Fight Aging! Newsletter, September 9th 2019

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  • Vascular Endothelium in Bone can be Targeted to Treat Osteoporosis in Mice
  • Inhibiting TGFß Receptors Reduces Chronic Inflammation and Plaque in Atherosclerosis
  • Greater Reductions in Blood Pressure in Hypertensive Patients Further Reduce Stroke Risk
  • Attempting a Unified View of Aging and Loss of Regenerative Capacity
  • Exploiting Senescence Associated β-Galactosidase to Selectively Destroy Senescent Cells
  • Declines in Limb Muscle Mass Correlate with Higher Mortality in Late Life
  • Potentially Damaging Ossified Particles Discovered in the Aging Bloodstream
  • Pressure Damage to Capillaries and Surrounding Cells in the Brain as a Contributing Cause of Cognitive Decline
  • Frailty as a Manifestation of Oxidative Stress
  • Destroying CD163 Tumor Associated Macrophages Allows the Immune System to Better Attack a Cancer
  • Work on Senolytic Rejuvenation Therapies Begins to Attract More Mainstream Notice
  • Senescent Cells Mediate Much of the Pulmonary Dysfunction Generated by Smoking
  • Fat Tissue Surrounds Skeletal Muscle to Accelerate Atrophy in Aging and Obesity
  • TAME Trial for the Effects of Metformin in Humans to Proceed this Year
  • Resistance Exercise Builds Muscle Equally for Both Sedentary and Athletic Older People

Vascular Endothelium in Bone can be Targeted to Treat Osteoporosis in Mice

Osteoporosis is the name given to the characteristic loss of bone mass and strength that occurs with age. In its later stages it becomes very dangerous, and bones can fracture even under normal load. Bone is a dynamic tissue, constantly restructured and rebuilt throughout life by the actions of osteoblasts responsible for creating the molecular structure of bone and osteoclasts responsible for breaking down that structure. At root, osteoporosis is an easy problem to visualize: the balance of activity slowly and systematically tips towards osteoclasts. The complexity of the problem lies in how and why that imbalance happens, and thus what might be the best strategy for the development of treatments. At present comparatively little can be done for patients, but that will hopefully change for the better in the years ahead.

Today's research materials discuss a new addition to existing potential approaches that might restore the balance between osteoblasts and osteoclasts, those that have been demonstrated in the laboratory in recent years. It is interesting in that the scientists involved don't yet know exactly why their basis for therapy works in animal models. That said, I think it fair to say that it probably falls into the category of increasing the activity of osteoblasts in order to restore the balance, while having all the appearance of a complex and indirect set of mechanisms that will take years to fully understand. Our biology is packed with complex and indirect mechanisms, which is one of the reasons why progress is always slower than we'd like.

Molecule Promoting Blood Vessel Growth in Bone Represents New Target for Osteoporosis Drugs

Researchers have shown that a substance, which is best known for spurring nerve growth, called SLIT3, both reversed the bone-weakening effects of osteoporosis and helped fractures heal when administered in mice. The research effort could fuel drug development efforts targeting the SLIT3 pathway in humans, enabling a new approach for blood vessel-directed therapy to treat bone loss, persistent fractures, and fragile bones. Existing drugs for osteoporosis work in one of two ways: Either they block the cells that destroy bone or they promote bone formation by cells called osteoblasts. "But only those promoting new bone formation will help you actually heal a bone fracture. Our findings have potentially demonstrated a third category: drugs that target blood vessel formation within bone, prompting new bone to form."

Researchers have investigation the cellular causes of osteoporosis in an effort to promote bone growth. Prior research using mice genetically engineered to lack an adaptor protein known as SHN3 showed that its absence conferred high bone mass. Building on that discovery, researchers decided to examine the resulting changes in bone blood vessels. They were surprised to find that osteoblasts secreted unchanged amounts of almost all known factors promoting blood vessel growth, but SLIT3 levels rose significantly. And when the mice were genetically altered to delete SLIT3, they exhibited low bone mass. "We next asked if we could use SLIT3 to treat mice with skeletal disease, especially osteoporosis and fracture healing. When we gave the rodents SLIT3, it reversed their osteoporosis and made their fractures heal faster and stronger. To my knowledge, this is the first example that we can develop a drug to treat bone disease in mice not by targeting the bone-forming cells, but instead by targeting special types of blood vessels that exist in bone."

Targeting skeletal endothelium to ameliorate bone loss

Recent studies have identified a specialized subset of CD31+ vascular endothelium that positively regulates bone formation. However, it remains unclear how endothelial tissue levels of these cells are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in the CD31+ subset of endothelial cells. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced the CD31+ subset population in the endothelium, resulted in low bone mass because of impaired bone formation, and partially reversed the high bone mass phenotype of Shn3-/- mice.

This coupling between osteoblasts and a subset of CD31+ endothelial cells is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.

Inhibiting TGFß Receptors Reduces Chronic Inflammation and Plaque in Atherosclerosis

Atherosclerosis involves the development of lipid deposits, called plaques, in blood vessel walls. Plaques narrow and weaken those vessels, ultimately producing the inevitable structural failure of a stroke or heart attack. Perhaps a sixth of humanity dies because of atherosclerosis, but means to treat the condition are so far only capable of somewhat slowing it down, with little reversal of existing plaque. Most approaches, such as statin drugs, focus on reducing the level of lipids in circulation in the bloodstream.

Why does a reduction of blood lipids work to slow atherosclerosis? Atherosclerosis is a condition of dysfunctional macrophages. The immune cells called macrophages are responsible for clearing lipid deposits from blood vessel walls. Where cells become disturbed by the presence of lipids, they secrete inflammatory signals calling for assistance. Macrophages arrive and set to work to ingest the lipids and hand them off to HDL particles in the bloodstream that can carry lipids to the liver for excretion. This all works quite well in youth. But with age, an ever greater fraction of lipids become oxidized in ways that macrophages cannot cope with. Macrophages become distressed, inflammatory, and die, adding their debris to a growing plaque. Their inflammatory signals attract ever more macrophages, in a feedback loop that accelerates the condition. When blood lipids are globally reduced, so are the problem oxidized lipids to the same degree, putting that much less stress on macrophage populations. But it is far from enough to cure the condition.

In the research noted here, scientists target TGF-β, an important signaling molecule. Of note, a sizable fraction of distressed macrophages are in fact senescent cells. Cellular senescence is an inflammatory state that cells adopt in response to damage or stress, and senescent cells secrete signals that encourage other cells to become senescent as well. TGF-β is prominently involved in the signaling produced by senescent cells, and it is plausible that sabotaging it can help to take some of the pressure off in the stressed environment of plaque-ridden blood vessel walls, in much the same way as reducing the input of oxidized lipids can take some of the pressure off. The degree to which it will be effective is something of an open question until tried in humans, however, as past lines of research into therapies for atherosclerosis have typically demonstrated quite poor correlations in reversal of plaque buildup between mouse models and humans.

Study offers promising approach to reducing plaque in arteries

Current treatments for plaque and hardened arteries, a condition known as atherosclerosis, can slow but not improve the disease. Experts believe that may be due to ongoing inflammation in blood vessels. To understand the factors contributing to this inflammation, the research team focused on a group of proteins, called transforming growth factor beta (TGFß), that regulates a wide range of cells and tissues throughout the body.

Using cultured human cells, the researchers discovered that TGFβ proteins trigger inflammation in endothelial cells - the cells that form the inner lining of artery walls - but not in other cell types. With a technique called single cell RNA-seq analysis, which measures the expression of every gene in single cells, they then showed that TGFβ induced inflammation in these cells in mouse models. This finding was notable because TGFβ proteins are known to decrease inflammation in other cells in the body. The researchers also showed that when the TGFβ receptor gene is deleted in endothelial cells, both the inflammation and plaque in blood vessels are significantly reduced.

To test this approach as a potential therapy, the team used RNAi to disrupt TGFß receptors. To deliver the drug only to endothelial cells in the blood vessel walls of mice, they employed nanoparticles. This strategy reduced inflammation and plaque as effectively as the genetic technique. The findings identify TGFß signaling as a major cause of chronic vessel wall inflammation, and demonstrate that disruption of this pathway leads to cessation of inflammation and substantial regression of existing plaque.

Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis

Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined.

Here we show that endothelial transforming growh factor β (TGF-β) signalling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGF-β signalling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These proinflammatory effects of endothelial TGF-β signalling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type-specific therapeutic intervention aimed at control of this disease.

Greater Reductions in Blood Pressure in Hypertensive Patients Further Reduce Stroke Risk

The data reported in this study can be added to the considerable weight of prior evidence showing that greater sustained reductions of blood pressure in hypertensive patients is better for long term health. Blood pressure should be lowered more aggressively than has been the case in the past, in other words. This is old news in some respects. The medical community has already adjusted its recommendations in recent years, reducing the pressure thresholds at which blood pressure is considered harmful and a risk to future health.

Raised blood pressure, hypertension, is very influential on the trajectory of age-related disease. It speeds up the development of atherosclerosis, and makes stroke and heart attack due to rupture of atherosclerotic plaques more likely. It causes a raised rate of rupture in small blood vessels, producing microbleeds that harm delicate tissues in the brain, kidney, and elsewhere. The size of these effects is large enough that forcing a reduction in blood pressure without addressing any of the underlying dysfunction that causes hypertension can still produce benefits.

The better path forward, however, would be to address the causes. This approach should be easier, in sense of being more efficient, more cost-effective, and also produce more extensive benefits by reducing the impact of all of the other problems that those underlying causes produce. Damage to tissues never has just one consequence. What causes hypertension? To a first approximation, this is a problem of stiffening of blood vessels. As blood vessels fail to contract and relax appropriately, the feedback mechanisms controlling blood pressure become distorted, resulting in hypertension.

Why do blood vessels stiffen? Because of cross-linking in the extracellular matrix of blood vessel walls, changing its structural properties, particularly elasticity, and separately because of loss of elastin in the extracellular matrix. Because senescent cells and other sources of chronic inflammation lead to calcification of blood vessel tissue, as well as dysfunction in the smooth muscle cells responsible for constriction. Those smooth muscle cells are further hampered by mitochondrial dysfunction, as illustrated by the point that ways of boosting mitochondrial activity reduce blood pressure in older individuals. There is never just one cause, but all of these causes can in principle be repaired. We just need to build the rejuvenation biotechnologies to do it.

Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke

In 2010, the absolute number of people with a first stroke in the world was 16.9 million, and the number with stroke-related deaths was 5.9 million. Therefore, prevention of primary and secondary stroke is a priority. Elevated blood pressure (BP) is the most relevant and prevalent risk factor for stroke. Reduction in BP is the most effective intervention to prevent both primary and secondary strokes. In clinical trials for primary prevention of cardiovascular events, including stroke, the lower the better seems acceptable for stroke prevention in hypertensive patients, with less than 115 mm Hg suggested as the optimum target level of systolic BP.

After a stroke, lowering BP in the chronic stage reduced the rates of recurrent stroke among both hypertensive and nonhypertensive patients in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). A post hoc analysis of the PROGRESS suggested that the optimum target level of systolic BP for the prevention of recurrent stroke is less than 120 mm Hg. In the Secondary Prevention of Small Subcortical Strokes (SPS3) randomized trial, the BP target was first evaluated in patients with recent stroke. The trial randomly assigned those with lacunar stroke to a systolic BP target of 130 to 149 mm Hg or less than 130 mm Hg, and the authors showed that the use of a systolic BP target less than 130 mm Hg is likely to be beneficial, especially for the prevention of hemorrhagic stroke.

A recent meta-analysis demonstrated that strict and aggressive control of BP with achieved mean systolic and diastolic BP levels less than 130 mm Hg and less than 85 mm Hg, respectively, seemed to be beneficial for secondary prevention. In primary prevention, the Systolic Blood Pressure Intervention Trial (SPRINT) proved the benefit of aggressive BP control, demonstrating that targeting a systolic BP less than 120 mm Hg resulted in lower rates of major cardiovascular events compared with less than 140 mm Hg. Although a pooled analysis of three studies (3632 participants) comparing different systolic BP targets suggested that intensive BP lowering reduced the rate of recurrent stroke, no clinical trials to date have tested the effect of such aggressive BP lowering for secondary stroke prevention.

In the Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study, we herein tested the hypothesis that targeting intensive BP lowering of systolic and diastolic blood BP less than 120 mm Hg and less than 80 mm Hg, respectively, reduces the rate of stroke recurrence compared with a standard BP-lowering regimen. In this randomized clinical trial that included 1263 patients with a history of stroke, intensive blood pressure control to less than 120/80 mm Hg tended to reduce stroke recurrence compared with standard blood pressure control (less than 140/90 mm Hg). When this finding was pooled with the results of prior trials of intensive blood pressure control for secondary stroke prevention in an updated meta-analysis, intensive blood pressure treatment significantly reduced stroke recurrence by 22%.

Attempting a Unified View of Aging and Loss of Regenerative Capacity

Today's open access paper from the AgeX Therapeutics folk discusses a conceptual framework for looking at aging and loss of regeneration in a unified way across: (a) evolutionary differences between highly regenerative lower species such as hydra and less regenerative higher species such as mammals, (b) the loss of regenerative capacity over the course of embryonic development, and (c) the loss of regenerative capacity that occurs with aging in individuals. It covers a lot of ground, and even the summaries could do with a shorter summary.

In essence this all ties back to the work being done at AgeX Therapeutics and elsewhere on the potential uses of induced pluripotency to produce regenerative therapies. The discovery that cells can be reprogrammed into what are essentially embryonic stem cells, known as induced pluripotent stem cells, was made a little over a decade ago. One of the most interesting outcomes of this process is that various markers of age found in the cells in old tissue are reversed. Damaged mitochondrial are cleared, restoring function. Epigenetic decorations characteristic of age are removed. A number of groups are working on ways to very carefully induce reprogramming-like outcomes in cells in the body in order to repair mitochondrial function and restore more youthful behavior.

This clearly cannot fix everything. It won't reverse stochastic nuclear DNA damage, for example. Further, since youthful cells cannot clear many of the forms of persistent metabolic waste that accumulate in and around long-lived cells, we should not expect this to greatly impact cross-linking or issues with dysfunctional lysosomes. We do know that mitochondrial dysfunction is very important in aging, however. It is implicated in the progression of many age-related conditions, particularly those of energy-hungry tissues such as the brain and muscles. It is worth chasing approaches that might effectively restore lost mitochondrial function. The major caveat here is cancer, of course. Methods of inducing pluripotency must be accomplished with great care.

Toward a unified theory of aging and regeneration

The advent of cell biology in the 19th century led to August Weismann's insightful hypothesis that heredity is transmitted by cells belonging to an immortal germ line, and that in most cases, the evolution of complex somatic cells and tissues is associated with a loss of immortal regeneration (somatic restriction) that results in aging. Thus, he correctly predicted the limited lifespan of cultured somatic cells due to cellular senescence. In 1957, George Williams hypothesized that aging evolved through a process of antagonistic pleiotropy, where traits benefitting fecundity early in life are selected for even though they simultaneously lead to age-related deterioration later in life. According to an emerging consensus view of the evolution of aging, primitive organisms showing negligible senescence have not traversed the Weismann barrier (loss of immortality and regeneration), while human somatic cell types cross the barrier early in development leading to downstream age-related change.

While certain evolutionarily primitive metazoans, and perhaps some vertebrates, show no evidence of aging, mammals typically show an exponential increase in the risk of mortality with age. Mammalian aging can be viewed as a global developmental program in many cells and tissues in the body wherein somatic cells are progressively restricted in their capacity for immortal regeneration. Accordingly, these steps begin with the repression of the expression of the catalytic component of telomerase TERT resulting in the antagonistic pleiotropic effect of decreased risk of cancer early in life but a finite replicative lifespan of somatic cells leading to cell and tissue aging later in life. Other genes such as TRIM71 also appear to be repressed at or around the time of the pluripotency transition, and the loss of expression may also play a role in restricting cell division. Moreover, subsequent developmental restrictions may also play a role in the cadence of developmental changes that repress tissue regeneration following the completion of organogenesis and subsequent growth. In summary, widespread gene expression changes, like TERT repression, occur early in the life cycle, in many tissues within the body, and these early changes may have an antagonistic pleiotropic effect later in life leading to tissue disrepair associated with aging.

Increasingly the theoretical framework underlying modern aging research is that progressive developmental transitions occur early in the life cycle that impact tissue regeneration and therefore aging in the body. The theory of somatic restriction highlights the dichotomy of the immortal regenerative potential of the germ-line compared to the terminal mortal phenotype of most differentiated somatic cell types. The theory posits that somatic restriction occurs progressively in stages (pluripotency to differentiating embryo, embryo to fetal, fetal to neonate, and neonate to fully grown adult) and that many of these transitions occur globally in multiple organ systems. This conceptual framework provides a context for more detailed analytical studies of developmentally-regulated molecular pathways that were selected for reproductive fitness early in the life cycle, but result in homeostatic decline and failure of organ systems in aging adults (antagonistic pleiotropy). We conclude that modern molecular approaches to regenerative medicine such as reprogramming cells to pluripotency or partially reprogramming to induce tissue regeneration effectively reverse most markers of aging and have significant potential for clinical application in aging.

Exploiting Senescence Associated β-Galactosidase to Selectively Destroy Senescent Cells

The accumulation of senescent cells with age is an important contributing cause of aging. Senescent cells are created constantly in the body, as somatic cells reach the Hayflick limit, or as a result of injury or toxins or potentially cancerous molecular damage. Near all either quickly self-destruct or are destroyed by the immune system, but a small fraction linger to cause harm over the long term. Senescent cells secrete a potent inflammatory mix of molecules that rouses the immune system to chronic inflammation, degrades nearby tissue structure, and changes the behavior of normal cells for the worse. The more senescent cells present in tissue, the worse the outcome.

Means to selectively remove 25% to 50% of senescent cells, and in only some tissues, reliably reverse aspects of aging and age-related disease in mice. Since the first compelling demonstration in 2011, many studies have been carried out using what have come to be called senolytic drugs. Researchers have demonstrated the ability to turn back Alzheimer's pathology, inflammatory conditions, fibrosis in hearts, lungs, and kidneys, the aging of skin, and many more pathologies characteristic of old age. A great deal of effort is now devoted towards finding new and better approaches to targeting senescent cells for destruction, to build upon the initial therapies.

The work here is an interesting example of the type. As the paper notes, to target senescent cells, one must find a way to interact with one or more mechanisms that are unique to senescent cells. The researchers choose the presence of senescence-associated β-galactosidase, which is still one of the most widely used markers of the senescent state. β-galactosidase is a part of the collection of enzymes that cells use when stressed in order to break down unwanted molecular waste, and senescent cells produce a lot of it. Thus giving cells carefully designed molecules that will be transformed into toxic compounds via the action of β-galactosidase is a potential approach to produce quite general senolytics, capable of destroying all varieties of senescent cells in all tissues.

Galactose-modified duocarmycin prodrugs as senolytics

Recent evidence drawn from genetic models has shown that eliminating senescent cells increases lifespan, improves healthspan, and benefits the outcomes of a wide range of diseases. These studies have led to a collective effort to identify 'senolytics', drugs that selectively kill senescent cells. Several senolytics have been identified including dasatinib and quercetin, piperlongumine, FOXO4 interfering peptides, HSP90 inhibitors, or the Bcl2 family inhibitors ABT-263 (navitoclax) and ABT-737. Currently, Bcl2 family inhibitors have become the gold-standard on senolysis. Bcl2 family inhibitors eliminate a range of senescent cells in vivo and reproduce the effects observed in transgenic mice modelling senescence ablation. However, ABT-263, causes severe thrombocytopenia and neutropenia, what might complicate its use on the clinic. Moreover, it is becoming evident than different senolytics might be necessary to eliminate different types of senescent cells. Therefore, there is a need to identify additional drugs with senolytic properties.

An alternative strategy for targeting senescence, is to exploit properties that differentiate senescent from normal cells. In this regard, the senescence-associated β-galactosidase activity (SA-β-gal) is one of the more conserved and defining characteristics of senescent cells. Senescent cells present an increased lysosomal mass. As a result, senescent cells display elevated levels of lysosomal enzymes such as β-galactosidase or α-fucosidases. Indeed, it has been shown that galacto-oligosacharide encapsulated nanoparticles (GalNP) preferentially release their content on senescent cells. Consequently, this GalNP can be used in combination with different cargos to either image or kill senescent cells.

Galactose-modification has been frequently used to improve the pharmacokinetic properties or the delivery of existing drugs. In addition, galactose modification can be used to generate prodrugs that rely on β-galactosidase for controlled activation. When combined with antibody-linked β-galactosidase, this approach is known as antibody-directed enzyme prodrug therapy (ADEPT). In ADEPT, a conjugate of a tumour-specific antibody and an enzyme, such as β-galactosidase, is combined with the application of a hardly cytotoxic prodrug. By means of the enzyme in the conjugate, the prodrug is selectively cleaved in cancer cells leading to the formation of a highly cytotoxic compound. Several of these galactose-modified cytotoxic prodrugs have been described. A class of such prodrugs are galactose-modified duocarmycin (GMD) derivatives.

Here, we investigated whether galactose-modified prodrugs can preferentially kill senescent cells. We have assessed the senolytic potential of several GMD derivatives and confirmed their senolytic potential in cell culture, ex vivo and in vivo. Given the increasing list of senescence-associated diseases and the positive effects associated with senolytic treatment, we propose GMD derivatives and more generally galactose-modified prodrugs are a new class of senolytic compounds with wide therapeutic promise.

Declines in Limb Muscle Mass Correlate with Higher Mortality in Late Life

Given that resistance training is shown to reduce mortality in older individuals, it makes sense that we would see the opposite effect when looking at low muscle mass in limbs. Skeletal muscle isn't an inert tissue, being quite involved in insulin metabolism, for example, and exercise has all sorts of interesting effects on the operation of metabolism, such as upregulation of beneficial cellular stress response mechanisms. Aging is associated with a progressive loss of muscle mass and strength, with the loss of stem cell activity being a leading cause. This ultimately results in frailty and the condition of weakness known as sarcopenia. In our modern societies of sedentary convenience, this loss is much faster that it would otherwise be if people were more active, and hence the point that resistance training improves matters from the present baseline. That is only the case because most older people do not undertake any sort of effort to maintain muscle mass and strength.

Evaluating body composition, especially appendicular muscle mass, can be an effective strategy for predicting longevity in people over 65 years of age, according to a new study. The appendicular muscles are the muscles that move the appendages or extremities - the arms and legs. They also play a key role in stabilizing the shoulders and hips. The researchers studied a group of 839 men and women over the age of 65 for approximately four years. They observed that all-cause mortality risk increased nearly 63-fold during the follow-up period in women with low appendicular muscle mass and 11.4-fold in men.

"We evaluated the body composition of this group, focusing on appendicular muscle mass, subcutaneous fat, and visceral fat. We then sought to determine which of these factors could predict mortality in the ensuing years. We concluded that the key factor was the amount of appendicular lean mass." Body composition was determined by dual energy X-ray absorptiometry (DXA), also known as bone density scanning, using a densitometer. The study sample comprised 323 men (39%) and 516 women (61%). The frequency of low muscle mass was approximately 20% for both men and women.

Generally, subjects who died were older, exercised less, and suffered more from diabetes and cardiovascular problems than those who remained alive. In the case of the women who died, they also had decreased BMI. The men who died were more likely to suffer falls. All these variables were fed into the statistical model and adjusted for the end-result to show which body composition factor correlated best with mortality risk. Only low muscle mass was found to be significant in the women, considering the adjustment variables, while visceral fat was also significant among the men.

Menopause-related hormone changes may help explain the difference between men and women. "The rapid and significant transition from a protective estrogenic environment to a deleterious hypoestrogenic environment, which is particularly adverse for the cardiovascular system, may make the protective metabolic role of skeletal muscles, including the production of anti-inflammatory cytokines, more important in the postmenopause period. This hormone change is far less abrupt in men."

In addition to their obvious importance in posture, balance and movement, the skeletal muscles have other functions that are essential to the body. They help regulate blood sugar by consuming energy during contraction and maintain the body temperature by trembling when cold. They also produce messenger hormones, such as myokinase, that assist communication with different organs and influence inflammatory responses. The good news is that sarcopenia is preventable and can even be reversed by physical exercise, especially muscle toning. Attention to protein ingestion is also recommended.

Potentially Damaging Ossified Particles Discovered in the Aging Bloodstream

Calcification is the inappropriate deposition of minerals into tissue, altering structural properties to cause a loss of elasticity. It is a feature of the aging cardiovascular system, in part caused by inflammatory signals and other harmful activities of senescent cells. The growing numbers of senescent cells in old tissues cause changes in the behavior of other cell populations, which leads to greater mineralization of tissues that should normally be flexible. Researchers here uncover another consequence of this process, which is the presence of what are effectively bone particles in the bloodstream. These particles are large enough to cause a variety of damage to blood vessels, and while the size of this effect is unknown, this adds to the existing set very good reasons to try to prevent and reverse calcification in aging tissues.

Blood vessels within bone marrow may progressively convert into bone with advancing age. Examination of these vessels led to the discovery of bone-like particles in the peripheral circulation. The findings suggest that ossified particles may contribute to diseases such as vascular calcification, heart attack, stroke, and inadequate blood supply to the limbs. In fact, some of the ossified particles are large enough to clog the smallest blood vessels in the vascular tree.

Approximately 610,000 people die each year from a heart disease-related event, making it the leading cause of death for both men and women in the United States, according to the Centers for Disease Control and Prevention. Vascular calcification is a common characteristic and risk factor for morbidity and mortality. These bone-like particles are potentially more dangerous because of their sharp edges. "Some of the ossified particles have sharp tips and edges that could damage the lining of blood vessels. This damage could initiate events leading to atherosclerosis, which can restrict blood flow over time. When looking for etiologies related to vascular calcification, heart attack and/or stroke, perhaps we should consider if and how ossified particles contribute to these diseases. We will examine these possibilities."

Pressure Damage to Capillaries and Surrounding Cells in the Brain as a Contributing Cause of Cognitive Decline

Progressive arterial stiffness with age causes hypertension, a state of chronically raised blood pressure, which in turn damages sensitive tissues in the brain and other organs. Over time that means a loss of function and cognitive decline. Researchers here suggest that even without the increase in blood pressure, stiffness in larger blood vessels will redistribute pressure in a way that will harm cells near to smaller capillary vessels. What causes arterial stiffening? A combination of damage and dysfunction such as, for example: persistent cross-links degrade elasticity in the extracellular matrix of blood vessel walls; senescent cells and the chronic inflammation that they cause creates calcification of tissue, as well as poor function of smooth muscle tissue responsible for blood vessel constriction and dilation; mitochondrial dysfunction in smooth muscle cells also contributes.

The fact that human memory is deteriorating with increasing age is something that most people experience sooner or later, even among those who avoid diseases such as Alzheimer's. Similarly, a connection between the ageing of the brain and the body is well known. However, the exact nature of this association is not known. Researchers have created an explanatory model that starts with the heartbeat, and carries through the largest arteries in the body all the way to the finest vessels in the brain. An important feature of the model is that it provides a rationale why some cognitive processes may be particularly at risk for the proposed mechanism.

As the human body ages, large arteries, such as the aorta, stiffen and lose a large portion of their ability to absorb the pressure increase generated as the heart ejects blood into the arteries. Such pressure pulsatility is instead transmitted to smaller blood vessels, for example those in the brain. The smallest blood vessels in the brain, the capillaries, are subjected to an increased stress that causes damage to cells within and surrounding the capillary walls. These cells are important in the regulation of the capillary blood flow. If the smallest blood vessels are damaged, this is detrimental to the ability to increase the blood supply to the brain when coping with demanding cognitive processes.

According to the researchers' model, the hippocampus in the brain is particularly vulnerable. The structure in that part of the brain is important for the episodic memory, that is, the ability to remember events from the past. The vulnerability of the hippocampus relates to the fact that it is located close to the large vessels and thus is exposed to the increased load early in the chain. In a young and healthy person, the pulsations are soft, but in an ageing person the pulsations can be so powerful that they affect the brain tissue and can damage the blood supply to memory processes.

Frailty as a Manifestation of Oxidative Stress

Oxidative stress is the name given to the presence of an overly large number of oxidative molecules in cells and tissues, a state that results in damage to protein machinery and degraded function as chemical reactions take place at a faster pace than altered proteins can be replaced. Oxidative stress is a feature of aging, resulting from mitochondrial dysfunction and processes related to chronic inflammation, among other issues. This open access paper discusses oxidative stress in connection with age-related frailty, but is non-committal on where in the chain of cause and consequence, from root causes to final manifestations of aging, oxidative stress is to be found. This is a problem in the field: without some view on which causes result in which consequences in aging, how to steer the research community towards the exploration of effective therapies, those that address causes rather than patching over consequences?

The free radical theory of aging connected oxidative stress with the aging process and aging-related diseases. Although this theory failed to completely explain the aging process, the prominent role of oxidative damage in the decline of function coursing with aging in different tissues is widely accepted. An imbalance between pro-oxidant and antioxidant species would result in oxidative molecular and cellular damage. However, despite their well-known deleterious role, it is now recognized that reactive oxygen species (ROS) are key physiological signaling molecules with regulatory functions. Physiological elevation of ROS generates responses that contribute to cellular hormesis while unmodulated excessive amount of ROS is what results in oxidative damage of molecular and cellular structures. In fact, adequate ROS signaling induces endogenous defense mechanisms and mitohormesis and would explain some contradictory adverse clinical outcomes obtained with antioxidant supplementation.

Oxidative stress has been proven to be associated with age-related diseases. In fact, oxidative stress is related to unsuccessful aging outcome rather than to the aging process by itself. This led us to hypothesize that, as a common background, oxidant injury contributes to functional decline in different tissues and organs and, depending on resilience of these systems, specific clinical alterations are manifested. For instance, specific isolated age-related exhaustion of functional reserve in brain would lead to cognitive impairment while dysfunctional kidney could result in chronic kidney disease, dysfunctional cardiovascular system in cardiovascular disease or dysfunctional lung in chronic obstructive pulmonary disease. In contrast, frailty status would involve a multisystemic failure that results in a condition prone to disability and mortality.

Although the association of frailty and sarcopenia is consistent, the fact that sarcopenia is absent in a significant proportion of frail subjects suggests that frailty and sarcopenia are related but distinct phenotypes of aging. We might consider sarcopenia as a clinical manifestation related to skeletal muscle dysfunction where oxidative stress seems to play a key role. This does not mean that the frailty phenotype in the absence of sarcopenia is unrelated to oxidative stress. In fact, aging-related diseases that could contribute to frailty development share oxidative stress as a common factor in their pathophysiological background. In this sense, there is substantial evidence of the important role played by ROS in the context of unsuccessful aging in organs and systems outside skeletal muscle, including vascular system, kidney, lung, metabolism, and nervous system.

It is important to highlight that aging-related diseases that favor the manifestation of frailty phenotype should not be considered isolated entities but interconnected clinical manifestations with multidirectional relationships and common pathophysiological environments such as oxidative damage. Thus, oxidative stress-related multisystem dysfunction could result in the performance deficit associated to frailty phenotype either including or not sarcopenia phenotype. Mitochondrial dysfunction related to oxidative stress is a key event in this process that affects skeletal muscle but also other tissues promoting the development of age-related diseases and frailty.

Destroying CD163 Tumor Associated Macrophages Allows the Immune System to Better Attack a Cancer

Cancers tend to subvert portions of the immune system into aiding and protecting growth of tumors. The innate immune cells known as macrophages are involved in growth and regeneration, and populations of macrophages resident in tumors become a part of the cancer process. Some of these macrophages have clear surface markers, and can thus be targeted for destruction. Researchers here demonstrate that doing this allows the rest of the immune system to more aggressively attack a tumor. This class of approach may turn out to be quite effective when combined with other forms of immunotherapy that are focused on making T cells more aggressive and capable of destroying cancerous cells.

A new form of immunotherapy that has so far been tested on mice makes it probable that oncologists in the future may be able to treat some of the patients who are not responding to existing types of immunotherapy. Instead of attacking the cancer cells directly, the new technique target and remove a subtype of immune cells known as macrophages, after which the immune system begins to attack the cancer. "We've studied what happens to the tumour when it is exposed to targeted treatment that removes precisely ten per cent of the macrophages that are supporting the cancer tumour instead of fighting it. The most important result is that the depletion of this specific type of macrophage causes the tumour to shrink, which is triggered by a subsequent mobilisation of new macrophages and, ultimately, also an activation of T cells which attack the tumour."

The type of macrophages which the researchers have removed express a specific receptor, CD163, on the cell surface. Unlike other macrophages, these are known to have an undesirable effect in connection with cancer. Instead of recognising cancer cells as unwanted tissue, the macrophage sees the tumours as normal tissue that needs help with regeneration. It is also widely recognised that survival rates are worse if there are many macrophages that express the CD163 receptor in the tumour.

"Our study suggests that the macrophages we're hitting function as a kind of 'peacekeeping' force that keeps the 'attackers' away. When the peacekeeping macrophages in the tumour are removed, the attackers can instead be mobilised, after which the T cells and a number of other macrophages collaborate to attack the tumour. What is interesting is that the whole thing happens by itself as soon as we remove the tenth of the macrophages that express CD163, and that these appear to want to 'decide' which immune cells can be allowed to get into and out of the tumour."

Work on Senolytic Rejuvenation Therapies Begins to Attract More Mainstream Notice

This popular science piece on the development of senolytic therapies capable of clearing harmful senescent cells from aging tissues is a cut above the average. It is important to see more publicity for this line of work. Not because it will aid the industry, but because the more attention that is given to the field, the faster that existing senolytic treatments such as the dasatinib and quercetin combination will become available through off-label prescription and physician networks. Tens of millions of patients with inflammatory age-related diseases caused in part by senescent cells, and the many cancer survivors with high burdens of senescent cells due to chemotherapy, and diabetics whose condition is mediated by senescent cells, and the obese whose visceral fat tissue spurs cellular senescence might benefit in the US alone, if they only knew that senolytics exist today.

The choice on whether to try now or wait for more human data for dasatinib and quercetin (or fisetin, or piperlongumine, or other easily obtained senolytics) should be one that people are permitted to make, not one they remain ignorant of because nobody bothered to tell them that it exists. My one complaint about the content of this article is that the author does conspicuously fail to mention that it is possible to obtain access to the first senolytic treatments today, at very low cost, and that older people in the self-experimentation community are indeed choosing to do this.

Imagine if instead of a pill you could take to live for ever there was a pill that could push back the ageing process - a medicine that could stave off the frailty, osteoarthritis, memory loss, macular degeneration, and cancers that plague old age. It could happen, with the science of senolytics: an emerging - and highly anticipated - area of anti-ageing medicine. Many of the world's top gerontologists have already demonstrated the possibilities in animals and are now beginning human clinical trials, with promising results. If the studies continue to be as successful as hoped, those who are currently middle-aged could become the first generation of oldies who are youthful for longer - with a little medical help.

Researchers are at work on senolytics, a branch of medicine that targets senescent cells; the various faulty cells that have been identified as instrumental in our eventual demise. These so-called "zombie" cells linger and proliferate as we age, emitting substances that cause inflammation and turn other healthy cells senescent, ultimately leading to tissue damage throughout the body. In 2011 a team showed that "using a genetic trick to get rid of these senescent cells can significantly improve health and lifespan" in prematurely aged mice. In 2016, the same group achieved similar results in naturally aged mice, releasing an arresting image of two elderly rodents born of the same litter. The one cleared of its senolytic cells seems spry and glossy, while its sibling is shrunken, greying and looks its age.

A new company, called Unity Biotechnology, was formed to raise funds to develop medicine that could safely clear zombie cells from the human body. Trials in senolytics are initially targeting specific conditions such as age-related macular degeneration, glaucoma, and chronic obstructive pulmonary disease (which includes emphysema). Most are in the fledgling stages, working on rodents or human tissue in petri dishes, although in February a small early human trial showed an improvement in the distance patients were able to walk. Also this year, a pre-clinical pilot trial for injecting a senolytic drug into the knees of people with osteoarthritis showed promising, if mixed results. It is hoped that, eventually, there will be a number of senolytic drugs that could potentially target different senescent cell types, but currently much of the research has involved a combination of a leukaemia drug called dasatinib and quercetin, a polyphenol common in plants.

Senolytics are particularly exciting because "they seem to still work very late in life. So it will be possible to study more quickly whether they actually work in humans, and they are applicable to people already at the end of their lives." In theory at least, it should prove impossible to build up a resistance to the drugs, "because senescent cells cannot proliferate". Even more importantly, there is significant data to show "that you don't have to treat these patients every single day. You just treat them once a week or once a month. Intermittent treatment is more than enough to have huge benefits." These aren't the only potential added benefits. Senescent cells "play a big role after cancer treatment", developing as a result of chemotherapy and radiation therapy. "If senolytics can be used to help eliminate the damaged cells before they can spread, a detrimental side-effect of cancer treatment could be alleviated."

Senescent Cells Mediate Much of the Pulmonary Dysfunction Generated by Smoking

Cells become senescent in response to a toxic, damaging environment. This is a first line of defense against the possibility of cancer. Senescent cells cease replication and begin to secrete a potent inflammatory mix of signals that usually serves to attract immune cells to destroy them, if they don't manage to self-destruct via their own programmed cell death processes. Unfortunately, the immune system becomes ever less functional with age, and thus lingering senescent cells will accumulate in ever greater numbers. This is probably why many of the progressive lung conditions arising from a toxic environment, such as that produced by smoking, tend to arise at a later age.

Researchers here show that a sizable fraction of the pulmonary dysfunction arising from smoking is mediated by the actions of senescent cells in lung tissue, which in turn suggests that senolytic therapies presently under development for age-related diseases will greatly reduce the consequences of smoking and other forms of particulate exposure. Not that is will ever make it smart to stab yourself repeatedly, just because you know that hospital staff can patch up the injury.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, and can be characterized as a disease of accelerated pulmonary aging. Characteristics of COPD include inflammation, tissue remodeling, and emphysematous alveolar destruction, leading to enlarged air spaces with less surface area capable of gas exchange. Lung exposure to contaminants and pollutants are risk factors for COPD, including cigarette smoking (CS). Aside from smoking cessation, no therapeutic intervention has been identified and research continues to investigate the molecular mechanisms driving disease progression.

Many of the pathological processes identified in COPD are mediated by CS, including altered homeostatic apoptosis proliferation, production of extracellular matrix (ECM)-degrading proteases and oxidative stress, as well as telomere dysfunction, leading to the activation of the DNA damage response pathway and ultimately cellular senescence. Senescent cells produce and secrete numerous harmful pro-inflammatory and degrading mediators, collectively called the senescence-associated secretory phenotype (SASP). SASP proteins have been shown to be upregulated in pathologies related to accelerated aging and are known to perpetuate inflammation and tissue remodeling in COPD. Development of effective therapeutics to combat senescent cells may provide clinical benefit.

A universal marker for cell senescence does not exist but most senescent cells express p16 (p16ink4A), a cell cycle inhibitor that targets cyclin-dependent kinases (CDKs) and is important in wound healing and tumor suppression. Removal of p16+ senescent cells has been shown to be an efficient way of extending healthspan and reversing senescence-associated pathologies. In the current study, we hypothesized that p16 plays a role in the pathological processes associated with smoking and COPD, and that deletion of p16 protects the lung from the development of emphysematous-like tissue remodeling. We examined human lung tissue from COPD patients and normal control subjects, and found a substantial increase in p16-expressing alveolar cells in COPD patients. Using a transgenic mouse deficient for p16, we demonstrated that lungs of mice lacking p16 were structurally and functionally resistant to CS-induced emphysema due to activation of IGF1/Akt regenerative and protective signaling.

Fat Tissue Surrounds Skeletal Muscle to Accelerate Atrophy in Aging and Obesity

Researchers here show that the fat tissue surrounding skeletal muscle that is observed in older and obese individuals contributes to declining muscle mass and strength. The most compelling evidence arises from transplantation of fat tissue between mice, showing that it produces harmful effects. The researchers further suggest that cellular senescence is an important factor in this process, which dovetails nicely with what is known of the way in which excess visceral fat tissue accelerates aging. The presence of larger than usual amounts of visceral fat increases the number of lingering senescent cells in the body, and senescent cells broadly disrupt tissue structure and function via their inflammatory signals. The accumulation of senescent cells with age is now accepted as a contributing cause of aging, and an energetic industry aiming to produce senolytic therapies capable of selectively destroying these cells is presently in its initial stages of growth.

Sarcopenia due to loss of skeletal muscle mass and strength leads to physical inactivity and decreased quality of life. The number of individuals with sarcopenia is rapidly increasing as the number of older people increases worldwide, making this condition a medical and social problem. Some patients with sarcopenia exhibit accumulation of peri-muscular adipose tissue (PMAT) as ectopic fat deposition surrounding atrophied muscle. However, an association of PMAT with muscle atrophy has not been demonstrated.

Here, we show that PMAT is associated with muscle atrophy in aged mice and that atrophy severity increases in parallel with cumulative doses of PMAT. We observed severe muscle atrophy in two different obese model mice harboring significant PMAT relative to respective control non-obese mice. We also report that denervation-induced muscle atrophy was accelerated in non-obese young mice transplanted around skeletal muscle with obese adipose tissue relative to controls transplanted with non-obese adipose tissue.

Notably, transplantation of obese adipose tissue into peri-muscular regions increased nuclear translocation of FoxO transcription factors and upregulated expression of FoxO targets associated with proteolysis (Atrogin1 and MuRF1) and cellular senescence (p19 and p21) in muscle. Conversely, in obese mice, PMAT removal attenuated denervation-induced muscle atrophy and suppressed upregulation of genes related to proteolysis and cellular senescence in muscle. We conclude that PMAT accumulation accelerates age- and obesity-induced muscle atrophy by increasing proteolysis and cellular senescence in muscle.

TAME Trial for the Effects of Metformin in Humans to Proceed this Year

Researchers and advocates have been trying for some years to launch the TAME trial to assess the effects of metformin on aging in humans. This is not with the hope of producing meaningful effects on the progression of aging. Metformin has a small effect size, being one of the less effective interventions that upregulates cellular stress responses, a strategy that in and of itself is weak in long-lived species such as our own. The goal is to push the FDA into accepting clinical trials that target mechanisms of aging rather than a specific named age-related condition. Metformin was chosen because its safety profile, widespread use, and length of time as an approved drug make it hard for the FDA to object on technical grounds.

I view this whole exercise as an example of the harmful distorting effect of regulation on progress in medicine: years of effort and tens of millions in funds will be wasted on an exercise that everyone involved knows will produce only tiny gains in health and longevity at the end of the day. In a sane world, those resources could have gone towards far more effective projects, those with a much greater expectation of extending healthy human life span and producing rejuvenation in the old.

After closing the final 40m of its required 75m budget with a donation from a private source, the first drug trial directly targeting aging is set to begin at the end of this year, lead researcher Dr Nir Barzilai has revealed. Back in 2015, when his revolutionary anti-aging trial TAME finally received FDA approval, it would have been forgivable to think that Dr Barzilai had, at last, got past the hard part. But TAME went into financial limbo, with many wondering if it would ever be able to escape. His trial TAME (Targeting Aging with Metformin) had been stalled for four years while he and his colleagues engaged in funding negotiations with the US NIH (National Institute of Health). "It was down to their conservative approach over there. They really didn't understand what we were trying to achieve."

For those accustomed to judging the success of a drug trial's funding acquisition by the safety and efficacy record of its drug, TAME's funding difficulties could look confusing. Safely used and widely prescribed, the trial's antidiabetic drug, metformin, has been US FDA approved since 1994. Its use in medical practice extends back into the Middle Ages, where it was extracted from the French lilac and later in France from the 1950s onwards, when the isolated compound was first successfully administered to diabetic patients.

But it is much more the trial structure, rather than the drug itself, that is on trial. Instead of following a traditional structure given to FDA approved trials (that look for a single disease endpoint) TAME has a composite primary endpoint - of stroke, heart failure, dementia, myocardial infarction, cancer, and death. Rather than attempting to cure one endpoint, it will look to delay the onset of any endpoint, extending the years in which subjects remain in good health - their healthspan.

In a retrospective 2014 analysis of 78,000 adult type 2 diabetics in their 60s, those who took metformin lived longer, on average, than healthy controls of the same age. This has led a growing body of doctors beginning to prescribe the drug off-label, so that their patients may benefit from its purported anti-aging effects. Such widespread speculation demands deeper scientific investigation. It is TAME's composite primary endpoint, created with the cooperation of the FDA, that excites Barzilai and his colleagues. They hope that Big Pharma will use it to develop drugs with even more powerful anti-aging effects.

Resistance Exercise Builds Muscle Equally for Both Sedentary and Athletic Older People

Older people should undertake resistance exercise, as it has been shown to reduce risk of mortality and age-related disease. Most older people do not do this, and are therefore living with unnecessarily poor health and prospects. In this context, it is interesting to see the data presented here, in which researchers show that overall level of fitness and training in older people has no effect on the ability of resistance training to produce added muscle in a previously untrained part of the body. Yes, there are all sorts of declines relating to muscle tissue function that take place during aging, but a sedentary individual is no worse off than a fit individual in this particular aspect of muscle physiology. Thus it is is never too late to start a program of resistance exercise in order to obtain benefits to health, even if one has been sedentary throughout life.

Skeletal muscle is vital for the maintenance of physical function, nutrient deposition, and basal metabolism. Aging leads to a progressive loss of skeletal muscle, termed sarcopenia, which progresses at a rate of 0.5-1% per annum from the 5th decade, alongside 3-5-fold greater reductions in strength. Accordingly, sarcopenia may drive the development, and progression, of many adverse age-related health events and force a dependence on external healthcare services. Sarcopenia progression is thought to be underpinned by inherent aging factors (i.e., hormonal changes) and aggravated by environmental and lifestyle factors (i.e., poor nutrition, obesity, and reduced activity), that blunt the muscle protein synthesis (MPS) response to normally robust anabolic stimuli, such as hyperaminoacidemia and resistance exercise.

This age-related muscle "anabolic resistance" may be underpinned by impairments in translational efficiency in the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. Whilst resistance exercise (RE) is effective at enhancing muscle anabolic sensitivity and augmenting muscle mass and strength in older individuals, myofibrillar adaptive remodeling responses are attenuated compared with younger individuals. However, chronic structured exercise training is known to alter acute muscle protein turnover rates in young and older individuals. Therefore, commencing exercise training in early adulthood, and continuing this practice through middle-to-older age, may offset or delay the onset of muscle anabolic resistance, with implications for age-related muscle loss.

Highly active older individuals who have maintained structured exercise training habits, Master Athletes (MA), display superior indices of physiological function (VO2max and strength), muscle morphology and, typically, a more favorable body composition than their untrained age-matched counterparts (OC). The only study to date to investigate MPS in MA, reported that highly trained master triathletes (older than 50 years) displayed lower MPS rates following a bout of downhill running than younger triathletes. However, rested-state MPS was not measured, preventing firm conclusions regarding the net MPS response to the exercise stimulus. The aim of the present study was to compare 48 hour rested-state and RE-induced integrated myofibrillar protein synthesis (iMyoPS) rates between MA and age-matched untrained individuals and to establish the acute intramuscular signaling response to an acute bout of RE contraction.

Our findings demonstrate no discernible difference in rested-state or exercise-induced iMyoPS rates between MA and OC. Furthermore, we observed no clear difference in the mTORC1-mediated signaling response to exercise between MA and OC. Taken together, these data suggest that despite divergent long-term exercise habits in MA, OC possess a similar capacity to upregulate intramuscular signaling and iMyoPS in response to unaccustomed exercise contraction.

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