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- Age-Related Arterial Calcification in the Context of Stroke
- An Approach to Reduce Harmful Inflammation in Cardiac Hypertrophy
- Trained Immunity Improves Function in Aged Innate Immune Cells
- Sitting Time Correlates with Mortality Risk
- Assessing the Causes of Aortic Stiffening in Aged Mice
- Phosphorylated TDP-43 in Muscle as a Biomarker for ALS
- Elastin Structure in Tissue is Complex, as is the Aging of that Structure
- Psychological Stress Accelerates Immune Aging via Lifestyle Choices
- BAG2 Condensates Show That There is Much Left to Explore in the Realm of Cellular Maintenance
- Towards Sabotaging the Link Between Hypertension and Cardiac Hypertrophy
- Combining Age-Slowing Interventions in Flies Doubles Life Span
- N-lactoyl-phenylalanine as a Link Between Exercise and Appetite Regulation
- Excess Cholesterol Provokes PERK Expression in Vascular Smooth Muscle Cells in Atherosclerosis
- Inflammaging and Its Contribution to the Development of Atherosclerosis
- Difference Between Ankles in Measurement in Blood Pressure Correlates with Arterial Stiffness
Age-Related Arterial Calcification in the Context of Stroke
Calcification in arteries is an age-related malfunction of cell behavior, in which cells in blood vessel walls inappropriately take on some of the behaviors of bone cells called osteoblasts. These errant cells deposit calcium structures characteristic of bone tissue into the extracellular matrix, and that is in turn disruptive of tissue properties, particularly to the elasticity needed for constriction and dilation of blood vessels. In effect, blood vessels, and other structures such as heart valves that are subject to calcification, are slowly turning into bone. This causes cardiovascular dysfunctions that, given time, will ultimately prove fatal.
As noted in today's open access review paper, calcification proceeds side by side with the development of atherosclerosis, the formation of fatty deposits in blood vessel walls that narrow and weaken blood vessels. These are two quite distinct processes, however. That they do coincide is most likely because both are influenced strongly by the state of inflammatory signaling, in the body at large, and localized to particular regions of blood vessel walls. Atherosclerosis produces inflamed areas of the blood vessel wall, where lesions form, by virtue of the way in which it derives from and interacts with the malfunction and inflammatory signaling of macrophage cells of the innate immune system. The surrounding vessel is thus more prone to calcification.
Arterial Calcification and Its Association With Stroke: Implication of Risk, Prognosis, Treatment Response, and Prevention
Vascular calcification (VC) is one of the characteristics of vascular aging and appears to specifically occur in arteries. It is defined as the deposition of calcium-phosphate complexes in the vessels. Apart from aging, pathological processes like diabetes mellitus, chronic kidney disease, and hereditary disorders might also be the risk factors for arterial calcification. Calcification at different locations in the arterial wall might be associated with different risk factors and outcomes. Intimal calcification is closely related to atherosclerosis and affects the stability of the plaque, while medial calcification, including calcification located in the tunica media and around the internal elastic lamina, is considered to cause arterial stiffening and reduce compliance.
Arterial calcification can take place in various vessels, such as the femoral artery, abdominal aorta, thoracic aorta, coronary artery, carotid artery, and cerebral arteries. Among these, the best-studied are coronary artery calcification (CAC), intracranial artery calcification (IAC), and carotid artery calcification. CAC has been used as a predictor of coronary heart disease and recent studies have shown that CAC can also predict the risk of atherosclerotic cardiovascular disease, including stroke. Similarly, IAC, especially intracranial internal carotid artery calcification (IICAC), and carotid artery calcification are also reported to be closely associated with stroke.
Arterial calcification including IAC, CAC, and carotid calcification can predict the risk of stroke and it also affects treatment response and prognosis of stroke patients. Arterial calcifications and stroke share many risk factors, and in fact, history of ischemic stroke is one of the risk factors for IAC. Arterial calcification might affect plaque stability or cause hemodynamic changes, and therefore increase the risk of stroke. Besides, IAC or CAC indicates atherosclerosis, which is one of the main causes of stroke. It is worth noting that besides the total amount of calcification, the morphology, distribution, and size (large or small) of calcification can also impact on the risk of stroke. Intimal calcification and medial calcification have distinct implications and should be studied separately.
An Approach to Reduce Harmful Inflammation in Cardiac Hypertrophy
Chronic inflammation is of great importance in age-related degeneration. In later life, inflammatory signaling becomes constant and unresolved, in contrast to the short-term, rapidly resolved inflammation that occurs in response to infection and injury in youth. This unresolved inflammation is highly disruptive of tissue function and structure. In response to unrelenting inflammatory signaling, cell behaviors change in pathological ways, such as the deposition of calcium into blood vessel walls, or increasing quiescence of stem cells that should be actively supporting tissue.
Researchers are in search of ways to suppress the excessive inflammation of aging, but so far the only compelling approaches involve removing the causes of inflammatory signaling, such as the growing population of senescent cells. Otherwise interfering in any specific inflammatory signal via the usual means, removing proteins, blocking receptors, and so forth, means suppressing both excessive and appropriate inflammation. It is certainly possible that some signaling is largely only involved in the excessive inflammation of aging, but to date it appears that any effective mechanism to be targeted in the reduction of chronic inflammation is likely also needed in the normal defense against pathogens and potentially cancerous cells.
A greater focus on the causes of chronic inflammation is needed. Beyond senescent cells, the age-damaged environment generates DNA debris, for example, that triggers the innate immune system in the same ways as infection and injury. It is unclear as to what the best solution to clearing this debris might be, but success here is likely to produce greater benefits with fewer side-effects than the search for novel portions of the complex mechanisms of inflammatory signaling that can be blocked to suppress inflammation.
CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure
Pathological cardiac remodeling, characterized by left ventricular (LV) hypertrophy, cardiac fibrosis, and inflammation, is a determinant of the clinical course of heart failure (HF). Aging and the activation of the rennin-angiotensin system play an important role in pathological cardiac remodeling. Anti-aging treatments, such as caloric restriction and rennin-angiotensin system-inhibitor use, potentially improve HF by reducing cardiac inflammation. Evidence corroborating the potential benefit of inflammation suppression in reducing cardiovascular disease is increasing. For example, canakinumab, a therapeutic human monoclonal antibody targeting IL-1β, has been shown to significantly lower major adverse cardiovascular event rates. However, the effectiveness of anti-inflammatory therapy in HF awaits full elucidation.
Chemokines and chemokine receptors are important components of the cytokines that orchestrate immune-cell migration and maintain homeostasis. Early research has established that C-C motif chemokine ligand 17 (CCL17) plays an important role in T cell development in the thymus, and it binds to C-C chemokine receptor 4 (CCR4). We have demonstrated that chemokine CCL17, an important regulator of atherosclerosis, is positively associated with coronary artery disease, independent of traditional cardiovascular risk factors. Chemokines are currently believed to be involved in all stages of cardiovascular response to injury and are considered a possible therapeutic target. However, the role of CCL17 in pathological cardiac hypertrophy is yet to be investigated.
Given the current lack of age-related molecules for HF treatment, the elucidation of underlying molecular mechanisms and discovery of potential targets through the combination of clinical cohorts and aging-disease models are warranted. Herein, we report CCL17's tendency to display an age-dependent increase in population studies and potential role as a critical participant in age-related and angiotensin II (Ang II)-induced cardiac hypertrophy and HF. Subsequent animal experiments further revealed that Ccl17 knockout significantly repressed aging and angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological cardiac remodeling in mice. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II-induced pathological cardiac hypertrophy and heart failure.
Trained Immunity Improves Function in Aged Innate Immune Cells
Both the innate and adaptive immune systems decline in function and run awry with age. Taken as a whole, researchers view this as the combination of inflammaging and immunosenescence. Without delving into the details, inflammaging is chronic, unresolved inflammatory signaling, an overactivation of the immune system that produces harmful changes in cell behavior throughout the body, while immunosenescence is a decline in the effectiveness of the immune response, leaving an individual more vulnerable to pathogens and potentially cancerous cells, while also allowing senescent cells to accumulate in tissues. The two broad categories of dysfunction interact in a number of ways. Rising numbers of senescent cells, resulting from faltering immune surveillance, contribute meaningfully to inflammaging via their pro-inflammatory signaling, for example.
The aging of the innate immune system is quite different from that of the adaptive immune system, and arguably a great deal more is known about how to effectively deal with the latter issue. Restoring proper T cell production, via regeneration of the thymus and the hematopoietic cell populations of the bone marrow, and clearing out dysfunctional T cell populations may solve a great deal of adaptive immune aging. The innate immune system, on the other hand, suffers more complex, less well explored issues in cell behavior, and is also provoked into inflammatory signaling by problems such as the DNA debris that characterizes the aged tissue environment, for which researchers as yet do not have good solutions, or even paths to solutions.
Given that, it is interesting to note studies such as this one, in which researchers note that aged innate immune cells seem to react as well as young innate immune cells to approaches such as trained immunity, essentially vaccination with specific compounds, that can improve function and suppress inflammation in conditions involved excessive inflammatory signaling, such as respiratory infection and sepsis.
Trained Immunity Enhances Human Monocyte Function in Aging and Sepsis
Over the past two decades there has been an increased incidence of sepsis and this trend is likely to continue due to our aging population, increased use of immunosuppressive drugs and invasive procedures, and the emergence of antibiotic resistant opportunistic pathogens. Age has emerged as an independent predictor of morbidity and mortality in sepsis. Indeed, 60% of sepsis cases occur in patients over 65 years of age. It is generally accepted that age related immune senescence increases susceptibility to infection and sepsis, which raises the question of whether it is possible to modulate the aging immune system to improve resistance to infection. One possible approach to enhancing immune function during aging is innate immune training.
There is a substantial literature demonstrating that the innate immune system can be trained to respond more rapidly and effectively to infection. This phenomenon is referred to as "trained immunity" or "innate immune memory". Trained immunity is characterized by metabolic and epigenetic reprogramming in leukocytes in conjunction with enhanced antimicrobial functions. However, there is very limited information available on the effect of trained immunity in aging and/or sepsis. In 2011, it was reported that BCG vaccination prevented respiratory infections and improved cytokine production in individuals 60-75 years of age. Additionally, a 2020 clinical trial found that BCG vaccination increased protection from infection in individuals over 65 years old. While trained immunity can increase inflammatory cytokine production upon restiumulation, interestingly it was found that BCG vaccination reduces systemic inflammation. It is now known that BCG, a potent immune training agent, induces the immune trained phenotype in humans, thus it is reasonable to speculate that the effect of BCG on respiratory infections in aging subjects may be mediated, in part, by trained immunity.
In this study, we examined innate immune training in monocytes isolated from healthy aging subjects and compared and contrasted their response to immune training with monocytes isolated from younger healthy individuals. We also examined innate immune training in monocytes derived from patients diagnosed with sepsis. We found that trained immunity increases metabolism and functionality of monocytes isolated from healthy aging subjects as well as in sepsis patients. In conclusion, this study confirms that innate immune training can be induced in aging healthy individuals as well as critically ill sepsis patients. We found that innate immune training can be induced regardless of age and there was no substantive difference in the immune trained phenotype as a function of age. We employed β-glucan as our immune training stimulus. The ability of glucan to induce the trained phenotype suggests that it may be possible to pharmacologically induce the immune trained phenotype in aging human immunocytes.
Sitting Time Correlates with Mortality Risk
For more than a decade, researchers have been turning out studies to show that more time spent sitting correlates with a greater risk of mortality. Today's research materials are a recent example of the type, the analysis carried out in a sizable study population. The most obvious cause to suggest is that people who spend more time sedentary also spend less time exercising, and it is the amount of exercise that actually matters. There are studies controlling for exercise level that show that sitting time correlates with mortality independently of exercise level, and there are studies that claim the opposite, that it is all about the degree of exercise rather than the time spent sitting. This is business as usual in the field of epidemiology; one can't take any one study at face value. On any question of this nature, a survey of a dozen or more studies is a good idea.
Why would greater time spent sitting raise the risk of mortality even in people who obtain the recommended level of exercise? One possible line of evidence to consider is the use of accelerometers in daily life to show that even light activity in older people, such as casual walking, gardening, and the like, is associated with reduced mortality. It is possible that more is always better, even given a normal exercise schedule. Further, work on establishing a dose-response curve for exercise has indicated that the presently recommended level of exercise is too low to be optimal. Which again might suggest that adding more, even light activity, could improve matters. Another way of looking at it is to consider whether altered metabolic states, both beneficial and harmful, may produce larger effects the longer that they are maintained. Thus lengthy immobility may produce a greater cost to health and shorter periods of immobility broken by up by light activity. Supporting any of these hypotheses with data is, of course, the challenge.
Association of Sitting Time With Mortality and Cardiovascular Events in High-Income, Middle-Income, and Low-Income Countries
This population-based cohort study included participants aged 35 to 70 years recruited from January 1, 2003, and followed up until August 31, 2021, in 21 high-income, middle-income, and low-income countries with a median follow-up of 11.1 years. Daily sitting time was measured using the International Physical Activity Questionnaire. The measured outcome was a composite of all-cause mortality and major cardiovascular disease (CVD), defined as cardiovascular death, myocardial infarction, stroke, or heart failure.
Of 105,677 participants, 61,925 (58.6%) were women, and the mean age was 50.4 years. During a median follow-up of 11.1 years, 6,233 deaths and 5,696 major cardiovascular events (2,349 myocardial infarctions, 2,966 strokes, 671 heart failure, and 1,792 cardiovascular deaths) were documented. Compared with the reference group (less then 4 hours per day of sitting), higher sitting time (more than 8 hours per day) was associated with an increased risk of the composite outcome (hazard ratio [HR] 1.19), all-cause mortality (HR 1.20), and major CVD (HR 1.21).
When stratified by country income levels, the association of sitting time with the composite outcome was stronger in low-income and lower-middle-income countries (≥8 hours per day: HR 1.29) compared with high-income and upper-middle-income countries (HR 1.08). Compared with those who reported sitting time less than 4 hours per day and high physical activity level, participants who sat for 8 or more hours per day experienced a 17% to 50% higher associated risk of the composite outcome across physical activity levels; and the risk was attenuated along with increased physical activity levels.
Assessing the Causes of Aortic Stiffening in Aged Mice
Aortic stiffness occurs with age, and produces raised blood pressure, hypertension, by sabotaging the usual feedback mechanisms that control blood pressure. Hypertension in turn results in structural damage to delicate tissues throughout the body, as well as producing further biochemical changes that encourage ventricular hypertrophy, among other forms of dysfunction. It causes enough harm that control of blood pressure can meaningfully reduce mortality even without addressing underlying causes of degenerative aging.
Why do arteries stiffen with age? As today's open access paper discusses, this is in part a complex set of changes in the extracellular matrix of blood vessel walls, and in part dysfunction of the smooth muscle cells responsible for constriction and dilation of blood vessels. In the absence of ways to fully reverse one or other of these issues, it remains unclear as to how much of the problem is caused by each of these two contributions, but we can hope that this will change in the near future, given greater investment in research into the mechanisms of aging.
The structure and composition of the extracellular matrix defines the physical properties of a tissue, such as elasticity. With age, elastin laid down in youth becomes damaged and disordered, while other macromolecules that should slide past one another become cross-linked together by persistent advanced glycation end-products such as glucosepane. Meanwhile, inflammatory signaling and other forms of age-related biochemical dysfunction cause impairment in vascular smooth muscle, a failure to respond appropriately to signals to contract or dilate blood vessels.
Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes
As human life expectancy continues to grow, the incidence of age-related cardiovascular diseases (CVD) rises. CVD has long since become the leading cause of death, resulting in an estimated 17.9 million deaths each year (i.e., 30% of global death). Arterial stiffening - defined as the impaired capacity of the large elastic arteries to smoothen pulsatile blood flow - results in increased cardiac afterload, reduced coronary perfusion pressure, and pulsatile strain on the microcirculation. As such, arterial stiffness has gained much recognition as a hallmark and independent predictor of CVD.
Elastic arteries display a distinctly non-linear stiffness-pressure relation, with a limited increase in stiffness in the physiological pressure range but exponential increase at high distending pressure. Interestingly, despite pronounced variation in structural properties and vessel size across species, elastic modulus at mean physiological pressure is highly conserved across all vertebrate and invertebrate species with a closed circulatory system, suggesting strong evolutionary pressure.
In the present study, a longitudinal cardiovascular characterization of spontaneously (i.e., age-dependent) ageing C57Bl/6 mice is presented to establish the temporal relation of aortic stiffness to associated CVD, i.e., cardiac hypertrophy and peripheral hypertension. Furthermore, an in-depth physiological and biomechanical investigation of the isolated ex vivo thoracic aorta was employed to identify the key mechanisms of spontaneous arterial stiffening. We demonstrated that aortic stiffening precedes peripheral blood pressure alterations and left ventricular hypertrophy in spontaneously ageing C57Bl/6 mice, underlining the importance of implementing arterial stiffness measurement as an early marker of cardiovascular ageing in standard cardiovascular care.
Contraction-independent stiffening (due to extracellular matrix changes) is pressure-dependent. Contraction-dependent aortic stiffening develops through heightened α1-adrenergic contractility, aberrant voltage-gated calcium channel function, and altered vascular smooth muscle cell calcium handling. Endothelial dysfunction is limited to a modest decrease in sensitivity to acetylcholine-induced relaxation with age. Our findings demonstrate that progressive arterial stiffening in C57Bl/6 mice precedes associated cardiovascular disease. Aortic aging is due to changes in extracellular matrix and vascular smooth muscle cell signalling, and not to altered endothelial function.
Phosphorylated TDP-43 in Muscle as a Biomarker for ALS
TDP-43 is one of the proteins more recently discovered to become phosphorylated and form harmful aggregates in aged tissues. These aggregates are connected to a range of neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS). Researchers here discuss a novel way to use TDP-43 as a biomarker for the early onset of ALS. Being able to quantify the progression of neurodegenerative conditions in their early stages is a necessary part of the development of effective means of prevention.
Clinicians diagnose ALS based on deteriorating motor function, such as weakness in the arms or legs or difficulty walking. Motor neurons in the brain and spinal cord of people with ALS contain cytoplasmic inclusions of TDP-43, but currently, these can only be detected after a person has died. Recently, other researchers had looked for TDP-43 in muscle biopsies from three cases, spotting inclusions within intramuscular nerve bundles.
To see if this held true in a larger sample, researchers analyzed bicep, quadricep, diaphragm, or tongue muscles postmortem from 10 sporadic ALS cases and 12 age- and sex-matched controls. Within the tissue, they saw intramuscular nerves that had atrophied and puncta of phosphorylated TDP-43 in nerve axons. Neither occurred in the control tissue. Hyperphosphorylated TDP-43 forms aggregates in ALS and other neurodegenerative diseases. The findings suggest that TDP-43 inclusions within muscle tissue could become a marker for late-stage ALS.
What about early stage disease? Researchers analyzed muscle biopsies taken from adults who were experiencing muscle weakness. Of the available biopsies from 114 participants, 71 had captured intramuscular nerve bundles. Of these samples, 33 contained TDP-43 inclusions in nerve axons. All 33 volunteers were subsequently diagnosed with ALS an average of five months after biopsy. Of the 38 participants whose biopsies contained nerve bundles but no TDP-43 inclusions, none developed ALS; rather, all were later diagnosed with a different neurodegenerative disease, such as spinal muscular atrophy.
Elastin Structure in Tissue is Complex, as is the Aging of that Structure
Elastin in the extracellular matrix is important in determining the elasticity of tissue. That elasticity is lost with age, as elastin structure changes in detrimental ways. Because the structure of elastin in tissue is complex, and largely only laid down during development, it seems likely that the best path towards repairing it in old tissues is some form of coercing or reprogramming cells to maintain the elastin structure as they did during the developmental portion of life. As yet, few approaches have made any meaningful inroads in this direction. A few small molecules like minoxidil appear to provoke elastin deposition to some degree, while the biotech company Elastrin is working on a way to remove damaged elastin molecules. This is an important topic, as loss of elasticity in blood vessels is a contributing factor in cardiovascular disease, but as yet is not receiving sufficient attention.
Aging-related degeneration of elastic fibres causes skin wrinkles and loss of elasticity. A correlation has been reported between dermal elastic fibre degradation and wrinkles. However, the mechanism of wrinkle formation is complex and unclear. To establish methods for treating wrinkles, it is necessary to understand the aging-related morphological alterations underlying elastin fibre degradation or disappearance. Recently, three-dimensional (3D) imaging combined with decolourization and fluorescent immunostaining has been used to facilitate the visualization of several tissues, organs, and whole mice. In this study, we aimed to apply the decolourization technique to excised human skin tissue and to observe the 3D structure of elastin fibres. Moreover, to evaluate the elastin fibre structure objectively and quantitatively, we established a computational 3D structural analysis method for 3D imaging.
The 3D observations of the inner skin structures revealed that the structures in the abdominal and eyelid tissues were fundamentally different. In the abdominal skin, oxytalan fibres, which are rich in fibrillin-1, exhibiting a candelabra-like structure, were observed just below the basement membrane, as previously reported. However, in the eyelid skin, a complex entangled network of elastin fibres was observed below the basement membrane, which did not show the candelabra-like structure. The image observation and analysis indicated that the proportion of fibrillin-1 in the eyelid skin was higher than that in the abdomen skin. Although it was unclear whether these differences were due to congenital differences during tissue development or acquired differences due to ultraviolet rays and mechanical movements, it was interesting to understand the mechanism of elastin fibre formation.
In the aged skin from the eyelid and abdomen, the elastin fibres had a short, shrunk and spherical shape compared to the young skin. Because these alterations were common in the eyelid and abdominal skin, they might be because of the intrinsic and chronic physiological process of aging, ischemia, and inflammation and might not depend on characteristic differences, such as on the effects of ultraviolet (UV) irradiation or mechanical irritation, between body parts. In contrast, although these altered parameters were common in the eyelid and abdominal skin, the degree of alteration with age was more significant in the eyelid skin. In addition, the number of fibre branches decreased with aging in the eyelid skin but not in the abdominal skin. It has been reported that the fibrous structure of the skin is associated with wrinkle formation and skin elasticity.
Truncation of fibrillin-rich microfibrils in photo-exposed skin, visualized in 2D, has been reported. The 3D observation and computational analysis performed in this study further support the previous data. Elastin-degrading enzymes, UV-induced reactive oxygen species and frequent mechanical movements might cause these changes in elastin fibres in the eyelid skin. Alternatively, it might also be due to the differences in basic fibre properties, such as the elastin fibre network in the eyelid and the high content of fibrillin-1, as mentioned above.
Psychological Stress Accelerates Immune Aging via Lifestyle Choices
Sustained psychological stress is well known to correlate with poor health and accelerated manifestations of aging, when looking at the epidemiology of sizable study populations. Here, researchers link stress to the age-related decline of the immune system, an important aspect of aging that affects tissue function throughout the body. It is tempting to point to inflammatory signaling as the mechanism of importance, but the conclusion here is that the effects of stress on health are in large part mediated by poor lifestyle choices, such as a worse diet and less exercise, that in turn produce a worse metabolism and more rapid degenerative aging.
To measure exposure to various types of social stress, the researchers analyzed responses from a national sample of 5,744 adults over the age of 50. They answered a questionnaire designed to assess respondents' experiences with social stress, including stressful life events, chronic stress, everyday discrimination, and lifetime discrimination. Blood samples from the participants were then analyzed through flow cytometry, a lab technique that counts and classifies blood cells as they pass one-by-one in a narrow stream in front of a laser.
As expected, people with higher stress scores had older-seeming immune profiles, with lower percentages of fresh disease fighters and higher percentages of worn-out white blood cells. The association between stressful life events and fewer ready-to-respond, naive T cells remained strong even after controlling for education, smoking, drinking, BMI, and race or ethnicity.
Some sources of stress may be impossible to control, but the researchers say there may be a workaround. T-cells - a critical component of immunity - mature in a gland called the thymus, which sits just in front of and above the heart. As people age, the tissue in their thymus shrinks and is replaced by fatty tissue, resulting in reduced production of immune cells. Past research suggests that this process is accelerated by lifestyle factors like poor diet and low exercise, which are both associated with social stress. "In this study, after statistically controlling for poor diet and low exercise, the connection between stress and accelerated immune aging wasn't as strong. What this means is people who experience more stress tend to have poorer diet and exercise habits, partly explaining why they have more accelerated immune aging."
BAG2 Condensates Show That There is Much Left to Explore in the Realm of Cellular Maintenance
There are likely many processes and components involved in cellular maintenance that remain poorly explored, with the work here on BAG2 condensates serving as an example of the type. Cells work to remove damage, and many lines of evidence show that enhancing that outcome improves cell and tissue function, slowing aging. Much of this work emerges from the study of calorie restriction as a means to extend life in short-lived species, but that is just one slice of a much broader area of research. It remains an open question as to whether any of this will lead to effective ways to slow aging in humans, however, given that ways to enhance, say, the processes of autophagy have so far proven disappointing in humans, failing to improve significantly upon the effects of exercise or a lowered calorie intake.
Biomolecular condensates are organelles that don't have the recognizable cell membrane enclosure, but instead, are separated from the surrounding cytoplasm by a difference in density that can be loosely compared to a drop of oil in water. This liquid-liquid phase separation creates a specialized, relatively concentrated environment for certain functions and reactions. For example, a stress granule is a membraneless organelle that appears when the cell is under stress - maybe there's too much glucose, maybe it's too hot or cold, maybe the cell is experiencing dehydration - and its job is to sweep up RNA floating around in the cytoplasm, storing those genetic instructions and pausing their translation into proteins.
"When there's stress, what happens to the proteins that are already in the cell? If they're under those stress conditions, some of those proteins could get damaged and they could misfold." Misfolds of the tau protein, for example, can become pathological and turn into the neurofibrillary tangles that characterize Alzheimer's disease. This is where the newly discovered BAG2 condensate comes in. Named for the BAG2 protein that it contains, the organelle is capable of sweeping up these faulty proteins in the cytoplasm and stuffing them into a proteasome - the cell's version of a trash can - located in the organelle. This inactivates and breaks down the protein. Many proteasomes are present in cells at any given time, he added, but what makes this particular proteasome (labeled 20S) special is that it can accept proteins that are already somewhat misfolded and would not fit in the other cellular trash cans.
Additionally, this method of protein degradation does not rely on the ubiquitination process, in which proteins meant for destruction are marked with a tiny ubiquitin protein tag before being grabbed by the proteasome. The role of the BAG2 protein in this context is not yet fully defined, but researchers suspects that it may have a role in helping organize the messy protein before it goes into the 20S proteasome. "What these BAG2 condensates seem to do, at least in the case of tau, is they can actually travel to the damaged tau and gobble it up. The BAG2 condensate really is an ideal place for damaged tau. It would be really nice to figure out how we can shuttle tau into this condensate at the early stages of its damage for the cell to get rid of it, before it gets worse."
Towards Sabotaging the Link Between Hypertension and Cardiac Hypertrophy
The heart becomes larger and weaker in response to the raised blood pressure of hypertension, though inflammatory signaling clearly also plays an important role. Note the study that showed clearance of senescent cells, and thus removal of their pro-inflammatory signaling, reversed cardiac hypertrophy in mice. In the research noted here, scientists discuss the sensing mechanisms that link blood pressure with hypertrophy of the heart. Sabotaging that system is not as good as prevention of hypertension, as targeting deeper issues should always be better than preventing just a few of their consequences, but will no doubt give rise to the development of small molecule drugs regardless.
Despite advances in cardiovascular medicine over the last 30 years, pathological left ventricular (LV) hypertrophy (LVH) secondary to pressure overload resulting from hypertension or aortic stenosis remains a powerful independent predictor of cardiovascular mortality and morbidity. Thus far, the only treatment available for this condition is blood pressure reduction with anti-hypertensive medications or replacement of a stenotic aortic valve. These strategies do not fully reverse the pathological remodeling that occurs once LVH is established.
We have shown recently that the Ca2+-activated TRPM4 ion channel acts as a positive regulator of pressure overload-induced cardiac hypertrophy. Given that TRPM4 is not activated by membrane stretch, the question remains as to the identity of the molecule at the start of the hypertrophic signaling cascade that senses changes in mechanical load within the myocardium and transduces that mechanical signal into a chemical signal that activates TRPM4. A prime candidate to act upstream of TRPM4 within this mechanosensory signaling cascade that drives LVH is the Ca2+-permeable mechanosensitive ion channel, Piezo1. Despite the significant evidence for a key role of Piezo1 channels in vascular physiology and pathophysiology, little is known about the role of Piezo1 in cardiac biology.
Here we show that Piezo1, which is both stretch-activated and Ca2+-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signaling via a close physical interaction with TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice inhibited the hypertrophic response. Piezo1 deletion prevented upregulation of the sodium-calcium exchanger and changes in other Ca2+ handling proteins after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, and as a potential therapeutic target.
Combining Age-Slowing Interventions in Flies Doubles Life Span
Very little work takes place on combinations of interventions known to target mechanisms of aging. This is largely, I suspect, for reasons relating to intellectual property and control of later development. The work that does take place usually looks at approaches known or likely to have minimal effects in long-lived species such as our own, even while producing sizable gains in short-lived species, and this open access paper follows that trend.
It is unfortunate that short-lived species exhibit a pace of aging that is so much more reactive to the environment than that of long-lived species, as it has biased a great deal of research into directions, such as analysis of the beneficial response to calorie restriction, that cannot possibly greatly extend human life span. Nonetheless, researchers presently know next to nothing about how different approaches to slowing aging interact with one another. Can ten or twenty different marginal approaches be combined to form a more impressive outcome? No-one knows, but projects such as this one may help to set expectations.
In this study, we investigated whether the combined application of several interventions with potential anti-aging action causes a cumulative effect on lifespan extension in flies. As for anti-aging drugs, we used rapamycin, the well-known mTOR signaling inhibitor, and two plant-derived compounds, particularly, alkaloid berberine and carotenoid fucoxanthin, whose geroprotective properties have been studied on different biological models.
We studied the effects of dietary restriction and co-administration of berberine, fucoxanthin, and rapamycin in constant darkness and low-temperature conditions using the D. melanogaster model. In addition, to address whether the long-lived strain demonstrates an enhanced geroprotective effect of the interventions' combinations, we studied the long-lived Enhancer of zeste (E(z)) mutant flies.
In the current study, using a combination of several geroprotective interventions, we managed to more than double the lifespan of flies, which is significantly more than using each intervention separately. This is the first report on the increase of maximum flies' lifespan to more than 200 days (120% increase). This result is most likely associated with the synergistic effect of interventions that led to a global metabolic network reorganization and ultimately to beneficially affected lifespan through the modulation of several molecular signaling pathways at once.
N-lactoyl-phenylalanine as a Link Between Exercise and Appetite Regulation
Exercise helps to downregulate appetite, among its many other beneficial outcomes. Researchers here point to raised levels of N-lactoyl-phenylalanine as an important part of this connection, one of a family of compounds formed as a result of exercise. In the present environment of prevalent obesity, a sizable amount of research into the biochemistry of exercise is directed towards its effects on consumption of food.
"Regular exercise has been proven to help weight loss, regulate appetite, and improve the metabolic profile, especially for people who are overweight and obese. If we can understand the mechanism by which exercise triggers these benefits, then we are closer to helping many people improve their health. We wanted to understand how exercise works at the molecular level to be able to capture some of its benefits. For example, older or frail people who cannot exercise enough, may one day benefit from taking a medication that can help slow down osteoporosis, heart disease, or other conditions."
Researchers conducted comprehensive analyses of blood plasma compounds from mice following intense treadmill running. The most significantly induced molecule was a modified amino acid called N-lactoyl-phenylalanine (Lac-Phe). It is synthesized from lactate (a byproduct of strenuous exercise that is responsible for the burning sensation in muscles) and phenylalanine (an amino acid that is one of the building blocks of proteins). In mice with diet-induced obesity (fed a high-fat diet), a high dose of Lac-Phe suppressed food intake by about 50% compared to control mice over a period of 12 hours without affecting their movement or energy expenditure. When administered to the mice for 10 days, Lac-Phe reduced cumulative food intake and body weight (owing to loss of body fat) and improved glucose tolerance.
The researchers also identified an enzyme called CNDP2 that is involved in the production of Lac-Phe and showed that mice lacking this enzyme did not lose as much weight on an exercise regime as a control group on the same exercise plan. Interestingly, the team also found robust elevations in plasma Lac-Phe levels following physical activity in racehorses and humans. Data from a human exercise cohort showed that sprint exercise induced the most dramatic increase in plasma Lac-Phe, followed by resistance training and then endurance training.
Excess Cholesterol Provokes PERK Expression in Vascular Smooth Muscle Cells in Atherosclerosis
Atherosclerosis is a condition of localized excesses of cholesterol in blood vessel walls, leading to fatty plaques that narrow and weaken those vessels, ultimately leading to stroke or heart attack. A lot of attention is given to the way in which excess cholesterol induces dysfunction in the macrophage cells responsible for clearing that cholesterol from blood vessel walls, thereby creating a feedback loop in which atherosclerotic plaques grow. Researchers here instead look at the effects of excess cholesterol on smooth muscle cells, and how it draws them into making the problem worse.
"We are trying to identify new pathways that cause atherosclerotic plaque buildup, in particular pathways that involve a certain cell type, called smooth muscle cells. For many years, researchers have been focused on other cell types, like endothelial cells and macrophages, but more recent studies have highlighted a role of smooth muscle cells in plaque formation. We found that if we block a specific protein in smooth muscle cells, we can effectively block the majority of plaque formation from occurring in an animal model."
Using a knockout method, researchers fed genetically modified mice a high fat diet and caused the mice to have high cholesterol levels in their blood to drive atherosclerotic plaque formation. Blocking a specific protein called PERK in these mice resulted in an 80% decrease of atherosclerotic plaque buildup in male mice. "This tells us that blocking PERK in smooth muscle cells is important in plaque formation. Interestingly, this protein is activated in smooth muscle cells by too much cholesterol in the cells. There are a lot of drugs on the market that block the smooth muscle cell pathway. Now that we know this buildup can be blocked by targeting smooth muscle cells, we can use medication that is already available and target this pathway to help patients with atherosclerotic plaque buildup. This is just another way we can block or lower the plaque buildup, especially for those who are unable to prevent atherosclerosis with lifestyle modifications or statins."
Inflammaging and Its Contribution to the Development of Atherosclerosis
Inflammaging describes the raised, unresolved inflammation characteristic of old tissues, a dysfunction of the immune system that in turn produces failures of tissue maintenance and function. It arises from issues such as the inflammatory signaling of senescent cells and the reaction of the innate immune system to DNA debris from age-damaged cells. That senescent cells can be cleared, and that clearance will soon enough become a part of everyday medicine, means that the burden of inflammaging for future generations will be diminished. As a result, many age-related diseases will be reduced in incidence and severity, including atherosclerosis.
An increasing number of reports show that aging is a driving factor of atherosclerosis. Aging is closely related to endothelial dysfunction and arterial stiffness, which are considered to be early events leading to CVD. The aging process involves promotion of a series of risk factors (i.e., oxidative stress, endothelial dysfunction, and pro-inflammatory cytokines), leading to endothelial dysfunction and vascular system damage. In addition, cellular aging induces the release of microvesicles, further contributing to the development and calcification of atherosclerotic plaques. Therefore, the incidence of atherosclerosis increases with chronological age, and accelerated aging is the main risk factor for the development of atherosclerotic plaques. Furthermore, atherosclerotic plaques represent a key index of cellular aging, which is characterized by reduced cell proliferation, increased DNA damage, and telomere shortening. In summary, a growing body of evidence indicates that atherosclerosis is promoted by cellular aging.
Atherosclerosis is closely related to inflamm-aging, along with oxidative stress, endothelial dysfunction, and inflammation. Inflamm-aging is defined as a chronic inflammatory process during aging and mainly characterized by chronic progressive strengthening of the pro-inflammatory response. In other words, inflamm-aging promotes the body's pro-inflammatory status with advancing aging, which is closely related to many aging diseases. A series of studies have shown that aging can promote atherosclerosis by damaging the connection between mitochondrial function and the intravascular inflammatory pathway. For example, chronic inflammation is the main cause of age-related atherosclerosis, possibly exerting its effect through the IL-6 signaling pathway. Furthermore, inflammatory factors released by senescent cells result in a senescence-associated secretory phenotype and even atherosclerosis. Selective targeting and elimination of these senescent cells has been shown to slow the growth of atherosclerotic lesions by reducing the release of inflammatory and adhesion factors.
However, the potential mechanism by which inflamm-aging induces atherosclerosis needs to be studied more thoroughly, and there is currently a lack of powerful prediction models. Here, an improved inflamm-aging prediction model was constructed by integrating aging, inflammation, and disease markers with the help of machine learning methods; then, inflamm-aging scores were calculated. In addition, the causal relationship between aging and disease was identified using Mendelian randomization. A series of risk factors were also identified by causal analysis, sensitivity analysis, and network analysis. Our results revealed an accelerated inflamm-aging pattern in atherosclerosis and suggested a causal relationship between inflamm-aging and atherosclerosis. Mechanisms involving inflammation, nutritional balance, vascular homeostasis, and oxidative stress were found to be driving factors of atherosclerosis in the context of inflamm-aging.
Difference Between Ankles in Measurement in Blood Pressure Correlates with Arterial Stiffness
This interesting paper notes that the difference in blood pressure assessed in left and right limbs correlates with measures arterial stiffening, but perhaps only in the legs rather than the arms. This is a consequence of human physiology, the structure of the circulatory system, and how stiffening affects control of blood pressure. The debate that the authors address is whether or not arms and legs are both relevant measurement sites on the body for this correlation. Their evidence points to ankle measurement of blood pressure as the more relevant site, and they theorize as to why this might be the case. It is all interesting! But as is true of a great deal of present day biometrics relating to aging, the purpose of rejuvenation research, such as those parts of the field that might ultimately eliminate arterial stiffening, is to render all of these measurements and considerations irrelevant.
In this population-based study using a simultaneous measurement of blood pressure and arterial stiffness, we evaluated the association between contralateral systolic blood pressure (SBP) differences and arterial stiffness by pulse wave velocity (PWV). We found that the prevalence of interankle differences in SBP of ≥10 mmHg and ≥15 mmHg were common, namely 25% and 12%. Our findings showed that higher body mass index (BMI), and lower ankle-brachial index (ABI) were significantly correlated to greater interarm SBP differences, while increased age, higher BMI, lower ABI, and greater contralateral differences in PWV were significantly correlated to greater interankle SBP differences.
Previous studies indicated SBP differences between arms carry prognostic information and that patients should have evaluation of blood pressure in both arms. In addition, the ankle has been suggested as an alternative and/or additional site for noninvasive blood pressure measurement. In the present study, blood pressure was measured simultaneously, bilaterally at both limbs. Compared with sequentially repeated measurements of blood pressure with a single-cuff that is typically conducted, the simultaneous measurement may be more precise as beat-by-beat differences in blood pressure can be accounted for and can improve diagnostic accuracy. Although brachial SBP was significantly associated with ankle SBP, interarm differences in SBP were not related to interankle differences in SBP suggesting that these contralateral differences in blood pressures may be modulated by different factors. Indeed, arterial stiffness was associated with interankle, but not with interarm, differences in SBP in the present study.
What are the explanations for the contribution of arterial stiffness to interankle SBP difference but a lack thereof to interarm differences? Arterial stiffening is a principal determinant of SBP and has been independently associated with stroke, coronary disease severity, and cardiovascular outcome. As the arterial wall stiffens, arterial wave reflection is a primary mechanism responsible for augmenting SBP. In the arterial tree, branching points, areas of alteration in arterial elastance (from elastic artery to muscular artery), and high-resistance arterioles can all give rise to wave reflection and the lower body is believed to be an important site of wave reflection. This cumulation of reflected waves along with the longer distance of the arterial tree to the ankle versus the upper arm is the reason that SBP at the level of the ankles is elevated in comparison to pressures measured in the arms in healthy humans. It appears plausible that contralateral differences in SBP may be influenced to a greater extent by the stiffness of arteries in the ankle.