Xenobiotic Detoxifying Enzymes are Critical to the Hormetic Increase in Life Span via Mitochondrial Oxidative Stress

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Researchers have for many years demonstrated that short-lived organisms such as the nematode worms C. elegans live longer when there is some increase in damaging reactive oxygen species released by mitochondria. This is a hormetic mechanism: processes of cell maintenance are triggered into greater activity, and the net result is improved tissue function and increased longevity. Unfortunately we know that these mechanisms do not have the same sizable effect on life span in long-lived species such as our own, even though they appear quite beneficial to short term measures of health.

Establishing the fine details of exactly which stress responses are important, and to what degree, is a work in progress. Metabolism is enormously complex, and there are only so many scientists and so much funding for ongoing investigations. Researchers here identify xenobiotic detoxifying enzymes as an important component of stress responses, and in this context it is interesting to look back at other recent research showing correlation between genetic variants of xenobiotic metabolizing enzymes and human longevity.


Lifespan extension in different species can be achieved by various genetic manipulations and treatments, such as disruption of insulin/IGF1 signalling, decrease in mitochondrial respiration, suppression of translation or caloric restriction. Despite very different origins of these longevity programmes, they all warrant increased resistance to various stresses like heat, oxidative stress or radiation. Although the concept that lifespan might depend on the capacity to withstand external stress cues is very old, little is currently known about signalling pathways underlying these cytoprotective responses and their ability to affect lifespan. Furthermore, how much an individual cytoprotective mechanism contributes to the lifespan extension induced by different manipulations is a key question that remains to be answered.

Transcription profiling of many long-lived mutants from worm to mouse has recently revealed that upregulation of a number of genes involved in xenobiotic detoxification is common to longevity-assurance pathways across different phyla. Xenobiotic detoxification includes activation of drug-metabolizing enzymes (DMEs), which are classified in two main groups: phase I, mainly cytochrome P450 oxidases (CYPs), and phase II, mainly UDP-glucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), sulfotransferases, and acetyltransferases, coupled to the activity of phase III transporters that mediate the efflux of metabolic end products out of the cells after the completion of phase II.

Interestingly, analyses of expression profiles from long-lived mice, including calorically restricted mice, different dwarf mice, or mice treated with rapamycin, revealed that many CYPs are upregulated and positively correlate with increased longevity. Moreover, increased expression of multiple cyp genes was reported in diverse long-lived C. elegans models, including mitochondrial mutants. Although interesting, these findings provided just a correlative connection to longevity.

Here we identify Krüppel-like factor 1 (KLF-1) as a mediator of a cytoprotective response that dictates longevity induced by reduced mitochondrial function. A redox-regulated KLF-1 activation and transfer to the nucleus coincides with the peak of somatic mitochondrial biogenesis that occurs around a transition from larval stage. We further show that KLF-1 activates genes involved in the xenobiotic detoxification programme and identified cytochrome P450 oxidases, the KLF-1 main effectors, as longevity-assurance factors of mitochondrial mutants. Collectively, these findings underline the importance of the xenobiotic detoxification in the mitohormetic, longevity assurance pathway and identify KLF-1 as a central factor in orchestrating this response.

Link: https://doi.org/10.1038/s41467-019-11275-w

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Older Adults Should Undertake Resistance Training

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The evidence from numerous studies of recent years makes it clear that resistance training produces significant benefits to the health and remaining life expectancy of older adults. To put it another way, most people do too little to maintain strength and their health suffers for it. The effects here seem to partially overlap with and partially be distinct from the benefits of aerobic exercise. But the benefits are broad, as indicated in this open access position paper on the subject.


Age-related loss of muscle mass (originally termed sarcopenia) has an estimated prevalence of 10% in adults older than 60 years (538), rising to greater than 50% in adults older than 80 years. Prevalence rates are lower in community-dwelling older adults than those residing in assisted living and skilled nursing facilities. Loss of muscle mass is generally gradual, beginning after age 30 and accelerating after age 60. Previous longitudinal studies have suggested that muscle mass decreases by 1.0-1.4% per year in the lower limbs, which is more than the rate of loss reported in upper-limb muscles. Sarcopenia is considered part of the causal pathway for strength loss, disability, and morbidity in older adult populations. Yet, muscle weakness is highly associated with both mortality and physical disability, even when adjusting for sarcopenia, indicating that muscle mass loss may be secondary to the effects of strength loss.

The rate of decline in muscle strength with age is two to five times greater than declines in muscle size. As such, thresholds of clinically relevant muscle weakness have been established as a biomarker of age-related disability and early mortality. These thresholds have been shown to be strongly related to incident mobility limitations and mortality. Given these links, grip strength (a robust proxy indicator of overall strength) has been labeled a “biomarker of aging“. Losses in strength may translate to functional challenges because decreases in specific force and power are observed. Declines in muscle power have been shown to be more important than muscle strength in the ability to perform daily activities. Moreover, a large body of evidence links muscular weakness to a host of negative age-related health outcomes including type 2 diabetes, disability, cognitive decline, osteoporosis, and early all-cause mortality.

Resistance training is considered an important component of a complete exercise program to complement the widely known positive effects of aerobic training on health and physical capacities. There is strong evidence that resistance training can mitigate the effects of aging on neuromuscular function and functional capacity. Various forms of resistance training have potential to improve muscle strength, mass, and power output. Evidence reveals a dose-response relationship where volume and intensity are strongly associated with adaptations to resistance exercise.

Despite the known benefits of resistance training, only 8.7% of older adults (older than 75 years of age) in the United States participate in muscle-strengthening activities as part of their leisure time. When performed regularly (2-3 days per week), and achieving an adequate intensity and volume (2-3 sets per exercise) through periodization, resistance exercise results in favorable neuromuscular adaptations in both healthy older adults and those with chronic conditions. These adaptations translate to functional improvements of daily living activities, especially when power training exercise is included. In addition, resistance training may improve balance, preserve bone density, independence, and vitality, reduce risk of numerous chronic diseases such as heart disease, arthritis, type 2 diabetes, and osteoporosis, while also improving psychological and cognitive benefits.

Link: https://doi.org/10.1519/JSC.0000000000003230

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How vitamin D keeps you young and thin

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Your body needs vitamins and certain nutrients to grow and develop normally. Vitamin D is one of them. Although not technically a vitamin — it’s actually a fat-soluble hormone that transforms into vitamin D in your body — it’s important to several different bodily processes. It’s not commonly found in foods, but is added to some processed foods. It’s also available in supplement form.1,2

Optimally, your body will make vitamin D when your skin is exposed to sunlight; hence, it’s also known as the sunshine vitamin.3 As mentioned, it plays a number of roles in the body, including helping the gut absorb calcium necessary for strong bones,4 modulating cell growth and optimizing your neuromuscular and immune functions.5

To date, the best indicator of vitamin D status is your serum (blood) concentration of 25-hydroxy Vitamin D, also called 25-OH vitamin D.6 Blood test results serve as a biomarker of your exposure to vitamin D.7

Chronic deficiency results in bone diseases, such as rickets and skeletal deformities. Research has also demonstrated that insufficiencies8 are associated with disease.9,10 Most recently scientists are now looking at the association between vitamin D and leptin,11 a hormone which controls your hunger,12 and the effects vitamin D may have on antiaging.13

Physiological link between leptin, vitamin D and adipose

Canadian researchers looked at the association between elevated leptin levels, vitamin D deficiency and their relationship to adipose tissue.14 They enrolled 113 men with a sedentary lifestyle who had abdominal obesity, were not taking a vitamin D supplement or had dyslipidemia.

The participants were involved in a lifestyle modification program over one year during which they were individually counseled by a nutritionist and kinesiologist every two weeks for the first four months. The goal was to reduce their calorie intake by 500 calories per day and increase their daily physical activity and exercise.15

After the first four months, the participants continued to be counseled once a month. At the beginning and end of the one-year study, a CT scan was done to map adipose deposits. Cardiometabolic biomarkers were also measured.

The researchers found that after making lifestyle changes, participants showed an increase in their vitamin D levels that was inversely correlated with their leptin levels.16 In other words, as their vitamin D levels rose, their leptin levels fell.

The participants were taking more steps per day and their heart rates were lower at a treadmill pace lower than their maximum effort after one year. Additionally, the researchers found an association between levels of vitamin D and the volume in adipose tissue deposits.17

The scientists felt this supported a possible physiological link between the two measurements which was independent from fat cell deposits. This led to a recommendation for lifestyle modifications to lower leptin levels in the clinical management of vitamin D deficiency.18

Interaction of leptin and weight management

The hormone leptin is directly connected to body fat and obesity, making it important for those who are struggling with weight management. It is an adipokine, or a cell signaling protein (cytokine) released by fat cells in proportion to the fat deposits.19 For a long time, fat tissue was considered to be the body’s inert tissue for storing energy.20

In 1994, the discovery of leptin marked an immediate change in an understanding of the function of body fat.21 There are two forms of fat tissue, white and brown. Brown adipose tissue is found more frequently in newborns, distributed above the collarbone and around the neck area.22 The primary function is generating heat.

White adipose tissue is located throughout the body, and sometimes referred to as subcutaneous or visceral fat.23 One of the physiological functions of white fat is to regulate metabolism through the secretion of leptin.24 Leptin sends signals to the hypothalamus, where it helps regulate your energy balance and turn on or turn off your hunger response.

For instance, lower levels of leptin will trigger an increase in your appetite. But, because leptin is secreted in proportion to the amount of fat cells in your body, as you lose weight, your appetite increases with lower levels of the hormone.25 This can make weight management more challenging.

As you produce more fat cells, they produce more leptin, which normally lowers the appetite. Your body does this to maintain a homeostatic level of fat deposits. However, with obesity, the body may become leptin resistant, which is a lack of sensitivity to the hormone.26

When this happens, you may continue eating because you don’t feel satisfied. The body then produces more leptin, which increases the levels and continues to drive resistance. Some people are born having a leptin deficiency; this signals uncontrollable hunger, increases energy intake and leads to both severe childhood obesity and delayed puberty.27

Is there a link between vitamin D and NAFLD?

Results of several studies evaluating links between vitamin D and nonalcoholic fatty liver disease (NAFLD) are not consistent, suggesting there may exist another factor not yet explored affecting the results of these studies, including the supplementation dosage of vitamin D that should be used.

A recent, community-based study performed in Taiwan28 sought to look at the association between levels of vitamin D and NAFLD. They studied concurrent symptoms of metabolic syndrome, high C-reactive protein and high levels of adipokines, including leptin.

Those who had viral hepatitis B or C, frequently drank alcohol, took a vitamin D supplement, steroid treatments, were pregnant or refused an abdominal ultrasound were excluded from the study. In the end, 564 individuals with fatty liver but no viral or alcoholic liver disease were included in the NAFLD group.

The control group contained 564 individuals matched for age and gender to the experimental group, who had normal ultrasound findings and liver function tests. The researchers found those who had deficient or insufficient vitamin D levels had a higher risk of metabolic syndrome.29

However, they did not find that vitamin D insufficiency or deficiency, as defined by the study protocol, increased the risk of having NAFLD as compared to those who had a sufficient vitamin D level.30 In this study, normal was considered 30 nanograms per milliliter (ng/mL), insufficiency was 20 to 30 ng/mL and those who had levels less than 20 ng/mL were considered deficient.

One systematic review of randomized controlled studies on the relationship between vitamin D deficiency and NAFLD found supplementation with vitamin D may improve symptoms.31 Another found epidemiological studies point toward an association and reinforce the rationale that supplementation may help manage NAFLD.32

Other research finds the common coexistence of vitamin D deficiency and NAFLD ay suggest a plausible treatment, but the limited number of prospective studies in humans and the lack of consensus in studies led the researchers to conclude it is premature to recommend supplementation with vitamin D for the specific treatment.33

The inconsistent evidence may be related to the supplementation dosages used to measure change in those with NAFLD or nonalcoholic steatohepatitis (NASH).34 NASH is a form of NAFLD, which includes hepatitis.35 In one study using daily supplementation of vitamin D with 2000 IUs for six months, low levels of vitamin D were not corrected.36

Vitamin D plays a role in antiaging

Vitamin D is metabolized in the liver to form 25-hydroxy (OH) vitamin D. This then travels to the kidneys where further hydroxylation forms 1,25 dihydroxyvitamin D.37 The authors of one study38 looked at the hypothesis that 1,25 dihydroxyvitamin D3 may have an antiaging effect.

They tested the theory that the vitamin would upregulate nuclear factor (erythroid derived 2)-like 2 (Nrf2), thus reducing reactive oxygen species and DNA damage.39 In the body, reactive oxygen species are balanced by an antioxidant system regulated by pathways to ensure response. Nrf2 is found to be one regulator of resistance to oxidants.40

Nrf2 has the effect of reducing reactive oxygen species and decreasing DNA damage. In combination with increasing cell proliferation and reducing cellular aging, researchers were able to demonstrate that mice deficient in 1,25 (OH)2 D3 survived only 3 months on average.

However, when the diets of the mice were supplemented with dietary calcium and phosphate, it prolonged their lifespan to more than eight months. These same types of mice were then supplemented with exogenous 1,25 (OH)2 D3, and it resulted in prolonging the average life of the experimental mice to more than 16 months.41

The researchers suggest the data demonstrate 1,25 (OH)2 D3 plays a part in extending life through the upregulation of Nrf2 and the subsequent inhibition of oxidative stress and DNA damage.42

The role that Nrf2 may play in a number of different conditions is now being explored, such as its effects on cardiovascular risk in metabolic disease,43 cancer44 and chronic diseases.45 Some are also evaluating the role Nrf2 transcription factor may have in protecting against Type 2 diabetes.46

Vitamin D insufficiency linked to negative health conditions

According to research47 published in June 2018, an estimated 40% of Americans are deficient in vitamin D. This means that they have a vitamin D blood level that is lower than 50 ng/mL. “Sufficiency” means having a level of 50 ng/mL or higher.

Seventy-seven percent of American adults and teens are deficient in vitamin D when a sufficiency level of 30 ng/mL is used.48 However, the sufficiency level recommended by the National Institutes of Health is not nearly high enough to prevent some chronic illnesses,49 which is currently recommended at greater than or equal to 20 ng/mL of serum vitamin D.50

Optimizing your vitamin D levels has been shown to have a powerful effect on health, helping to protect against a wide variety of diseases, including dry eye, cardiovascular disease, Alzheimer’s disease and obesity. You’ll find more of the health conditions affected by vitamin D in my past article, “Top 5 Signs of Vitamin D Deficiency.”

What affects your vitamin D level?

There are several factors that influence your personal vitamin D levels. By knowing and understanding these, you may determine the best way to attain optimal levels. According to Harvard Health publishing, these are the top six factors:51

Geography — The farther away you are from the equator, the less UVB light you get during the winter months.

Air pollution — Carbon particles in the air will slow vitamin D production as they absorb UVB rays.

Sunscreen — Liberal use of sunscreen may prevent sunburn, but it also lowers vitamin D production.

Skin color — People with dark skin need more UVB exposure than those with light skin.

Weight — Body fat absorbs vitamin D, as it’s a fat-soluble vitamin. Obesity is correlated with low vitamin D levels, which may also affect bioavailability.

Age — Older individuals will produce less vitamin D than younger people.

Optimize your vitamin D levels

Although it is best to optimize your vitamin D levels with safe sun exposure, you may need additional supplementation if you are affected by one or more of the factors discussed above.

Research52 involving a community-based group of 3,667 participants with a mean age of 51.3 years, produced data that suggest it would require 9,600 IUs of vitamin D per day to get 97.5% to reach 40 ng/mL.

However, individual requirements vary widely based on a variety of factors, and you need to take whatever dosage required to get you into the optimal range. The only way to gauge how much you need is to have your levels tested, ideally twice a year.

You should test once in the early spring, after the winter months to make sure you took enough throughout the winter, and again in the early fall when your level is at its peak. You are aiming for a level between 60 and 80 ng/mL, with 40 ng/mL being the lowest cutoff for sufficiency.53,54 In fact, new research in 2018 showed that the optimal levels for cancer prevention are between 60 and 80 ng/mL.

Aside from determining your ideal dose of vitamin D3, you also need to make sure you’re getting enough vitamin K2 (to avoid complications associated with excessive calcification in your arteries), calcium and magnesium.

Research55,56 has shown that taking high doses of vitamin D with an insufficient magnesium level reduces your body’s ability to utilize vitamin D. Magnesium is required for the activation of vitamin D so, when it’s low, vitamin D may be stored in its inactive form.

This may help explain why so many people may need rather high doses of vitamin D to optimize their levels. According to this review, as many as 50% of Americans taking vitamin D supplements may not get significant benefit due to insufficient magnesium levels.

It’s vital that you take vitamin D with sufficient amounts of vitamin K2 (MK7) as both are required to slow the progression of arterial calcification.57Vitamin K2 in the MK-7 form has been found to be bioactive. It regulates atherosclerosis, cancer, inflammatory diseases and osteoporosis.58

Vitamin K2 may lower the risk of damage to the cardiovascular system by activating a protein that prevents calcium from depositing in the walls of your blood vessels.59

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Being Overweight Correlates with Faster Brain Aging

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Does carrying excess body weight, meaning inflammatory visceral fat tissue that distorts metabolism in many ways, actually accelerate the processes of aging, or just make all later life health issues worse and shorten life expectancy via unrelated mechanisms? The evidence leans in the direction of actually accelerating aging. Regardless, by now we should all be used to the headlines announcing that yet another aspect of age-related degeneration proceeds faster in overweight individuals.


Having a bigger waistline and a high body mass index (BMI) in your 60s may be linked with greater signs of brain aging years later, according to a new study that suggests that these factors may accelerate brain aging by at least a decade. “People with bigger waists and higher BMI were more likely to have thinning in the cortex area of the brain, which implies that obesity is associated with reduced gray matter of the brain. These associations were especially strong in those who were younger than 65, which adds weight to the theory that having poor health indicators in mid-life may increase the risk for brain aging and problems with memory and thinking skills in later life.”

The study involved 1,289 people with an average age of 64. Participants’ BMI and waist circumference were measured at the beginning of the study. An average of six years later, participants had MRI brain scans to measure the thickness of the cortex area of the brain, overall brain volume and other factors. Having a higher BMI was associated with having a thinner cortex, even after researchers adjusted for other factors that could affect the cortex, such as high blood pressure, alcohol use, and smoking. In overweight people, every unit increase in BMI was associated with a 0.098 millimeter thinner cortex and in obese people with a 0.207 mm thinner cortex. Having a thinner cortex has been tied to an increased risk of Alzheimer’s disease. Having a bigger waist was also associated with a thinner cortex after adjusting for other factors.

“In normal aging adults, the overall thinning rate of the cortical mantle is between 0.01 and 0.10 mm per decade, and our results would indicate that being overweight or obese may accelerate aging in the brain by at least a decade. These results are exciting because they raise the possibility that by losing weight, people may be able to stave off aging of their brains and potentially the memory and thinking problems that can come along with brain aging. However, with the rising number of people globally who are overweight or obese and the difficulty many experience with losing weight, obviously this is a concern for public health in the future as these people age.”

Link: http://med.miami.edu/news/study-shows-extra-weight-in-60s-may-be-linked-to-brain-thinning

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Physical Exercise Reduces Brain Inflammation and Microglial Dysfunction

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Regular exercise has many beneficial effects on health because it triggers stress response mechanisms that work to maintain cell quality and function. It is worth noting that it isn’t as good at this as the practice of calorie restriction, however. This might be expected from the differing effects of exercise and calorie restriction on life span in short lived species such as laboratory mice. Calorie restriction can improve maximum life span by as much as 40%, while exercise can only improve healthy life span. This isn’t a case of do one or the other, of course. Do both.

Age is associated with rising levels of chronic inflammation, and in the brain this correlates with the dysfunction of microglia, supporting immune cells with a range of important roles. They don’t just clear up debris, but also participate in many of the functions of neurons and neural connections. Needless to say, when they start to be inflammatory and overactive, this is not good for brain health. It is connected to the progression of all of the most common neurodegenerative conditions. Exercise is well known to reduce inflammation, and the research here adds to the existing mountain of data on this front.


Exercise impacts our body at multiple levels, including the central nervous system (CNS). In responding to exercise-related stress (e.g., hypoxia, heat, free radicals, etc.) and injuries, the body launches multiple endogenous protective and repair systems by altering gene expression and releasing a range of factors that prepare the body for the next challenge. These factors, amongst others, involve trophic effects, anti-oxidation, energy metabolism, and anti-inflammation.

Some of these factors enhance brain function and ameliorate brain disorders by inducing neuroplasticity, increasing metabolic efficiency, and improving anti-oxidative capacity. Others maintain brain homeostasis and protect brain from pathological insults by regulating glial activation and neuroinflammation. Activated microglia and several pro-inflammatory cytokines play active roles in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). It has been well-documented that although acute, high-intensity exercise may cause muscle injury and induce inflammation, long-term exercise at low-to-moderate intensity negatively regulates the inflammatory response.

Considerable evidence also suggests that exercise may inhibit microglial activation by downregulation of the levels of pro-inflammatory factors. However, the mechanism for the exercise-related downregulation of pro-inflammatory factors is less clear, as pro-inflammatory cytokines can be secreted from various sources (e.g., injured neurons, astrocytes, and microglia). Thus, the anti-microglial activation effect of exercise can be interpreted indirectly by upregulating the levels of trophic factors, which then lead to reduced neuronal injury and degrees of microglial activation.

Furthermore, there are a few reports suggesting that physical exercise can shift the composition of the gut microbiome, which then affects both peripheral and central inflammation, including microglial activation in the CNS. Although some mechanisms are still waiting to be determined, it should be emphasized that physical activity represents a natural strong anti-inflammatory strategy to improve brain function.

Link: https://doi.org/10.3390/cells8070691

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Impaired Monocyte to Macrophage Transition Implicated in Cardiovascular Disease

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The innate immune cells called macrophages are vitally important to the health and function of tissues. They help to coordinate the intricate dance of stem cells, somatic cells, and immune cells that produces tissue regrowth and tissue maintenance. They destroy errant cells and pathogens. They have a variety of other roles as well. But where do macrophages come from? While some macrophages are generated within tissues, it is generally the case that in damaged or diseased tissues, most macrophages were originally monocytes. Circulating monocytes in the bloodstream enter tissues in response to chemical cues and then transform into macrophages that set to work to try to aid in repair and regeneration. Monocytes themselves are generated by cell populations in the bone marrow that descend from hematopoietic stem cells. At any given time about half of the monocytes in the body reside in the spleen, acting as a reserve that can leap into action when required.

Thus in any given situation of injury or disease in which the presence of macrophages would be beneficial, any process that prevents monocytes from arriving and transforming into macrophages will make things worse. Interestingly, it isn’t always the case that more macrophages will improve the situation. Atherosclerosis, for example, is a condition in which fatty lesions that narrow and weaken blood vessels form because the macrophages responsible for repairing the problem become overwhelmed by cholesterol and die, adding their debris to the lesion. Adding more macrophages accelerates the process, which is why animal models of atherosclerosis often use angiotensin II to cause monocytes to leave the spleen and enter the bloodstream, to make lesions form faster.

In today’s open access research materials, the authors report on a mechanism operating in heart tissue that impairs the ability of monocytes to become macrophages of a type and behavior suitable for tissue regeneration. Blocking this mechanism improves tissue maintenance, heart structure, and heart function. It is a recent example of many research results published over the past few years that, collectively, demonstrate the great importance of macrophage dynamics to normal tissue function. Macrophages have several phenotypes or polarizations, states distinguished by different markers and behaviors. The ones of interest are M1, inflammatory and aggressive, versus M2, anti-inflammatory and regenerative. A lot of issues in aging are marked by the presence of too many M1 macrophages, and there is considerable interest in the research community regarding the development of means to alter this balance.

Disrupting immune cell behavior may contribute to heart disease and failure


A new study provides evidence that when circulating anti-inflammatory white blood cells known as monocytes fail to properly differentiate into macrophages – the cells that engulf and digest cellular debris, bacteria and viruses – certain forms of heart disease may result. The research shows the presence of a specific protein prevents this monocyte-to-macrophage transition from occurring in the heart. This triggers a cascade of events that can cause heart muscle inflammation, or myocarditis; remodeling of the cardiac muscle structure; enlargement of the heart, or dilated cardiomyopathy; and weakening of the organ’s ability to pump blood. Eventually, this can result in heart failure.

In previous live mouse and “test-tube” laboratory studies, researchers determined that IL-17A stimulates spindle-shaped cardiac cells called fibroblasts to release a mediator that causes one type of monocyte, an inflammatory cell known as Ly6Chi to accumulate in greater numbers in the heart than the anti-inflammatory type known as Ly6Clo.

“The good news, also shown by our study, is that blocking a key protein, known as interleukin-17A or IL-17A, permits the differentiation of anti-inflammatory monocytes, promotes healthy cardiac function, and allows the newly created macrophages to protect, rather than attack, cardiac muscle. We knew that cardiac fibroblasts stimulated by IL-17A are potent producers of a protein, granulocyte-macrophage colony-stimulating factor, or GM-CSF, that is a cytokine, a molecule that evokes an immune response and inflammation in tissues. So, thinking that GM-CSF might be the key to why differentiation is disrupted, we added antibodies against GM-CSF to a mix of cardiac fibroblasts, IL-17A, and Ly6Clo and found that we could counter IL-17A’s influence on the fibroblasts, and in turn, restore normal Ly6Clo monocyte-to-macrophage differentiation,”

The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis


Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6Chi and Ly6Clo cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation.

We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6Chi MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6Clo monocytes resume their differentiation into MHCII+ macrophages. We propose that MHCII+Ly6Clo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae.

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Fight Aging! Newsletter, July 29th 2019

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Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,
please visit:
https://www.fightaging.org/newsletter/

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Contents

  • More Evidence for Defects in the Formation of Autophagosomes to be Important in the Age-Related Decline of Autophagy
  • The Role of mTOR as a Regulator of Lifespan
  • p53, Hsp90β, and Cellular Senescence in Muscle Regeneration and Muscle Aging
  • Fat Cell Exosomes Demonstrated to Impair the Ability of Macrophages to Remove Cholesterol from Blood Vessel Walls
  • Commentary on the Developing UK Government Position on Healthy Longevity
  • Oxidative Stress in the Aging Brain Accelerates the Spread of α-synuclein
  • Myeloid Skew Arises from Age-Related Changes in Bone Marrow Niches
  • PGC-1α as a Target to Treat Age-Related Kidney Disease
  • Hippocampal Neurogenesis in Aging
  • Investigating the Mechanisms of FOXO3 Effects on Longevity
  • A Consistent Transcriptomic Signature of Cellular Senescence
  • An Interview with María Blasco on Telomeres and Telomerase
  • GM1 Reduces Aggregation of α-Synuclein in an Animal Model of Parkinson’s Disease
  • Damage to Lymphatic Vessels Impairs Drainage of Cerebrospinal Fluid with Age
  • Reversing Somatic Mosaicism in Aged Tissue

More Evidence for Defects in the Formation of Autophagosomes to be Important in the Age-Related Decline of Autophagy

https://www.fightaging.org/archives/2019/07/more-evidence-for-defects-in-the-formation-of-autophagosomes-to-be-important-in-the-age-related-decline-of-autophagy/

Autophagy is a collection of cellular maintenance processes that act to recycle damaged structures in the cell, thereby maintaining cell health and function. On the one hand, the efficiency of autophagy declines with age, and this loss of function is associated with numerous age-related diseases, particularly of the central nervous system and its population of very long-lived neurons. On the other hand, increased autophagy is an important component of many of the interventions shown to slow aging in short-lived species, such as via calorie restriction. A fair number of research groups are working on ways to upregulate autophagy in our species, but this has been going on for a while with little concrete movement towards the clinic.

Autophagy is a complicated process of multiple steps, and at every step there are plausible proximate causes for a faltering of the system with age. The formation of autophagosomes to encapsulate materials to be recycled can break down, as is the case in today’s open access paper. The mechanisms by which autophagosomes are transported to a lysosome for deconstruction of their contents are degraded. The lysosome itself becomes filled with metabolic waste that it struggles to break down, making it bloated and inefficient.

In the case of defects relating to autophagosomes it is unclear as to why the breakage happens, how it relates to the underlying molecular damage that causes aging. Given this, approaches to therapy tend to focus on overriding proximate changes. Researchers find regulatory systems that can be adjusted in order to force the relevant mechanism to work despite its normal reaction to systemic damage in and around cells. In principle this should always be worse as a strategy than identifying and repairing the damage, but it can produce benefits in some cases. In the example here, researchers find a way to override the failure to form autophagosomes that is observed in old neurons.

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons


Unlike most of the cells in our body, our neurons are as old as we are: while other cell types are replaced as they wear out, our neurons must last our entire lifetime. The symptoms of disorders such as Alzheimer’s disease and ALS result from neurons in the brain or spinal cord degenerating or dying. But why do neurons sometimes die?

One reason may be that elderly neurons struggle to remove waste products. Cells get rid of worn out or damaged components through a process called autophagy. A membranous structure known as the autophagosome engulfs waste materials, before it fuses with another structure, the lysosome, which contains enzymes that break down and recycle the waste. If any part of this process fails, waste products instead build up inside cells. This prevents the cells from working properly and eventually kills them.

Aging is the major shared risk factor for many diseases in which brain cells slowly die. Could this be because autophagy becomes less effective with age? Researcher isolated neurons from young adult, aging and aged mice, and used live cell microscopy to follow autophagy in real time. The results determined that autophagy does indeed work less efficiently in elderly neurons. The reason is that the formation of the autophagosome stalls halfway through. However, increasing the amount of one specific protein, WIPI2B, rescues this defect and enables the cells to produce normal autophagosomes again.

As long-lived cells, neurons depend on autophagy to stay healthy. Without this trash disposal system, neurons accumulate clumps of damaged proteins and eventually start to break down. The results identify one way of overcoming this aging-related problem. As well as providing insights into neuronal biology, the results suggest a new therapeutic approach to be developed and tested in the future.

The Role of mTOR as a Regulator of Lifespan

https://www.fightaging.org/archives/2019/07/the-role-of-mtor-as-a-regulator-of-lifespan/

The mTOR gene is deeply involved in the regulation of cellular activities in response to nutrient sensing. It is also implicated in the many, many changes that occur to slow aging in response to a restricted calorie intake, including processes known to be important to aging such as mitochondrial function and cellular senescence. Given that most research to date on intervention in the aging process has focused on the calorie restriction response and related upregulation of stress response mechanisms, it is no surprise that mTOR has attracted a lot of attention. The first mTOR inhibitor drugs are already going through clinical trials, developed by companies such as resTORbio and Navitor Pharmaceuticals.

It is unfortunate that this strategy for modulating the pace of aging has far larger effects on life span in short-lived species than in long-lived species such as our own: calorie restriction extends life by 40% in mice, but by no more than a few years for us. This is thought to be a consequence of the seasonal nature of famine. A famine lasts a large fraction of a mouse life span, but very little of a human life span, so only the mouse has the evolutionary pressure to develop a large plasticity of life span in response to calorie restriction.

The end result of these factors is that upregulation of stress response mechanisms just doesn’t do as much in our species as it does in mice, or in any other short-lived laboratory species. Thus we shouldn’t expect therapies targeting mTOR to do much more than can already be achieved via the practice of calorie restriction. That means some degree of improved health, as illustrated in clinical trials for immune function in later life, for example, but no great extension of life span.

mTOR as a central regulator of lifespan and aging


Consistent with its role in coordinating protein synthesis, energy metabolism, and autophagy in cancer, emerging evidence suggests that mTOR may act as a central node that orchestrates many aspects of cellular and organismal biology related to aging phenotypes. Inhibition of the mTOR pathway by rapamycin or genetic means has profound effects on life span and age-associated phenotypes across a wide array of organisms. However, the underlying mechanisms are still unclear as it has been reported that during aging mTOR activity is both increased and decreased, depending on, for example, tissue or sex. It was suggested that, in spite of these variations, overall aging does not result in a generalized increase in mTOR signaling. If this is the case, it is possible that mTOR activity aligns with the antagonistic pleiotropy theory of aging, whereby its levels are beneficial during development but limit the health span in adult life.

Owing to its central role in age-related processes, mTOR represents an appealing target to ameliorate age-related pathologies. Despite its capacity to expand life span, the function of rapamycin (and of rapalogs) as an immunosuppressant might be of concern, as a decline in immune function (immunosenescence) already occurs in the elderly, leading to infection-related morbidity and mortality. Intriguingly, several studies in both mice and humans suggest that mTOR inhibitors could reduce immunosenescence. In mice, rapamycin can restore the self-renewal and hematopoiesis of hematopoietic stem cells and enable effective vaccination against the influenza virus. A randomized trial testing the effects of rapalog RAD001 in a cohort of healthy elderly patients also showed an enhanced response to the influenza vaccination.

Another limitation of rapamycin is that its chronic exposure in mice leads to mTORC2 inhibition in, for example, hepatocytes. Active-site mTOR inhibitors also inhibit mTORC2. Strikingly, selective suppression of mTORC2 reduces life span and is associated with changes in endocrinology and metabolism (for example, insulin resistance), which have a negative impact on health span. Thus, developing specific inhibitors which effectively suppress all mTORC1 outputs, but do not exert a major effect on mTORC2, appears to be warranted as a strategy to target age-related pathologies and improve health span. Interestingly, in a recent trial of healthy elderly patients, the combination of low-dose RAD001 (rapalog) and BEZ235 (dual mTOR/PI3K catalytic inhibitor) was proposed to selectively inhibit mTORC1 and not mTORC2 and led to enhanced immune function and a reduction in infections. However, it is important to note that complete inhibition of mTORC1 can be deleterious.

Biguanides (for example, metformin) are pharmaceuticals which are thought to have a beneficiary effect (in aging) that indirectly impinges on mTOR. Metformin is a first-line anti-diabetic drug which has been used for more than 60 years in the clinic and has very few side effects. It was shown to modulate life span in model organisms, to affect several processes dysregulated in aging (for example, cellular senescence, inflammation, autophagy, and protein synthesis), and to improve cognitive function and neurodegeneration in humans. By inhibiting mitochondrial complex I, metformin causes energetic stress which results in mTORC1 inhibition through AMPK-dependent and independent mechanisms.

Although many studies have uncovered possible targets of metformin action in the cell in the context of aging, the full extent of metformin’s mechanism of action at the cellular and organismal levels is still incompletely understood. Nonetheless, clinical trials in which metformin is used to improve health span or aging-related conditions are being proposed. For instance, in the TAME (targeting aging with metformin) clinical trial, a placebo-controlled multi-center study of about 3000 elderly patients who are 65 to 79 years old, the effects of metformin on the development of age-associated outcomes like cardiovascular events, cancer, dementia, and mortality will be monitored.

p53, Hsp90β, and Cellular Senescence in Muscle Regeneration and Muscle Aging

https://www.fightaging.org/archives/2019/07/p53-hsp90%ce%b2-and-cellular-senescence-in-muscle-regeneration-and-muscle-aging/

Senescent cells are a mechanism of aging, but also a mechanism of regeneration. When entering a senescent state, a cell shuts down replication and begins to secrete a mix of inflammatory and other signals, rousing the immune system and altering the behavior of surrounding cells. In addition to the other ways in which cells become senescent, in response to the Hayflick limit on cellular replication, or to potentially cancerous DNA damage, senescent cells also arise in response to injury. Their secretions help to guide the complicated dance of immune cells, stem cells, and somatic cells that takes place during the consequent regeneration. Afterwards, the senescent cells self-destruct via apoptosis, or are destroyed by the immune system.

Unfortunately, it is never the case that all senescent cells are destroyed. Those resulting from injury are a tiny fraction of the somatic cells that become senescent on reaching the Hayflick limit, but we can still hypothesize that cellular senescence is important in, say, the way in which joint injuries can become lasting disabilities, or bring on early arthritis. As lingering senescent cells accumulate in tissues, secreted signals that are beneficial in the short term become instead the cause of chronic inflammation and disruption of normal tissue function. Senescent cells are thus a cause of aging, and we will all benefit from therapies capable of removing those that linger in our bodies.

Today’s open access paper is an example of the widespread and ongoing deeper investigations of the biochemistry of senescent cells. The present growth of a biotechnology development community focused on producing therapies to destroy senescent cells helps to ensure that ever more funding is provided for fundamental research. In the present environment any novel examination of cellular senescence might turn up mechanisms that can give rise to startup biotechnology companies, which tends to encourage more such research. In this case the focus is on one of the many protein interactions underlying the behavior of senescent cells in muscle regeneration and aging.

Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration


Skeletal muscle acts as a key regulator of systemic aging in humans. The negative effects of senescence on skeletal muscle were recognized since loss of muscle mass during aging results in frailty and decrease in life qualify. Reduction of quiescent muscle stem cells through senescence leads to the decline in muscle regeneration in aged mice. It is noteworthy that the senescence-associated secretory phenotype (SASP) plays a key role in regulating the beneficial action of senescence during tissue regeneration.

Notably, transient, but not aberrant or prolonged, exposure to the SASP enhances stemness and induces cell plasticity, both of which are beneficial for regeneration. However, a p53-dependent persistent senescence impairs muscle repair, indicating that the accurate temporal regulation of p53-induced senescence is pivotal for ensuring accomplishment of muscle regeneration. Interestingly, a recent report showed that activated Notch-p53 is important for the expansion of muscle stem cell in aged animal. Moreover, p53 also regulates the balance between myoblast differentiation and quiescence. These findings indicate that the roles of p53 in modulating muscle homeostasis are complicated.

Here, we found that Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90β-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90β interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90β in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.

Fat Cell Exosomes Demonstrated to Impair the Ability of Macrophages to Remove Cholesterol from Blood Vessel Walls

https://www.fightaging.org/archives/2019/07/fat-cell-exosomes-demonstrated-to-impair-the-ability-of-macrophages-to-remove-cholesterol-from-blood-vessel-walls/

Carrying excess visceral fat tissue, the fat packed around organs in the abdomen, accelerates all of the common conditions of aging. This is most likely largely mediated by chronic inflammation, the overactivation of the immune system that fat tissue produces. Numerous mechanisms contribute to this inflammation: fat tissue generates an outsized number of lingering senescent cells that secrete inflammatory signals; dying fat cells produce DNA debris that triggers an immune response; fat cells burdened by a lot of lipids generate similar signals to those released by infected cells; and so forth.

Chronic inflammation is particularly important in the progression of atherosclerosis. Cholesterols in the bloodstream find their way into blood vessel walls, and must be removed by the innate immune cells known as macrophages, which hand off the cholesterol to high-density lipoprotein (HDL) particles for it to be carried back to the liver for excretion. With age, rising levels of inflammation and oxidative stress generate ever more oxidized cholesterols, and these damaged molecules, particularly 7-ketocholesterol, cause macrophages to become dysfunctional. Further, chronic inflammation causes macrophages to act inappropriately, becoming inflammatory themselves rather than usefully engaging in removing cholesterol from blood vessel tissue. The result is fatty lesions, formed of cholesterols and the debris of dead macrophages, overwhelmed trying to help. The more inflammatory signaling there is, the more macrophages are called in to their doom.

In the research results I’ll point out today, scientists have found another way in which fat tissue can degrade the ability of macrophages to remove cholesterol from blood vessel walls, operating independently of inflammatory mechanisms. Exosomes, a form of membrane-bound extracellular vesicle packed with signal molecules, are released by fat cells and, when taken up by macrophages, impair the ability of those macrophages to carry out the action of passing a cholesterol molecule to an HDL particle. While the study was carried out in young people, I would expect the mechanism to operate in older individuals as well. There are already countless very good reasons to avoid becoming fat: it is arguably the case that being overweight literally accelerates the aging process. Nonetheless, here is another one.

MicroRNAs from human fat cells can impair macrophage ability to eliminate cholesterol


In atherosclerosis, blood vessels that carry oxygen-rich blood throughout the body become inflamed, and macrophages settle in the vessel wall and become overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away. Extracellular vesicles (EVs) seemed likely troublemakers since they enable intercellular communication. “We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol. Fat isn’t just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world.”

Because heart disease can have its roots in adolescence, the researchers enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the “lean” group, 15 youth whose BMI was lower than 22 and the “obese” group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. The researchers collected visceral adipose tissue during abdominal surgeries. “We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight. It’s still an open question whether young people who are healthy can tolerate obesity – or whether there are specific differences in fat tissue composition that up kids’ risk for heart disease.”

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs


Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide. Although primarily a disease of adults, youth with obesity show evidence of subclinical ASCVD which places them at increased risk as adults for coronary heart disease and stroke. The mechanisms by which obesity confers cardiovascular risk are not fully understood, but inflammation within visceral adipose tissue (VAT) is thought to be contributory. Further, the impact of excess adipose tissue on distal sites such as arterial wall monocytes/macrophages, direct participants in ASCVD, are also thought to contribute to disease pathogenesis.

In this study we show, for the first time, significant alterations in cholesterol efflux capacity in adolescents throughout the range of BMI, a relationship between six circulating adipocyte-derived EVs microRNAs targeting ABCA1 and cholesterol efflux capacity, and in vitro alterations of cholesterol efflux in macrophages exposed to visceral adipose tissue adipocyte-derived EVs acquired from human subjects. These results suggest that adipocyte-derived EVs, and their microRNA content, may play a critical role in the early pathological development of ASCVD.

Commentary on the Developing UK Government Position on Healthy Longevity

https://www.fightaging.org/archives/2019/07/commentary-on-the-developing-uk-government-position-on-healthy-longevity/

One option for patient advocacy for the treatment of aging as a medical condition is to petition governments and large international organizations such as the World Health Organization to adjust their positions on research funding and goals in medicine. This a fairly popular path, for all that I think it not terribly effective at speeding up the cutting edge of research and development. Large organizations of any sort are inherently conservative, and tend to get meaningfully involved in new fields of human endeavor only long after their support would have been truly influential.

Nonetheless, numerous examples of government focused initiatives have emerged from our community over the past decade. They include the Longevity Dividend initiative, petitioning the US government for greater public funding for translational aging research; the small single issue political parties focused on longevity in Germany, Russia, and elsewhere; efforts to influence the contents of the International Classification of Diseases produced by the World Health Organization, in order to classify aging as a disease; and so forth. In recent years, an informal collaboration between advocates, investors, and others in the UK has been making inroads into influencing thinking on aging and longevity in government circles in that country. One of their successes is noted here.

Success, yes, and somewhat more than has been achieved elsewhere. Nonetheless, progress in these efforts in any part of the world tends to be painfully slow and incremental. Persuading bureaucrats to think about making a formal goal of the addition of just a few years to life expectancy over the next few decades is considered a victory. But this is far too little. We live now in an era of biotechnology in which much larger gains in life expectancy are possible and plausible given sufficient investment in research and development. The implementation of rejuvenation therapies, of which senolytic treatments to clear senescent cells are only the first, will up-end all these minor expectations of a few years here and a few years there. That should be the goal.

UK Government Prioritizes Healthy Longevity as a Major National Priority in New Green Paper


This week the UK Government published the green paper of its Preventive Medicine National Strategy, entitled “Advancing our health: prevention in the 2020s – consultation document”. In practice, this indicates that the UK will be the first country to officially implement P4 (Personalized, Preventive, Precision and Participatory) medicine into its national healthcare system.

This is the newest development in a series of large steps that the UK government has made in recent years towards the development of a proactive, progressive and technology-driven national Healthy Longevity development strategy, beginning with the formation of the Ageing Industrial Grand Challenge (prioritizing the problem of ageing population as one of four key national industrial development challenges for the nation) in 2017, followed by the launch of the 98 million Government-led Healthy Ageing Industrial Strategy Challenge Fund in 2018, and the launch of the All-Party Parliamentary Group for Longevity in 2019.

These are some of the major factors that led to the UK being ranked first in Aging Analytics Agency’s National Longevity Development Plans analytical report, which used quantitative metrics to rank the strength, proactivity and relevance of various nations’ Longevity development projects and initiatives.

Advancing our health: prevention in the 2020s – consultation document


Thanks to developments in public health and healthcare, we’ve made great progress in helping people to live longer lives. For example, life expectancy has increased by almost 30 years over the past century. Cancer survival rates are up and mortality rates from heart disease and stroke are down. However, these improvements in life expectancy are beginning to slow, and over 20% of years lived are expected to be spent in poor health.

Last year, the government set a mission as part of the Ageing Society Grand Challenge to “ensure that people can enjoy at least 5 extra healthy, independent years of life by 2035, while narrowing the gap between the experience of the richest and poorest”. The green paper proposals will not deliver the whole ‘5 years’. But they will help us towards achieving this mission. Further details on this will be provided later in the year, through a government response to the green paper.

Oxidative Stress in the Aging Brain Accelerates the Spread of α-synuclein

https://www.fightaging.org/archives/2019/07/oxidative-stress-in-the-aging-brain-accelerates-the-spread-of-%ce%b1-synuclein/

Parkinson’s disease, like many neurodegenerative conditions, is associated with the age-related aggregation of a specific protein, in this case α-synuclein. The protein aggregates have a halo of harmful biochemistry, causing dysfunction and cell death in neurons. Researchers here propose that the increased levels of oxidative stress observed in old tissues spur the spread of α-synuclein protein aggregates from cell to cell as the disease progresses. Oxidative stress can arise from mitochondrial dysfunction, as mitochondria produce oxidative molecules as a byproduct of their normal operation, but is also associated with chronic inflammation. Both are also features of aging and thought to be important in the progression of neurodegenerative conditions.


At the microscopic and pathological levels, Parkinson’s disease is characterized by accumulation of abnormal intraneuronal inclusions. They are formed as a result of aggregation of a protein called α-synuclein. In the course of the disease, these inclusions progressively appear in various brain regions, contributing to the gradual exacerbation of disease severity. The mechanisms behind this advancing pathology are poorly understood. Research now indicates that oxidative stress, i.e. an excessive and uncontrolled production of reactive oxygen species, could play an important role in the pathological spreading of α-synuclein.

In a series of experiments, researchers studied mice that overproduced α-synuclein in a specific brain region, namely the dorsal medulla oblongata, known to be a primary target of α-synuclein pathology in Parkinson’s disease. Under this condition, the researchers were able to show oxidative stress, formation of small α-synuclein aggregates (so called oligomers) and neuronal damage. Increased production of α-synuclein also led to its “jump” from donor neurons in the medulla oblongata into recipient neurons in neighboring brain regions that became affected by progressive α-synuclein accumulation and aggregation.

Interestingly, treatment of mice with paraquat, a chemical agent that generates substantial amounts of reactive oxygen species and thus triggers an oxidative stress, exacerbated α-synuclein pathology and resulted in its more pronounced spreading throughout the brain. “Our findings support the hypothesis that a vicious cycle may be triggered by increased alpha-synuclein burden and oxidative stress. Oxidative stress could promote the formation of alpha-synuclein aggregates which, in turn, may exacerbate oxidative stress. Jumping from neuron to neuron, this toxic process could affect more and more brain regions and contribute to progressive pathology and neuronal demise.”

Myeloid Skew Arises from Age-Related Changes in Bone Marrow Niches

https://www.fightaging.org/archives/2019/07/myeloid-skew-arises-from-age-related-changes-in-bone-marrow-niches/

Hematopoietic stem cells (HSCs) resident in bone marrow generate immune cells, and their activity is thus vital to the correct function of the immune system. Like all stem cell populations, HSCs are sustained by a niche of supporting cells. One of the interesting questions relating to the aging of stem cells and the decline of stem cell activity in later life is whether this is a problem inherent to the stem cells themselves, or it arises from change and damage in the niche. There is evidence for both to be the case, but it is possible to argue that, until extreme old age, the loss of activity is more a matter of the niche than actual incapacity on the part of stem cells.

One of the ways in which HSC behavior changes with age, and that alters the immune system for the worse, is that ever more myeloid and ever fewer lymphoid daughter cells are created. This myeloid skew is a well studied phenomenon, but as for all complex systems in the body, the causes and their relations to one another are much debated. Here, researchers discuss some specific mechanisms in the HSC niches in the bone marrow that may contribute to this phenomenon.


Hematopoietic aging is characterized by expansion of hematopoietic stem cells (HSCs) with impaired function, such as reduced engraftment, quiescence, self-renewal, unfolded protein response, and lymphoid differentiation potential, leading to myeloid-biased output both in mice and humans. Myeloid malignancies are more frequent in the elderly, but whether changes in the aged HSCs and/or their microenvironment predispose to these malignancies remains unclear.

Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological or natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the bone marrow microenvironment promotes myelopoiesis in premature and physiological aging.

During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased bone marrow noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal or premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.

PGC-1α as a Target to Treat Age-Related Kidney Disease

https://www.fightaging.org/archives/2019/07/pgc-1%ce%b1-as-a-target-to-treat-age-related-kidney-disease/

The research reviewed here is a great example of the presently dominant paradigm in efforts to treat age-related disease. Scientists analyze the disease state, find regulator proteins that are differently expressed in normal and diseased tissue, and look for ways to force expression in diseased tissue to look more like that of normal tissue. There is no consideration of trying to fix the underlying molecular damage that caused this change. It is a little like pressing the accelerator harder in a car with a failing engine. This strategy is why most efforts to treat age-related disease in the past have either failed or produce only minor benefits. Without fixing the underlying damage, it will continue to cause all of the downstream consequences that lead inexorably to failure of tissue function and death.


Aging is a progressive disruption of the homeostasis of physiological systems with age. It results in structural destruction, organ dysfunction, and increased susceptibility to injuries and diseases. The kidney is one of the most susceptible organs to aging. Aging-associated complications can lead to kidney dysfunction, including a decreased glomerular filtration rate, tubular dysfunction, and glomerulosclerosis. Furthermore, kidney aging has important implications for aging-associated comorbidities, especially cardiovascular diseases.

While the molecular mechanism underlying kidney aging remains unclear, chronic kidney disease (CKD) shares many phenotypic similarities with aging, including cellular senescence, fibrosis, vascular rarefaction, loss of glomeruli, and tubular dysfunction. The pathogenic mechanisms involved in CKD may thus provide insight into the molecular pathways leading to kidney aging. They might also provide potential targets against kidney aging.

Recent efforts to overcome aging have shifted from the discovery of risk factors to the determination of endogenous protective factors that might neutralize the adverse effects of aging. Among the various endogenous protective factors reported are AMP-activated protein kinase (AMPK), fibroblast growth factor 21 (FGF21), insulin, and vascular endothelial growth factor (VEGF).

Recent studies have shown that aging-related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose metabolism and lipid metabolism. PGC-1α is abundant in tissues, including kidney proximal tubular epithelial cells, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC-1α by genetic or pharmacological means prevents telomere shortening and aging-related changes in the skeletal muscle, heart, and brain. The activation of PGC-1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC-1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

Hippocampal Neurogenesis in Aging

https://www.fightaging.org/archives/2019/07/hippocampal-neurogenesis-in-aging/

In at least some portions of the brain, new neurons are created throughout life in a process called neurogenesis. This is vital to memory and learning, but declines with age. Faltering neurogenesis is arguably implicated in the development of some neurodegenerative conditions. As most of the evidence for neurogenesis in adult individuals has been established in mice, and in recent years there has been some debate over whether or not these same processes do in fact operate in humans. So far, the most recent evidence leans towards supporting the existence of human adult neurogenesis. Given this, the research community remains interested in developing means of increasing the pace of neurogenesis as a basis for therapies to enhance cognitive function in the old, but progress towards this goal remains slow.


Adult hippocampal neurogenesis has been proposed to be a key element in ensuring and maintaining functional hippocampal integrity in old age. Neurodegenerative diseases due to the age-dependent rapid and continuous loss of neurons (such as Parkinson’s disease and Huntington’s disease) have been suggested to reflect the contraposition of the neurogenic process such that under homoeostatic conditions a fine balance between neurodegeneration and neuroregeneration exists, and under pathological conditions, the balance is disturbed and a disease manifests. Even though little evidence has accumulated in support of this theory, if it proves correct, it in combination with findings regarding the high potential of stem-cell-based strategies for the treatment of age-related neurodegenerative disorders, make the hypothesis that adult neurogenesis holds a key to novel therapeutic approaches in the treatment of age-related neurodegenerative disorders rather attractive.

Decreased hippocampal neurogenesis is proposed as an important mechanism underlying age-related cognitive decline as well as neurodegenerative disorders such as Alzheimer’s disease (AD) and various types of dementia. Evidence in this regard was recently published in two separate recent studies examining hippocampal neurogenesis in human tissue from people suffering mild cognitive impairment and AD. Both studies demonstrated a dramatic decrease in the number of neural progenitor cells and neuroblasts in hippocampal tissue from AD patients which was related to the stage of the disease. Interestingly, a decrease in the number of newborn neurons was observed in AD patients at the very early stage of the disease when the characteristic neurofibrillary tangles and senile plaques had not become prevalent. This suggests a potential for using neurogenesis levels as an early biomarker of the disease.

The mechanisms underlying the age-related decline in hippocampal neurogenesis remain poorly understood. It has been proposed that within the senescent brain the neurogenic niche may be deprived of the extrinsic signals regulating the neurogenic process or that the aged neural progenitor cells are less responsive to normal signalling within the niche, or both. The evidence accumulated thus far points to changes in the properties of the neurogenic niche with age, rather than changes in the phenotype of the stem cells or progenitor cells themselves. For instance, it has been reported that the numbers of neural stem cells and neural progenitor cells as well as the proportion of astrocytes to neurons in the hippocampus of young and aged rats remained the same; however, there was a decrease in the number of cells actively undergoing mitosis in the aged animals.

Investigating the Mechanisms of FOXO3 Effects on Longevity

https://www.fightaging.org/archives/2019/07/investigating-the-mechanisms-of-foxo3-effects-on-longevity/

The relationship between normal genetic variations and consequence differences in life expectancy is enormously complex. Countless genetic variations have tiny, contingent, interacting effects on health and late life resilience to the damage of aging. Correlations found in epidemiological studies are rarely replicated between study populations. FOXO3 is one of the very small number of genes for which effects on longevity are found in multiple species and human populations. These effects are not large: a modestly increased chance of living longer. It is also worth noting recent research that downgraded the expected size of effect for FOXO3 based on more rigorous assessment of data. Here, researchers discuss some of the low-level mechanisms that might explain this association.


Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs.

FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes.

Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.

A Consistent Transcriptomic Signature of Cellular Senescence

https://www.fightaging.org/archives/2019/07/a-consistent-transcriptomic-signature-of-cellular-senescence/

As numerous senolytic therapies to clear senescent cells continue their progress towards the clinic, the research and development communities find themselves in ever greater need of better biomarkers for cellular senescence. Those that presently exist, such as staining tissue samples for senescence-associated β-galactosidase, are good enough for much of the present scope of research use, but not a suitable basis for either clinical assays or more sophisticated investigation of the mechanisms of senescence. As (a) there are numerous paths by which cells become senescent, prompted by different circumstances, and (b) senescence may vary in other ways between tissue types, and (c) different senolytics have different degrees of effectiveness across these varied classes and cells, it is the case that better and more consistent biomarkers would help to speed progress in this field.


Senescence is a state of indefinite growth arrest. It can be induced by various sublethal stresses, including telomere shortening, genomic injury, epigenomic damage and signaling from oncoproteins. Senescence is also characterized by a senescence-associated secretory phenotype (SASP) whereby cells produce and secrete pro-inflammatory cytokines. Senescence is beneficial for tissue remodeling, embryonic development, wound healing, and tumor suppression in young individuals. However, in old individuals it promotes aging-associated declines and diseases.

Progress to identify senescent cells in order to exploit them therapeutically has been hampered by a lack of robust and universal measurable traits. Thus far, senescence has been studied in a range of cell types induced by diverse triggers such as replicative exhaustion, DNA damage, oxidation and other stress conditions like signaling through oncoproteins. Due to this heterogeneity, finding broad biomarkers of senescence has been challenging and senescent cells are currently found through the combined detection of multiple biochemical markers such as p16, p53, p21 and SA-βGal, despite the fact that they are not exclusively nor consistently induced in senescence.

In this study, we sought to identify universally expressed transcripts across various senescent cell models. We performed RNA sequencing (RNA-seq) analysis after triggering senescence in human WI-38 and IMR-90 fibroblasts, human umbilical vein endothelial cells (HUVECs) and human alveolar endothelial cells (HAECs) through replicative exhaustion (WI-38, IMR-90), exposure to ionizing radiation (WI-38, IMR-90, HUVEC, HAEC) or doxorubicin (WI-38) or expression of an oncogene (oncogene-induced senescence, OIS) (WI-38). Comparisons of all the patterns of expressed transcripts revealed 68 RNAs that were increased (50 RNAs) or decreased (18 RNAs) across all senescence models, although a mimimum of 5 RNAs were sufficient to identify senescent cells bioinformatically. Most RNAs altered during senescence were protein-coding transcripts, but the long non-coding RNA PURPL (p53-upregulated regulator of p53 levels) was one of the most strikingly elevated transcripts.

An Interview with María Blasco on Telomeres and Telomerase

https://www.fightaging.org/archives/2019/07/an-interview-with-maria-blasco-on-telomeres-and-telomerase/

The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed María Blasco, on the occasion of her presentation at the Ending Age-Related Diseases conference in New York earlier this month. Blasco is one of the leading researchers in the field of telomere biology, particularly the role of telomerase and the prospects for developing telomerase gene therapies to slow aging by lengthening telomeres globally throughout the body. This should have the effect of putting damaged cells back to work, resulting in better tissue maintenance and function, but quite possibly at the cost of increased cancer risk.

Telomerase gene therapy works to achieve this goal in mice, extending life and actually reducing cancer risk, possibly because of improved immune suppression of cancer overwhelming any increased generation of cancerous cells. There is some debate over whether or not the same approach will be safe in humans. Humans and mice have very different telomere dynamics, and the balance of effects may or may not be similar. It seems likely that we’ll find out the direct way as human trials and clinical therapies become more widespread over the next decade.


You and your team recently showed that it is the rate of telomere shortening that predicts the lifespan of a species rather than the total length of telomeres. Does this discovery confirm the role of telomere attrition as a primary cause of aging rather than a consequence?

I think this study that means that telomeres are important in determining a species’ longevity. It’s not something that happens only in humans, where it’s already clear that in humans, telomere length matters, because there are humans that have mutations in telomerase, and they are going to have diseases associated with telomere shortening, which means that telomere shortening rates are very limiting for humans. We didn’t know whether this was general to other species or only something particular to humans. In this study, we see that telomeres seem to matter across evolution in different species, from birds to mammals. It’s not the telomere length that matters but the rate of telomere shortening. So, we see that the rate of telomere shortening actually fits into a power law curve, and this predicts the longevity of a given species.

Could it mean that telomere shortening rate could be a suitable aging biomarker to test interventions against aging with?

I think so; telomere shortening rate is important in humans in order to determine if anyone is at risk of prematurely developing diseases associated with short telomeres. It’s not as important to measure telomeres once, because this probably is not going to be very informative, but the rate at which telomeres shorten may be more informative of the risk of developing any disease related to short telomeres.

Telomerase has many effects that are independent of telomeres. Can you see that they matter in aging?

Well, it is interesting because we have, in the past, demonstrated that we can extend the lifespan of mice by using telomerase, but it must be wild-type telomerase; if we use catalytically dead telomerase, then we don’t see this lifespan extension. So I would say that in order to see effects of telomerase in lifespan, you need it to be catalytically active telomerase, and this is the canonical pathway of telomerase, which is elongating the telomeres. At least in our hands, this is the mechanism by which telomerase can increase longevity: by extending short telomeres.

Would you say that the telomere mechanisms and the dynamics are really that different between mice and people?

I think humans and mice are not that different. What is very different is the rate at which mice experience shortening telomeres, or in other words, mice are much worse than humans at maintaining their telomeres. So, I think this makes a difference. So mice shorten their telomeres really fast, we still don’t understand why compared to humans, but now we also know that different species shorten their telomeres at different rates, and I think it’s very interesting to study that. We don’t know why. For example, the elephant and the flamingo have the same rate of telomere shortening and they have similar longevity; why is that? Then a mouse has a much faster rate of telomere shortening and a shorter longevity. I think this is a very interesting question to solve in the future.

GM1 Reduces Aggregation of α-Synuclein in an Animal Model of Parkinson’s Disease

https://www.fightaging.org/archives/2019/07/gm1-reduces-aggregation-of-%ce%b1-synuclein-in-an-animal-model-of-parkinsons-disease/

Parkinson’s disease, like most other neurodegenerative conditions, is characterized not just by chronic inflammation and cell death, but also by protein aggregation. Solid deposits of α-synuclein form in the brain, bringing with them a halo of toxic biochemistry that harms and kills neurons. It is expected that finding ways to clear these aggregates will prove to be an effective treatment for the condition, though there remain questions about the ordering of cause and effect. Does chronic inflammation or mitochondrial dysfunction lead to protein aggregation, or vice versa? As is usually the case, the easiest way to answer these questions is to clear the aggregates in a good disease model, or in the real thing in human patients, and see what happens.


Scientists have investigated the therapeutic potential of GM1 in Parkinson’s disease for nearly 30 years. Previous research showed that Parkinson’s patients have less GM1 than healthy patients in the part of the brain most affected by Parkinson’s, the substantia nigra. Other researchers followed this work to show in cell culture models that GM1 interacts with a protein called alpha-synuclein. In Parkinson’s disease, alpha-synuclein can form clumps, which can become toxic to brain cells in the substantia nigra and lead to cell death.

In new work, researchers have shown that giving daily GM1 doses to animals that overproduce alpha-synuclein inhibits the toxic effects of the protein. “When we looked in the brains of these animals, not only did we find we could partially protect their dopamine neurons from the toxic effects of alpha synuclein accumulation, we had some evidence that these animals had smaller and fewer aggregates of alpha-synuclein than animals that received saline injection instead of GM1.” In addition to protecting brain cells from death, the treatment also reversed some early motor symptoms.

The researchers suspect that less GM1 in the brains of Parkinson’s disease patients may facilitate the aggregation of alpha-synuclein and increase its toxicity. “By increasing GM1 levels in the brains of these patients, it would make sense that we could potentially provide a slowing of that pathological process and a slowing of the disease progression, which is what we found previously in a clinical trial of GM1 in Parkinson’s disease patients.” The team is now following up on their results to find out what other effects GM1 might have on alpha-synuclein.

Damage to Lymphatic Vessels Impairs Drainage of Cerebrospinal Fluid with Age

https://www.fightaging.org/archives/2019/07/damage-to-lymphatic-vessels-impairs-drainage-of-cerebrospinal-fluid-with-age/

Impaired drainage of cerebrospinal fluid (CSF) with age is a hot topic in the field of neurodegeneration at the moment. In younger individuals, passage of CSF out of the brain via a number of routes is thought to provide a way to maintain normally low levels of metabolic waste, such as the amyloid-β associated with Alzheimer’s disease. Reduced fluid flow due to the damage and dysfunction of aging then contributes to the raised levels and aggregation of these waste products, and thus to neurodegenerative conditions. A number of companies are developing therapies based on this vision of brain aging, such as Leucadia Therapeutics. Thus we should expect to see impaired CSF drainage decisively proven or disproven as a major cause of neurodegeneration in clinical trials over the next few years. Even in advance of those trials, the evidence to date is quite compelling, however.


Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain’s cleansing mechanism. Scientists have now reported the basal side of the skull as the major route, so called “hotspot” for CSF drainage. They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain’s major drainage system, specifically basal mLVs are impaired with aging.

Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question – where is the main exit for the CSF? Though mLVs in the upper part of the skull were reported as the brain’s clearance pathways in 2014, no substantial drainage mechanism was observed in that section.

The researchers used several techniques to characterize the basal mLVs in detail and verified that specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs.

It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. By mapping out a precise route for the brain’s waste clearance system, this study may be able to help find ways to improve the brain’s cleansing function, enabling a new strategy for eliminating the buildup of aging-related toxic proteins.

Reversing Somatic Mosaicism in Aged Tissue

https://www.fightaging.org/archives/2019/07/reversing-somatic-mosaicism-in-aged-tissue/

Somatic mosiacism is the tendency for aged tissues to display a mix of mutations, spread through cell lineages from an original mutation in a stem cell or progenitor cell. The consensus in the research community is that this degrades tissue function, contributing to the aging process, but there is a lack of evidence for whether or not this is significant across the present human life span. Clearly eventually it has to become a problem, given ways to deal with all of the other aspects of aging, but without a grasp of the size of the effect, it is hard to say whether or not this issue should be targeted now or later.

How does one go about repairing somatic mosiacism in any case? This is a tough question. Repairing diverse mutations in living tissue is possible in the grand scheme of things, given sufficiently advanced molecular nanotechnology, but it is possible with the tools of the next twenty years or so? That would likely mean programmable, highly efficient gene therapies, but in the open access paper here researchers demonstrate that, in the case of at least one gene, there may be other, simpler possibilities.


Normal tissues progressively accumulate cells carrying somatic mutations, some of which are linked to neoplasia and other diseases. This process is exemplified by human esophageal epithelium (EE), in which mutations generated by cell-intrinsic processes colonize the majority of normal epithelium by middle age. The most common mutations are under strong positive selection, meaning that there is an excess of protein altering over silent mutations within each gene. This indicates that these mutations confer a competitive advantage over wild-type cells and drive clonal expansions in normal tissue.

We speculated that, as in other systems of competitive selection, altering the tissue environment may change the relative fitness of particular mutations and their prevalence in the tissue. In this study, we focused on p53 mutations because these are the most enriched during malignant transformation. p53 is mutated in 5%-10% of normal EE but in almost all esophageal squamous cell carcinomas (ESCCs). This argues that ESCC emerges from the p53 mutant cell population in normal epithelium and that mutation of p53 is required for cancer development.

We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue.

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Commentary on the Developing UK Government Position on Healthy Longevity

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One option for patient advocacy for the treatment of aging as a medical condition is to petition governments and large international organizations such as the World Health Organization to adjust their positions on research funding and goals in medicine. This a fairly popular path, for all that I think it not terribly effective at speeding up the cutting edge of research and development. Large organizations of any sort are inherently conservative, and tend to get meaningfully involved in new fields of human endeavor only long after their support would have been truly influential.

Nonetheless, numerous examples of government focused initiatives have emerged from our community over the past decade. They include the Longevity Dividend initiative, petitioning the US government for greater public funding for translational aging research; the small single issue political parties focused on longevity in Germany, Russia, and elsewhere; efforts to influence the contents of the International Classification of Diseases produced by the World Health Organization, in order to classify aging as a disease; and so forth. In recent years, an informal collaboration between advocates, investors, and others in the UK has been making inroads into influencing thinking on aging and longevity in government circles in that country. One of their successes is noted here.

Success, yes, and somewhat more than has been achieved elsewhere. Nonetheless, progress in these efforts in any part of the world tends to be painfully slow and incremental. Persuading bureaucrats to think about making a formal goal of the addition of just a few years to life expectancy over the next few decades is considered a victory. But this is far too little. We live now in an era of biotechnology in which much larger gains in life expectancy are possible and plausible given sufficient investment in research and development. The implementation of rejuvenation therapies, of which senolytic treatments to clear senescent cells are only the first, will up-end all these minor expectations of a few years here and a few years there. That should be the goal.

UK Government Prioritizes Healthy Longevity as a Major National Priority in New Green Paper


This week the UK Government published the green paper of its Preventive Medicine National Strategy, entitled “Advancing our health: prevention in the 2020s – consultation document“. In practice, this indicates that the UK will be the first country to officially implement P4 (Personalized, Preventive, Precision and Participatory) medicine into its national healthcare system.

This is the newest development in a series of large steps that the UK government has made in recent years towards the development of a proactive, progressive and technology-driven national Healthy Longevity development strategy, beginning with the formation of the Ageing Industrial Grand Challenge (prioritizing the problem of ageing population as one of four key national industrial development challenges for the nation) in 2017, followed by the launch of the £98 million Government-led Healthy Ageing Industrial Strategy Challenge Fund in 2018, and the launch of the All-Party Parliamentary Group for Longevity in 2019.

These are some of the major factors that led to the UK being ranked first in Aging Analytics Agency’s National Longevity Development Plans analytical report, which used quantitative metrics to rank the strength, proactivity and relevance of various nations’ Longevity development projects and initiatives.

Advancing our health: prevention in the 2020s – consultation document


Thanks to developments in public health and healthcare, we’ve made great progress in helping people to live longer lives. For example, life expectancy has increased by almost 30 years over the past century. Cancer survival rates are up and mortality rates from heart disease and stroke are down. However, these improvements in life expectancy are beginning to slow, and over 20% of years lived are expected to be spent in poor health.

Last year, the government set a mission as part of the Ageing Society Grand Challenge to “ensure that people can enjoy at least 5 extra healthy, independent years of life by 2035, while narrowing the gap between the experience of the richest and poorest”. The green paper proposals will not deliver the whole ‘5 years’. But they will help us towards achieving this mission. Further details on this will be provided later in the year, through a government response to the green paper.

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p53, Hsp90β, and Cellular Senescence in Muscle Regeneration and Muscle Aging

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Senescent cells are a mechanism of aging, but also a mechanism of regeneration. When entering a senescent state, a cell shuts down replication and begins to secrete a mix of inflammatory and other signals, rousing the immune system and altering the behavior of surrounding cells. In addition to the other ways in which cells become senescent, in response to the Hayflick limit on cellular replication, or to potentially cancerous DNA damage, senescent cells also arise in response to injury. Their secretions help to guide the complicated dance of immune cells, stem cells, and somatic cells that takes place during the consequent regeneration. Afterwards, the senescent cells self-destruct via apoptosis, or are destroyed by the immune system.

Unfortunately, it is never the case that all senescent cells are destroyed. Those resulting from injury are a tiny fraction of the somatic cells that become senescent on reaching the Hayflick limit, but we can still hypothesize that cellular senescence is important in, say, the way in which joint injuries can become lasting disabilities, or bring on early arthritis. As lingering senescent cells accumulate in tissues, secreted signals that are beneficial in the short term become instead the cause of chronic inflammation and disruption of normal tissue function. Senescent cells are thus a cause of aging, and we will all benefit from therapies capable of removing those that linger in our bodies.

Today’s open access paper is an example of the widespread and ongoing deeper investigations of the biochemistry of senescent cells. The present growth of a biotechnology development community focused on producing therapies to destroy senescent cells helps to ensure that ever more funding is provided for fundamental research. In the present environment any novel examination of cellular senescence might turn up mechanisms that can give rise to startup biotechnology companies, which tends to encourage more such research. In this case the focus is on one of the many protein interactions underlying the behavior of senescent cells in muscle regeneration and aging.

Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration


Skeletal muscle acts as a key regulator of systemic aging in humans. The negative effects of senescence on skeletal muscle were recognized since loss of muscle mass during aging results in frailty and decrease in life qualify. Reduction of quiescent muscle stem cells through senescence leads to the decline in muscle regeneration in aged mice. It is noteworthy that the senescence-associated secretory phenotype (SASP) plays a key role in regulating the beneficial action of senescence during tissue regeneration.

Notably, transient, but not aberrant or prolonged, exposure to the SASP enhances stemness and induces cell plasticity, both of which are beneficial for regeneration. However, a p53-dependent persistent senescence impairs muscle repair, indicating that the accurate temporal regulation of p53-induced senescence is pivotal for ensuring accomplishment of muscle regeneration. Interestingly, a recent report showed that activated Notch-p53 is important for the expansion of muscle stem cell in aged animal. Moreover, p53 also regulates the balance between myoblast differentiation and quiescence. These findings indicate that the roles of p53 in modulating muscle homeostasis are complicated.

Here, we found that Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90β-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90β interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90β in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.

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An Interview with María Blasco on Telomeres and Telomerase

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The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed María Blasco, on the occasion of her presentation at the Ending Age-Related Diseases conference in New York earlier this month. Blasco is one of the leading researchers in the field of telomere biology, particularly the role of telomerase and the prospects for developing telomerase gene therapies to slow aging by lengthening telomeres globally throughout the body. This should have the effect of putting damaged cells back to work, resulting in better tissue maintenance and function, but quite possibly at the cost of increased cancer risk.

Telomerase gene therapy works to achieve this goal in mice, extending life and actually reducing cancer risk, possibly because of improved immune suppression of cancer overwhelming any increased generation of cancerous cells. There is some debate over whether or not the same approach will be safe in humans. Humans and mice have very different telomere dynamics, and the balance of effects may or may not be similar. It seems likely that we’ll find out the direct way as human trials and clinical therapies become more widespread over the next decade.


You and your team recently showed that it is the rate of telomere shortening that predicts the lifespan of a species rather than the total length of telomeres. Does this discovery confirm the role of telomere attrition as a primary cause of aging rather than a consequence?

I think this study that means that telomeres are important in determining a species’ longevity. It’s not something that happens only in humans, where it’s already clear that in humans, telomere length matters, because there are humans that have mutations in telomerase, and they are going to have diseases associated with telomere shortening, which means that telomere shortening rates are very limiting for humans. We didn’t know whether this was general to other species or only something particular to humans. In this study, we see that telomeres seem to matter across evolution in different species, from birds to mammals. It’s not the telomere length that matters but the rate of telomere shortening. So, we see that the rate of telomere shortening actually fits into a power law curve, and this predicts the longevity of a given species.

Could it mean that telomere shortening rate could be a suitable aging biomarker to test interventions against aging with?

I think so; telomere shortening rate is important in humans in order to determine if anyone is at risk of prematurely developing diseases associated with short telomeres. It’s not as important to measure telomeres once, because this probably is not going to be very informative, but the rate at which telomeres shorten may be more informative of the risk of developing any disease related to short telomeres.

Telomerase has many effects that are independent of telomeres. Can you see that they matter in aging?

Well, it is interesting because we have, in the past, demonstrated that we can extend the lifespan of mice by using telomerase, but it must be wild-type telomerase; if we use catalytically dead telomerase, then we don’t see this lifespan extension. So I would say that in order to see effects of telomerase in lifespan, you need it to be catalytically active telomerase, and this is the canonical pathway of telomerase, which is elongating the telomeres. At least in our hands, this is the mechanism by which telomerase can increase longevity: by extending short telomeres.

Would you say that the telomere mechanisms and the dynamics are really that different between mice and people?

I think humans and mice are not that different. What is very different is the rate at which mice experience shortening telomeres, or in other words, mice are much worse than humans at maintaining their telomeres. So, I think this makes a difference. So mice shorten their telomeres really fast, we still don’t understand why compared to humans, but now we also know that different species shorten their telomeres at different rates, and I think it’s very interesting to study that. We don’t know why. For example, the elephant and the flamingo have the same rate of telomere shortening and they have similar longevity; why is that? Then a mouse has a much faster rate of telomere shortening and a shorter longevity. I think this is a very interesting question to solve in the future.

Link: https://www.leafscience.org/an-interview-with-dr-maria-blasco/

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