Fight Aging! Newsletter, April 12th 2021

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  • A New Model Suggests a Higher Burden of Death Due to Particulate Air Pollution
  • Delivery of Recombinant Serum Albumin Extends Life Span in Old Mice
  • A View of Early Modern Trends in Longevity Derived from Data on European Scholars
  • Recent Thought on Alzheimer's Disease as a Lifestyle Condition
  • The Latest Data from the Interventions Testing Program: Nicotinamide Riboside has No Effect on Mouse Life Span
  • Measuring Gene Expression Changes in the Brain as a Result of Heart Failure
  • A Feedback Loop Between Chronic Inflammation and Pressure Sensing Drives Osteoarthritis
  • 7.2% of All Deaths Worldwide are Attributable to Physical Inactivity
  • Methionine Restriction Greatly Reduces Measures of Cognitive Decline in Mice
  • Senescent T Cells Cause Changes in Fat Tissue that are Harmful to Long-Term Health
  • Regular Exercise Reduces Measures of Immunosenescence in Old Individuals
  • A Non-Invasive Biomarker to Measure the Effectiveness of Senolytic Drugs
  • Better Diet and Regular Exercise Improve Cardiometabolic Health in Later Life
  • Blood-Brain Barrier Dysfunction Predicts Progression of Cerebral Small Vessel Disease
  • Mesenchymal Stem Cell Derived Extracellular Vesicles Slow the Accelerated Aging of Progeroid Mice

A New Model Suggests a Higher Burden of Death Due to Particulate Air Pollution

Particulate air pollution is generally agreed upon to be harmful to long-term health, particularly from sources prevalent in poorer regions of the world such as the smoke from wood fires used for cooking. Exposure to these airborne particles raises the burden of chronic inflammation, thus accelerating the onset and progression of all of the common age-related diseases, including cardiovascular disease and dementia, and increasing age-related mortality. The mechanism is fairly cut and dried, but the size of the effect on mortality is up for debate, as is often the case. Just how many deaths does it cause?

In today's research materials, researchers report on the outcome of using updated models of mortality risk due to particular exposure. They argue that the data of recent years shows that low doses of particulates are worse than thought, while the increasingly negative effects at high doses do not plateau as early as thought. Applying this to the model gives a much greater impact of particulate air pollution on human mortality than previously though. This is nonetheless a model, in which the many different connecting parts can be adjusted one way or another based on underlying arguments for the right or wrong way to do it. This paper is one position in an ongoing debate of many positions on the topic. It is not a great plan to sit in front of a wood fire every day, but it remains hard to pin down just how bad this is.

Pollution from fossil fuel combustion deadlier than previously thought

A new study found that fine particulate pollution generated by the burning of fossil fuels was responsible for one in five early deaths worldwide in 2018-far more than previously thought. The people most at risk are those "who can least afford it." The study found that, worldwide, 8 million premature deaths were linked to pollution from fossil fuel combustion, with 350,000 in the U.S. alone. Fine particulate pollution has been linked with health problems including lung cancer, heart attacks, asthma, and dementia, as well as higher death rates from COVID-19.

Global mortality from outdoor fine particle pollution generated by fossil fuel combustion: Results from GEOS-Chem

The burning of fossil fuels - especially coal, petrol, and diesel - is a major source of airborne fine particulate matter (PM2.5), and a key contributor to the global burden of mortality and disease. Previous risk assessments have examined the health response to total PM2.5, not just PM2.5 from fossil fuel combustion, and have used a concentration-response function with limited support from the literature and data at both high and low concentrations.

This assessment examines mortality associated with PM2.5 from only fossil fuel combustion, making use of a recent meta-analysis of newer studies with a wider range of exposure. We also estimated mortality due to lower respiratory infections (LRI) among children under the age of five in the Americas and Europe, regions for which we have reliable data on the relative risk of this health outcome from PM2.5 exposure.

We used the chemical transport model GEOS-Chem to estimate global exposure levels to fossil-fuel related PM2.5 in 2012. Relative risks of mortality were modeled using functions that link long-term exposure to PM2.5 and mortality, incorporating nonlinearity in the concentration response. We estimate a global total of 10.2 million premature deaths annually attributable to the fossil-fuel component of PM2.5. The greatest mortality impact is estimated over regions with substantial fossil fuel related PM2.5, notably China (3.9 million), India (2.5 million) and parts of eastern US, Europe and Southeast Asia.The estimate for China predates substantial decline in fossil fuel emissions and decreases to 2.4 million premature deaths due to 43.7% reduction in fossil fuel PM2.5 from 2012 to 2018 bringing the global total to 8.7 million premature deaths.

This study demonstrates that the fossil fuel component of PM2.5 contributes a large mortality burden. The steeper concentration-response function slope at lower concentrations leads to larger estimates than previously found in Europe and North America, and the slower drop-off in slope at higher concentrations results in larger estimates in Asia.

Delivery of Recombinant Serum Albumin Extends Life Span in Old Mice

An interesting result is reported in today's open access preprint paper. The authors find that the life span of mice is extended by 20% or so after treatment every few weeks with serum albumin, beginning in mid-life. The researchers base their approach on noting that aging is characterized by modification of circulating serum albumin molecules, and theorize that a significant fraction of the issues arising with age are reactions to that damaged albumin. By delivering unmodified serum albumin, the damaged fraction of albumin is reduced, and the harmful reactions diminish. This is, in effect, sabotaging one of the many feedback loops in aging wherein forms of molecular damage act as signals to provoke maladaptive responses and further molecular damage.

This is most interesting when considered in the context of the beneficial effects that are reported to result from dilution of blood in old animals. Dilution studies have been carried out as a part of the ongoing debate over whether contributions to aging result from a loss of beneficial factors in circulating blood, or from the addition of harmful factors to circulating blood. That this dilution is enough to produce some degree of reversal of aspects of aging, such as chronic inflammation, argues for the harmful factor model. It is important to note that the dilution protocol involves adding albumin, as albumin is one of the few essential items present in the bloodstream that will result in major issues should it fall to lower levels. Is the added compensatory albumin the primary cause of benefits? Further studies will be needed to clarify and replicate these results.

Young and Undamaged rMSA Improves the Longevity of Mice

Here we report that a single protein recombinant mouse serum albumin (rMSA) improved the lifespan and healthspan of C57BL/6N mice. The median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. The rMSA used in this study is young and almost undamaged. We define the concept "young and undamaged" to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no advanced glycation end-product, no carbonylation, and no homocysteinylation. Here "young and undamaged" rMSA is much younger and less damaged than the endogenous serum albumin from young mice at 1.5 months of age. We predict that young and undamaged proteins altogether can further improve the longevity.

Human serum albumin (HSA) is the most abundant protein in blood plasma with a serum half-life of about 21 days. Damages or unnecessary modifications of HSA are related to many pathological conditions and increase with age. Firstly, the single free thiol in Cys-34 residue of HSA has been proposed to account for approximately 80% of the total free thiols in plasma, whose oxidation is intimately linked with aging and age-related diseases. Secondly, in oxidative environments, carbonyls are also formed especially on the side chains of residues in proteins. Elevated carbonyl levels in HSA have been found to be related to aging and varieties of diseases. Thirdly, the AGE accumulation of HSA is another important factor found to be involved in aging. It is widely reported that AGE formation impairs normal functions of albumin and can induce inflammatory responses, which is connected with aging and the progression of serious diseases. Fourthly, it has been widely reported that homocysteine (Hcy) increases with age and is associated with age-related degenerative disorders. HSA is a major target for homocysteinylation, thus it can efficiently protect other proteins from the toxicity of Hcy.

Therefore, treatment of freshly prepared recombinant serum albumin with no damages or unnecessary modifications is most likely to extend lifespan and healthspan. Here we report that young and undamaged recombinant mouse serum albumin (rMSA)-treated groups in natural aging mouse model obtained significantly extended lifespan with increased skeletal muscle strength and cognitive ability compared with saline-treated groups.

A View of Early Modern Trends in Longevity Derived from Data on European Scholars

Upward trends in longevity started as least as early as the 16th century in some parts of the world, and earlier elsewhere. In England, it is thought that an intertwined slow growth in life expectancy and economic productivity over hundreds of years laid the foundations for the Industrial Revolution. People who expect to live longer are better stewards of long-term capital investment, and even small gains year over year compound over time to become large. Greater wealth in turn gives rise to the byproduct of technological progress, including that relating to medicine and public health. This results in a virtuous cycle of accelerating gains in wealth, health, technological prowess, and longevity.

Today's research materials are a novel view of the earlier trends in life expectancy over the last few hundred years, based on data for European scholars. One interesting observation is that groups of higher socioeconomic status exhibited the slow historical gains in life expectancy earlier than was the case for the broader population. Control of infectious disease has been a major driver of improved life expectancy. Prior to the advent of 20th century medical technologies such as antibiotics, that control largely involved public health measures such as improved sanitation, as well as personal health measures deriving from cultural practices. We might argue that the deployment and adoption of these measures was uneven, explaining the observed data. That medical scholars exhibited a shorter life expectancy than scholars of other disciplines, at least until the development of germ theory, might also reflect the importance of infectious disease on early trends in human longevity.

Leaders and Laggards in Life Expectancy Among European Scholars From the Sixteenth to the Early Twentieth Century

In this article, we focus on the European scientific elite: scholars active at universities or academies of sciences. Observing each scholar's first appointment or nomination to a scientific institution helps to overcome common methodological issues in historical populations given that the appointment can be used to define the entry into the population at risk. More importantly, taking into account each scholar's scientific field and potential membership in an academy of sciences provides new insights into the role of medicine and social status in the process of mortality improvements. Finally, in a world where face-to-face communication was essential for both knowledge transmission and enhancement, the length of productive life among the elite was an important determinant of the extent to which members of the elite were able to influence their cultural and economic environments.

Drawing on local evidence and data on specific social groups, historians and demographers have already shown that mortality gains were made in the seventeenth and eighteenth centuries. Longevity started rising as early as 1400 and continued to increase over the fifteenth century. However, this first phase has been observed in Ireland and the United Kingdom only and these findings are subject to considerable uncertainty. Even though the total sample size is large, when stretched over several centuries, the uncertainty regarding any specific time point becomes large. This phase of longevity improvements was followed by another after 1650 that has been observed throughout Europe in other studies as well. Building a database drawn from the Index Bio-bibliographicus Notorum Hominum, which contains entries on famous people from about 3,000 dictionaries and encyclopedias, researchers found no trend in adult longevity among individuals born before the second half of the seventeenth century. Their findings also suggest that permanent improvements in longevity preceded the Industrial Revolution by at least a century. The longevity of famous people increased steadily starting with the generations born in the 1640-1649 period and grew by a total of roughly nine years in the following two centuries.

Although these studies are important, they are not without weaknesses. In the populations they studied, who belonged to the sample and when people entered the population at risk could not be precisely defined. Some of the individuals in these populations, such as famous martyrs, might have entered at death; others, such as artists, may have entered post mortem; and still others, such as members of royal families, entered at birth. In this study, we present data that overcome such weaknesses and use these data to reanalyze the timing of mortality improvements among the European elite. Furthermore, using information about relative status within the elite, we investigate whether differences in socioeconomic position were already influencing mortality when secular changes in mortality first started, or whether this pattern is more recent. Finally, we exploit information about the scientific fields in which the scholars in our database were working to examine whether there were leaders or laggards by discipline. A particular focus of our analysis is on medicine, which may have had both positive and negative effects on longevity, depending on whether the benefits of medical knowledge offset the added hazards resulting from exposure to pathogens.

We build a large, new data set with more than 30,000 scholars covering the sixteenth to the early twentieth century to analyze the timing of the mortality decline and the heterogeneity in life expectancy gains among scholars in the Holy Roman Empire. The large sample size, well-defined entry into the risk group, and heterogeneity in social status are among the key advantages of the new database. After recovering from a severe mortality crisis in the seventeenth century, life expectancy among scholars started to increase as early as in the eighteenth century, well before the Industrial Revolution. Our finding that members of scientific academies - an elite group among scholars - were the first to experience mortality improvements suggests that 300 years ago, individuals with higher social status already enjoyed lower mortality. We also show, however, that the onset of mortality improvements among scholars in medicine was delayed, possibly because these scholars were exposed to pathogens and did not have germ theory knowledge that might have protected them. The disadvantage among medical professionals decreased toward the end of the nineteenth century. Our results provide a new perspective on the historical timing of mortality improvements, and the database accompanying our study facilitates replication and extensions.

Recent Thought on Alzheimer's Disease as a Lifestyle Condition

The overwhelming majority of type 2 diabetes patients suffer their condition because they became significantly overweight. Being significantly overweight clearly produces the metabolic syndrome that leads to type 2 diabetes, and the more visceral fat tissue, the worse off you are. In this sense type 2 diabetes is a lifestyle condition, a choice. Attempting to explain Alzheimer's disease in the same way runs into an immediate challenge, in that there is no such very clear cause and effect. Too large a fraction of significantly overweight people do not develop Alzheimer's, and being overweight doesn't appear to correlate with the better explored aspects of cellular biochemistry known to precede Alzheimer's disease.

Nonetheless, insulin metabolism is dysfunctional in the Alzheimer's brain, and clear parallels can be drawn with the insulin resistance and related mechanisms of diabetes. This has led some researchers to think of Alzheimer's disease as a type 3 diabetes, a metabolic condition. It is a popular enough idea. While type 3 diabetes is not formally recognized as a designation, when evidence for an unrelated, new form of age-related diabetes was later discovered, it had to be put forward as a type 4 diabetes to avoid confusion.

Where does this leave us on the question of whether Alzheimer's disease is a lifestyle condition that can be avoided? It is unclear as to whether this is the case or not. The idea that Alzheimer's is driven by the consequences of persistent infection (raised amyloid levels and chronic inflammation) is presently popular, and it does provide a more satisfying answer to the question of why it is that only some people with the risk factors go on to develop the condition. It is not yet conclusively proven, however, and, in any case, it is somewhat harder to choose to avoid persistent infections than it is to choose to avoid putting on weight.

New research on Alzheimer's Disease shows 'lifestyle origin at least in some degree'

For years, research to pin down the underlying cause of Alzheimer's Disease has been focused on plaque found to be building up in the brain in AD patients. But treatments targeted at breaking down that buildup have been ineffective in restoring cognitive function, suggesting that the buildup may be a side effect of AD and not the cause itself. A new study finds novel cellular-level support for an alternate theory that is growing in strength: Alzheimer's could actually be a result of metabolic dysfunction in the brain. In other words, there is growing evidence that diet and lifestyle are at the heart of Alzheimer's Disease.

Researchers examined RNA sequences in 240 post-mortem Alzheimer's Disease-impacted brains. They were looking specifically at the gene expression of nervous system support cells during two types of metabolism: glucose metabolism, where carbohydrates are broken down to provide energy, and something called ketolytic metabolism. The researchers found widespread glucose metabolism impairment in those nervous system support cells of the brains of former Alzheimer's Disease patients, but limited ketolytic metabolism impairment. The finding is significant because the brain is like a hybrid engine, with the ability to get its fuel from glucose or ketones, but in the Alzheimer's brains studied, there appears to be a fundamental deficit in the brain's ability to use glucose.

"We've turned the hybrid engine of our brains into a mono-fuel system that just fails to thrive. And so, the brain, which is progressively becoming deficient in its ability to use glucose, is now crying out for help; it's starving in the midst of plenty. The body is swimming in a sea of glucose, but the brain just can't use it. The inability to use glucose increases the value of ketones. However, because the average person is eating insulin-spiking foods so frequently, there's never any ketones available to the brain. I look at these findings as a problem we've created and that we're making worse."

Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression

Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes.

In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.

The Latest Data from the Interventions Testing Program: Nicotinamide Riboside has No Effect on Mouse Life Span

The Interventions Testing Program (ITP) at the National Institute on Aging runs very rigorous, costly life span studies in large numbers of mice, picking a few interventions to test each year. The usual outcome is that a treatment with some interesting past results is found to have absolutely no effect on life span when run through the rigor of the ITP process. We should all bear this in mind whenever modest life span extension in mice is reported by researchers elsewhere in the community. Based on past ITP data, a great many such results are the result of chance or poor experimental design.

Will the ITP ever get around to testing senolytics or other potential rejuvenation therapies? Not soon, I'd imagine. Their bias is towards existing, approved drugs and supplements, calorie restriction mimetics, and similar classes of intervention that affect metabolism in well-explored ways: insulin signaling; blood pressure; inflammation; and so forth. Senolytics are likely not yet a well trodden enough path to get past the selection process.

Today's open access paper reports the latest set of interventions to have shown minimal, gender specific, or no effects at all on mouse life span in the ITP process. Of interest to the community here, nicotinamide riboside supplementation is one of these, and does not extend mouse life span. We might compare that outcome to the 2016 paper in which mouse life span does increase modestly, the human trial in which benefits to cardiovascular function result, and all of the other data showing improved stem cell and tissue function in mice and humans.

We might view the ITP as a steamroller encouraging us to run faster, to aim higher, to stop messing around with approaches to aging that do not and cannot have large enough effects to matter at the end of the day. The only goal worth aiming for is robust, sizable rejuvenation of the old. We have excellent starting points in the form of the SENS proposals for repair of cell and tissue damage, and the existence of the senolytics industry indicates just how fast things can move once impressive data is produced in animal studies. More of that sort of thing is much needed if we are to realize the promise of modern biotechnology.

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

The interventions for the present study were chosen for the following reasons:

(a) 17-α-estradiol (17aE2) is a relatively "non-feminizing" estrogen which shows reduced activation of classical estrogen receptors compared with 17-β-estradiol. It was reported that in UM-HET3 mice fed 4.8 mg 17aE2/kg (4.8 ppm) diet from 10 months of age, median male lifespans increased 12%, while 17aE2 did not alter female lifespan. Other researchers showed that using a threefold higher dose (14.4 ppm) from 10 months of age, pooled median male lifespans increased 19%; the 90% lifespan increased 12%, but females still did not benefit. Thus, only males were tested in the present study. To determine whether 17aE2 treatment is effective when initiated in older mice, males were treated beginning at 16 or 20 months of age, choosing middle age, and early old age before many natural deaths.

(b) Nicotinamide riboside (NR) is a precursor of nicotinamide adenine dinucleotide (NAD) via the cell's salvage pathway. Total NAD levels decline with age, in a wide range of species. Importantly, increasing NAD levels benefit a wide variety of tissues in species including mice and human beings. it has been suggested that NAD+ boosters may "..delay aging and age-related physical decline." It was reported that NR delays senescence of neural stem cells (SCs) and melanocyte SCs and increases mouse life span, even when given in old age (5% increase at 20 months of age).

It was reported that in mice and humans NR is bioactive when given by mouth, unlike most other nicotinamide derivatives. In a 2016 study NR improved liver function and protected against diabetic neuropathy. When fed to C57BL/6 J mice from 10 weeks of age, NR protects against high-fat diet (HFD)-induced obesity and promotes oxidative metabolism by increasing the NAD+/NADH ratio in muscle, liver, and brown adipose tissue. Researchers found that increasing NAD+ stores with NR supplementation improved muscle function and alleviated heart defects in a mouse model of muscular dystrophy. It was reported that an NR metabolite, nicotinamide, did not increase lifespan when started at 12 months in C57BL/6 J mice but improved some health outcome measures. Due to its benefits in a variety of diseases, and reports of benefits in mouse lifespans, NR treatment was proposed to increase lifespan in UM-HET3 mice.

c) Candesartan cilexetil (CC) is an angiotensin-receptor blocker, which lowers blood pressure and improves cardiovascular function and insulin sensitivity in obese, hypertensive patients. Importantly, angiotensin-receptor knockout increases lifespan of mice. Because CC is effective against age-related diseases, and sensitizes the body to insulin, and because the angiotensin-receptor knockout increases lifespan of mice, treatment with CC was hypothesized to increase lifespan.

(d) To maintain good quality protein in the body, heat shock proteins (HSPs) are vital. Geranylgeranylacetone (GGA) induces heat shock protein (Hsp70) in mammalian tissues and promotes insulin sensitivity in old mice, while it increases HSP expression in atrial tissue after heart surgery. Long-lived species, compared with related short-lived species within the same order, have elevated HSP levels in conjunction with better proteostasis. To test whether treatment with an established HSP inducer can increase lifespan in a mammalian model, UM-HET3 mice were treated with GGA.

(e) MIF098 ((3-(3-hydroxybenzyl)-5-methylbenzo[d]oxazol-2(3H)-one) is a macrophage migration inhibition factor (MIF) antagonist that regulates CD44 binding. MIF is a proinflammatory cytokine, so MIF098 reduces inflammation. This may include the chronic inflammation that increases with age, as suggested by the finding that MIF-knockout mice live significantly longer than controls. Because it is orally bioavailable and shows MIF inhibitory activity in mouse models of hyperoxic lung injury, as well as in other diseases, treatment with MIF098 was proposed to increase lifespan by decreasing chronic inflammation and disease.

Our new data show that nicotinamide riboside (NR) failed to increase lifespan. Only 17aE2 increased lifespan, and benefits in males occurred even when the drug was not fed until late middle or early old age (16 and 20 months of age, respectively). The range of ages for which treatment is effective suggests that benefits from 17aE2 do not depend on effects earlier in life, such as growth alteration. Interventions that are effective when started at a late age have considerable translational potential.

Measuring Gene Expression Changes in the Brain as a Result of Heart Failure

Heart failure causes harm to the brain by reducing the supply of blood, and thus the supply vital nutrients and oxygen, to brain cells. The precise details of how this leads to cognitive decline are yet to be fully mapped. Researchers here assess changes in gene expression the brains of mice suffering from heart failure, as a starting point for further investigation of specific mechanisms. The best path forward for this class of contribution to neurodegenerative conditions is to prevent or reverse vascular aging, which has numerous components. There is the narrowing of blood vessels via atherosclerosis; the failure of smooth muscle tissue to appropriately contract and dilate blood vessels, due to cellular senescence, chronic inflammation, and other mechanisms of aging; stiffening of blood vessels via cross-linking in the extracellular matrix; and so forth.

In heart failure, the heart muscle is too weak to pump enough blood through the body and is therefore abnormally enlarged. Physical fitness and quality of life suffer as a result. Moreover, affected individuals have an increased risk of developing dementia. "People with cardiological problems and heart failure in particular may experience noticeable cognitive deficits and increased risk of developing Alzheimer's disease. Possible reasons include impaired blood supply to the brain and dysfunction of the hippocampus, which is the memory's control center. Yet, there is a lack of therapies to effectively treat cognitive deficits in people with heart problems. This is because it is completely unclear which deficiencies are triggered in neurons. There was no data on this so far."

Researchers observed in mice that impaired gene activity developed in the hippocampus as a result of heart problems. "In memory tests, mice with heart failure performed significantly worse than their healthy mates. We then examined the neurons of the hippocampus. In the mice with heart failure, we found increased cellular stress pathways and altered gene activity in neurons."

The genome of a mouse - and also of humans - comprises around 20,000 genes. In any given cell, however, only a part of them is active, switched on, so to speak. This is not a mere on or off state: the activity can be strong or less strong. This depends, among other things, on how tightly the DNA of the genome is wound and how accessible the genes on it are. In both mice and humans, the DNA is more than a meter long. But in a cell, the molecule is so tightly packed that it fits into the nucleus. "Genes can only be active if they are accessible to the cell's machinery. To this end, the DNA needs to be wound a little more loosely at the relevant sites. This is similar to a ball of yarn with loops sticking out of it." In the current study, the DNA was found to be more tightly wound in neurons of mice with heart problems than in healthy mates. Various genes important for hippocampal function were therefore less active than in healthy mice.

A Feedback Loop Between Chronic Inflammation and Pressure Sensing Drives Osteoarthritis

Researchers here present an interesting view of how chronic inflammation affects cartilage tissue to cause the progression of osteoarthritis. A feedback loop is established between mechanisms of inflammation and mechanisms of pressure sensing, leading to the outcome of cartilage degeneration. Novel points of intervention will no doubt arise as the result of this work, with researchers seeking to break the feedback loop. The best approach still appears to be prevention of the chronic inflammation of aging, given the degree to which rising inflammation contributes to myriad age-related conditions.

An unfortunate biological "feed-forward" loop drives cartilage cells in an arthritic joint to actually contribute to progression of the disease. Cartilage is the highly lubricated, low-friction, elastic tissue that lines joint surfaces, cushioning movements and absorbing millions of cycles of mechanical compression. As cartilage breaks down in painful osteoarthritis, the ends of bones can come together bone-on-bone, increasing pain even more.

The cells that build and maintain cartilage are called chondrocytes, and on their surface can be found ion channels that are sensitive to force, called Piezo1 and Piezo2. In response to mechanical loads on the joint, Piezo channels send signals into the cell that can change gene activity in that cell. Normally, chondrocytes produce extracellular matrix, the structural proteins and other biomolecules that give cartilage its mechanical stiffness, elasticity and low friction. But in osteoarthritis, degeneration and malfunction of these cells - which are incapable of repair by cell division - contribute to the progressive breakdown of cartilage.

One of the other hallmarks of osteoarthritis is chronic, low-grade inflammation, driven by a signaling molecule called interleukin-1 alpha. Using cartilage cells from pigs and from human joints removed for replacement surgeries, the researchers wanted to see how inflammation affects chondrocytes. They found that interleukin signaling tells the cell to produce more Piezo channels, making the cell even more sensitive to pressure and resulting in what the researchers call a harmful 'feed-forward' loop that leads to more breakdown of the cartilage. "Interleukin reprograms the chondrocytes so that they're more sensitive to mechanical trauma. The feed-forward cycle slowly grinds them down and the cell cannot be replaced. It's cartilage reprogramming itself to do more damage."

7.2% of All Deaths Worldwide are Attributable to Physical Inactivity

Humans evolved in an environment of physical exertion, and our biochemistry requires physical exertion in order to trigger mechanisms of cell maintenance and metabolic regulation. Populations that exercise vigorously into late old age, such as the Tsimane in Bolivia, exhibit very much lower levels of cardiovascular disease. Further, living a sedentary lifestyle shortens life expectancy and increases disease risk when compared to people who exercise even the moderate amount that is the present recommended level. The dose-response curve data for physical activity suggests that the recommended level should be a good deal higher.

Physical inactivity is a risk factor for premature mortality and several non-communicable diseases. The purpose of this study was to estimate the global burden associated with physical inactivity, and to examine differences by country income and region. Population-level, prevalence-based population attributable risks (PAR) were calculated for 168 countries to estimate how much disease could be averted if physical inactivity were eliminated. We calculated PARs (percentage of cases attributable to inactivity) for all-cause mortality, cardiovascular disease mortality and non-communicable diseases including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression, and cancers.

Globally, 7.2% and 7.6% of all-cause and cardiovascular disease deaths, respectively, are attributable to physical inactivity. The proportions of non-communicable diseases attributable to physical inactivity range from 1.6% for hypertension to 8.1% for dementia. There was an increasing gradient across income groups; PARs were more than double in high-income compared with low-income countries. However, 69% of total deaths and 74% of cardiovascular disease deaths associated with physical inactivity are occurring in middle-income countries, given their population size. Regional differences were also observed, with the PARs occurring in Latin America/Caribbean and high-income Western and Asia-Pacific countries, and the lowest burden occurring in Oceania and East/Southeast Asia.

Methionine Restriction Greatly Reduces Measures of Cognitive Decline in Mice

Researchers here applied three months of a methionine restricted diet to old mice, and found that it greatly reduced age-related cognitive decline, as measured in maze tests. The methionine restricted animals perform more like young animals than like their unrestricted peers. Methionine is an essential amino acid essential to all protein synthesis. Methionine sensing is one of the more important triggers by which the beneficial response to calorie restriction is activated. Near every aspect of metabolism shifts into a more healthy, life-span-prolonging mode of operation. A methionine restricted diet thus mimics a sizable fraction of calorie restriction without eating less. The methionine restricted mice actually ate more food than their unrestricted counterparts, while having a lower body weight.

Methionine restriction (MR) extends lifespan and delays the onset of aging-associated pathologies. However, the effect of MR on age-related cognitive decline remains unclear. Here, we find that a 3-month MR ameliorates working memory, short-term memory, and spatial memory in 15-month-old and 18-month-old mice by preserving synaptic ultrastructure, increasing mitochondrial biogenesis, and reducing the brain malondialdehyde (MDA) level in aged mice hippocampi.

Transcriptome data suggest that the receptor of fibroblast growth factor 21 (FGF21)-related gene expressions were altered in the hippocampi of MR-treated aged mice. MR increased FGF21 expression in serum, liver, and brain. Integrative modelling reveals strong correlations among behavioral performance, MR altered nervous structure-related genes, and circulating FGF21 levels.

Recombinant FGF21 treatment in cell culture balanced the cellular redox status, prevented mitochondrial structure damages, and upregulated antioxidant enzymes HO-1 and NQO1 expression by transcriptional activation of Nrf2. Moreover, knockdown of Fgf21 by injection of adeno-associated virus abolished the neuroprotective effects of MR in aged mice.

In conclusion, the MR exhibited the protective effects against age-related behavioral disorders, which could be partly explained by activating circulating FGF21 and promoting mitochondrial biogenesis, and consequently suppressing the neuroinflammation and oxidative damages. These results demonstrate that FGF21 can be used as a potential nutritional factor in dietary restriction-based strategies for improving cognition associated with neurodegeneration disorders.

Senescent T Cells Cause Changes in Fat Tissue that are Harmful to Long-Term Health

There is a much greater awareness in the scientific community of the importance of cellular senescence to aging. Senescent cells are influential in the progression of many facets of aging and age-related disease, and a new industry is working to produce senolytic therapies to clear senescent cells from old tissues. Further, there is funding and interesting for investigations of the many specific ways in which senescent cells cause harm. The open access paper noted here is an example of this sort of research, which the inflammatory signaling of senescent T cells is implicated as a contributing cause of detrimental age-related changes in fat tissue metabolism.

It has become evident that adipose tissue plays an endocrine function, not merely an energy reservoir pool, and exerts a fundamental influence on metabolic regulation. Adipose tissue is classified as white adipose tissue (WAT) and brown adipose tissue (BAT). BAT has been considered a key for thermogenesis to maintaining body temperature, while WAT stores and releases lipids and is involved in promoting inflammation. BAT "whitening" refers to acquisition of white adipocyte characteristics with enlarged lipid droplets and loss of normal structure and function of brown adipocyte. Age-related alteration in adipose tissues is manifested on the distribution and composition, as well as a decline in adipose tissue quality and function.

Immune cells particularly T cells accumulate in adipose tissue with advancing age, and there exists a cross talk between T cell and preadipocyte, contributing to age-related adipose tissue remodeling. Here, we compared the difference in morphology and function of adipose tissue between young (3-month-old) and old (18-month-old) mice and showed the phenomenon of brown adipose tissue (BAT) "whitening" in old mice. Flow cytometry analysis suggested an increased proportion of T cells in BAT of old mice comparing with the young and exhibited senescent characteristics.

We take advantage of coculture system to demonstrate directly that senescent T cells inhibited brown adipocyte differentiation of preadipocytes in adipose tissue. Mechanistically, both in vitro and in vivo studies suggested that senescent T cells produced and released a higher level of IFN-γ, which plays a critical role in inhibition of preadipocyte-to-brown adipocyte differentiation. Taken together, the data indicate that senescent T cell-derived IFN-γ is a key regulator in brown adipocyte differentiation.

Regular Exercise Reduces Measures of Immunosenescence in Old Individuals

Regular exercise improves many aspects of health in later life. It reduces incidence of age-related disease and mortality risk by a significant degree. It improves near all aspects of metabolism, and reverses the downward decline of many metrics of health and aging. Hunter-gatherer populations that sustain high levels of physical activity into later life exhibit a fraction of the cardiovascular disease of populations in wealthier parts of the world. The work here illustrates another known relationship: that active older individuals have a better immune function than their less active peers, as exercise improves the measured immune cell population metrics.

Regular physical activity has a profound effect on normal functioning of the immune system. For decades it has been accepted that prolonged periods of high-intensity exercise could depress immunity. However, current evidence from epidemiological studies shows that leading a physically active lifestyle is likely to be beneficial rather than harmful to the immune function. Exercise-induced improvements in immunity can be related to reduction in inflammation, maintenance of thymic mass, changes in the composition of memory and naïve T lymphocytes or enhanced immunosurveillance. Indeed, physical activity is a powerful intervention that has a great potential to improve immune and health outcomes in the older adults, the obese, and patients with cancer and chronic viral infections. The benefits of regular physical activity undertaken by the older adults are much less documented than the effects of regular physical activity on the immune system in young individuals.

In recent years the effects of regular physical activity on T lymphocytes have attracted a considerable interest and plenty of evidence showed the lifestyle exercise may lead to rejuvenation of the immune system and may exert a positive effect on thymic output. The active older adults in our study were observed to have a statistically significantly increased percentage of blood CD4+CD45RA+ T lymphocytes in comparison to the inactive older adults. This may be associated with elevated IL-15 levels that affect the immune homeostasis which is caused by the induction of a better survival rate of naïve T lymphocytes.

Attempts to determine the relationships between cytomegalovirus (CMV)-seropositivity and changes in the count of T lymphocytes have been undertaken by scientists for many years. The results of the research carried out due to the health condition of the examined patients, genetic background and/or many others factors in highly diverse human populations are varied. Most researchers agree that CMV infection at least accelerates the age-related decrease in the number of naïve T lymphocytes and the increase in memory T lymphocytes.

In our study, we showed that, regardless of CMV-seropositivity, in the physically active older adults there was an increase in the count of CD4+CD45RA+ T lymphocytes as well as in the CD4+CD45RA+/CD4+CD45RO+ ratio compared to the inactive CMV-seropositive older adults. This emphasises the beneficial effect which the activity of older adults exerts on their immune system functioning. Latent infection in people with normal immunity frequently shows no symptoms, but it could be dangerous for immune compromised ones. This is associated with CD4/CD8 < 1 identified in immune-risk individuals, which induces a high risk of mortality due to weaker immune response. In our study, the inactive older adults CMV-seropositive individuals showed a lower CD4/CD8 ratio compared to the active older adults CMV-seropositive adults. Interestingly, older active CMV-seronegative adults obtained the CD4/CD8 ratio of 2.8 ± 1.5 which is higher than that observed in the active older CMV-seropositive adults (2.5 ± 1.0) as well as in the inactive CMV-seropositive individuals (2.1 ± 0.9).

A Non-Invasive Biomarker to Measure the Effectiveness of Senolytic Drugs

Researchers here note the discovery of a non-invasive biomarker that can measure the pace of destruction of senescent cells. This could be used to more rapidly quantify the effectiveness of potential senolytic treatments, those capable of destroying senescent cells, thus speeding up development of the next generation of senolytic drugs. Readily available small molecule treatments (such as the dasatinib and quercetin combination) can destroy a fraction of senescent cells throughout the body, and in doing so produce rejuvenation in animal studies. Alongside bringing those first treatments to the clinic, the next goal in line is to achieve a much greater level of clearance. A great deal of work lies ahead in that optimization process.

Researchers have discovered and are developing a novel, non-invasive biomarker test that can be used to measure and track performance of senolytics: a class of drugs that selectively eliminate senescent cells. "The list of age-related diseases definitively linked to cellular senescence keeps growing, as does the number of biotech companies racing to develop drugs to eliminate senescent cells. While the field has never been more promising, the lack of a simple biomarker to measure and track efficacy of these treatments has been a hindrance to progress. We are excited to bring this new biomarker to the field and look forward to it being used in the clinic."

This work, performed in human cell culture and mice, shows that senescent cells synthesize a large array of oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. "Lipid components of the senescence-associated secretory phenotype (SASP) have been vastly understudied. The biosynthesis of these signaling lipids promotes segments of the SASP and reinforces the permanent growth arrest of senescent cells." Oxylipins are implicated in many inflammatory conditions including cardiovascular disease and pain response. Many commonly used drugs, such as aspirin and ibuprofen, act by preventing oxylipin synthesis.

Senescent cells change their fatty acid metabolism and they do it in such a way that free polyunsaturated fatty acids accumulate inside the arrested cells where they are used to manufacture oxylipins. Researchers identified one of these fatty acids, 15-deoxy-delta-12,14-prostaglandin J2 (dihomo-15d-PGJ2), as unique to senescent cells; it accumulates inside senescent cells and is released when the cells die. In this study, mice were given chemotherapy which induces widespread senescence, followed by a senolytic drug. The biomarker was only detected in the blood and urine of mice treated with both chemotherapy and the senolytic, but not with either on its own, confirming specificity for senolysis.

Better Diet and Regular Exercise Improve Cardiometabolic Health in Later Life

A sensible diet and adherence to a program of regular exercise have a meaningful effect on late life health, as illustrated by this epidemiological study. Therapies that target the mechanisms of aging are still in the early stages of development, and few have shown impressive results in mice, let alone humans. Exercise and the practice of calorie restriction outperform near all such treatment for which robust animal or human data has been established. This will change in years ahead, but it will never be a good idea to neglect the basics of good health.

Following a routine of regular physical activity combined with a diet including fruits, vegetables, and other healthy foods may be key to middle-aged adults achieving optimal cardiometabolic health later in life, according to new research using data from the Framingham Heart Study. Cardiometabolic health risk factors include the metabolic syndrome, a cluster of disorders such as excess fat around the waist, insulin resistance, and high blood pressure. Presence of the metabolic syndrome may increase the risk of developing heart disease, stroke, and Type 2 diabetes.

Researchers noted it has been unclear whether adherence to both the U.S. Department of Health and Human Services' 2018 Physical Activity Guidelines for Americans and their 2015-2020 Dietary Guidelines for Americans - as opposed to only one of the two - in midlife confers the most favorable cardiometabolic health outcomes later in life. The physical activity guidelines recommend that adults achieve at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week, such as walking or swimming. The dietary guidelines, which were updated in January 2021, offer suggestions for healthy eating patterns, nutritional targets, and dietary limits.

In an analysis of data from participants of the Framingham Heart Study, which began more than 70 years ago in Framingham, Massachusetts, investigators examined data from 2,379 adults ages 18 and older and their adherence to the two guidelines. They observed that meeting a combination of the two recommendations during midlife was associated with lower odds of metabolic syndrome and developing serious health conditions as participants aged in their senior years in 2016-2019 examinations. Participants who followed the physical activity recommendations alone had 51% lower odds of metabolic syndrome. Participants who adhered to the dietary guidelines alone had 33% lower odds. Participants who followed both guidelines had 65% lower odds of developing metabolic syndrome.

Blood-Brain Barrier Dysfunction Predicts Progression of Cerebral Small Vessel Disease

Cerebral small vessel disease is characterized by the accumulation of small volumes of damaged tissue in the brain, the results of the rupture or blockage of tiny blood vessels. Researchers here show that the state of the blood-brain barrier predicts the pace at which this damage grows over time. The blood-brain barrier functions to ensure that only certainly molecules and cells can move back and forth from brain and bloodstream, but like all tissues it becomes dysfunctional with age. This contributes to chronic inflammation in the brain, as unwanted substances find their way into the central nervous system. It may be case that blood-brain barrier issues and the breakage of small blood vessels that produces damaged brain tissue are distinct outcomes of the same underlying mechanisms of aging and their downstream effects. To pick an obvious example, the raised blood pressure of age-related hypertension is destructive to blood vessel walls and the delicate tissues that surround them.

"Previous research has shown that disruption of the blood-brain barrier is increased in people with cerebral small vessel disease. People with cerebral small vessel disease also may have brain lesions called white matter hyperintensities. Such lesions are visible by MRI and believed to be signs of brain damage and a marker of the severity of disease. For our study, we wanted to see if a leaky blood-brain barrier was linked to degeneration of brain tissue even before these brain lesions appear. We looked at normal brain tissue, surrounding and close to the brain lesions, because we consider this 'tissue at risk.'"

The study involved 43 people with cerebral small vessel disease with an average age of 68. Researchers used MRI at the start of the study to measure the leakiness of the blood-brain barrier for each participant. They then used another brain imaging technique to measure the integrity of the tissue's microstructure surrounding brain lesions. This imaging technique was repeated two years later to see whether the brain tissue integrity has decreased.

Researchers measured the relationship between blood-brain barrier leakage and changes in brain tissue. They found the higher the tissue volume with blood-brain barrier leakage at the start of the study, the greater the loss of brain tissue integrity was around brain lesions two years later. For every 10% increase in leakage volume at the start of the study, after two years the diffusivity of the brain tissue increased by 1.4%, representing a decrease in brain tissue integrity. They also found a similar relationship involving the leakage rate of the blood-brain barrier - a higher leakage rate at the start of the study resulted in more loss of tissue microstructure around the brain lesions.

Mesenchymal Stem Cell Derived Extracellular Vesicles Slow the Accelerated Aging of Progeroid Mice

Researchers here show that, in a progeroid mouse model that exhibits high levels of cellular senescence and accelerated manifestations of aging, delivering extracellular vesicles harvested from mesenchymal stem cells has much the same effect as delivering the cells as a therapy. This illustrates the point that many of these first generation approaches to stem cell therapy produce benefits via a brief period of signaling of the transplanted cells. The cells themselves die quite quickly and near entirely fail to integrate into patient tissue. Extracellular vesicles are more easily produced, stored, quality controlled, and used, overall a much better prospect from a logistical point of view. This is why there is presently such a focus on the development of therapies based on this approach.

A characteristic of aging is the loss of regenerative capacity, which leads to an impaired ability to respond to stress and therefore increased morbidity and mortality. This has led to the hypothesis that aging is partly driven by the loss of functional adult stem cells necessary for maintenance of tissue homeostasis. Indeed, mice greater than two years of age have a significant reduction in the number and proliferative capacity of various types of adult stem cells.

We previously demonstrated that muscle-derived stem/progenitor cells (MDSPC) are adversely affected upon aging. MDSPCs isolated from old and Ercc1-/∆ progeroid mice have reduced proliferative capacity and impaired differentiative potential, and this dysfunction directly contributes to age-related degeneration given that transplantation of young MDSPCs extended health span and life span in ERCC1-deficient progeroid mouse models. Transplanted MDSPCs did not differentiate or migrate from the site of injection, suggesting that the therapeutic effect of MDSPCs was mediated by secreted factors acting systemically. Concordantly, co-culture of young MDSPCs with old MDSPCs resulted in renewal of old MDSPC proliferative and differentiative potential, yet the identification of factors responsible for the rejuvenation of aged MDSPCs remained elusive.

Here, we identified bone marrow-derived mesenchymal stem cells (BM-MSCs) from young animals, and lineage-directed hESC-derived BM-MSC surrogates, as a novel source of EVs with senotherapeutic activity. We demonstrate that transplantation of BM-MSCs from young, but not old mice, prolonged life span and health span in ERCC1-deficient mice. Further, conditioned media (CM) from young BM-MSCs rescued the function of aged, senescent stem cells and senescent murine embryonic fibroblasts (MEFs) in culture.

Importantly, injection of EVs from BM-MSCs from young mice extended the life span of ERCC1-deficient mice. Similarly, treatment with EVs isolated from human embryonic stem cell-derived MSCs (hESC-MSC) was capable of significantly reducing the expression of markers of senescence in cultured senescent fibroblasts as well as naturally aged wild-type and Ercc1-/∆ mice, and improving measures of healthspan in vivo. These novel results identified EVs as key factors released by young, functional stem cells that can rescue cellular senescence and stem cell dysfunction in culture and reduce senescent cell burden in vivo. Thus, functional stem cell-derived EVs represent a novel therapeutic to reduce the senescent cell burden and extend health span.


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