Is α-synuclein, Like Tau, Driven to Aggregate by the Activities of Inflammatory Microglia?

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What are the important steps in the progression of neurodegenerative diseases characterized by the presence of protein aggregates? These aggregates are misfolded or otherwise altered proteins that precipitate to form solid deposits. This means α-synuclein in the case of Parkinson’s disease, or amyloid-β and tau in the cause of Alzheimer’s disease, to pick the best known examples. A growing body of evidence is pointing to dysfunction and inflammation in the immune cells known as microglia, a type of macrophage resident in the central nervous system. Like macrophages elsewhere in the body, microglia are responsible for chasing down pathogens and clearing up debris. They also participate in a range of other supporting activities that assist the function of neurons.

In Alzheimer’s disease, there is compelling evidence for microglia to be driven into an inflammatory state by the presence of amyloid-β. They act as the bridge between the mild earlier stage of the condition, in which amyloid-β accumulates, and the later stage in which tau aggregates form and neurons die. It is the chronic inflammation and dysfunction of microglia in brain tissue that drives this more severe tau pathology. Inflammatory behavior in microglia appears to involve significant numbers of senescent microglia, and researchers have shown that removing these senescent cells can turn back tau pathology in mouse models and reduce levels of neuroinflammation. Lingering senescent cells of any cell type cause harm through secreting inflammatory and other signals, the senescence-associated secretory phenotype (SASP). This actively maintains a disordered tissue environment, and we’d all benefit from its removal in old age.

Given that microglia have this role in Alzheimer’s disease, are they also causing similar issues in other neurodegenerative disease processes? Most likely yes. The article here examines the role of microglia in α-synuclein aggregation, an important part of the progression of Parkinson’s disease. This continues to add support for the idea that senolytic therapies, capable of removing senescent cells and dampening the inflammation that they cause, will prove to be a useful treatment for neurodegenerative conditions. Indeed, they should be a useful preventative treatment prior to the advent of neurodegenerative disease. Chronic inflammation drives many of the common diseases of aging, and to the extent that the causes of that inflammation can be prevented, then age-related disease – and aging itself – will be pushed back.

Do Immune Cells Promote the Spread of α-Synuclein Pathology?

How does α-synuclein pathology spread? Researchers say immune cells bear some of the blame. Certain types of inflammation in the intestine modulate α-synuclein accumulation there. In mice, experimental colitis at a young age accelerated α-synuclein pathology in the brain 18 months later, consistent with the idea that misfolded protein can travel from gut to brain. Other research implicates brain immune cells in propagation. Mutant α-synuclein oligomers that were incapable of forming fibrils still stimulated aggregation in brain. They appeared to work their mischief by firing up inflammation, suggesting that microglia somehow mediate α-synuclein spread.

First, peripheral immunity. Scientists know that intestinal infections or inflammation can pump up α-synuclein production in the gut, perhaps as part of an antimicrobial defense. This strengthened the idea that Parkinson’s disease might start in the intestine and travel from there to the brain. People who suffer from inflammatory bowel disorders are at elevated risk of Parkinson’s disease, and genetic studies have found shared risk between the two. While the links are suggestive, no one had yet shown directly that gut inflammation triggered brain pathology.

Researchers provoked colitis in 3-month-old transgenic α-synuclein mice by adding dextran sulfate sodium (DSS) to their water. This irritant caused macrophages to invade the lining of the gut wall. In response, enteric neurons lying just below the mucosa, in the submucosal plexus, began to accumulate α-synuclein. The researchers aged the mice to 12 or 21 months. At 12 months, they saw no difference between the brains of control transgenics and those that had colitis as youngsters. By 21 months, however, the colitis group had six times more α-synuclein aggregates in brainstem regions than controls did. These mice had but half as many dopaminergic neurons as controls, suggestive of neurodegeneration.

Researchers are also interested in how α-synuclein aggregates propagate within the brain. When researchers injected aggregated material into mouse brain, it was quickly cleared to undetectable levels. Then, after an incubation period, aggregates appeared and spread through brain. The leading theory holds that this occurs through templated seeding of endogenous α-synuclein by the injected aggregates. To test this idea, researchers used a mutant form of α-synuclein, V40G, that forms unstructured oligomers but is incapable of forming fibrils. In a test tube, V40G blocks fibrillization of wild-type α-synuclein as well. Thus, this form should prevent templated seeding in vivo.

The researchers injected either V40G or wild-type α-synuclein into the striata of wild-type mice. To their surprise, V40G seeded aggregates even better than wild-type α-synuclein did. Four weeks after injection, mice that had received V40G had far more α-synuclein pathology in the rhinal cortex than did mice treated with wild-type protein. Why might this be? The researchers analyzed gene expression in injected brains to glean clues. They found heightened inflammatory and innate immune responses in V40G-treated animals relative to those treated with wild-type α-synuclein. Supporting this, levels of the inflammatory cytokine IL-1β shot up in numerous brain regions after V40G administration, and this spike preceded the spread of α-synuclein aggregates to these regions. Treating mice with the anti-inflammatory drug lenalidomide along with V40G prevented this spike in IL-1β.

Based on these findings, researchers proposed a new model of α-synuclein propagation. Perhaps α-synuclein oligomers kick off microglial activation and cytokine release, and this inflammatory microenvironment then aggravates nearby neurons, causing α-synuclein to clump up in their cell bodies. By this logic, rather than α-synuclein aggregates passing directly from neuron to neuron, microglia would be essentially the conveyor belt for α-synuclein pathology.

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An Unrecognized Sign of High Blood Pressure

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Blood pressure is a measurement of the force your blood exerts as it pushes against your arteries. Blood pressure will normally rise and fall throughout the day but when it remains consistently high it becomes a significant concern as this pressure may damage your heart and cause other health problems.

In 2017, the American Heart Association (AHA) and the American College of Cardiology, along with nine other health organizations,1 changed the cutoff used to diagnose high blood pressure from 140/90 to 130/80.2 This slight shift increased the number of people diagnosed to include many who had previously been considered healthy.

According to the AHA, an estimated 103 million U.S. adults have high blood pressure using these new measurements.3 Your blood pressure may be measured at a health care professional’s office, or at home using a self-measured blood pressure monitoring system.4

The top number of your blood pressure measurement is called the systolic blood pressure and measures the pressure inside your arteries as your heart beats. The bottom number, called the diastolic number, measures the pressure in your vessels when your heart is at rest.

Both numbers are important in determining how much damage may occur over time to your blood vessels and other organ systems. Usually, there are no warning signs or symptoms of high blood pressure.

The only way to know for certain is to have your pressure measured.5 A recent study published in the Journal of the American Heart Association6 found urinating at least twice nightly may be a symptom of uncontrolled high blood pressure.

Nocturia May Indicate Unrecognized High Blood Pressure

Nocturia is a condition causing you to awaken at night to urinate. It may be related to high fluid intake late in the evening, sleep disorders or bladder obstruction.7 Researchers from Cedars-Sinai and UCLA School of Medicine8 sought to determine if nighttime urination is a potentially reversible symptom of uncontrolled high blood pressure.

The researchers conducted in-person health interviews and measured blood pressure in a large community-based sample of 1,673 black men, 35 to 49 years old. Those with high blood pressure were 56% more likely to get up at night to urinate.

They found men with untreated high blood pressure were 39% more likely to experience nocturia than men with normal blood pressure or those whose high blood pressure was under control. They concluded:9

“Uncontrolled hypertension was an independent determinant of clinically important nocturia in a large cross‐sectional community‐based study of non‐Hispanic black men aged 35 to 49 years.”

Results from another study were presented at the 83rd Annual Scientific Meeting of the Japanese Circulation Society in Yokohama, Japan.10 According to the researchers, previous research from Japan had found high salt intake was associated with nocturia in a country where individuals eat more salt compared to Western countries.

The study looked at the association between high blood pressure and nighttime urination in the general population, enrolling 3,749 residents who had an annual checkup in 2017. There were 1,882 who completed the questionnaires. The researchers used 140/90 as the cutoff for high blood pressure and not the new cutoff of 130/80.11

Nocturia was described as getting up during the night one or more times, as opposed to the study in the Journal of the American Heart Association,12 which defined it as two or more nocturnal bathroom visits. Despite these differences, the Japanese researchers found similar results, as urinating during the night was linked to a 40% greater chance of having high blood pressure.13

Potassium Deficiency Raises Blood Pressure

Potassium is a naturally occurring mineral your body uses as an electrolyte. It is one of the most abundant intracellular cations and is essential for normal cell function.14 The potassium and sodium relationship is strong, and is the main regulator of extracellular fluid volume, including your plasma (blood).

You may lose potassium through diarrhea, vomiting, excessive sweating or the use of some drugs, including excessive alcohol.15 However, the most common reason potassium levels are not within normal limits is related to your dietary intake.

According to the U.S. Department of Agriculture,16 the average intake of potassium in the U.S. population is 2,640 milligrams (mg) per day, which has remained unchanged since the mid-1990s. However, the Institute of Medicine recommends 4,700 mg per day for adequate intake.

Your body works most efficiently when there is a balance in your potassium and sodium.17 Potassium helps relax the walls of your arteries and lowers your blood pressure. Potassium also helps protect against muscle cramping, and Harvard Health18 states those with a high systolic blood pressure may reduce their blood pressure simply by increasing their potassium intake.

Many potassium-rich foods are also low in calories and carbohydrates, such as broccoli, spinach and other leafy greens. For those with current kidney problems, it’s important to seek your physician’s advice before using any potassium supplements as it may lead to irregular heart rhythms.19

Excessive salt consumption may contribute to an imbalance in potassium and sodium, which is more important than your overall salt intake. An imbalance in this ratio not only may lead to high blood pressure, but also kidney stone formation,20osteoporosis,21 cataracts22 and increased pain with rheumatoid arthritis.23

High Blood Pressure Triggers Health Concerns

According to the Centers for Disease Control and Prevention,24 13 million U.S. adults with high blood pressure are not aware they have it and are not being treated. Of those with high blood pressure, almost half don’t have it under control.

Uncontrolled high blood pressure is the leading cause of heart disease and stroke and raises your risk of heart of kidney and heart failure.25 High blood pressure increases the workload on your heart muscle, which may result in heart failure and damage the arteries supplying the muscle with oxygen, leading to a potential heart attack.

High blood pressure may also damage small arteries, reducing the amount of oxygen delivered to your organs such as your kidneys and eyes. Over time, this may result in kidney failure and vision loss.26

The term for damage to smaller blood vessels is microvascular disease and it may lead to angina,27 or chest pain that occurs when the heart muscle doesn’t get enough oxygen, as well as sexual dysfunction.28

Another form of damage occurring to the arterial system from high blood pressure is atherosclerosis,29 which may lead to peripheral vascular disease. Atherosclerosis is narrowing of the arteries that may occur in the arteries feeding the legs, arms, stomach or head, triggering pain and fatigue.

Important Dietary Strategies to Maintain Normal Blood Pressure

In addition to eating foods rich in potassium, there are additional dietary strategies you may use to maintain normal blood pressure. The Mediterranean region is known for rich olives and olive oil, fresh vegetables, fruits, seafood and infrequent red meat consumption. The people living there are known to be some of the healthiest, longest-living people in the world.30

Most of the diet’s health benefits are likely due to being low in sugar, with moderate protein and high in fresh fruits and vegetables, along with healthy fats. Dr. Stephen Sinatra’s PAMM, or Pan-Asian Modified Mediterranean, diet is a modification of the Mediterranean diet.31

The PAMM diet highlights the crucial nature of eating a “high-fiber, healthy-fat, Mediterranean-type, heart-healthy diet,” and emphasizing healthy fats and vegetables while minimizing synthetic fats.32

There has also been success33 reducing blood pressure using the Dietary Approaches to Stop Hypertension (DASH) diet, which consists largely of fresh vegetables, fruits, lean protein, whole grain and low-fat dairy. Although it’s often believed the results are from the low sodium in the diet, it’s more likely the diet is effective as it’s low in sugar and fructose.

Eating right to help optimize your blood pressure, thereby lowering your risk of kidney disease, heart disease, stroke and dementia is extremely important. It’s also important to note that what you don’t eat is as crucial as what you do eat, and I recommend avoiding the following foods, which are notorious for causing blood pressure levels to rise:34

  • Sugar, processed fructose and processed foods, grains
  • Partially hydrogenated oils (synthetic trans fats), found in many processed foods, including packaged cookies, crackers, chips and other snacks
  • Processed omega-6 oils, especially those in vegetable oils such as corn, canola, soy and safflower oils

Include Exercise to Keep Blood Pressure Under Control

Inactivity and blood pressure are also closely related — so closely that exercise is considered a first line of treatment by several health authorities, including the World Health Organization, the International Society of Hypertension and the U.S. Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure.35

Research shows inactive individuals have a 30% to 50% greater risk for high blood pressure than their active counterparts.36 As noted in a literature review on exercise and high blood pressure, published in Australian Family Physician:37

“Depending upon the degree the patient’s BP has been normalized by drug therapy, regular aerobic exercise significantly reduces BP the equivalent of 1 class of antihypertensive medication (chronic effect) …

Overall, resistance training has a favorable chronic effect on resting BP, but the magnitude of the BP reductions are less than those reported for an aerobic based exercise program …

For most hypertensive patients, exercise is quite safe. Caution is required for those over 50 years of age, and those with established cardiovascular disease (CVD) (or at high CVD risk) and in these patients, the advice of a clinical exercise physiologist is recommended.”

The key is to participate in activities to raise your heart rate and increase your blood flow. Many activities may accomplish this, including yard work, brisk walking, swimming, bicycling and sports such as tennis, skiing, rowing and soccer. Boosting your nitric oxide release also helps to normalize your blood pressure by relaxing your arteries.

The Nitric Oxide Dump is one high-intensity exercise I recommend, which you may easily incorporate into your daily routine at home or at work. Read more about it in my previous article, “Incorporate the Nitric Oxide Dump.”

More Drug-Free Methods to Control Your Blood Pressure

Factors that may influence your blood pressure are varied. Although diet and exercise are important strategies to control high blood pressure, there are others you may incorporate to positively affect your blood pressure and improve your overall health.

Some of these factors include lifestyle choices, such as quitting smoking and addressing your potassium to sodium ratio. Walking barefoot to ground to the earth, intermittent fasting and reducing stress may also impact your blood pressure measurements.

You’ll discover more recommendations to improve your cardiovascular health in my previous articles, “Top Foods to Help Lower Blood Pressure,” and “How Potassium Can Help Your High Blood Pressure.”

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Nematodes are Probably Not Useful Models of Mitochondrial Aging

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Mitochondria, the power plants of the cell, carry their own DNA, encoding a few proteins essential to mitochondrial operation. Mutational damage to these genes can result in broken mitochondria that take over cells and cause the export of oxidizing molecules, contributing to the progression of aging. Not all mitochondrial DNA damage is the same, however: point mutations versus deletion mutations, for example. Researchers have struggled to produce consistent data in mice and nematodes with increased levels of mitochondrial DNA damage of various sorts. Some mice engineered to have greater mutation rates in mitochondrial DNA exhibit accelerated aging, while others do not, with little sign of a coherent explanation as to why beyond the sentiment that short-lived species are not useful models in this case.

The work here in nematodes, using radiation to produce mitochondrial DNA damage, should probably taken as more in the same vein. The researchers find no correlation between damage levels and life span, and this may well be because they are not introducing the right sort of mutational damage that occurs over the course of aging in longer-lived species. It is thought that deletion mutations, or other equally drastic damage, is necessary, for example. But nematodes do not accumulate such damage over the course of their very short lives. They may just be a very poor model for any consideration of the mitochondrial contribution to the aging process.

The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage.

Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in reactive oxygen species detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan.

In order to more directly test the relevance of mtDNA damage in the context of lifespan determination, we introduce damage to mtDNA directly by exposing young C. elegans to UV– or γ-radiation. Sufficiently high levels of UV-radiation cause extensive mtDNA damage and this indeed shortened C. elegans lifespan. However, we found that lower levels of this stressor still significantly increase mtDNA damage but without causing significant detriments and that some levels even resulted in lifespan extension and healthspan improvements.

This is consistent with the concept of hormesis; that exposure to mild stress, through evoking adaptive responses and strengthening stress defense mechanisms can lead to lifespan extension. However, it is worth noting that in our experiments, even under conditions where UV damage results in hormetic benefits, damage remained detectably elevated, even on the day following exposure. The lack of evidence for a tight relationship between mtDNA damage burden and lifespan in C. elegans is consistent with our recent finding that, most likely due to the short lifespan of nematodes, mtDNA deletion do not accumulate with age in C. elegans.


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Mitochondrial Function and the Association Between Health and Intelligence

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Intelligent people tend to have a longer life expectancy. Is this because they also tend to have more education, be wealthier, and make better lifestyle choices? This web of correlations is hard to untangle. Might there also be underlying physical mechanisms that contribute to this well known association between intelligence and long-term health, however? Are more intelligent people a little more physically robust, on average? There is some evidence for this sort of effect to be present in other species, and some genetic studies suggest that common variants affect both traits, while twin studies also add evidence in favor of physical mechanisms that influence both intelligence and longevity.

Here, researchers argue that variations in mitochondrial function is the mechanism of greatest interest in this matter, as this can affect the energy-hungry tissues of both brain and heart muscle. Mitochondria are the power plants of the cell, packaging chemical energy store molecules to power cellular processes. It is well known that mitochondrial function is important in aging, and declines with age. If an individual has a slightly more efficient mitochondrial population, or mitochondria that are just a little more resilient to the molecular damage of aging, perhaps that will be enough for both improved brain function throughout development and adult life, and a slower decline into age-related disease and mortality.

For over 100 years, scientists have sought to understand what links a person’s general intelligence, health and aging. In a new study, scientists suggest a model where mitochondria, or small energy producing parts of cells, could form the basis of this link. This insight could provide valuable information to researchers studying various genetic and environmental influences and alternative therapies for age-related diseases, such as Alzheimer’s disease. “There are a lot of hypotheses on what this link is, but no model to link them all together. Mitochondria produce cellular energy in the human body, and energy availability is the lowest common denominator needed for the functioning of all biological systems. My model shows mitochondrial function might help explain the link between general intelligence, health, and aging.”

The insight came while working on a way to better understand gender-specific vulnerabilities related to language and spatial abilities with certain prenatal and other stressors, which may also involve mitochondrial functioning. Mitochondria produce ATP, or cellular energy. They also respond to their environment, so habits such as regular exercise and a diet with fruits and vegetables can promote healthy mitochondria. “These systems are being used over and over again, and eventually their heavy use results in gradual decline. Knowing this, we can help explain the parallel changes in cognition and health associated with aging. Also with good mitochondrial function, the aging processes will occur much more slowly. Mitochondria have been relatively overlooked in the past, but are now considered to relate to psychiatric health and neurological diseases. Chronic stress can also damage mitochondria and that can affect the whole body – such as the brain and the heart – simultaneously.”


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Poor Sense of Smell Correlates with Increased Mortality in Older Individuals

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It is quite easy to find correlations between the many varied aspects of aging. People age at different rates, largely due to differences in lifestyle choices: exercise, calorie intake, smoking, and so forth. Genetics are less of an influence. While there is tremendous interest in the genetics of aging, I have to think that this is something of a case of a hammer in search of a nail. This is an era of genetic technologies and genetic data, in which the cost of the tools has fallen so low and the scope of the capabilities has expanded so greatly that everyone is tempted to use it in every possible circumstance. Yet outside of the unlucky minority who suffer severe inherited mutations, genetic variations only become important in later life, and even then the contribution of genetics to life expectancy is much smaller than that of lifestyle choices.

Nonetheless, the point is that different people age at different rates. For any given person, however, the many aspects of aging are fairly consistent with one another – nothing races ahead in isolation. Aging is a body-wide phenomenon of multiple processes of damage accumulation that proceed in an entangled fashion, feeding one another and all contributing to systemic downstream consequences, such as chronic inflammation or vascular dysfunction. In this sort of a system, if any one organ or biological system is more aged and damaged in a given individual, then it is very likely that all of the others are as well. This works for correlations with mortality as well as specific age-related diseases or metrics.

In the research results noted below, a poor sense of smell in older individuals correlates with a significantly raised risk of mortality over a ten year horizon. For the reasons given above, this shouldn’t be terrible surprising. Loss of sense of smell is a reflection of levels of neurodegeneration, loss of function in the brain. That in turn tends to match up with loss of function elsewhere in the body, particularly in the cardiovascualar system. Failing sense of smell is further specifically associated with Alzheimer’s disease, as the olfactory system in the brain is where the condition starts. You can look at the work of Leucadia Therapeutics for evidence that Alzheimer’s disease begins in this way because clearance of cerebrospinal fluid in that part of the brain is impaired with age, leading to increased molecular waste and cellular dysfunction.

Poor Sense of Smell and Risk for Death in Older Adults

Many older adults have a poor sense of smell, which can affect their appetite, safety, and quality of life. It is also associated with increased risk for death and may be an early sign of some diseases, like Alzheimer’s disease and Parkinson’s disease. Most previous studies have studied people with a poor sense of smell for relatively short periods of time, and they did not examine whether there are differences by race or sex. We also need a better understanding of the factors that might explain the relationship between poor sense of smell and increased risk for death.

Researchers analyzed data on the members of an ongoing study that was done in 2 communities in the United States (Memphis, Tennessee, and Pittsburgh, Pennsylvania). There were 2289 adults, aged 71 to 82 years, at baseline. The participants completed a Brief Smell Identification Test (BSIT). As part of the test, they smelled 12 common odors and were asked to identify each odor from 1 of 4 options. Each correct response was given a point. Using the BSIT scores, the researchers classified the participants as having good, moderate, or poor sense of smell. Participants attended several clinical study visits, where they were examined and had cognitive tests. In these visits, patients were identified as having dementia or Parkinson’s disease, and staff measured participants’ body weights. The main end points for the study were death from any cause; death from dementia or Parkinson’s disease; and death from cardiovascular disease, cancer, or respiratory causes.

A poor sense of smell was associated with older age, male sex, black race, alcohol drinking, and smoking. It was also associated with dementia, Parkinson’s disease, and chronic kidney disease. Participants with a poor sense of smell had a nearly 50% higher risk for death at 10 years. A poor sense of smell was also associated with increased risk for death from dementia or Parkinson’s disease and death from cardiovascular disease. The investigators did some exploratory statistical analyses and found that weight loss and a history of dementia or Parkinson’s disease could explain only part of the relationship between poor sense of smell and death.

Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults: A Cohort Study

To assess poor olfaction in relation to mortality in older adults and to investigate potential explanations, 2289 adults aged 71 to 82 years at baseline underwent the Brief Smell Identification Test in 1999 or 2000 (baseline). All-cause and cause-specific mortality was assessed at 3, 5, 10, and 13 years after baseline. During follow-up, 1211 participants died by year 13. Compared with participants with good olfaction, those with poor olfaction had a 46% higher cumulative risk for death at year 10 and a 30% higher risk at year 13.

However, the association was evident among participants who reported excellent to good health at baseline but not among those who reported fair to poor health. In analyses of cause-specific mortality, poor olfaction was associated with higher mortality from neurodegenerative and cardiovascular diseases. Mediation analyses showed that neurodegenerative diseases explained 22% and weight loss explained 6% of the higher 10-year mortality among participants with poor olfaction.

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The DNA Damage Response Falters in Old Stem Cells

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Efficient DNA repair is necessary to prevent cells from becoming dysfunctional or senescent in response to stochastic nuclear DNA damage. This is particularly important in stem cell populations, as there is no outside source to replace their losses, or repair persistent dysfunction. Researchers here note that the DNA damage response fails to trigger sufficiently in old intestinal stem cell populations, and this may be an underlying contributing cause of higher levels of cellular senescence in these cells.

Aging is related to disruption of tissue homeostasis, which increases the risks of developing inflammatory bowel diseases (IBDs), and colon cancer. However, the molecular mechanisms underlying this process are largely unknown. Various age-related dysfunctions of adult tissue-resident stem/progenitor cells (TSCs, also known as somatic stem cells) are associated with perturbation of tissue homeostasis. Restoration of stem cell functions has attracted much attention as a promising therapeutic strategy for geriatric diseases.

The intestinal epithelium is one of the most rapidly renewing tissues in the body. Lgr5expressing intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. Therefore, dysfunction of ISCs may be important for the disruption of intestinal homeostasis and subsequent induction of functional disorders. However, the influence of aging on the functions of ISCs and induction of diseases is largely unknown.

Recent studies demonstrated that accumulation of senescent cells promotes organismal aging. Cells become senescent in response to various aging stresses, such as oxidative stress, telomere shortening, inflammation, irradiation, exposure to chemicals, and the mitotic stress, all of which induce DNA damage. Numerous types of DNA damage occur naturally and are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. The mutation rate is highest in the small and large intestines. However, the influence of aging on the DDR in ISCs has not been studied.

Here, we compared induction of the DDR, inflammation, and mitochondrial biogenesis upon irradiation between young and old mouse ISCs in vivo. Induction of the DDR and expression of associated proteins were decreased in old ISCs. The DDR was sustained in old differentiated cells, suggesting that only the responsiveness to DNA damage was perturbed and DDR capacity was potentially sustained in old ISCs. Our results suggest that the competence of the DDR in ISCs declines with age in vivo.


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Aging, Metabolic Rate, and the Differences Between Birds and Mammals

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There is a strong association in mammalian species between metabolic rate, size, and life span. When pulling in bird species to compare, however, it is observed that they tend to have higher metabolic rates and longer life spans at a given size. So the question here is what exactly is going on in bird metabolism that allows for this more heated operation of cellular metabolism, necessary to meet the demands of flight, without the consequences to life span observed in mammalian species. The open access paper here is illustrative of research in this part of the comparative biology of aging field. Is there anything in this ongoing work on metabolism and aging that might one day lead to methods of extending mammalian life? Perhaps, perhaps not. Altering the operation of metabolism is a poor second best to repairing the damage that causes aging, but one never knows what might emerge from fundamental research at the end of the day.

Mitonuclear communication is at the heart of metabolic regulation, especially in fundamental processes such as cellular respiration. All endothermic organisms have evolved high metabolic rates for increased heat production. However, birds and mammals evolved endothermy independently of each other, and demonstrate some stark differences. Birds live significantly longer lives compared with mammals of similar body size, despite having higher metabolic rates, body temperatures, and blood glucose concentration.

The underlying physiological mechanisms that explain differences between mammals and birds are varied, and include differences at tissue- and cell-levels. For both of these groups, mass-specific basal metabolic rate (BMR) decreases with body size and body size accounts for much of the variation in BMR, however, much variation among species still remains to be explained. Because BMR is defined fundamentally as the sum of tissue metabolic rates, it follows that variation in BMR may relate to the relative size of central organs.

Alternatively, cellular machinery of the tissues of birds and mammals may differ. Metabolic intensity of tissues is thought to vary because of differences in numbers of mitochondria within cells, concentrations of metabolic enzymes, activity or quantity of the membrane sodium-potassium ATPase pump, and the number of double bonds in fatty acids of cell membranes. Because of differences in whole-organism metabolic rate, we may also expect differences within the rates of cellular processes, including oxidative stress.

Oxidative stress is a balance, inherent to all aerobic organisms, between the potential damage that could be accrued by reactive oxygen species (ROS) and the resources cells have to thwart that damage through the antioxidant system. This process has gained momentum in the ecological physiology literature because it has been implicated in determining rates of aging. Here, we sought to quantify parts of the oxidative stress system in a diverse group of birds and mammals. Our question was two-fold: does oxidative stress (a product of aerobic respiration and thus BMR) scale with body mass in these two groups? And are there differences in oxidative stress between birds and mammals?

Our first finding is that cellular metabolism and every parameter that we measured to quantify oxidative stress in birds and mammals does not scale with body mass. This implies that differences at the cellular level might make small contributions to scaling at the organ level, pointing to the fact that scaling of metabolism may reside in higher levels of organization. An obvious explanation may be that organ sizes between similarly-sized birds and mammals may be disproportionally larger in birds compared with mammals, leading to higher BMR.

Secondly, birds showed significantly lower basal cellular oxygen consumption, lipid oxidative damage, and lower activities of catalase. These results together imply several possible physiological mechanisms, none of which are mutually exclusive: (i) birds may have cells with significantly fewer mitochondria or with mitochondria that are more uncoupled; (ii) birds may be less burdened by ROS production compared with mammals; or (iii) birds may have membranes with lower membrane polyunsaturation compared with mammals.


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Towards Restoration of Neural Stem Cell Function in the Old

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Every tissue in the body supported by its own specialized small stem cell populations. The vast majority of cells in the body, known as somatic cells, are limited in the number of times they can divide. Their telomeres shorten with each cell division, and they become senescent or self-destruct when reaching the Hayflick limit on replication, triggered by short telomeres. Stem cells have no such limitation, and use telomerase to maintain telomere length regardless of the number of divisions they undergo. They divide asymmetrically to generate daughter somatic cells with long telomeres that can replace lost somatic cells in order to maintain tissue function. This split between a small privileged cell population and a large, limited cell population most likely evolved because it greatly reduces the risk of cancer.

Unfortunately, stem cell activity declines with age, producing a slow decline of tissue function, ultimately causing disease and death. This may also be an adaptation that exists to reduce cancer risk. From a mechanistic point of view, it appears to be a reaction to rising levels of molecular damage, and the consequences of that damage, such as chronic inflammation and other forms of altered signaling between cells. While some stem cell populations are damaged and diminished in and of themselves in older individuals, such as hematopoietic stem cells, others, such as muscle stem cells, have been shown to be just as capable in old age as in youth, but much less active. The stem cells lapse into extended quiescence and cease to create daughter somatic cells.

Neural stem cells appear more akin to muscle stem cells than hematopoietic stem cells in the matter of whether or not they still exist in old individuals and are capable of activity, given the right instructions. The activity of neural stem cells is an important portion of neuroplasticity, the ability of the brain to generate new neurons that integrate into existing neural circuits or form new neural circuits. This is the basis of cognitive function and also of repair in the brain. To the degree that the supply of new neurons declines, this is a slow road to neurodegeneration. Many other issues need to be fixed in the aging brain, such as chronic inflammation, slowed drainage of cerebrospinal fluid, and the aggregation of proteins associated with neurodegenerative conditions. Nonetheless, stem cell function must be restored in some way.

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As we age, our brains’ stem cells ‘fall asleep’ and become harder to wake up when repairs are needed. Despite efforts to harness these cells to treat neurological damage, scientists have until recently been unsuccessful in decoding the underlying ‘sleep’ mechanism. Now, researchers studying brain chemistry in mice have revealed the ebb and flow of gene expression that may wake neural stem cells from their slumber.

The team focused their attention on protein Hes1, which is strongly expressed in the adult cells. This normally suppresses the production of other proteins such as Ascl1, small amounts of which are periodically produced by active stem cells. Monitoring the production of the two proteins over time, the team pinpointed a wave-like pattern that leads to stem cells waking up and turning into neurons in the brain. When they knocked out the genetic code needed to make Hes1, the cells started to make more Ascl1, which then activated almost all the neural stem cells.

“It is key that the same genes are responsible for both the active and quiescent states of these stem cells. Only the expression dynamics differ between the two. A better understanding of the regulatory mechanisms of these different expression dynamics could allow us to switch the dormant cells on as part of a treatment for a range of neurological disorders.”

High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain

Somatic stem/progenitor cells are active in embryonic tissues but quiescent in many adult tissues. The detailed mechanisms that regulate active versus quiescent stem cell states are largely unknown. In active neural stem cells, Hes1 expression oscillates and drives cyclic expression of the proneural gene Ascl1, which activates cell proliferation. Here, we found that in quiescent neural stem cells in the adult mouse brain, Hes1 levels are oscillatory, although the peaks and troughs are higher than those in active neural stem cells, causing Ascl1 expression to be continuously suppressed.

Inactivation of Hes1 and its related genes up-regulates Ascl1 expression and increases neurogenesis. This causes rapid depletion of neural stem cells and premature termination of neurogenesis. Conversely, sustained Hes1 expression represses Ascl1, inhibits neurogenesis, and maintains quiescent neural stem cells. In contrast, induction of Ascl1 oscillations activates neural stem cells and increases neurogenesis in the adult mouse brain. Thus, Ascl1 oscillations, which normally depend on Hes1 oscillations, regulate the active state, while high Hes1 expression and resultant Ascl1 suppression promote quiescence in neural stem cells.

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Rejuvenate Bio to Launch a Gene Therapy Trial for Heart Failure in Dogs

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One of the many possible paths towards developing a new medical technology is to first focus on veterinary use. It is considerably less costly in time and resources to develop a therapy for dogs, say, than it is to develop a therapy for humans. Later, given robust success in veterinary medicine, the therapy can be brought into the sphere of human medicine. This is the approach taken by Rejuvenate Bio for their class of regenerative gene therapies. As noted here, the company is moving forward to trials in companion animals, starting later this year.

Back in 2015, the Church lab at Harvard began testing a variety of therapies focused on age reversal using CRISPR, a gene editing system that was much easier and faster to use than older techniques. Since then, Professor Church and his lab have conducted a myriad of experiments and gathered lots of data with which to plan future strategies for tackling aging. Last year, we learned that Rejuvenate Bio had already conducted some initial studies with beagles and were planning to reverse aging using CRISPR gene therapy. The goal was to move these studies forward to a larger scale as a step towards bringing similar therapies to humans to prevent age-related diseases.

Choosing to develop therapies for dogs helps pave the way for therapies that address the aging processes in humans and could support their approval, which would otherwise be much more challenging. If Rejuvenate Bio can produce robust data in dogs showing that some processes of aging have been reversed, it lends considerable justification for human trials. The company is also taking a different tack; instead of focusing on increasing lifespan, it is instead targeting an age-related disease. Rejuvenate Bio will be launching a gene therapy trial in dogs during the fall this year to combat mitral valve disease (MVD), a condition commonly encountered in the Cavalier King Charles Spaniel breed and directly caused by the aging processes. The study will initially focus on this particular breed and expand to include other dogs with MVD as time passes.

This gene therapy is focused on adding a new piece of DNA into the cells of the dogs in order to halt the buildup of fibrotic scar tissue in the heart, which is linked to the progression of MVD and other forms of heart failure. Fibrotic tissue is the result of imperfect repair, which occurs when a more complete repair is not possible due to a lack of replacement cells or high levels of inflammation. The therapy may also be useful for other heart conditions, such as dilated cardiomyopathy (DCM). If the initial results are successful, we could see more dog breeds included as well as other conditions, including DCM, added to the program.


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Mitochondrial Dysfunction as a Contributing Cause of Osteoporosis

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Bone is constantly remodeled throughout life through the actions of osteoblasts, cells that build bone, and osteoclasts, cells that break down bone. The proximate cause of osteoporosis, the age-related loss of bone mass and strength, is a growing imbalance between these cell types that favors osteoclasts. Why does this happen? Chronic inflammation generated by the presence of senescent cells appears to be one cause, as cells react to inflammation in ways that favor osteoclast ativity over osteoblast activity. Researchers here provide evidence for the age-related decline in mitochondrial function to be important as well, another mechanism that ensures more osteoclasts than osteoblasts are introduced into bone tissue.

Some risk factors for osteoporosis such as being older and female or having a family history of the condition cannot be avoided. But others can, like smoking cigarettes, consuming alcohol, taking certain medications, or being exposed to environmental pollutants. But until now researchers haven’t gained a firm picture of how these exposures link up with bone loss. A new study reveals a mechanism by which these factors and osteoporosis may be linked. Damage to mitochondria – key cellular organelles and energy generators – leads to a surge in the creation of cells called osteoclasts, which are responsible for breaking down bone.

The scientists took a close look at how problems with mitochondria affected a type of immune cell known as macrophages. Macrophages are a front line for the immune system, engulfing and digesting foreign invaders to the body. But macrophages can also diversify, transforming into osteoclasts when the circumstances are right. To understand how mitochondrial damage could be linked to osteoporosis through the work of macrophages, the researchers induced damage to a key enzyme responsible for energy production in mitochondria, cytochrome oxidase C, in lab-grown mouse macrophages. Doing so led the macrophages to release a variety of signaling molecules associated with an inflammatory reaction and also seemed to encourage them to go down the path toward becoming osteoclasts.

Looking closely at what was going on, they observed an anomaly with a key molecule, RANK-L, that helps regulate the bone-rebuilding process and is released by bone-building cells as a means of inducing bone break-down. When mitochondria were damaged, they underwent stress signaling and transformed into osteoclasts at a much faster rate, even when RANK-L levels were low. These osteoclasts led to greater rates of bone resorption, or break down. The researchers confirmed their findings in a mouse model, showing that animals with a mutation that leads to dysfunctional mitochondria had increased production of osteoclasts. Because some of the same environmental risk factors that seem to promote osteoporosis, like smoking and some pharmaceuticals, can also impact mitochondrial function, the team posits that this stress signaling might be the pathway by which they are acting to affect bone health.


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