In addition, BubR1 is expressed in radial glia-like NSCs (RGCs) and is reduced in an age-dependent manner. We hypothesized that age-dependent regulation of BubR1 plays a possible role in hippocampal neurogenesis.

Using adult BubR1 H/H mice with reduced hippocampal BubR1 levels, we first showed significantly reduced cell proliferation in the SGZ and subventricular zone. Progenitor cell types vulnerable to BubR1 insufficiency included significant reductions in activated RGCs, intermediate progenitor cells (IPCs), and neuroblasts. Subsequently, BubR1 H/H mice exhibited a significant decrease in the density of mature new neurons, while survival of new cells was not affected. Thus, these results indicate that the reduction in hippocampal neurogenesis may result primarily from a decrease in neural progenitor proliferation, rather than affecting survival.

In this study, we have identified several novel functions of BubR1 in the adult brain. First, we show BubR1 level is significantly reduced with age. Given that BubR1 insufficiency contributes to age-related pathology including short lifespan, our findings extend the established function of BubR1 to aging and cognitive decline. Second, BubR1 is primarily known as a key regulator for mitosis. We identify an adult-specific mitotic function of BubR1 in ensuring a precise number of neural progenitors are proliferated and an effective rate of neurogenesis is maintained. Third, we show a critical postmitotic function of BubR1. Rather than affecting cell survival, BubR1 insufficiency impairs neuronal maturation and impairs dendrite morphogenesis. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging-related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age-related cognitive deficits.

Reviewing the Aging of Microglia

Microglia are a form of specialized immune cell resident in the central nervous system, responsible for mounting a defense against pathogens and clearing out harmful waste materials from brain tissue. They also assist more directly in the function of neurons and neural connections, however. Like all other parts of the immune system, microglia become damaged and dysfunctional with advancing age, and the research community is attempting to better understand this failure in order to address it in some way. There have been initial attempts to try to reverse the signaling environment for microglia in older animals, for example, though it may be that delivering young microglia will turn out to be a more effective stopgap approach. Ultimately, the underlying damage that causes aging and all its dysfunction will have to be repaired in order to put a stop to this and all other forms of degeneration.

The effects of aging on the central nervous system (CNS) are widespread, as are systemic changes in peripheral tissues. The importance of communication between the CNS and the periphery is increasingly recognized, and may be mediated by systemic factors, the autonomic nervous system, commensal bacteria (i.e., the microbiome) and/or the neuro-immune axis. Age-related changes in CNS homeostasis are not solely intrinsic in nature, but are mediated through bidirectional communication between the CNS and the systemic environment. Differences in neuronal function have been observed in the CNS with age, but it is becoming increasingly apparent that it is possible to slow, or even reverse, aging by restoring "youthful" peripheral tissue compartments. This includes the bone marrow niche that gives rise to the body's immune system, which can have a beneficial positive feedback effect on distant areas including the CNS.

No cell is protected from the detrimental effects of aging, and this includes the primary immune cell of the CNS, the resident tissue macrophages known as microglia. These cells represent 5%-15% of all brain cells, and are considered to be the housemaids of the CNS, providing nourishment and support to neighboring neurons, clearing debris, and being the first responders to foreign stimuli. Like their neuronal counterparts, microglia are believed to be post-mitotic and long-lived, with minimal, if any, turnover. Although recent depletion studies imply the existence of latent microglia progenitors, it is not clear what role this proposed population of cells may have in replenishing microglia populations under normal homeostatic conditions across the lifespan. Thus, these cells may still be viewed as especially vulnerable to the cumulative effects of aging, and thus poised to negatively impact the neurovascular niche as a result of a compromised ability to perform essential 'house-keeping' functions. While the role of aging on circulating macrophages and other lymphoid-associated myeloid cells has received significant attention in recent years, our understanding of the age-related changes in the function of CNS-resident microglia is less clear.

Young microglia gradually transition from a ramified morphological state to a deramified, spheroid formation with abnormal processes with chronological age. Several cytoplasmic features are hallmarks of microglial senescence including increased granule formation, autofluorescent pigments such as lipofuscin, and process fragmentation. Age-related neuronal loss reduces the overall level of immunoinhibitory molecules required to maintain microglia in a quiescent state. Basal increases in inflammatory signaling are associated with enhanced reactive oxygen species (ROS) production which results in the generation of free radicals, lipid peroxidation, and DNA damage. This positive feedback loop is further compounded by defects in lysosomal digestion and autophagy, resulting in the potentially toxic buildup of indigestible material. Concurrent reductions in process motility and phagocytic activity lead to decreased immune surveillance and debris clearance, resulting in plaque formation. In turn, microglia activation triggers astrocyte activation and promotes the recruitment of T cells into the aging brain.

These pathological features of microglial aging are highly influenced by the systemic environment. Diminished levels of circulating anti-aging factors in conjunction with increased concentrations of pro-aging factors are critical drivers of microglial senescence. For example, diminished estrogen levels in older females are associated with elevated expression of macrophage-associated genes in the brain. Therapeutic interventions intended to increase anti-aging factors and decrease pro-aging factors appear to be able to halt or delay microglia aging, enhance neurogenesis, and improve cognitive function.

An Interview with João Pedro de Magalhães

João Pedro de Magalhães is one of a number of people from the small online transhumanist community of twenty years past who went on to focus on aging research. The present all too short human life span is the most pressing and harmful of limits upon the human condition, and the more people who seek to do something about that, the better. Like many of the more established researchers in the field, de Magalhães has come to think that radical life extension of decades or more in our lifetimes is unlikely, however. To my eyes that is only true if the SENS approach based on repair of root cause molecular damage fails to gather significantly greater support over the next two decades. There is a lot of room yet to achieve great things, especially now that the first SENS approaches are close to the clinic, such as senescent cell clearance.

What are you currently working on?

Although my work integrates different strategies, its focal point is developing and applying experimental and computational methods to help decipher the genome and how it regulates complex processes like ageing. In practice, that means developing and employing modern methods for genome sequencing and also bioinformatics to analyze large amounts of data, for example networks with hundreds of genes. We now know that aging and longevity, like many other biological processes, derive from many genes interacting with each other and with the environment. My lab develops methods to survey and analyze data from thousands of genes simultaneously to identify the most important ones. More specifically, we are now studying new genes associated with aging and longevity as well as new cancer and Alzheimer's disease genes. If we can identify which are the key genes modulating aging or age-related diseases than this will open new opportunities for developing therapeutics. We are also studying new life extending compounds using animal models.

What do you think is the most important contribution you've made to the field?

I am probably best known for the online collection of databases I created, the Human Ageing Genomic Resources (HAGR). I designed HAGR to help researchers study the genetics of human ageing using modern approaches such as functional genomics, network analyses, systems biology and evolutionary analyses. They have been cited hundreds of times and are used widely by the biogerontology research community, facilitating a lot of studies. I am also known for the work I did on sequencing genomes of long-lived species, in particular the naked mole rat and bowhead whale. Lastly, my lab developed various computational approaches to analyze large amounts of data as well as predict new genes, processes and drugs associated with aging and longevity.

What is the approach to fighting ageing you find most promising, besides the one you're pursuing?

There is certainly a lot of promise in stem cells and regenerative medicine. So I am optimistic that there will be new advances and therapies, although things normally take a long time in clinical translation. I'm not sure that telomeres and telomerase will play much of a role. I think telomerase may be used in regenerative medicine and to treat specific diseases, but it is unlikely to become a source of anti-ageing therapies because it also promotes tumorigenesis. Besides, mice have lots of telomerase and yet they age much faster than us. It's some years old but I wrote a review on this topic where I expressed my skepticism of telomerase as a therapy for aging.

Do you expect to see the day ageing is finally defeated? What you will do after that?

I don't think we will defeat aging within my lifetime. I mean, we can't even defeat aging in simple animal models, or defeat a number of simpler human diseases (I have a nasty cold as I write this, like I have every year). So I don't think we will cure aging in the foreseeable future. Like many others in the life extension community, I think cryopreservation may be a plan B, even though it's not a very attractive one (but it's still better than dying!). That's why in the past few years I have become more involved in cryobiology and cryonics. While I am not convinced that the current techniques used in cryonics allow preservation of the self, I think the field can progress rapidly to the point of us as developing reversible human cryopreservation well before aging is defeated.

Tomatidine as a Mitophagy Enhancer

It is well understood in the research community that enhancement of the cellular maintenance process of autophagy, and in particular the recycling of damaged mitochondria known as mitophagy, is a desirable goal. Many of the methods of modestly slowing aging in laboratory species feature enhanced autophagy, and decline of mitochondrial function is a prominent aspect of the aging process. That part of the aging research community interested in slowing human aging, as opposed to aiming for rejuvenation, includes a number of groups that work on autophagy. Still, little progress has been made towards clinical therapies based on safely increased levels of autophagy. There are many examples of research papers like this one from the past decade, as the life span of short-lived species is very plastic in response to circumstances and metabolic adjustments, but nothing of practical use for humans has yet emerged.

Aging is a major international concern that brings formidable socioeconomic and healthcare challenges. Small molecules capable of improving the health of older individuals are being explored. Small molecules that enhance cellular stress resistance are a promising avenue to alleviate declines seen in human aging. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in C. elegans, an animal model of aging which shares many major longevity pathways with mammals. Tomatidine improves many C. elegans behaviors related to healthspan and muscle health, including increased pharyngeal pumping, swimming movement, and reduced percentage of severely damaged muscle cells.

Microarray, imaging, and behavioral analyses reveal that tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy. This mechanism occurs in C. elegans, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions for diseases of aging.

MicroRNA-210 Stabilizes Atherosclerotic Plaques

Researchers here find a way to stabilize the fatty plaques that form in blood vessels as a part of atherosclerosis. On its own this is a pretty poor treatment option, better than nothing, but worse than any approach that removes plaques or prevents them from forming. It will probably be a useful adjunct to any form of removal or reduction of plaque, however, helping to avoid rupture of larger sections of plaque during that process. It is the disintegration of fragile plaques that makes atherosclerosis lethal, as the fragments can then block critical blood vessels to cause a stroke or heart attack.

The molecule microRNA-210 stabilises deposits in the carotid artery and can prevent them from tearing. Thus, it may prevent dangerous blood clots from forming. The most common cause for the narrowing of the carotid artery is atherosclerosis, where so-called plaques build up on the vessel walls. If a plaque ruptures, blood clots can form that either further occlude the site that is already narrowed, or are carried away by the blood flow, which could lead to vascular occlusion at a different site. If this happens in the carotid artery, it could lead to a stroke. How easily a plaque ruptures depends on how thick the tissue layer surrounding its core is. The thicker this fibrous cap, the more stable and therefore more harmless the vessel deposit.

"New imaging procedures enable us to detect dangerous plaques with increasing precision; but the therapies currently available for removing these unstable plaques and thus preventing a stroke entail a certain amount of risk that the plaques will rupture during the procedure. This is why these therapies are not used on individuals with a narrowed carotid artery who have so far not experienced any symptoms. Traditionally, physicians try to reduce the size of the deposits in the vessels in order to widen the narrowed sites. For narrowed carotid arteries, though, the notion of stabilising the plaques is becoming ever more prevalent. Unlike in the coronary vessels, in the carotid artery plaques rupturing is more dangerous than the narrowing."

Researchers compared material from patients with stable and unstable deposits in the carotid artery. They particularly focused on microRNAs. These molecules are involved in the gene regulation in about 60 percent of mammals' genes. They can prevent gene information that has already been read from being translated into proteins, and have become a focus of biomedical research as active ingredients and starting points for new therapies in recent years. The scientists discovered that microRNA-210 was reduced the most in the blood samples of patients with unstable plaques. These were blood samples that were obtained locally near the vessel deposits. Further examinations showed that microRNA-210 is primarily present in the fibrous caps of plaques and that it inhibits the expression of the APC gene. As a consequence, fewer smooth muscle cells die in the fibrous cap and it becomes more stable. Moreover, the animal model could show that fewer plaques rupture when microRNA-210 is administered.

The scientists are currently researching how microRNA-210 can be applied locally. The risk of adverse events in other organs is much too high if microRNA modulators are administered systemically. The main concern with microRNA-210 is that tumour cells that are possibly already in existence will multiply, because the expression of APC is inhibited. This is because APC is a tumour suppressor gene which inhibits the growth of tumours in the healthy body. In order to avoid such off-target effects, the researchers are currently testing coated stents or balloons that are inserted directly into the carotid artery.

Similarities Between Alzheimer's Disease and Parkinson's Disease

Many of the better known age-related neurodegenerative conditions involve aggregates of damaged or misfolded proteins, but there are other similarities as well. This is too be expected, given that aging is at root caused by a small variety of forms of molecular damage. This damage spirals out into a much larger set of secondary and later consequences, ultimately leading to the wide variety of age-related diseases. Simple processes acting in a complex system, such as human biochemistry, tend to produce complex outcomes. Thus if starting at the point of any two age-related diseases, dig far enough back into their roots and you will arrive at shared origins. Somewhat in that vein, this open access review paper looks over some of the commonalities in Alzheimer's disease and Parkinson's disease:

Alzheimer's disease and Parkinson's disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson's disease are primarily motor deficits, while the patients of Alzheimer's disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case.

These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases. In the case of Alzheimer's disease, the peptide amyloid beta (Aβ) is responsible for the proteinopathy, while α-synuclein plays a similar role in Parkinson's disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins - as oligomers or in aggregated forms - cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions.


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