Top Tips to Relieve Hemorrhoids

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Although they aren’t life-threatening, hemorrhoids may be painful and affect your daily activities.1 They more often affect adults from 45 to 65 years old, but younger adults and children may experience them as well. While they are common in both women and men, women have an increased risk during pregnancy, due to the pressure of carrying the baby and straining during delivery.2

In one retrospective study3 using reimbursement claims data from 33,034 patients in Taiwan, researchers evaluated the relationship between hemorrhoids and the subsequent development of coronary heart disease. Over a 12-year follow-up, the researchers found those with hemorrhoids experienced a 127% higher risk of coronary heart disease compared to those without hemorrhoids.

According to the National Institute of Diabetes and Digestive and Kidney Diseases,4 it’s estimated half the people in the U.S. will have hemorrhoids by age 50. Aside from age and pregnancy, other risk factors for developing hemorrhoids include activities that increase your abdominal pressure, such as straining during a bowel movement, lifting heavy objects, obesity or sitting on the toilet for long periods of time.5,6

What Are Hemorrhoids?

To understand how to prevent hemorrhoids and why these tips help alleviate the pain and discomfort associated with them, it’s helpful to know exactly what hemorrhoids are and how they are formed.

Inside the anus and lower rectum are veins. When those inside the wall of the rectum or anus become swollen or inflamed they are called internal hemorrhoids. You can’t usually see or feel these hemorrhoids, but if they become irritated from straining, you may experience bleeding.7

Hemorrhoids may also form under the skin around the anus, called external hemorrhoids.8 When these become irritated they cause itching or bleeding. In some cases, hemorrhoids may not cause symptoms or pain, and you won’t be aware you have them unless a physician does an internal examination. When symptoms do occur, you may experience:9,10

  • Bright red blood after passing stool in the toilet or on toilet tissue
  • An itchy bottom
  • A lump outside the anus, which may need to be pushed back after passing stool
  • Redness, soreness and swelling around the anus
  • Pain or achiness while sitting around your anus

Hemorrhoids are similar to varicose veins in your legs. In other words, the veins bulge and swell, sometimes in response to added abdominal pressure. At other times, you may not be able to identify a cause.11 The swelling causes irritation to the wall of the veins, and the subsequent symptoms.12

Top Tips to Relieve Hemorrhoid Pain at Home

When you are experiencing pain and discomfort from hemorrhoids, it’s likely you’ll want relief as quickly as possible. In some cases, your relief may be as close as your kitchen cabinet.

Use a bidet — Since hemorrhoids are irritated veins, using a bidet is an effective, less irritating and low-cost way to clean your backside after a bowel movement. If you don’t have one installed at home now, there are several do-it-yourself kits that make installing one on your current toilet safe and simple.

Soften your stool — Since hemorrhoids are aggravated by straining during a bowel movement, it’s important to keep your stool soft. An important strategy is eating enough dietary fiber. Fiber comes in two types: soluble, which easily dissolves in water, and insoluble, which doesn’t dissolve but stays intact as it moves through your colon.

Both are important for digestion. I believe 50 grams of fiber for every 1,000 calories is ideal to maintain optimal health, but most Americans don’t get nearly this much.13

Taking an organic psyllium dietary fiber supplement daily, which contains both soluble and insoluble fiber, may assist in softening your stool and has benefits for your cardiovascular system, weight control and blood sugar support.

Stay hydrated — Constipation results in hard dry stool that is difficult to pass and irritates your rectum. One of the more common causes is dehydration. Staying hydrated is a key component of optimal health and, according to a Harvard study,14 54.5% of children and adolescents are chronically dehydrated. This has repercussions for health and academic performance.

Urine concentration and color is one of the best ways to track your individual hydration status from day to day. Ideally you want to drink enough pure, filtered water to turn your urine a light-colored yellow. This may mean drinking more, or less, than the often-repeated eight 8-ounce glasses of water per day, giving your body enough fluid to properly form stool and detoxify waste products.

Try a potty stool — If you live in the U.S., it’s likely you haven’t put much thought into the best position to be in while having a bowel movement. However, sitting on a toilet is not the best position and may contribute to difficulty defecating, leading to hemorrhoids and other problems such as urologic disorders, rectal prolapse and anal fissures.15

Squatting places your digestive system in an anatomically correct position to improve elimination and reduce constipation. Squatting on top of the toilet requires strength, flexibility and balance. Another option is to use a simple footstool to help get into a squatting position.

Limit your time on the toilet — Sitting on the toilet for long periods of time places additional pressure on hemorrhoids, increasing irritation to the veins and, therefore, your symptoms. Limit your time on the toilet to only what is needed to complete your bowel movement.

Apply cool witch hazel — While there isn’t scientific evidence for use, witch hazel has been a home treatment of choice for decades. The Cleveland Clinic16 reports it contains tannins and oils that may help bring down inflammation and some say it tightens the skin as a natural anti-inflammatory.17

Natural witch hazel is an astringent that helps the tissue shrink and has antioxidant properties, according to one study.18 It helps to reduce pain, itching and bleeding until the hemorrhoids fade, but provides only symptom relief and cannot speed healing.

Some find greater relief when the witch hazel is cooled in the refrigerator. Do not dilute witch hazel with alcohol as this may dry and irritate the tissue. Add a small amount to a cotton swab and dab the witch hazel on the hemorrhoid.

Aloe vera — Aloe vera has anti-inflammatory properties and some over-the-counter hemorrhoid creams and pads are impregnated with aloe vera to help soothe the inflammation of the engorged veins.

The Cleveland Clinic19 reports there is no current research available for its use with hemorrhoids, but aloe vera has demonstrated benefit for other inflammatory skin conditions, and they recommend trying it, provided it’s pure aloe and not used in a cream or pad with other ingredients.20

Epsom and glycerin — This home treatment may help painful hemorrhoids and is simple to compound at home.21 Mix 2 tablespoons of Epsom salts with 2 tablespoons of glycerin. Place on a gauze pad over the painful area and leave it in place for up to 20 minutes. Repeat every four to six hours until the pain eases.

Coconut Oil — This natural moisturizer also has anti-inflammatory properties. Applying coconut oil may help reduce irritation and swelling and may help reduce your urge to scratch.22

Ice packs — Ice packs and cold compresses may help combat the pain, inflammation and swelling. Do not apply ice cubes directly to the skin; first wrap them in a small towel to prevent skin damage. Leave them in place for about 15 minutes and continue to use them every one or two hours until the pain subsides.

Loose fitting clothing — You may support healing by wearing loose-fitting clothes that don’t rub the area. It helps to prevent the hemorrhoids from becoming irritated by excess sweat and reduces symptoms.

It’s All in How You Sitz

The word sitz comes from the German verb “sitzen” mean which means “to sit.”23 A sitz bath was also called a hip bath and is a type of soaking done to include only the hips and buttocks. The purpose was to speed healing for patients who had undergone rectal surgery, or experienced hemorrhoids, uterine cramps or prostate infections.24

Warm sitz baths are one of the easiest and effective ways to reduce the pain of hemorrhoids. They are a European tradition in which only the pelvis and abdominal area are submerged in water. Others have used a cool sitz bath to help reduce constipation or tone the muscles of the bladder or bowel.25

On some occasions, you may feel dizzy when getting up from a hot sitz bath, but when using them for hemorrhoids, the water should be warm and not hot. A sitz bath may help relieve the itching, irritation and spasms of the sphincter muscle occurring with pain from hemorrhoids.

Small plastic portable tubs that fit over the toilet seat may be used, or you may use a regular bathtub with a few inches of warm water. Many experts recommend a 20-minute bath after each bowel movement, in addition to another two or three during the day to relieve hemorrhoids.26

Afterward, gently pat the area dry. Do not rub as it irritates the hemorrhoid. Alternatively, you may want to use the cool air from a hair dryer to dry the area. Soaking in mild temperature water helps to speed the healing process by boosting blood supply. It doesn’t cure the condition, but it will help reduce irritation.

Refrain from adding shower gel, bubble bath or soap products to the water, as it can cause irritation.27 However, epsom salts in a sitz bath is soothing to the skin and helps reduce irritation and symptoms.

Don’t Use These for Hemorrhoid Pain

In addition to the methods of reducing pain listed above, there are a few things you should avoid doing as they increase your symptoms and discomfort. As mentioned above, steer clear of using any soap products on the area as it dries the skin and increases the risk of bleeding.

Additionally, commercial baby wipes and perfumed toilet paper are irritating and may increase itching and pain. While some have considered using apple cider vinegar, the Cleveland Clinic28 recommends avoiding this as it may burn irritated skin and exacerbate problems over time.

Since there are several other natural strategies to reduce symptoms, it’s wise to steer clear of apple cider vinegar. Tea tree oil is another antiseptic and anti-inflammatory essential oil some recommend to decrease symptoms. However, as this strategy hasn’t been well studied, experts recommend avoiding it.29

Do not wait to have a bowel movement.30 When you prolong the urge to defecate there’s a tendency the stool will become harder and more difficult to pass. This increases pressure, straining and the symptoms of hemorrhoids. Instead, consider setting up a schedule to help establish regular bowel habits. When your hemorrhoids are inflamed and irritated, it’s best to avoid blood thinning medications, such as aspirin, if it all possible, as they increase the risk of bleeding.31

Nonsurgical Hemorrhoid Relief

There are several types of nonsurgical treatments your physician may use to get rid of hemorrhoids. Before undergoing any of them, discuss the pros and cons of each with your physician and be sure you are comfortable with your decision.

One of my favorite preventives is the use of the polyphenolic bioflavanoid rutin which is a more potent derivative of quercetin. It works to heal hemorrhoids naturally by stabilizing and tightening the walls of blood vessels.

Rubber band ligation — This procedure is used in the doctor’s office to treat prolapsing or bleeding internal hemorrhoids.32 During the procedure, a specialized rubber band is placed at the base of the hemorrhoid, which cuts off the blood supply. Within a week, the banded area shrivels and falls off, leaving scar tissue.

While this procedure has the lowest risk of recurrence, it is not suitable for those using anticoagulant medications or who have a bleeding disorder.33 It may also lead to increased bleeding, pain and blood clots or infections. If you have several hemorrhoids, the procedure will need to be repeated. Specialized equipment is used, and the physician will monitor your condition; you should never attempt to do this at home.34

Infrared coagulation — This procedure may be used to address small hemorrhoids. The physician will use a tool that directs infrared light.35 The heat causes scar tissue to form, which eliminates the blood supply and usually shrinks the hemorrhoid. A local anesthetic will be used to reduce your discomfort. With multiple hemorrhoids, you may require multiple treatments. The recovery period takes several days and care must be taken to reduce constipation and straining to prevent reopening the scar.

Sclerotherapy — During this procedure the physician injects a solution directly into the hemorrhoid, triggering a local reaction and ultimately shrinking the hemorrhoid. The procedure is effective and safe for those with cirrhosis who have bleeding hemorrhoids, and is preferred over banding in this case.36

Despite treatment, there’s a risk the hemorrhoids will return after a few years and some experts believe this procedure to be less effective than a rubber band ligation.37

When to See Your Doctor

In most cases, you’ll be able to treat the symptoms of hemorrhoids at home using home remedies. However, you should seek medical care immediately if you experience severe anal pain and bleeding that may or may not be associated with abdominal pain, diarrhea or fever.38

Hemorrhoids may also progress to the point where they become thrombosed. In this situation the hemorrhoid is pushed outside of the anus and is filled with blood clots. This makes everyday activities exceedingly uncomfortable.

The symptoms are similar to hemorrhoids, but the pain and itching will increase, as will the swelling around the anus. Thrombosed hemorrhoids may also become infected and can lead to an abscess, which causes additional symptoms such as fever.39

Acutely thrombosed external hemorrhoids may require additional treatment from your physician. In some cases, they will resolve on their own, but in others it may require surgical intervention, especially if they become strangulated and the tissue begins to die (necrosis).40

The severity of the pain is most intense within the first 48 hours and will usually gradually resolve. As a result, surgical removal is usually offered with severe pain within the first 48 hours, and then only if the hemorrhoid progresses to strangulation and necrosis.41

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Thymic Epithelial Cell Exosomes As a Tool to Regrow the Aged Thymus

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The thymus is where T cells of the adaptive immune system mature: thymocytes are generated in the bone marrow, migrate to the thymus, and become T cells there. Unfortunately, the thymus atrophies with age, and the resultant reduction in the supply of new T cells is most likely an important contributing cause of the age-related decline of the immune system. Over the years, the research community has investigated a broad range of methods by which the thymus might be regrown, most of which focus on providing signal proteins or regulatory proteins in order to spur greater replication and activity of the thymic epithelial cells that carry out the important work of T cell maturation. Researchers here demonstrate a novel approach in this category, using exosomes that home to the thymus and, based on results in cell studies, may then act to spur some degree of regrowth.


Transcription factor FoxN1 is the mastermind of thymus organogenesis and identity, and is also an acknowledged direct molecular target of the glycolipoprotein Wnt4. As a consequence, Wnt4 plays a key role during embryonic thymus development and the maintenance of its identity in adulthood. Thymic epithelial cells secrete less Wnt4, while their Frizzled receptors (Fz4 and Fz6) become up-regulated indicating a potential compensatory mechanism and possibly enhanced Wnt4-binding. This loss of Wnt4 expression weakens thymic epithelial identity and allows for thymic adipose involution to occur. This latter process leads to the expansion of thymic adipose tissue orchestrated by transcription factor PPARgamma. The Wnt/b-catenin pathway and PPARgamma have been reported to act as mutual inhibitors of one another in several tissue contexts, including the thymus. We have previously shown that the addition of exogenous Wnt4 reinforces thymic epithelial identity and confers resistance in a steroid-induced model of senescence through suppressing PPARgamma.

Recent publications of various tissue contexts have suggested that Wnt molecules (including Wnt4) travel in conjunction with extracellular vesicles (EVs), more specifically exosomes. It has also been reported that a significant portion of the Wnts – including Wnt4 – may actually be displayed on exosomal surfaces. EVs are released by most cell types of all phyla and mediate various biological effects. Biological functions attributed with exosomes encompass several physiological and pathological conditions, including cell and tissue regeneration. The thymus epithelium has also been reported to be a rich source of exosomes with key immunological relevance e.g., in thymocyte selection. Yet to date, TEC (thymic epithelial cell) exosomes have not been linked with thymus tissue regeneration.

Our goal was to evaluate the Wnt4 and miR27b levels of Wnt4-transgenic thymic epithelial cell (TEC)-derived exosomes, show their regenerative potential against age-related thymic degeneration, and visualize their binding and distribution both in vitro and in vivo. First, transgenic exosomes were harvested from Wnt4 over-expressing TECs and analyzed by transmission electron microscopy. For functional studies, steroid-induced TECs were used as cellular aging models in which steroid-triggered cellular aging was efficiently prevented by transgenic exosomes. Finally, DiI lipid-stained exosomes were applied on the mouse thymus sections and also iv-injected into mice, for in vitro binding and in vivo tracking, respectively. In vivo injected DiI lipid-stained transgenic exosomes showed detectable homing to the thymus.

In summary, our findings indicate that exosomal Wnt4 and miR27b can efficiently counteract thymic adipose involution. Although extrapolation of mouse results to the human setting needs caution, our results appoint transgenic TEC exosomes as promising tools of immune rejuvenation.

Link: https://doi.org/10.3389/fimmu.2019.00862

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Epigenetic Changes May Act to Accelerate Progression of Alzheimer's Disease

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Observing epigenetic changes in cells is to observe their reactions to circumstances, as epigenetic mechanisms determine the timing and amount of proteins produced from their genetic blueprints. Protein levels are the switches and dials of the machinery of the cell, determining behavior. These epigenetic changes have consequences, but it is important to remember that they are not root causes. They are a middle portion in a longer process, and thus most likely not the best place to intervene. The present state of technology makes it much easier to examine epigenetic changes than to trace back to root causes, unfortunately, which might tend to bias the medical development emerging from the research community towards less useful approaches.


The primary neuropathological signs of Alzheimer’s disease (AD) are intraneuronal neurofibrillary tangles and extracellular β-amyloid (Aβ) plaques, along with accompanying synaptic and neuronal loss. In general, the distribution of neurofibrillary tangles in the AD brain follows a stereotypic pattern; beginning in the entorhinal/perirhinal cortex, progressing to limbic structures including the hippocampus, and then finally spreading neocortically across the frontal, temporal, and parietal cortex. Loss of neurons and severity of cognitive impairments in AD correspond closely with the burden of tangle pathology.

The neurodegenerative process is also mediated by excessive production and accumulation of Aβ peptides forming plaques. Generation of pathogenic Aβ peptides requires β-secretase (BACE1), which cleaves amyloid precursor protein (APP); the rate-limiting step in Aβ production. Synaptic dysfunction in AD, which is evident long before substantial neuronal loss, has been attributed to elevated BACE1 levels prompting the overproduction of toxic Aβ at synaptic terminals. Recently, it has been demonstrated that Aβ plaques create an environment that enhances the aggregation of tau, which in turn forms intracellular neurofibrillary tangles. Consequently, Aβ and neurofibrillary tangles jointly cooperate in the progression of AD. However, AD is not a normal part of aging and the biological mechanisms causing some individuals, but not others, to develop disease pathology remain unclear.

Epigenetic mechanisms could contribute to AD, as many manifestations of aging, including age-dependent diseases, have an epigenetic basis. Epigenetic marks like DNA methylation regulate gene transcription, are responsive to environmental changes, and show widespread remodeling during aging. Enhancers are genomic elements that modulate the complex spatial and temporal expression of genes, and are subject to epigenetic regulation. Prior genome-wide studies examining DNA methylation changes in the AD brain report a significant overlap between differential methylation and enhancer elements, suggesting that epigenetic disruption of enhancer function contributes to AD. Hence, in this study we perform a genome-wide analysis of DNA methylation at enhancers in neurons from AD brain.

We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated in AD neurons. Methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.

Link: https://doi.org/10.1038/s41467-019-10101-7

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Differential Access to Healthcare has Surprisingly Little Effect on Mortality

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Today’s open access review paper summarizes the results and methodologies of a number of epidemiological studies in which the authors found there to be surprisingly little variation in mortality resulting from unequal access to healthcare. The analysis of data attributes something like 5% to 15% of overall variation in mortality to differences in healthcare access. Lifestyle choices such as smoking, diet, exercise, and obesity are the largest contribution, accounting for perhaps as much as half or more of the total variation in mortality across populations.

What might we conclude from this sort of analysis? One possibility is that access to healthcare is in fact not all that unequal where it really matters, such as treatment of dangerous infectious disease. The truly vital services, those that are proven, low cost thanks to expiration of patents and economies of scale in production, and that have the most significant effects on mortality in specific cases, are available to near everyone in the study populations. That also implies that those paying for more expensive healthcare services are, on average, obtaining little benefit for the added expense, beyond the signaling effects that attend any conspicuous form of high end consumption.

Another possibility, quite familiar to this audience, is that when it comes to age-related diseases, the medical technologies of the past few decades are just not all that good. Treatments have failed to address the causes of aging, and instead took on the impossible task of trying patch over the consequences in a failing system. The result, with very few exceptions, such as treatments to control blood pressure and blood cholesterol, is therapies offering only marginal, unreliable benefits and little impact to mortality. It remains the case that in the matter of aging, maintaining fitness and slimness is more reliable or even more effective than most of what has been offered by medical science over recent decades. Only with the advent of true rejuvenation therapies, those targeting important mechanisms of aging, such as senolytic treatments that selectively clear senescent cells, will this state of affairs begin to change.

Contributions of Health Care to Longevity: A Review of Four Estimation Methods


It is often argued that improvements in population health, and life expectancy in particular, are best pursued via investments in medical services. Over the last few decades evidence has accumulated, showing that more powerful determinants of health and life expectancy lie elsewhere. Making high-yield investments to extend life expectancy requires an understanding of the relative contributions of health care and other determinants of health to health outcomes. It is estimated that a lack of access to medical care accounts for only about 10% of premature deaths. The methodology underlying these estimates, however, remains obscure. In this article we review four different estimates of the contributions of health care to premature mortality and other health outcomes.

The estimates converge around Schroeder’s conclusion that health care accounts for between 5% and 15% of the variation in premature death. The various methods were consistent in showing that social and behavioral factors account for a much higher percentage of the variation in premature mortality than health care does. For example, the McGinnis/Schroeder method estimates that social circumstances account for about 15% of the variance in early mortality. The Wennberg method estimates that social circumstances account for 29% of variability, and the Park model estimates that social effects account for 46%. Similarly, the McGinnis/Schroeder method estimates that behavior patterns account for 40% of the variability in early mortality, the Wennberg method estimates 65%, and the Park method estimates 29%. In sum, these methods indicate that social and behavioral factors account for substantially more of the variability in premature mortality than health care does.

The suggestion that health care services account for only a small percentage of the variation in national life expectancy has important implications. Both personal and institutional health care expenditures are justified by confidence that health care spending enhances longevity and other indices of population health. Efforts to model the value of health care spending often assume that 100% of the variation in health outcomes is attributable to health care services. Even the most sophisticated models assume that 50% of the variation in population health is attributable to health care. Our analyses reaffirm the belief that health care is one component of a larger set of influences on health outcomes.

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HSV-1 Accelerates the Formation of Amyloid Plaques in Mice

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Why do only some people suffer Alzheimer’s disease? The condition appears to be caused in its earliest stages by progressively increased levels of amyloid-β plaques in the brain, and different people have different degrees of this form of damage. Why does amyloid-β accumulate? It may be due to impaired drainage of cerebrospinal fluid, and thus a failure to clear out this and other forms of metabolic waste. In addition, amyloid-β may play a role in the innate immune response to infection. People with persistent infections such as herpesviruses will tend to generate more amyloid-β over time. As supporting evidence for this latter view of Alzheimer’s disease as a consequence of lingering infection, researchers here demonstrate that the herpesvirus HSV-1 is capable of accelerating the formation of amyloid-β plaques in mice.


New research shows that viruses interact with proteins in the biological fluids of their host which results in a layer of proteins on the viral surface. This coat of proteins makes the virus more infectious and facilitates the formation of plaques characteristic of neurodegenerative diseases such as Alzheimer’s disease. Before entering a host cell, viruses are just nanometer-sized particles, very similar to artificial nanoparticles used in medical applications for diagnosis and therapy. Scientists have found that viruses and nanoparticles share another important property; they both become covered by a layer of proteins when they encounter the biological fluids of their host before they find their target cell. This layer of proteins on the surface influence their biological activity significantly.

Researchers studied the protein corona of respiratory syncytial virus (RSV) in different biological fluids. The virus remains unchanged on the genetic level, but acquires different identities by accumulating different protein coronae on its surface depending on its environment. This makes it possible for the virus to use extracellular host factors for its benefit, and many of these different coronae make RSV more infectious.

Researchers also found that viruses such as RSV and herpes simplex virus type 1 (HSV-1) can bind a special class of proteins called amyloid proteins. Amyloid proteins aggregate into plaques that play a part in Alzheimer’s disease where they lead to neuronal cell death. The mechanism behind the connection between viruses and amyloid plaques has been hard to find till now, but researchers found that HSV-1 is able to accelerate the transformation of soluble amyloid proteins into thread-like structures that constitute the amyloid plaques. In animal models of Alzheimer’s disease, they saw that mice developed the disease within 48 hours of infection in the brain. In absence of an HSV-1 infection the process normally takes several months.

Link: https://www.eurekalert.org/pub_releases/2019-05/su-cop052319.php

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Delivery of Mesenchymal Stem Cell Exosomes is Protective Against D-Galactose Accelerated Cardiac Aging in Mice

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D-galactose is used in laboratory studies to accelerate aging in mice. As for any method of accelerating aging, it is really just a way of inducing cell and tissue damage in the hopes that the higher level manifestations of disease and system failure are roughly equivalent. This depends on the distribution and types of damage: natural aging is a given mix, and all of the methods of accelerating aging produce a different mix, sometimes very different. The damage induced by D-galactose isn’t as distant from normal aging as, say, DNA repair deficiencies known as progeroid syndromes: it produces a greater burden of oxidative stress, senescent cells, chronic inflammation, and metabolic dysfunction via a variety of mechanisms. These are all important in normal aging.

Here, researchers show that delivery of exosomes derived from mesenchymal stem cells is protective against the cardiac aging induced in mice by D-galactose. This effect may translate to normal aging, but that must still be tested. The most widely available of present stem cell therapies produce benefits via the signals generated by the transplanted stem cells; these cells die quite quickly rather than integrate into tissues. Given this, why not just deliver the signals? Much of cell signaling is carried via extracellular vesicles such as exosomes, and harvesting exosomes for use in therapy is a somewhat simpler prospect than the transplantation of cells. Thus this is an area of energetic exploration, and we might expect that much of the range of present day stem cell therapies will be replaced in the years ahead with some form of extracellular vesicle therapy.


Aging is a risk factor for cardiovascular disease, and oxidative stress has been considered as a possible mechanism underlying aging-related pathologies. It was hypothesized that oxidative stress is associated with inflammation, which is an important contributor of aging. However, the signaling pathway connecting oxidative stress, inflammation, and aging remains undefined, and there is no effective therapeutic approach to alleviate aging-associated cardiovascular disease. Tumor necrosis factor-α (TNF-α), one of major inflammatory cytokines, is regulated by nuclear factor kappa B (NF-κB). It was reported that ischemic injury triggers the activation of NF-κB, which activates the transcription of inflammatory cytokines such as TNF-α. However, whether NF-κB regulates TNF-α in the aging process is not known.

It is known that mesenchymal stem cells (MSC) can improve heart function after infarction, and the beneficial effect of MSCs is mediated by paracrine factors which are transported by exosomes. Exosomes contain functional miRNAs and long noncoding RNAs (lncRNA) and serve as intercellular shuttles to deliver important messages to alter the gene expression and cellular functions of distant organs. We and others have reported that bone marrow MSC-derived exosomes improve heart function after infarction, and several miRNA-mediated exosomes’ repair functions. However, it is unknown whether exosomes could prevent aging-induced cardiac dysfunction.

Because lncRNAs are more tissue-specific and developmental stage-specific compared to miRNA, we chose to investigate the role of lncRNA in exosomes. More recently, one report showed that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with the aging process. However, it is unknown whether MSC exosomes contain lncRNA MALAT1 and whether lncRNA MALAT1 in exosomes could have a functional role in preventing aging-induced cardiac dysfunction. In this study, we explored whether umbilical mesenchymal stem cell (UMSC) derived exosomes could prevent aging-induced cardiac dysfunction and determined whether the potential mechanism was mediated by the exosome/lncRNA MALAT1/NF-κB/TNF-α pathway.

We discovered that human umbilical cord mesenchymal stem cell- (UMSC-) derived exosomes prevent aging-induced cardiac dysfunction. Silencer RNA against lncRNA MALAT1 blocked the beneficial effects of exosomes. In summary, we discovered that UMSC-derived exosomes prevent aging-induced cardiac dysfunction by releasing novel lncRNA MALAT1, which in turn inhibits the NF-κB/TNF-α signaling pathway. These findings will lead to the development of therapies that delay aging and progression of age-related diseases.

Link: https://doi.org/10.1155/2019/9739258

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Embryonic Stem Cell Exosomes Clear Senescent Cells and Promote Wound Healing

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Skin ulcers and other forms of non-healing wound are a major problem for the elderly. Chronic inflammation, the presence of senescent cells, decline in stem cell function, and other features of aging conspire to degrade regenerative capacity. First generation stem cell therapies have shown some utility in promoting regeneration in older individuals, but it appears that benefits are near entirely mediated by the signals delivered by transplanted cells in the short period of time before they die. Thus, why not just deliver the signals, and skip the cells? This is an easier task from a logistical point of view.

As it turns out, a sizable fraction of signals carried between cells are transported within extracellular vesicles such as exosomes. These are small membrane-wrapped packages containing a highly varied mix of proteins that is yet to be catalogued in any extensive and reliable way. Harvesting exosomes from a cell culture and then delivering them to a patient is a very viable form of therapy, however, with far fewer attendant challenges than delivering cells. In the past few years, researchers have demonstrated benefits in numerous animal studies.

Today’s open access paper is interesting for the effect on senescent cells noted when exosomes are delivered to ulcers in mice. These wounds exhibit significant numbers of senescent cells, and it might be presumed that these cells are disruptive to the healing process. Normally, in young animals, senescent cells are created during the healing process, but are quickly destroyed after delivering pro-growth signals that help to coordinate regeneration. When they linger, however, they instead generate chronic inflammation and interfere in other ways with regenerative processes. After delivery of exosomes, however, there are fewer senescent cells and improved regeneration. Is this reduction in senescent cells because the exosomes cause them to self-destruct, or because they help the immune system to destroy them? That is a question for further research, but it is most interesting to see that we might consider delivery of exosomes from embryonic stem cells to be a senolytic therapy to some degree.

Human embryonic stem cell-derived exosomes promote pressure ulcer healing in aged mice by rejuvenating senescent endothelial cells


Aging is an inevitable biological process. Senescent cells accumulating in various tissues during aging contribute to organismal aging and disrupt wound healing after injury. Pressure ulcer wounds, particularly for elderly populations, have been reported to heal poorly, because of aging-related changes in skin tissue. Stem cells, holding great therapeutic promise for various aging-related disorders, have been demonstrated to accelerate wound healing in aged mice, though the underlying mechanisms remain unclear. And, whether stem cell-derived exosomes could promote wound healing in aged individuals is barely reported. In this study, exosomes from human embryonic stem cells (ESC-Exos) were locally applied to treat pressure ulcer wounds in an aged mice model induced by D-gal treatment. We found that chronic ESC-Exos treatment effectively rejuvenate endothelial cell senescence and promote angiogenesis, enhancing wound healing.

Angiogenesis, the process by which new blood vessels are formed, plays vital roles in wound healing. We have previously reported that the underlying mechanisms of tissue recovery after exosome treatment partly involve exosome-mediated pro-angiogenesis effects, including cutaneous wound healing, ischemic hindlimb injury repair, and bone regeneration. Vascular endothelial cells are major effector cells in the angiogenic process of pressure ulcer healing; aging-related endothelial dysfunction and impaired angiogenesis likely contribute to delayed wound healing in the elderly. And applying anti-aging agents to wound beds could rejuvenate cutaneous cell viability, promote neo-vascularization, and enhance wound healing in aged skin. Thus, rejuvenating endothelial senescent cells and reversing aging-associated angiogenic dysfunction seem to comprise a promising therapeutic approach for wound healing in aged individuals.

In our study, we found that the number of senescent endothelial cells at wound beds was significantly reduced after chronic application of ESC-Exos. Also, D-gal-induced senescence in HUVECs was used to evaluate the rejuvenative effects of ESC-Exos in vitro; we found that endothelial senescence is correlated with a decrease in endothelial function (e.g., proliferative, migrative, and tube formation capacities), which is in accordance with the results of previous research. Moreover, chronic ESC-Exos treatment could reduce the aging hallmarks and recover the compromised function. Thus, the therapeutic effects of ESC-Exos on pressure ulcer healing in aged skin may be mainly attributed to their function in rejuvenating endothelial senescent cells and recovering angiogenic function.

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A Dysfunctional T Cell Population Associated with Impaired Vaccination Response

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When surveying immunological research of the past decade or two, there are many cases in which specific subsets of adaptive immune system cell populations can be identified as problematic or actively harmful in older individuals. This goes beyond the obvious candidates such as senescent and exhausted T cells, and includes such things as the inflammatory T regulatory cells that emerge following heart injury. Researchers here describe another apparently harmful population of T cells associated with a failed influenza vaccine response. Would a targeted removal of these cells help? Since targeted removal of problem immune cells has helped in other circumstances and other studies, it sounds worth a try.


Decline in immune function has been well described in the setting of physiologic aging manifesting as impaired vaccine responses and diminution of antibody (Ab)-secreting cells with reduced numbers of lymph node germinal centers (GCs). CD4 T cells provide help to antigen-primed B cells to undergo proliferation, isotype switching, and somatic hypermutation resulting in the generation of long-lived plasma cells and memory B cells (MBCs).

This help is mediated by a specialized CD4 T-cell subset known as T follicular helper (Tfh) cells, characterized by the expression of CXCR5, which is required for the cells to migrate to the GC. We and others have described a circulating counterpart of CXCR5+ Tfh cells known as peripheral Tfh (pTfh) cells that are easily accessible from patient blood samples and are able to induce B cell differentiation. Studies in healthy adults have documented the importance of pTfh expansion at day 7 or day 28 post vaccination for their association with influenza vaccine response.

In order to understand the Ab response to influenza vaccine and the effect of aging with or without HIV infection, we conducted the present study in young and old HIV+ and HIV-uninfected healthy control [HC] participants who had already been classified as vaccine responders (VRs) and vaccine nonresponders (VNRs) based on their serologic responses to seasonal influenza vaccine. We focused on antigen-specific pTfh (Ag.pTfh). In this study, ex vivo quantitative and qualitative assessment of Ag.pTfh revealed key features of Ag.pTfh that favored vaccine responsiveness. In VRs, magnitude of response was impacted by both quality and quantity of Ag.pTfh cells, and these were compromised in old age in HCs and in young and old HIV+ individuals. In VNRs, in contrast, Ag.pTfh were heavily weighted towards an inflammatory phenotype irrespective of age or HIV status.

Our findings demonstrate that dysfunctional Ag.pTfh cells with an altered IL-21/IL-2 axis contribute to inadequate vaccine responses. Approaches for targeting inflammation or expanding functional Tfh may improve vaccine responses in aging and those aging with HIV infection.

Link: https://doi.org/10.1371/journal.pbio.3000257

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A Review of the State of Stem Cell Therapy for Stroke Patients

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The author of this open access review asks whether or not we can consider stem cell therapy to aid recovery from stroke to be a solved problem. Given that clinical trials are underway, is it just a matter of time and we can all agree that viable treatments exist? Unfortunately matters might not be that cut and dried, and recent clinical trials have failed for reasons that can be hypothesized to center around differences in the production of cells for transplantation. Nothing is ever straightforward in biology and medicine. Further, in the long term, why would we ever want medical technologies that only work after the damage is done? The more desirable goal in regenerative medicine is to prevent the deterioration that causes stroke and other traumatic damage to the brain, and thus never wind up in the position of needing greatly enhanced regenerative capacities.


In the late 1980s, researchers ushered one of the pioneering laboratory investigations in cell therapy for stroke, demonstrating the survival of rat fetal neocortical grafts in ischemic adult rat cortex. Subsequent studies showed that these grafted fetal cells integrated with the ischemic brain received afferent fibers and vascularization from the host intact tissue and responded to contralateral sensory stimulation with increased metabolic activity. Equally promising are the observations that stroke animals transplanted with fetal striatal cells into the ischemic striatum displayed some improvements in a simple cognitive task of passive avoidance, as well as in a more complex water maze learning test.

Over the next four decades of preclinical research, additional evidence of graft survival, migration, differentiation, and functional integration in the ischemic brain, modest anatomical reconstruction, and remodeling of brain circuitry, neurochemical, physiological, and behavioral recovery have been documented. Several mechanisms have also been postulated to mediate the therapeutic effects of cell transplants in stroke; although initially designed as a cell replacement for dead or ischemic cells, the current view puts robust bystander effects of the grafted cells to secrete therapeutic substances.

The recognition that stroke not only affects neurons but also other neural cell types, especially vascular cells, prompted the search for alternative regenerative processes that rescue in tandem neural and vascular cells, under the theme of attenuating the impaired neurovascular unit. Toward stimulating these non-neuronal repair processes, the stem cells’ by-stander effects have been proposed, including the grafted cells’ ability to secrete substances that promote neurogenesis, angiogenesis, vasculogenesis, anti-inflammation, among other therapeutic substances. Over the last five years, additional novel stem cell component-based mechanisms have been demonstrated to accompany stem cell therapy, such as the transfer of stem cell-derived mitochondria, exosomes, microvesicles, and microRNAs into the ischemic area.

Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. This cell-based regenerative medicine remains designated as “experimental” in the clinic. Equally disappointing, two recently concluded clinical trials indicated stem cells are safe but not effective in stroke patients. These failed clinical trials may be due to a loss in translation of optimal laboratory stem cell transplantation protocols to clinical trial designs. The Good Manufacturing Practice (GMP)-manufactured stem cells are likely different from the laboratory-grade stem cells, in that the phenotype and biological properties originally designed to treat a specific disease in the laboratory may now have a different disease indication in the clinic. This highlights the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy.

Link: https://doi.org/10.1002/sctm.19-0076

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Decreased Cerebrospinal Fluid Flow is Associated with Cognitive Decline

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Many neurodegenerative conditions are associated with the accumulation of forms of metabolic waste in the central nervous system, protein aggregates that form solid deposits between or within cells. Tauopathies such as frontotemporal dementia are associated with tau aggregates, synucleinopathies such as Parkinson’s disease with α-synuclein, and amyloidoses with varying forms of amyloid, such as the amyloid-β found in elevated amounts in Alzheimer’s disease patients. Alzheimer’s itself is an amyloidosis that also becomes a tauopathy in its later stages. These protein aggregates and their surrounding halos of harmful biochemistry disrupt normal brain function and, in the worse cases, kill neurons. Eventually they kill the patient.

With the exception of certain inherited conditions, in which cellular biochemistry is broken due to an unfortunate and unlucky mutation, why is it that protein aggregates form in significant amounts only in older individuals? This seems an important question to keep in mind when working towards therapies for neurodegenerative conditions. In Alzheimer’s disease, amyloid-β builds up for a decade or more prior to the point at which its consequences become noticeable. But why? In recent years researchers have found ever more supporting evidence for the hypothesis that impaired drainage of cerebrospinal fluid is an important factor. Metabolic wastes in the brain can be carried away for disposal via the various pathways for drainage of cerebrospinal fluid. These pathways falter or become occluded with age, however, and the degree to which that happens in any given individual may well be an important determinant of risk of dementia.

Several groups are working on approaches to the treatment and prevention of neurodegenerative conditions based on the impaired drainage hypothesis. Some of these lines of work have left the laboratories and entered commercial development. To pick two examples, Leucadia Therapeutics is quite far along towards means of restoring cerebrospinal fluid drainage through the cribriform plate, while EnClear Therapies is working on filtration of harmful metabolic waste from cerebrospinal fluid in a process akin to apheresis of blood. We can hope that these first efforts will be joined by others in the years ahead, and also hope that means of rejuvenation that target the underlying molecular damage of aging will prove to at least partially reverse loss of drainage of cerebrospinal fluid.

Decreased Cerebrospinal Fluid Flow Is Associated With Cognitive Deficit in Elderly Patients


The cerebrospinal fluid (CSF) is an important part of the central nervous system, as it allows exchange of water, small molecules, and proteins between the brain parenchyma and arterial and venous blood, by either passive diffusion or active transport. The CSF therefore plays an important role in regulating brain homeostasis, waste clearance, as well as intracranial pressure and blood supply. During aging, CSF turnover can be disrupted which could contribute to the etiology of age-related neurocognitive disorders. Several studies revealed that patients with Alzheimer’s disease (AD) have disrupted CSF pressure, turnover, and oscillations. Moreover, biomarkers for AD are found in the CSF, and their abundance was shown to have predictive value for clinical progression.

The increase of intracranial pressure during the cardiac cycle causes a flow from the blood and brain interstitial fluid to the CSF, and a net CSF flow toward its extracerebral compartment and venous blood. Since this CSF flow is important for protein clearance from the brain, it is possible that impaired CSF flow could be associated with cognitive decline. Moreover, CSF flow is linked with brain perfusion, defects of which are known causes of neurocognitive disorders in the elderly. A number of studies suggested that the choroid plexus and the ventricular walls degenerate with the progression of AD, but none could determine whether disrupted CSF flow causes cognitive decline, or whether it is a by-product of AD or normal aging.

To the authors’ knowledge, there are no published studies that investigated the relationship between CSF flow alterations and cognitive deficit in the elderly, adjusting for cardiovascular risk factors for the development of neurocognitive disorders. The purpose of this study was therefore to evaluate the association of CSF flow in the brain ventricles and cervical spine with cognitive deficit in a cohort of elderly patients admitted to our geriatric unit for non-acute reasons. The hypothesis was that reduced CSF flow would be associated with cognitive deficit.

The cohort comprised 71 women and 21 men, aged 73 to 96 years. Patients with lower CSF flow had significantly worse memory, visuo-constructive capacities, and verbal fluency. It is therefore possible that CSF flow alterations are responsible for at least a part of the cognitive deficit observed in our patients. Better diagnosis and treatment of CSF flow alterations in geriatric patients suffering from neurocognitive disorders is therefore recommended.

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