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- Does Mitochondrial Dysfunction Meaningfully Contribute to the Development of Atherosclerosis?
- Mesenchymal Stem Cell Exosomes to Treat Disc Degeneration
- Macrophages in Visceral Fat Tissue Produce Inflammatory Signals that Accelerate Atherosclerosis
- Is the Gut a Significant Source of Amyloid-β in Alzheimer's Disease?
- Innate Immune Signaling and the Inflammation that Drives Cerebrovascular Disease
- Extracellular Vesicles in the Development of Neurodegenerative Conditions
- Antihypertensive Drug Rilmenidine is a Calorie Restriction Mimetic
- Obesity Considerably Raises the Risk of Later Life Frailty
- A Discussion of the Biochemistry of Cardiac Fibrosis
- PI3K Inhibition Modestly Extends Life in Mice
- Physical Activity Reduces Dementia Risk
- A Mechanism by Which Calorie Restriction Improves Muscle Stem Cell Activity in Aging
- PKR Inhibition Slows Vascular Aging in Mice
- Arguing Semantics in the Matter of Normal Aging
- Reviewing Efforts to Measure Biological Age
Does Mitochondrial Dysfunction Meaningfully Contribute to the Development of Atherosclerosis?
Mitochondria are the power plants of the cell, producing the chemical energy store molecule ATP, but are also integrated into a wide range of fundamental cellular processes. Mitochondrial function declines with age, likely an important contribution to age-related declines in energy-hungry tissues such as the brain and muscles. It is also known that mitochondrial dysfunction can provoke chronic inflammation via the mislocation of mitochondrial DNA into parts of the cell where it will act as a damage-associated molecular pattern. This upregulation of inflammatory signaling is a reasonable proposal for the way in which mitochondrial aging can contribute meaningfully to atherosclerosis.
Atherosclerosis is considered an inflammatory condition. Fundamentally, atherosclerosis results from the dysfunction of the macrophage cells responsible for clearing excess cholesterol from blood vessel walls. Greater inflammatory signaling reduces the ability of macrophages to undertake repair-related activities, encouraging them to instead enter an inflammatory mode of activity. Once a tipping point is reached in the establishment of toxic deposits of excess cholesterol in blood vessels walls, the lesions will grow over time as ever more macrophages are attracted to the problem, become overwhelmed, and die. Greater inflammatory signaling causes that tipping point to occur more readily.
The second plausible pathway for mitochondrial aging to contribute to atherosclerosis is via the increased generation of oxidative molecules observed to take place in the mitochondrial of cells in aged tissues. Oxidation of cholesterol, other lipids, and lipid carriers such as LDL particles can produce additional stress on the macrophages responsible for cleaning up this metabolic waste. Again, the tipping point in fatty lesions present in blood vessel walls occurs more readily given greater oxidative stress and consequent production of toxic lipids.
Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?
The atherosclerotic process is very often responsible for several cardiovascular and cerebrovascular diseases. It is now well accepted and documented that atherosclerosis starts from endothelial dysfunction and lipid deposition, which progresses through macrophage infiltration, smooth muscles://en.wikipedia.org/wiki/Smooth_muscle">smooth muscle cell migration, and blood borne material deposition, and becomes clinically relevant due to complications, eventually leading to local intravascular thrombus formation. Modified lipoproteins, mainly oxidized low-density lipoproteins (oxLDL), are considered the major contributors to the genesis, progression, and immunological response occurring during the atherosclerotic process.
The first report linking mitochondria to atherosclerosis is from 1970. However, only in the last few years has increasing evidence really underlined the key role of mitochondrial dynamics in the pathogenesis of atherosclerosis. Vascular cells, such as endothelial and smooth muscle cells, due to their metabolic functions and their barrier role are the main targets of mitochondrial dysfunction. In the atherosclerosis process, dysfunctional mitochondria might cause alterations in cellular metabolism and respiration resulting in the excessive production of reactive oxygen species (ROS), leading to oxidative stress. While low levels of ROS exert important signaling functions, elevated ROS production induces the damage of cellular structures, alters DNA, proteins, and other molecules. These conditions can become chronic, thereby favoring atherosclerosis progression and destabilization.
Atherosclerosis is a multifactorial disease. Multiple clinical trials and basic studies have clearly demonstrated that the management of the known risk factors only is not enough to limit the burden of this condition which underlies most cardiovascular diseases. Increasing evidence suggests an important role for mitochondria in the initial steps of this process. They regulate the inflammatory response and oxidative stress, two key steps that, once dysfunctional, might modulate initiation and progression of the atherosclerotic lesion. Thus, the modulation of mitochondrial function could delay the development of endothelial dysfunction, which represents the primum movens of the atherosclerotic process. In this context, it will be important for research, at both preclinical and clinical levels, to define the precise therapeutic interventions focusing on mitochondrial functions.
Mesenchymal Stem Cell Exosomes to Treat Disc Degeneration
First generation stem cell therapies involve sourcing immune privileged cells from sources such as umbilical cord blood, or a patient's own cells from fat tissue or similar, expanding the cells in culture, and then injecting them. Only minimal modifications are permitted to cells prior to transplantation in the US, before it would be classed as a therapy that must go through the IND process with the FDA for specific approval. Outside the US, in the medical tourism market, a range of approaches are undertaken with the goal of altering cultured cell behavior to improve patient outcomes. Unfortunately very little of this is backed by published human trial data.
This class of cell therapy produces little to no engraftment of the transplanted cells. Benefits result from the signals generated by the transplanted cells in the short time before they die. The primary outcome is a reduction in inflammatory signaling, dampening the chronic inflammation associated with aging and disease, with some hope of improved tissue maintenance and regeneration. Beneficial outcomes beyond a reduction in inflammation have proven to be quite unreliable, however.
Given that signaling is the mechanism, and that a sizable fraction of molecular traffic between cells is carried in extracellular vesicles such as exosomes, researchers and clinicians have increasingly focused on harvesting these vesicles as a basis for therapy. It is much easier (and thus cheaper) to store, transport, and use exosomes than to store, transport, and use cells. Based on the evidence to date, the outcomes are broadly similar.
Mechanism of Action of Mesenchymal Stem Cell-Derived Exosomes in the Intervertebral Disc Degeneration Treatment and Bone Repair and Regeneration
Exosomes are bilayered extracellular functional vesicles that are released by different cells with a diameter ranging between 40-120nm. Exosomes carry out their functions by fusing with cell membranes or binding membrane proteins of the recipient cells. They contain functional proteins, nucleic acids (mRNA, miRNA, lncRNA, etc.) and lipids, and are carriers of intercellular communication between donor and recipient cells. Exosomes originate from a wide range of sources, and almost all cells can secrete exosomes. The exosomes secreted under normal and pathological conditions are different, even for the same cells.
Currently, exosomes are widely viewed as effective therapeutic components derived from mesenchymal stem cells (MSCs), and the secretion of exosomes is an important way for MSCs to promote the repair of surrounding tissue injuries. There is ongoing research into the benefits of therapy with MSC-Exos for IDD, as well as bone defects and injuries. The core underlying pathophysiologic mechanism of intervertebral disc degeneration (IDD) are abnormalities and a reduced number of nucleus pulposus cells (NPCs). The functional substance in MSC-Exos can regulate the cell metabolism and function by transferring to NPCs, endplate chondrocytes and annulus fibrosus cells, thus inhibiting IDD. Additionally, MSC-Exos also showed great therapeutic potential in terms of repair in bone defects and injuries via promoting osteogenic differentiation and angiogenesis and regulating the immune response, and similar results have been illustrated with respect to its therapeutic and preventive effects against cartilage injuries and osteoporosis.
Furthermore, the application of novel biomaterials such as hydrogels could prolong the duration of exosomes at the bone injury site and maintain the function and stability of intracapsular proteins and miRNA. In order to enable MSCs to play a better role in repairing tissue injury, studies should continue the exploration of new methods to promote the delivery of bioactive substances in exosomes more efficient and novel biomaterials that can maintain the physiological state of MSC-Exos.
Macrophages in Visceral Fat Tissue Produce Inflammatory Signals that Accelerate Atherosclerosis
Visceral fat tissue is known to produce chronic inflammation via a range of mechanisms that rouse the immune system to futile, self-defeating action. Here researchers investigate the signals produced by macrophages of the innate immune system in fat tissue and their contribution to the progression of atherosclerosis. Atherosclerosis is the buildup of fatty deposits in blood vessel walls, the largest single cause of human mortality. It is a condition driven by macrophage dysfunction, as macrophages are responsible for clearing excess cholesterol, toxic forms of altered cholesterol, and cholesterol carriers such as LDL particles from blood vessel walls. The degree to which macrophages falter at this task determines the tipping point at which a small amount of cholesterol deposition can grow to become an atherosclerotic plaque.
One of the factors determining macrophage activity is their response to the signaling environment. Macrophages can adopt a variety of states depending on levels of various inflammatory signal molecules. The most useful state for clearing cholesterol is M2, an anti-inflammatory, pro-regenerative collection of behaviors. Inflammatory signaling tends to make macrophages adopt the aggressive M1 state optimized for hunting down pathogens, however, and these macrophages give up on cholesterol clearance. Thus the more inflammation, the less effort goes into to attempting to repair atherosclerotic lesions and the cholesterol deposits that will become atherosclerotic lesions.
In today's open access paper, researchers identify some of the more important signals emerging from macrophages in visceral fat tissue. They note that blocking these signals can remove the effects of fat tissue on the progression of atherosclerosis. A more practical approach is to avoid becoming overweight in the first place, but it is worth noting that as aging progresses, a state of chronic inflammation will arise regardless; visceral fat just makes it considerably worse. Solving the underlying causes of that chronic inflammation will be necessary. Even blocking the important signals is only a patch on the problem, and a patch that also tends to disable some of the necessary working of the immune system following injury and infection. That is not ideal!
Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis
Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr-/- recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors.
By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis diseaseburden in the expanding older population.
Is the Gut a Significant Source of Amyloid-β in Alzheimer's Disease?
The early stages of Alzheimer's disease are characterized by rising levels of amyloid-β in the brain and the formation of misfolded amyloid aggregates. It is presently thought that this is a necessary precursor for the more harmful later stages of the condition, in which chronic inflammation and tau aggregation cause widespread cell death in the brain. It has been noted that amyloid-β exists outside the brain, and there is evidence for levels of amyloid-β in the vasculature to be in dynamic equilibrium with amyloid-β in the brain. Clearing amyloid-β from the bloodstream has shown some promise as an approach to reduce levels in the brain.
You may recall that the misfolded α-synuclein aggregates found in Parkinson's disease are now thought to originate in the gut in a sizable number of patients and thereafter spread to the brain. Analogously, in today's open access paper, researchers present evidence for the gut to provide a significant source of amyloid-β that is transported to the brain via the vasculature. This coincides with the evidence for Alzheimer's patients to have a significantly altered gut microbiome composition. Perhaps this affects the risk of disease via increased microbiome-spurred inflammation, but perhaps it is also generating increased amyloid-β to the point of overwhelming the clearance mechanisms in brain tissue.
In this context, it is worth noting the point that a major route of clearance of molecular waste from the brain is via drainage of cerebrospinal fluid. These drainage pathways become impaired with age, and this may also contribute to a continued imbalance in the generation and clearance of amyloid-β. Further, given that amyloid-β is an antimicrobial peptide, persistent infections may also be involved in increasing levels of amyloid-β. A tipping point exists, and multiple mechanisms may be in play to push a patient into sufficient accumulation of amyloid-β to trigger the onset of Alzheimer's pathology.
Gut-derived β-amyloid: Likely a centerpiece of the gut-brain axis contributing to Alzheimer's pathogenesis
Peripheral β-amyloid (Aβ), including those contained in the gut, may contribute to the formation of Aβ plaques in the brain, and gut microbiota appears to exert an impact on Alzheimer's disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived Aβ in aging, gut microbiota, and AD pathogenesis.
To achieve this goal, the expression levels of Aβ and several key proteins involved in Aβ metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aβ was detected throughout the gut in both mice and human, and gut Aβ42 increased with age in wild type and mutant amyloid precursor protein/presenilin 1 (APP/PS1) mice.
Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APP/PS1 mice and fecal microbiota transplantation (FMT) of aged APP/PS1 mice increased gut BACE1 and Aβ42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aβ combined with vagotomy was also performed to investigate the transmission of Aβ from gut to brain. The data showed that, in aged mice, the gut Aβ42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APP/PS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology.
Taken together, this study suggests that the gut is likely a critical source of Aβ in the brain, and gut microbiota can further upregulate gut Aβ production, thereby potentially contributing to AD pathogenesis.
Innate Immune Signaling and the Inflammation that Drives Cerebrovascular Disease
In the progression of degenerative aging, a process of constant, unresolved inflammatory signaling is one of the most important ways in which low-level molecular damage gives rise to widespread dysfunction of tissue and organs. In today's open access paper, researchers discuss what is known of the way in which the innate immune system reacts to molecular signs of aging, the damage-associated molecular patterns such as DNA debris from dysfunctional mitochondrial and stressed and dying cells. This reaction is amplified by the rest of the immune system into a constant, disruptive state of chronic inflammation that changes cell behavior for the worse and degrades tissue structure and function.
Certain common mechanisms of signaling and regulation, such as the better studied forms of inflammasome, are interesting targets for those seeking to develop therapies to effectively suppress inflammation. The challenge in such efforts has always been to suppress inflammatory signaling in a way that only interferes in excessive inflammation, and not the necessary inflammation required for defense against pathogens, regeneration following injury, and so forth. Existing therapies, such as the biologics used to treat autoimmune conditions, tend to focus on inhibition of specific single signal molecules involved in the inflammatory process, and thus indiscriminately suppress inflammation. There is some hope that targeting inflammasomes will prove to be a better option.
The NLRP3 Inflammasome in Age-Related Cerebral Small Vessel Disease Manifestations: Untying the Innate Immune Response Connection
An inflammasome is a multiple protein complex, comprised of sensor proteins such as pattern recognition receptors (PRRs), an effector protein (i.e., caspase-1 in canonical inflammasome, and an adaptor protein (i.e., apoptosis-associated speck-like protein, ASC, containing a caspase activation and recruitment domain, CARD). An inflammasome modulates the innate immune signaling where PRRs respond to pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs), which results in the activation and accumulation of caspase-1 that cleaves pro-interleukin (IL)-1β and pro-interleukin (IL)-18 to their active forms. The activated pro-inflammatory cytokines modulate inflammation in a series of disorders, including chronic inflammatory disease and neurodegenerative disease.
The pathophysiological basis of cerebral small vessel disease (CSVD) involves changes in the structure and function of cerebral microvasculature that penetrates in deep subcortical regions, such as arteries and/or arterioles as well as lipohyalinosis, microthrombosis, necrosis, and fibrinolysis. CSVD is common with aging and is frequently discovered as an incidental finding after neuroimaging. It is often overlooked by physicians due to its covert nature (i.e., asymptomatic). The neuroimaging manifestation of CSVD includes white matter hyperintensities (WMHs) of presumed vascular origins, enlarged perivascular spaces (ePVS), lacunar infarcts, cerebral microbleed (CMBs), and cortical microinfarcts. Alarmingly, these manifestations account for approximately 25% of the total global cases of ischemic stroke, and over 70% of vascular dementias.
An increase in systemic inflammatory agents such as IL-1β, IL-6, and C-reactive protein (CRP) plays the most important roles in the genesis of neuroinflammation in CSVD and ischemic stroke. The heightened pro-inflammatory agents alongside endothelial dysfunction (i.e., due to the formation and accumulation of cell-derived microparticles and disrupted purinergic signaling) may further aggravate endothelial injury. For example, microthrombi and/or microparticles may aggregate on the endothelial surface, worsening blood-brain barrier (BBB) permeability and leading to microvascular bleeding. Furthermore, inflammation may disrupt cell-cell interactions, exacerbating the cellular injury that results in luminal narrowing, reduced cerebral blood flow, hypoxia, neuronal cell death, and parenchyma damage.
Following parenchyma injury, sequences of pathological changes that ensue could eventually elicit the activation of the NLRP3 inflammasome. The activated NLRP3 inflammasome may further worsen the parenchyma injury through a cascade of inflammatory signaling. As aforementioned, the NLRP3 inflammasome is crucial in the genesis of atherosclerosis, arteriosclerosis, and arteriolosclerosis and increases the likelihood of CSVD and ischemic stroke. Thus, here we hypothesize plausible pathophysiological mechanisms that underlie the NLRP3 inflammasome-linked CSVD through the NLRP3-mediated neuro-thrombo-inflammation, its influence on disease progression and potential therapeutic target.
In our hypothesis, blood-brain barrier (BBB) breakdown caused by elevated thrombo-inflammation, neuronal injury, and activation of neuroglial cells mediates the mitochondrial dysfunction leading to increased production of reactive oxygen species (ROS). ROS activated the NLRP3 inflammasome leading to pyroptosis and secondary neuronal injury that may lead to the development and progression of cerebral small vessel disease (CSVD). Besides, cellular oxidative stress also causes hypoxia-mediated NF-κB pathway activation that subsequently led to NLRP3 inflammasome activation.
Extracellular Vesicles in the Development of Neurodegenerative Conditions
A broad discussion of extracellular vesicles is really a broad discussion of cell communication, as much of the traffic of molecules between cells is carried inside vesicles. Researchers here discuss what is known of the roles played by vesicle-mediated communication in neurodegenerative conditions, still a very broad topic. One of the noteworthy contributions is that this traffic of vesicles enables the spread of prion-like altered and misfolded proteins, such as tau and α-synuclein, that are capable of seeding the generation of more such harmful molecules in the destination cell. Whether there are ways to selectively prevent this process of spread and seeding remains an open question; it seems a daunting prospect, since every part of the vesicle communication infrastructure performs useful functions.
Many neurodegenerative disorders are characterized by the abnormal aggregation of misfolded proteins that form amyloid deposits which possess prion-like behavior such as self-replication, intercellular transmission, and consequent induction of native forms of the same protein in surrounding cells. The distribution of the accumulated proteins and their correlated toxicity seem to be involved in the progression of nervous system degeneration. Molecular chaperones are known to maintain proteostasis, contribute to protein refolding to protect their function, and eliminate fatally misfolded proteins, prohibiting harmful effects. However, chaperone network efficiency declines during aging, prompting the onset and the development of neurological disorders.
Extracellular vesicles (EVs) are tiny membranous structures produced by a wide range of cells under physiological and pathological conditions, suggesting their significant role in fundamental processes particularly in cellular communication. They modulate the behavior of nearby and distant cells through their biological cargo. In the pathological context, EVs transport disease-causing entities, including prions, α-synuclein, and tau, helping to spread damage to non-affected areas and accelerating the progression of neurodegeneration. However, EVs are considered effective for delivering therapeutic factors to the nervous system, since they are capable of crossing the blood-brain barrier (BBB) and are involved in the transportation of a variety of cellular entities.
Here, we review the neurodegeneration process caused mainly by the inefficiency of chaperone systems as well as EV performance in neuropathies, their potential as diagnostic biomarkers and a promising EV-based therapeutic approach.
Antihypertensive Drug Rilmenidine is a Calorie Restriction Mimetic
Researchers here use nematode worms to demonstrate that a commonly used antihypertensive drug is a calorie restriction mimetic. The beneficial response to calorie restriction, resulting in improved health and longevity, evolved very early in the development of life, and the underlying mechanisms are surprisingly similar across near all species, even if the end results vary in degree. Long-lived species do not exhibit the sizable gains in life span observed in short-lived species, for example, even though the health benefits remain noteworthy. In the nematode study, the drug produces less impressive results than actual calorie restriction in this species, always the case with these compounds, but the extension of life span is the same ballpark as the results obtained using various other calorie restriction mimetic strategies and related genetic alterations in nematodes.
Repurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. Here, we searched for known compounds that elicit a similar gene expression signature to caloric restriction and identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating Caenorhabditis elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, health span, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1-imidazoline receptor nish-1, implicating this receptor as a potential longevity target.
Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to calorically restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine-induced longevity required the transcription factors FOXO/DAF-16 and NRF1,NRF2,NRF3/SKN-1. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine.
Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound.
Obesity Considerably Raises the Risk of Later Life Frailty
As might be expected, epidemiological data shows that obesity in mid-life raises the risk of suffering frailty in later life. Excess visceral fat tissue increases the pace at which senescent cells accumulate in the body and generates chronic inflammation, disruptive of tissue structure and function. In that sense it literally accelerates aging and the onset of age-related conditions, particularly those known to be driven in large part by chronic inflammation.
The present study followed 4,509 community-dwelling participants from the population-based Tromsø study from 1994 to 2016 to examine the association between general and abdominal obesity and the risk of frailty. This study suggests an increased likelihood of pre-frailty/frailty among those with baseline obesity. Increased likelihood of pre-frailty/frailty was also observed among those with high or moderately high waist circumference (WC) at baseline.
Participants with baseline obesity (adjusted odds ratio [OR] 2.41), assessed by body mass index (BMI), were more likely to be pre-frail/frail than those with normal BMI. Participants with high (OR 2.14) or moderately high (OR 1.57) baseline WC were more likely to be pre-frail/frail than those with normal WC. Participants in the 'overweight to obesity' or the 'increasing obesity' trajectories had increased odds of pre-frailty/frailty compared with those in the stable normal BMI trajectory. Additionally, participants with a high WC at baseline, whose WC gradually or steeply increased throughout the follow-up period, had increased odds of being pre-frail/frail compared with those in a stable normal WC trajectory.
There are different mechanisms through which obesity might contribute to pre-frailty/frailty. Increased adiposity leads to increased secretion of pro-inflammatory adipokines, thus contributing to inflammation, which is also associated with frailty among older adults. Obesity leads to increased fat mass and increased lipid infiltration in muscle fibres resulting in reduced muscle strength and function. When coupled with an age-related decline in muscle mass and strength, it causes 'sarcopenic obesity', which is linked to an increased risk of frailty and disability.
A Discussion of the Biochemistry of Cardiac Fibrosis
Fibrosis is a malfunction of tissue maintenance, in which excessive amounts of extracellular matrix structure are created, forming scar-like features that disrupt normal tissue function. Fibrosis is a feature of aging and can rise to the level of life-threatening issue in organs such as the lung, liver, kidneys, and heart. This is particularly the case because there are no truly effective therapies to treat fibrosis; it is an inexorable condition that leads towards organ failure. Progress towards the reversal of fibrosis has been slow, unfortunately, despite the comparatively recent discovery that senescent cells appear to drive fibrosis in many organs, including the heart.
Cardiac fibrosis is a common feature of acute myocardial infarction (MI) and various other chronic diseases, such as hypertension, diabetes mellitus, and chronic kidney disease. Numerous studies emphasized that the severity of cardiac fibrosis correlates with adverse cardiac events and mortality. Cardiac fibrosis is defined as an increase in the myocardial extracellular matrix (ECM) protein deposition, mainly collagen I and collagen III, that impairs cardiac function.
Two types of cardiac fibrotic lesions have been defined depending on their localization and the feature of ECM protein deposition. The first one is a reparative process, also named replacement fibrosis, that is observed as scar tissue. In this ischemic disease, oxygen deprivation of the heart muscle results in the necrosis and apoptosis of cardiomyocytes, leading to a loss of large amounts of cardiac cells that are essential for cardiac function. Cardiomyocyte death initiates a triphasic immune response that aims at clearing cell debris and promoting the replacement of the injured myocardium to maintain cardiac function.
The second type of fibrotic lesion is interstitial fibrosis, characterized by the diffuse deposition of collagen in the endomysium and perimysium. This interstitial fibrosis frequently comes with perivascular fibrosis and is specifically observed as secondary to chronic injuries, such as a pressure overload (aortic stenosis, hypertension), cardiac inflammation (myocarditis), and metabolic disorders (obesity, diabetes mellitus) as well as aging. Diffuse fibrosis is also frequently observed in the surviving infarcted heart, where it develops in remote areas. The myocardial interstitial fibrosis development alters myocardial architecture and physiology, modifying left ventricular compliance, diastolic function, and electrical connectivity, leading to arrythmia and adverse outcomes (hospitalization, mortality).
Whatever the context, interstitial cardiac fibrosis is correlated with cardiac dysfunctions and is known to contribute to HF with or without preserved ejection fraction. Thus, understanding the molecular pathways involved in cardiac fibroblast activation will permit the development of new therapeutic strategies to fight cardiac fibrosis and reverse HF.
PI3K Inhibition Modestly Extends Life in Mice
Long term treatment of mice that results in a modest extension of life span, such as the example here involving inhibition of a subunit of PI3K, is unlikely to be interesting as a basis for human medicine to target aging. Life span is more plastic in short-lived mammals in response to altered metabolic states. Of the known approaches to slowing aging where one can compare humans and mice directly, there is no large extension of life in humans. The most interesting approaches to aging are those that can be applied very intermittently later in life, and which repair damage or enhance function sufficiently well for even one treatment to improve matters noticeably. Senolytics or the restoration of stem cell and immune function following the use of CASIN, for example.
Treatment of healthy mice frommiddle-age (one year) with alpelisib, a cancer drug that targets the p110α subunit of an enzyme called PI3K, can increase their lifespan byan average often percent. In thisstudy, mice werefeda control diet or the same diet with the addition of a drug called alpelisib. Not only did the mice fed the drug containing diet live longer, they showed some signs of being healthier in old age such as improved coordination and strength. However, the researchers are cautious about application to humans since the mice treated with the drug also had some negative markers of ageing like lower bone mass.
"We are not suggesting that anyone should go out and take this drug long-term to extend lifespan, as there are some side effects. However, this work identifies mechanisms crucial to ageing that will be of use in our long-term efforts to increase lifespan and health-span. It also suggests a number of possible ways in which shorter term treatments with this drug could be used to treat certain metabolic health conditions and we are following this up now."
Physical Activity Reduces Dementia Risk
The quality of data resulting from studies of exercise and disease risk has increased greatly since the advent of low-cost accelerometer devices. Self-reported activity data has many issues, not least of which being the challenge of assessing just how much low intensity activity is actually taking place. Nonetheless, the evidence for a greater degree of physical activity to reduce the risk of age-related disease was extensive even prior to the commonplace use of accelerometers in such studies, and has only grown since. The example here is one of a great many studies focused on exercise in the context of dementia risk.
Because few large studies have examined device measures of movement and sitting in relation to mild cognitive impairment and dementia, much of the published research on the associations of physical activity and sedentary behavior with cognitive decline and dementia is based on self-reported measures. For this study, the researchers sampled data from 1,277 women as part of two Women's Health Initiative (WHI) ancillary studies - the WHI Memory Study (WHIMS) and the Objective Physical Activity and Cardiovascular Health (OPACH) study. The women wore research-grade accelerometers and went about their daily activities for up to seven days to obtain accurate measures of physical activity and sitting.
The activity trackers showed the women averaged 3,216 steps, 276 minutes in light physical activities, 45.5 minutes of moderate-to-vigorous physical activity and 10.5 hours of sitting per day. Examples of light physical activity could include housework, gardening or walking. Moderate-to-vigorous physical activity could include brisk walking. The researchers reported that, among women aged 65 or older, each additional 31 minutes per day of moderate-to-vigorous physical activity was associated with a 21 percent lower risk of developing mild cognitive impairment or dementia. Risk was also 33 percent lower with each additional 1,865 daily steps. The study findings also showed that higher amounts of sitting and prolonged sitting were not associated with higher risk of mild cognitive impairment or dementia.
A Mechanism by Which Calorie Restriction Improves Muscle Stem Cell Activity in Aging
It is known that the practice of calorie restriction slows the characteristic loss of muscle mass and strength that takes place with age, leading to sarcopenia. Researchers here identify a mechanism by which lowered calorie intake improves muscle stem cell activity in the context of aging. Other work suggests that declining stem cell activity is the most important factor in the development of sarcopenia. An understanding of the mechanisms involved may lead to improved ways to mimic the specific protective effects of calorie restriction in this context.
In this study, we used a calorie restriction (CR) model of elderly mice with muscle-specific 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) knockout mice and 11β-HSD1 overexpression mice to confirm that CR can delay muscle aging by inhibiting 11β-HSD1 which can transform inactive glucocorticoid (cortisone) into active glucocorticoid (cortisol). The ability of self-renewal and differentiation into muscle fibers of these mouse muscle stem cells (MuSCs) was observed in vitro. Additionally, the mitochondrial function and mitochondrial ATP production capacity of MuSCs were measured by mitochondrial oxygen consumption.
It was found that the 11β-HSD1 expression level was increased in age-related muscle atrophy. Overexpression of 11β-HSD1 led to muscle atrophy in young mice, and 11β-HSD1 knockout rescued age-related muscle atrophy. Moreover, CR in aged mice reduced the local effective concentration of glucocorticoid through 11β-HSD1, thereby promoting the mitochondrial function and differentiation ability of MuSCs.
Together, our findings highlight promising sarcopenia protection with CR in older ages. Furthermore, we speculated that targeting an 11β-HSD1-dependent metabolic pathway may represent a novel strategy for developing therapeutics against age-related muscle atrophy.
PKR Inhibition Slows Vascular Aging in Mice
Endothelial dysfunction in blood vessel walls is thought to precede many of the other issues of vascular aging, promoting the development of atherosclerosis and loss of regulation of contraction and dilation of blood vessels. Researchers here investigate the degree to which inflammatory signaling and cellular senescence in the context of endothelial aging may be regulated by one specific signaling pathway.
Protein kinase R (PKR) plays an important role in regulating various signal pathways of innate immune diseases. In the past, it was considered that PKR could only be activated by infectious agents, toll-like receptor ligands, cytokines, and other inherent immune-related factors, to regulate the activation of immune signal pathways and release of immune inflammatory factors. In our recent studies, PKR has been revealed to be a key target in promoting endothelial cell senescence and pulmonary hypertension mediated endothelial injury.
In normal physiological conditions, the endothelium is a crucial regulator of vascular physiology and produces several substances to protect the layer of arteries. However, injured endothelial cells become the initial contributor to promote the development of cardiovascular diseases in a pathological phenotype. We previously reported that PKR triggered IL-1β and HMGB1 release to induce PH development, although how endothelial PKR promotes IL-1β and HMGB1 release in vascular aging still need to be further investigated.
We try to in-depth evaluate whether PKR mediated inflammatory factors release is because of mediating endothelial cell hyperactivation. Despite this, how endothelial PKR-mediated inflammatory factors release induces vascular smooth muscle cells (VSMCs) senescence is still unknown. As the main cell type within the vasculature, VSMCs are responsible for maintaining vascular homeostasis. It can present as contraction phenotype and secretory phenotype.
The phenotype transforming of VSMCs from contraction phenotype to secretory phenotype is a remarkable symbol of vascular aging. In normal blood vessel, contraction phenotype VSMCs is the vast majority type of VSMCs. During the aging process, VSMCs gradually lose the contractile phenotype and acquire the proliferative and secretory phenotype, which eventually contributes to vascular degeneration and vascular remodeling via abnormal self-proliferation and promotes the vascular stiffness by the excessive deposition of collagen and decrease of elastin. Therefore, we hypothesize that endothelial PKR-mediated inflammatory factors release can induce the phenotype transforming of VSMCs to induce vascular aging.
Global knockout of PKR exhibits significantly delayed vascular aging compared to wild-type mice at the same age. Invitro, using PKR siRNA or the cell hyperactivation inhibitor glycine or disulfiram can effectively inhibit H2O2 or palmitic acid-induced endothelial cell hyperactivation, IL-1β and HMGB1 release, and co-cultured VSMC phenotype transforming. These results demonstrate that endothelial PKR activation induces endothelial cell hyperactivation torelease HMGB1 and IL-1β, which promotes the phenotype transforming of VSMC and subsequent accelerates the process of vascular aging.
Arguing Semantics in the Matter of Normal Aging
Researchers here complain about the term "normal aging", suggesting that it is misleading. There is certainly no shortage of problematic language in the description of aging. "Healthy aging" is a contradiction in terms that is widely used to justify a focus on marginal therapies that cannot even in principle achieve rejuvenation, for example. Does it help progress for language to be aligned with goals? Likely, though perhaps only in the longer term. It is clear that a good portion of the research community is already interested in treating aging as a medical condition, regardless of the language used - but more widespread interest in that goal is always better!
Everyone increases in chronological age once a year, which is considered a normal event and celebrated (or not) on a regular basis. But is there such a thing as normal aging? Normal aging is a descriptive term used frequently in published scientific literature to indicate processes and pathways that similarly change with increasing age in a majority of the population in the absence of overt disease. However, if we take a look beneath the surface, deep into pathological changes that occur in cells with increasing age, nothing appears normal. And in fact, changes become more abnormal with increasing chronological age. So-called "normal" histological changes are considered lesions because they are different from the histology seen at younger ages. Is there such a thing as a normal lesion? We think not, even though many pathologists view the presence of age-related lesions as a normal occurrence for older age groups.
The point of this brief discourse is to provide a convincing argument that the term "normal aging" should not be used because it is scientifically incorrect. Aging consists of abnormal changes that occur over time and in varying degrees in every living creature. In human aging, we know that some individuals are more resilient, so maintain a physically and mentally fit condition with increasing age, while others are less resilient and become increasingly compromised with increasing age. There is thus a tendency to label resilience to aging as normal aging and lack of resilience as abnormal aging. Again, this description lacks scientific merit because changes are still occurring in both resilient and non-resilient groups, but in relative degrees.
Thus, "resilient" aging would be a more correct term to represent a major emphasis on investigating mechanisms and therapeutic targets for resilience, rather than a label of "normal" aging that is misleading and currently receives relatively little attention.
Reviewing Efforts to Measure Biological Age
An increasingly diverse set of approaches are under development with the aim of measuring biological rather than chronological age. Assessing the age-related burden of damage and dysfunction with sufficient accuracy would enable cost-effective quantification of any potential rejuvenation therapy. It would hopefully steer the research community away from marginal treatments and towards more effective treatments in the near term. Unfortunately, despite a proliferation of such measures, it remains far from clear that any of them can be trusted once one starts in on treating aspects of aging. A given measure of aging may or may not be less sensitive or overly sensitive to the results of a therapy that only addresses one mechanism of aging, but there is no way to know in advance whether or not this is the case without extensive, lengthy calibration in animal and then human studies.
There is no single universal biomarker yet to estimate overall health status and longevity prospects. Moreover, a consensual approach to the very concept of aging and the means of its assessment are yet to be developed. Markers of aging could facilitate effective health control, more accurate life expectancy estimates, and improved health and quality of life. Clinicians routinely use several indicators that could be biomarkers of aging. Duly validated in a large cohort, models based on a combination of these markers could provide a highly accurate assessment of biological age and the pace of aging.
Biological aging is a complex characteristic of chronological age (usually), health-to-age concordance, and medically estimated life expectancy. This study is a review of the most promising techniques that could soon be used in routine clinical practice. Two main selection criteria were applied: a sufficient sample size and reliability based on validation. The selected biological age calculators were grouped according to the type of biomarker used: (1) standard clinical and laboratory markers; (2) molecular markers; and (3) epigenetic markers. The most accurate were the calculators, which factored in a variety of individual biomarkers. Despite their demonstrated effectiveness, most of them require further improvement and cannot yet be considered for use in standard clinical practice.