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- Exosome Signaling Appears to Mediate Age-Related Changes in Bone Tissue Maintenance Leading to Osteoporosis
- Methionine Restriction Should Slightly Slow Aging in Humans
- A Lengthy Discussion of Oxidative Stress in the Progression of Alzheimer's Disease
- Results from Another Trial of a Tissue Engineered Retinal Pigment Epithelium Patch
- Uncertainty Over Whether or Not Adult Neurogenesis Occurs to Any Significant Degree
- Finding a Causal Relationship Between Exercise and Longevity in Human Data is More Challenging than One Might Imagine
- Long Lived Species May Require Greater Accuracy in Protein Translation
- A Demonstration that Smooth Muscle Cell Dysfunction Contributes Significantly to Age-Related Vascular Stiffening
- A Correlation Between More AGEs in the Skin and Worse Pulmonary Function
- No Sign of Benefits in a Study of Higher Protein Intake in Older Individuals
- Greater Aerobic Fitness Correlates with Better Memory Function in Later Life
- A Marker for Cancer Stem Cells that Might Also Lead to a Cell-Killing Treatment
- Calorie Restriction Slows the Age-Related Accumulation of DNA Damage, Inflammation, and Cellular Senescence in Fat Tissue
- Better Understanding Why the Liver is a Highly Regenerative Organ
- How Great is the Dormant Potential for Regeneration in Tissues?
Exosome Signaling Appears to Mediate Age-Related Changes in Bone Tissue Maintenance Leading to Osteoporosis
Bone might be more solid than other tissues, but it is just as dynamic: maintenance of bone is a constant, balanced process of creation by osteoblast cells and destruction by osteoclast cells. With age, this balance breaks down, however. Osteoblasts accomplish proportionally less work, and osteoclasts accomplish more. As a result, bone becomes weakened, porous, and fragile, leading to the clinical condition of osteoporosis. This is a significant component of frailty and mortality, as fractures and breaks of bone in elderly individuals can happen with little provocation, and when they do, that trauma often marks the beginning of the final spiral downwards.
In seeking to understand osteoporosis, researchers are largely working backwards from the disease state, looking for mechanisms that change the balance of osteoblast and osteoclast cell populations and activity. There are a sizable number of plausible candidates. Chronic inflammation, for example, is thought to be a part of the problem, and it certainly disrupts many other important systems of cellular coordination related to regeneration and tissue maintenance. Senescent cells are a significant source of inflammation in older individuals, and researchers have demonstrated that removing them can partially reverse osteoporosis in mice.
Without a deep examination of the causes, researchers are also mapping changes in the signaling mechanisms by which cells communicate. These communications steer cellular behavior, so in at least some cases it is though that benefits might be obtained by interfering in the signaling responses to the underlying damage of aging, rather than by fixing the damage itself. Much of this signaling is not in the form of molecules secreted unprotected into the intercellular spaces, but rather via vesicles of various types. These are membrane-wrapped packages of molecules, much smaller than cells, and classified by size into classes such as exosomes, microvesicles, and so forth. Research into vesicles is currently blossoming, with scientists hoping to be able to use them to beneficially influence cell behavior in any number of ways. First, however, a certain amount of mapping and experimentation must take place, as is illustrated in this open access paper.
It is worth considering, however, that is probably better to repair the underlying damage that causes signaling changes. That damage causes all sorts of issues, not just the ones that a research team is presently narrowly focused on. It isn't cost-effective, and may not even be possible to intercept and prevent every downstream change without actually repairing the root cause. Here it is hard to even make the argument that all of the important root causes are mysterious and unassailable at this time, given that cellular senescence appears to be significant, and dealing with that via senolytic therapies is almost certainly cheaper right now than working with exosomes.
Involvement of serum-derived exosomes of elderly patients with bone loss in failure of bone remodeling via alteration of exosomal bone-related proteins
Normal bone remodeling is activated by osteoclasts that are unique in their function of bone resorption, followed by a constructive process in which new bone is generated by osteoblasts. The coordinated regulation of these important cell types is critical for maintaining physiological bone remodeling, which is tightly controlled by physical cell-cell interactions, secretory signals, and the endocrine system. Osteoclast activation occurs after binding of receptor activator of nuclear factor κB (RANKL) to its receptor RANK, which is expressed in the membrane of osteoclast precursors.
Recent studies have revealed that various key factors involved in bone remodeling are packaged in spherical bilayered membrane vesicles called exosomes. These organelles function as cell-cell communicators by transferring biologically active molecules to adjacent or distant cell. Various cell types secrete exosomes. With an average diameter of 40-150 nm, exosomes are released into the circulation and transfer the biologically active molecules contained within to target cells.
Recent reports indicate the involvement of bone-associated exosomes in regulating bone remodeling, mainly via the transfer of critical molecules required for the regulation of osteoclasts and osteoblasts. However, the comprehensive changes among the proteins in serum-derived exosomes (SDEs) of aged patients with osteoporosis or osteopenia and their functions in bone remodeling remain largely unclear. Here, to determine the biological functions of SDEs in osteoporosis and osteopenia, we compared the proteomic profiles of exosomes purified from the serum of elderly patients with osteoporosis and low bone mass with those of aged and young normal volunteers.
In the present study, we discovered that the SDEs from osteoporosis patients inhibited osteoblastic bone matrix mineralization and promoted osteoclast differentiation. In contrast, SDEs from osteopenia patients enhanced both osteoblast function and osteoclast activation, leading to a compensatory increase in bone remodeling. The SDEs from aged normal volunteers might play a protective role in bone health through facilitating adhesion of bone cells and suppressing aging-associated oxidative stress. The differently expressed proteins identified were involved in different processes and functions intrinsic to bone, including mechanosensation, inflammation, and cell senescence, which are the apparent protagonists in bone remodeling.
Methionine Restriction Should Slightly Slow Aging in Humans
The beneficial effects of calorie restriction on health and longevity are well researched in mammals, but while a sizable fraction of those benefits are thought to be mediated via sensing of amounts of specific proteins such as methionine and cysteine, there is comparatively little investigation of protein restriction strategies - usually meaning a reduced dietary intake of one or more proteins, while overall calorie intake remains at the same level. Work in this part of the field is taking place, and shows extension of life span to some degree in rodent studies, but it has a long way to go to catch up to the breadth of research into calorie restriction.
Calorie restriction is, of course, not yet decisively proven to slow aging extend life in humans, through the existing data makes a strong argument for this to be the case. It isn't expected to have much more than a five year effect on human life span, however. While the short term benefits of calorie restriction are similar in different mammalian species, the measured effects on longevity scale down with species life span. The reasons for this to be the case remain to be determined.
While specific aspects of the biochemistry of the calorie restriction response are quite well investigated, such as its effects on autophagy, there is enormous complexity in the way in which all of the changes fit together with the details of metabolism to determine the pace of aging. Meaningful progress towards a full map of the biochemistry and progression of aging still lies ahead - and will likely still be an ongoing project well after rejuvenation therapies based on the SENS model of damage repair are a going concern.
In this open access review, the authors argue that there is enough evidence at the present time to expect protein restriction strategies such as methionine restriction to produce benefits in our species. We should be looking at protein restriction in much the same way as we look at exercise and calorie restriction: a reliable, demonstrated way to slightly slow the aging process and obtain benefits to long term health, a method just one step short of the final decisive proof and calibration of the size of the effect.
Sulfur amino acid restriction could amount to new dietary approach to health
Amino acids are the building blocks of all proteins in the body. A subcategory called sulfur amino acids includes methionine (Met) and cysteine (Cys), which not only make up proteins but also play many roles in metabolism and health. Researchers have been interested in dietary sulfur amino acid restriction since the 1990s, when studies began to show health benefits in animals fed Met-restricted diets. In one early study involving rats, 80 percent Met restriction increased average and maximum lifespans by between 42 and 44 percent.
Scientists have long known that animals on calorie-restricted diets live longer and healthier, but they've been searching for ways bring about the improvements without asking people to eat less. In new review of studies, sulfur amino acid restriction consistently demonstrated a range of beneficial effects including enhanced lifespan - without calorie restriction. The analysis found that Met restriction has been associated with delayed aging and longer lifespans in human cells, yeast, and animals including fruit flies and rodents. Animals fed sulfur amino acid-restricted diets also had health improvements including reductions in body weight, fat and oxidative stress; fewer cancerous tumors; enhanced insulin sensitivity; and more efficient fuel-burning.
"This review describes a number of studies which provide some hints that sulfur amino acid restriction might achieve some of the benefits observed in animal models, including cancer inhibition and reducing risks for cardiovascular disease." Researchers are now overseeing the first tightly controlled feeding study of dietary sulfur amino acid restriction in human subjects, which may provide more direct evidence of health benefits.
Disease prevention and delayed aging by dietary sulfur amino acid restriction: translational implications
Sulfur amino acids (SAAs) play numerous critical roles in metabolism and overall health maintenance. Preclinical studies have demonstrated that SAA-restricted diets have many beneficial effects, including extending life span and preventing the development of a variety of diseases. Dietary sulfur amino acid restriction (SAAR) is characterized by chronic restrictions of methionine and cysteine but not calories and is associated with reductions in body weight, adiposity, and oxidative stress, and metabolic changes in adipose tissue and liver resulting in enhanced insulin sensitivity and energy expenditure. SAAR-induced changes in blood biomarkers include reductions in insulin, insulin-like growth factor-1, glucose, and leptin and increases in adiponectin and fibroblast growth factor 21.
On the basis of these preclinical data, SAAR may also have similar benefits in humans. While little is known of the translational significance of SAAR, its potential feasibility in humans is supported by findings of its effectiveness in rodents, even when initiated in adult animals. To date, there have been no controlled feeding studies of SAAR in humans; however, there have been numerous relevant epidemiologic and disease-based clinical investigations reported. Here, we summarize observations from these clinical investigations to provide insight into the potential effectiveness of SAAR for humans.
A Lengthy Discussion of Oxidative Stress in the Progression of Alzheimer's Disease
Alzheimer's disease is very complex and incompletely understood because the brain is very complex and incompletely understood. Efforts to make progress towards therapies for Alzheimer's disease have progressed in parallel with, and often driven and funded, efforts to map the works of the brain at the detail level of cellular biochemistry. Even though Alzheimer's will turn out to have easily stated causes, a set of comparatively simple biochemical processes, even simple origins expand - over time and through chains of cause and effect - to produce end state conditions that are as complex as their environment.
Researchers tend to specialize. There is too much biochemistry to hold it all in one mind, even for a single medical condition. So the research community tends to act in practice much like the blind men and the elephant, everyone focused on their particular facet of the larger condition. Focus is necessary to make progress on understanding that facet, but at the end of the day someone needs to occasionally review all of the facets together to see if the picture still makes sense. Synthesis is an increasingly important function in modern life science research, becoming ever more challenging as the facets grow in size, but sadly undervalued. Alzheimer's research and development still awaits a definitive synthesis, the theory and proof that will show us which of the facets of the condition are important, which are primary and which are secondary.
The open access paper here discusses the oxidative stress view of Alzheimer's disease, a basis for considering progression of the condition that doesn't get as much attention as work on aggregates of amyloid-β and tau. Oxidative stress refers to the rising level of oxidative molecules and signs of the damage they do to molecular machinery inside and outside cells. Oxidation is a fact of life in cells, a necessary part of the way in which biology works: damage happens constantly, and is repaired constantly. Ever more oxidative damage and oxidative molecules are present in the body and brain with the progression of aging, alongside a growth in chronic inflammation - oxidative stress and inflammation are usually found together, linked by a number of mechanisms. Alzheimer's and most other neurodegenerative conditions appear to have a strong inflammatory component, and thus there is oxidative stress to observe as well.
A Long Journey into Aging, Brain Aging, and Alzheimer's Disease Following the Oxidative Stress Tracks
Nowadays, Alzheimer's disease (AD) is the most diagnosed type of dementia. For a long time, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) have been considered unquestionably the main cause of AD pathogenesis, but many other theories have been proposed, including oxidative stress and neuroinflammation, to explain a still unknown disease.
For many years, the amyloid cascade hypothesis has dominated AD thinking, modeling, and therapeutic approach. Amyloid proteins are beta-sheet proteins that can easily aggregate. Aβ is a proteolytic degradation product of a larger molecule called amyloid-β protein precursor (AβPP). The amyloid cascade hypothesis postulates an overproduction of Aβ, which leads to neuronal dysfunction and apoptosis causing AD clinical manifestations. According to this hypothesis, amyloid accumulation represents the "upstream" event in AD pathogenesis. This point of view has been overcome by the possibility that soluble Aβ oligomers, more than mature amyloid plaques, are the key toxic moieties. In fact, it has been demonstrated that amyloid oligomers may access intracellular organelles, including mitochondria, and compromise their function. Amyloid deposition causes local inflammatory and immunologic alterations for a direct neurotoxicity with microglial recruitment and astrocyte activation. It is also associated with the release of cytokines, nitric oxide, and other radical species that can promote neuroinflammation and neurodegeneration.
In addition to the amyloid cascade, intracellular neurofibrillary tangles (NFTs) are found in AD brain. They consist of hyperphosphorylated tau protein. Interestingly, NFTs correlate more closely with the severity of dementia than plaque counts. The association of tangles with a variety of brain damage supports the "tauopathy" concept of neurodegeneration, although tauopathy as a primary cause of neurodegenerative diseases is currently demonstrable only in a subgroup of familial frontotemporal dementia. However, the recent failures of drugs targeting amyloid pathways have raised questions not only about this approach but also on the validity of the amyloid cascade hypothesis itself.
Oxidative stress is a condition where reactive oxygen species (ROS) production exceeds the cellular antioxidant defense system. The brain is highly susceptible to an oxidative imbalance due to its high-energy demand, high oxygen consumption, an abundance of easily peroxidable polyunsaturated fatty acids, high level of potent ROS catalyst iron, and a relative paucity of antioxidant enzymes, this latter more evident in AD brain. Mitochondria are prone to oxidative damage. Mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage. The simultaneous increased oxidation of mtDNA and deficiency of DNA repair could enhance the lesion to mitochondrial genome, potentially causing neuronal damages. On this basis, it is reasonable that oxidatively mediated damage to biomolecules is extensively reported in AD, suggesting that oxidative stress plays a critical role in the disease pathogenesis. As the main source of ROS generation and a major target of oxidative damage, progressive impairment of mitochondria has been implicated in aging and AD.
It is generally accepted that mitochondrial function progressively declines along with age when compensation is no longer possible. In summary, the mitochondrial cascade hypothesis proposes that every single person has a genetically determined mitochondrial starting line, that together with environmental factors determine the age at which clinical disease may ensue. Thus, the "mitochondrial cascade hypothesis" places the mitochondrial dysfunction as the leading factor in the late-onset AD pathology cascade, underlying the individual genetic background able to regulate since birth its mitochondrial function and sustainability. For this reason, the rate at which age-related mitochondrial dysfunction proceeds differs among individuals. When the mitochondrial function declines and falls below a critical threshold, AD-typical dysfunction at the cellular level may ensue, including Aβ production, tau phosphorylation, synaptic degeneration, and oxidative stress.
Results from Another Trial of a Tissue Engineered Retinal Pigment Epithelium Patch
Just a few weeks ago I noted the results from an early trial of a form of retinal patch, in which the patients involved showed striking signs of improved vision, considering their age and the degree to which their macular degeneration had advanced. Today another set of clinical trial results were published by a separate group using a similar approach - human embryonic stem cells are used to derive sufficient retinal pigment epithelium cells to create a structured patch, resembling retinal tissue in at least some aspects. The patch is then implanted into the retina, and sufficient cells survive and integrate to restore some function to areas damaged by the progression of age-related macular degeneration. That two teams are seeing positive outcomes from this type of approach is good news for the broader field.
The advance over prior efforts to produce a cell therapy for macular degeneration, present in both of these trials, lies in the methodologies that allow cells to form a more life-like retinal structure prior to implantation. Cells transplanted into the retina without that support largely die before they can do much good, and this is an issue across the entire spectrum of cell therapies. Many present cell therapies are only marginally beneficial precisely because the transplanted cells last a few days or a few weeks at most. They change the balance of local signaling for a while, and this can have quite useful effects, such as the suppression of inflammation achieved via mesenchymal stem cell therapies, but this doesn't realize the potential of cell therapies to achieve regeneration and replacement of tissue.
The tissue engineering community has, over the past few years, made meaningful progress towards the delivery of structured patches rather than cells on their own. For example, heart muscle patches have recently demonstrated much higher rates of cell survival and integration. Just like the retinal patches noted here, these are cells and scaffolds that are similar to the native tissue, more resilient and more effective. We should expect to see this type of approach spread widely throughout the field, now that it has been proven effective in multiple different tissues - though it will take some time, as each tissue type requires the establishment of its own recipes and methods.
Researchers test stem cell-based retinal implant for common cause of vision loss
The treatment, which consists of a layer of human embryonic stem cell-derived retinal pigment epithelium cells on an ultrathin supportive structure, was implanted in the retina of four patients. The patients were followed for up to one year to assess its safety. There were no severe adverse events related to the implant or the surgical procedure, indicating that the treatment was well-tolerated. There was also evidence that the implant integrated with the patients' retinal tissue, which is essential for the treatment to be able to improve visual function.
"This is the first human trial of this novel stem cell-based implant, which is designed to replace a single-cell layer that degenerates in patients with dry age-related macular degeneration. This implant has the potential to stop the progression of the disease or even improve patients' vision. Proving its safety in humans is the first step in accomplishing that goal." Dry age-related macular degeneration is the most common type of age-related macular degeneration. Over time, it can lead to loss of central vision, which can diminish people's ability to perform daily tasks like reading, writing, driving and seeing faces.
As part of the study, the research team also performed a preliminary assessment of the therapy's efficacy. One patient had improvement in visual acuity, which was measured by how many letters they could read on an eye chart, and two patients had gains in visual function, which was measured by how well they could use the area of the retina treated by the implant. None of the patients showed evidence of progression in vision loss.
A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration
Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies may delay disease progression or restore vision. A prospective, interventional, U.S. Food and Drug Administration-cleared, phase 1/2a study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC-RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane.
We report an interim analysis of the phase 1 cohort consisting of five subjects. Four of five subjects enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation. The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function, at least in the short term, in some patients with severe vision loss from advanced NNAMD.
Uncertainty Over Whether or Not Adult Neurogenesis Occurs to Any Significant Degree
Does the adult human brain normally produce a significant number of new neurons, integrating them into new networks? This process is called neurogenesis, and until the 1990s, the answer was thought to be no. Then studies in rodents found that animals of those species do produce new neurons at an appreciable pace, and that this was important to memory, learning, degree of recovery from damage such as stroke, as well as aging and neurodegeneration, as the pace of neurogenesis declines with age. Studies in humans followed to provide supporting evidence that looked convincing enough to believe that rodents were a good model for other mammalian species, including our own. Then, just recently, a well-conducted study in humans found no evidence of any significant level of neurogenesis in adult human brains. Given the degree to which the scientific community is enthusiastically in search of ways to enhance regeneration in the central nervous system, this has produced the expected level of debate.
For today, and as a further illustration of what a field in flux looks like, I'll point out another new study in which the researchers feel fairly confident in claiming that adult neurogenesis both occurs and proceeds at similar levels in both old and young humans. Science is never a matter of absolute confidence in any piece of knowledge; as a layperson, one has to weigh the studies and the discussions of experts, for and against. Here, however, the situation is disordered and uncertain: not enough time has passed for the research community to properly process the new discoveries. Expect that to require some years to reach a new consensus; it takes a year at minimum to complete a suitably weighty investigation, and another year to pass the peer review gauntlet and be published.
The overwhelming weight of evidence remains in favor of adult neurogenesis in rodents, while in humans the results and methodologies are in a sudden state of uncertainty. Yet a great deal of work has proceeded in recent years based on the assumed existence of adult neurogenesis, and various neurological phenomena shared by humans and rodents have been linked by theories that prominently feature adult neurogenesis. So it isn't just a matter of a battle of a few cell-level studies of the brain, but rather of the validity of a broad segment of scientific endeavor over the past few decades. That is not to mention the hopes of an easier road in the future towards ways to induce functional regeneration in the aging brain.
Older adults grow just as many new brain cells as young people
Researchers show for the first time that healthy older men and women can generate just as many new brain cells as younger people. There has been controversy over whether adult humans grow new neurons, and some research has previously suggested that the adult brain was hard-wired and that adults did not grow new neurons. This studycounters that notion, and the findings may suggest that many senior citizens remain more cognitively and emotionally intact than commonly believed.
"We found that older people have similar ability to make thousands of hippocampal new neurons from progenitor cells as younger people do. We also found equivalent volumes of the hippocampus (a brain structure used for emotion and cognition) across ages. Nevertheless, older individuals had less vascularization and maybe less ability of new neurons to make connections. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.
Human Hippocampal Neurogenesis Persists throughout Aging
Healthy aging is crucial in a growing older population. The ability to separate similar memory patterns and recover from stress may depend on adult hippocampal neurogenesis (AHN), which is reported to decline with aging in nonhuman primates and mice. New neurons are generated in the dentate gyrus (DG) of the adult human hippocampus, even after middle age, but the extent to which neurogenesis occurs in humans is highly debated and quantitative studies are scarce.
Phylogenetic differences between humans and rodents mandate assessment of the different stages of neuronal maturation in the human DG. For example, striatal neurogenesis is found only in humans, while olfactory bulb neurogenesis is absent in humans but present in other mammals. Previous analyses of human AHN did not address the effects of aging, although studies have examined AHN in older populations. Using histological techniques that could not distinguish mature and immature neurons, several groups estimated that DG neurons did not decline in aging humans.
AHN and angiogenesis are co-regulated. Exercise enhances cerebral blood volume, which results in more AHN in mice and better cognitive performance in humans, but it may have a reduced impact in older people. Thus, we quantified AHN, angiogenesis, and DG volume and their relationship in people of different ages, hypothesizing that they would concurrently decrease with aging and correlate with each other. Given the different functions of the rostral and caudal DG, we assessed the anterior, mid, and posterior hippocampus postmortem from 28 women and men 14 to 79 years of age. In each region, we characterized and quantified angiogenesis, volume, and cells at different maturational stages in the DG neurogenic niche, using unbiased stereological methods. To avoid confounders, subjects studied had no neuropsychiatric disease or treatment.
In medication-free subjects with no brain disease and no reported cognitive impairment, good global functioning as per Global Assessment Scale, and low recent (last 3 months) life event-related stress, quantified by St. Paul-Ramsey Life Experience Scale, we found persistent AHN into the eighth decade of life, and stable DG volume over a 65-year age span. In contrast, we found declining neuroplasticity and angiogenesis with older age, and a possibly diminished multipotent quiescent radial-glia-like type I neural progenitor cells (QNPs) pool selectively in anterior-mid DG, while the QNP pool remained unchanged in posterior DG, possibly reflecting less cognitive and emotional resilience with aging.
Older nonhuman primates and rodents have more granule neurons (GNs) and less AHN than younger ones, contrary to our findings in humans. Since new GNs may assist in pattern separation and old GNs in pattern completion, steady AHN and concurrent elimination of older GNs likely supports human complex learning and memory and emotion-guided behavior throughout a long lifespan. Persistent AHN is vital for preserving cognitive flexibility and allowing memory-guided decision-making without the interference of irrelevant outdated information. Our findings of thousands of new intermediate neural progenitors (INPs) and immature neurons at the time of death, in anterior, mid, and posterior human subgranular zone, suggest that the number of newly generated neurons could be sufficient for them to have a relevant impact on the DG circuit.
Finding a Causal Relationship Between Exercise and Longevity in Human Data is More Challenging than One Might Imagine
It is straightforward enough to prove that exercise extends healthy (but not average or overall) life span in studies of mice. It is far less straightforward to demonstrate that same proof in human epidemiological data. We can't put humans into carefully controlled groups stratified by life-long differences in exercise and follow them from birth to death, as is the case for mice. As a consequence, near all studies of physical activity and longevity produce only correlations, as there is no practical way to derive causation given the data to hand. It is felt that these correlations likely reflect causation because of the extensive animal studies and the essential similarities of biochemistry between the mammalian species involved, but that isn't the same thing as a rigorous determination. The editorial here is a discussion of this point; the authors look at the limitations and challenges that face any attempt to generate better evidence in support of the generally accepted proposition that exercise causes extended healthy life span in humans.
While epidemiological findings show that increased physical activity (PA) lengthens the life span, it has been argued that intervention studies do not support PA causing a reduced risk of death, and that limitations in previous observational studies may have led to spurious conclusions. This coincides with the publication of findings from the large-scale Prospective Urban Rural Epidemiologic (PURE) study of 130,843 participants, which identified a graded lower rate of mortality among those individuals achieving moderate and high levels of PA compared with those with low PA. While this study is undeniably an impressive endeavour, collecting prospective data on participants from 17 countries, the findings are, as so often, unable to fully assert a causal (rather than correlational) role for PA levels in reducing mortality.
Epidemiological study designs are vulnerable to limitations that may skew or distort observational associations and impede the distinction between correlation and causation. Such distortions of observed relationships may arise due to confounding by measured/unmeasured lifestyle, behavioural, and biological factors (such as higher fitness, lower body mass index (BMI), genetic variation, and socioeconomic factors) correlated with both PA and longevity. If not appropriately accounted for, confounding factors make the ascertainment of underlying causal mechanisms and pathways exceptionally complex. Such was illustrated by the noted London busmen study, where confounding by baseline adiposity biased findings that bus conductors had lower risk of coronary heart disease than their less-active driver counterparts.
The possibility of reverse causation may also lead to misinterpretation of observed associations. For example, the notion that reducing PA increases the risk of becoming overweight/obese is as plausible as the reverse, where being overweight/obese renders PA difficult. Studies of older adults or those with many comorbidities are particularly vulnerable to reverse causation. For example, aged individuals who are healthy enough to participate in PA due to a lack of chronic illness will seemingly have a reduced risk of death compared with their less-fit peers. Furthermore, comparing estimates of risk for physically demanding versus sedentary occupations may suffer reverse causation, particularly when high fitness and good health are criteria for recruitment into such physically demanding occupations.
Related to this, in the setting of evaluating potential causes of mortality, both selection and survival biases, which influence participation rates in epidemiological studies, can also lead to distortion of associations among respondents. In these cases, the population under study (and therefore the observed associations) may differ from the population not selected or who were unable/unwilling to participate (due to morbidity or lack of interest in surveys relating to health).
Long Lived Species May Require Greater Accuracy in Protein Translation
This commentary on research results from last year is a good introduction to the topic of protein translation errors and their relationship with species longevity. Translation is one of the steps in the complex process of gene expression, in which genes are used as a blueprint to assemble proteins. Nothing is perfect and errors take place in translation, as everywhere else. Such errors are in effect a form of damage, causing issues for the cell until the broken protein is removed.
It is fairly well established that greater levels of the cellular maintenance processes of autophagy, responsible for removing damaged proteins, metabolic waste, and failing cellular structures, can result in slowed aging in a range of species. It sounds plausible that reducing the rate at which malformed proteins are produced would be beneficial for similar reasons, but this is harder to prove one way or another. The present laboratory is made up of the biochemistry of similar species with different life spans, translation machinery, and error rates. Unfortunately there are also many other differences: the study of aging is made very challenging by the inability to completely isolate mechanisms of interest, and dial them up or down without changing anything else.
When a protein is made by the cell, the genetic information is first decoded into mRNA, then this mRNA directs the protein synthesis. This is the flow of genetic information in cells from DNA to RNA to protein, the central dogma of molecular biology. The "error catastrophe" theory of aging, proposed in the 1960s, posits that translation errors decrease the fidelity of translation, setting in motion a vicious cycle of increasingly inaccurate protein synthesis, ultimately causing a failure of the gene expression machinery. However, in the 1980s, several approaches including enzymatic assays of protein synthesis errors, as well as analysis of proteins on 2D gels in aged animals and senescent cells, did not detect a significant increase in mistranslated proteins during aging and cellular senescence. These negative results were not consistent with the error catastrophe theory and errors in translation were largely discounted as being a contributing factor to aging.
Recent work brings the protein translation fidelity back into the spotlight of aging research. Importantly, the assays used to detect aberrant proteins in the 1980s had limited sensitivity to detect rare aberrant proteins, but in 2013 a new highly sensitive luciferase-based assay was developed to measure the rate of mistranslation in mammalian cells. This new assay showed that mouse fibroblasts make up to 10 times more errors in protein translation than fibroblast from the longest-lived rodent species, the naked mole rat. This was the first indication that a longer-lived species may evolve more accurate protein translation machinery. Later work compared the fidelity of protein translation in fibroblasts from 17 rodent species with diverse lifespans, and demonstrated that translation fidelity at the first and second codon positions correlates positively with species maximum lifespan, i.e. longer-lived species have more accurate translation.
The relationship between species maximum lifespan and translation fidelity shows that longer-lived species evolve more accurate protein synthesis. This, however, does not imply that protein translation errors lead to aging in individual organisms. This would be important to test using the new sensitive assays. In the future, a knock-in mouse model with luciferase reporters can be generated to examine the accumulation of mistranslated protein in different organs during aging. Mistranslated proteins may not impact cellular proteostasis significantly at young age, largely due to rapid protein turnover and efficient protein clearance. However, protein turnover rates, proteasome activity, and autophagy decline with age, making aged organisms more sensitive to errors in protein translation. Thus, even if protein translation fidelity does not change over the course of lifespan, long-lived species may require more accurate protein synthesis.
A Demonstration that Smooth Muscle Cell Dysfunction Contributes Significantly to Age-Related Vascular Stiffening
A few different mechanisms plausibly contribute to the stiffening of blood vessels that takes place with aging. This is one of the most harmful aspects of aging, as it causes hypertension by upsetting the feedback mechanisms that control blood pressure. Hypertension in turn damages organ tissues, weakens the heart, and raises the risk of fatal rupture of a weakened blood vessel. The mechanisms of interest include (a) calcification, which may be secondary to inflammation and cellular senescence, (b) the formation of persistent cross-links in the extracellular matrix, degrading structural properties such as elasticity, and (c) dysfunction in the smooth muscle responsible for contraction and dilation of blood vessels.
We can hope that calcification will be improved by senolytic therapies to clear senescent cells, and that near future cross-link breakers based on programs funded by the SENS Research Foundation will make short work of that contribution of cross-links to degenerative aging. Dysfunctional smooth muscle cells are more of a problem, however, as it is far from clear as to what exactly is going wrong and how it might be effectively addressed. In this paper, the researchers mount what I think is a fairly convincing demonstration that this cellular dysfunction is significant and distinct from other factors related to vascular stiffening, and is inherent to the cells rather than being caused directly by the environment of the surrounding aged tissue. This calls for more attention to be directed towards this part of the problem.
Increased aortic stiffness, whatever the underlying cause, is also an independent predictor of outcomes of cardiovascular diseases in the elderly. It is well known that hypertension is a highly age-related human disease. Despite a widely held belief that increased aortic stiffness in hypertensive patients is largely a manifestation of long-standing hypertension-related damage, a recent statement from the American Heart Association (AHA) asserts that aortic stiffening is a cause rather than a consequence of hypertension in middle-aged and older individuals.
Our recent studies with atomic force microscopy (AFM) have demonstrated similar characteristics of aortic vascular smooth muscle cells (VSMCs) in both aging and hypertension, indicating that VSMC-mediated regulation is a fundamental basis of aortic stiffening in both conditions. However, the underlying mechanisms are not fully understood. It is conceivable that, in addition to intracellular effects, VSMCs are able to contribute to aortic stiffening via extracellular effects. However, it is difficult to discern the extracellular effects of VSMCs in intact aortic tissue in vivo.
In our previous study, integrin β1 was found to be significantly increased in VSMCs from stiffened aortas in aging monkeys, indicating that integrin β1 may contribute to aortic stiffening. Other recent studies emphasize the potential role of Lysyl oxidase (LOX) in vascular remodeling and the regulation of the biomechanical properties of the extracellular matrix (ECM). Different patterns of LOX expression/activity have been associated with distinct vascular pathological processes. For example, downregulation of LOX has been associated with destructive remodeling of arteries during aorta aneurysm (AA) development. Deletion of the mouse LOX gene promotes fragmentation of elastic fibers and VSMC discontinuity in the aortic wall. Loss-of-function mutations of LOX can cause AAs and aortic stiffening in humans. These studies indicate an essential role of LOX in maintaining the tensile and elastic features of blood vessels.
The present study tests our hypothesis that aortic VSMCs contribute to aortic wall stiffness via both increased intrinsic stiffness and extracellular dysregulation mediated through altered regulation of integrin and LOX signaling. Firstly, aortic stiffening was confirmed in spontaneously hypertensive rats (SHRs) versus Wistar-Kyoto (WKY) rats. Vascular smooth muscle cells were isolated from thoracic aorta and embedded into an in vitro 3D model to form reconstituted vessels. Reconstituted vessel segments made with SHR VSMCs were significantly stiffer than vessels made with WKY VSMCs. SHR VSMCs in the reconstituted vessels exhibited different morphologies and diminished adaptability to stretch compared to WKY VSMCs, implying dual effects on both static and dynamic stiffness. Mechanistically, compared to WKY VSMCs, SHR VSMCs exhibited an increase in the levels of active integrin β1- and bone morphogenetic protein 1 (BMP1)-mediated proteolytic cleavage of lysyl oxidase (LOX).
A Correlation Between More AGEs in the Skin and Worse Pulmonary Function
The researchers here show an association between greater presence of advanced glycation end-products (AGEs) in skin and worse pulmonary function - which sounds plausible if we think of AGEs as a cause of loss of elasticity in tissues. Cross-links are formed by AGEs, and by linking and restricting the dynamics of structural proteins, they degrade the important structural properties of tissues, particularly elasticity. The details always bear examining however. In this study, the level of AGEs in skin was assessed using fluorescence, and based on the research of recent years, the important AGE when it comes to aging, glucosepane, is not fluorescent. Glucosepane forms truly persistent cross-links that human biochemistry struggles to remove, while other AGEs are transient in their effects, and more amenable to removal.
In people who do not have an abnormal metabolism characterized by raised levels of various AGEs, as is observed in diabetic patients, it is entirely plausible that glucosepane levels are fairly well correlated to levels of other, fluorescent AGEs. But it still makes this paper one that is most likely observing a relationship based on inflammation rather than structural properties: short-lived (and fluorescent) AGEs can induce inflammation via their interaction with RAGE, and this is one of the ways in which the abnormal diabetic biochemistry causes further harm, for example. There is a fair amount of evidence to suggest that chronic inflammation negatively affects pulmonary function. Now that it is possible to reduce inflammation by removing senescent cells, there is even data in mice to show that this reverses loss of lung tissue elasticity to some degree. Every decline in aging has multiple contributing factors.
According to recent studies, the level of advanced glycation end products (AGEs) increases with age and is higher in smokers and chronic obstructive pulmonary disease (COPD) patients. AGEs are bioactive molecules formed by the nonenzymatic glycation or peroxidation of proteins, lipids, and nucleic acids. AGEs increase inflammation by binding to receptors for AGE (RAGE), which are present on cell surfaces in tissues. Therefore, AGE accumulation may play a role in the pathogenesis of COPD by increasing inflammation. Several AGEs, such as pentosidine and Nε-(Carboxymethyl)-L-lysine (CML), have been reported to emit a characteristic fluorescence in human skin. AGEs assessed by skin autofluorescence (SAF) could help in the rapid evaluation of AGE accumulation in clinical settings.
Investigating factors associated with deteriorations in pulmonary function could help develop strategies to prevent the development of COPD in people with normal spirometry results, particularly given the serious impact of COPD on the risk of chronic disabilities and mortality. Therefore, we focused on the relationship between AGEs and pulmonary function in a general population with normal spirometry results. Moreover, given that aging is accompanied by an increase in AGEs and a decrease in pulmonary function, it would be informative to compare relationships between AGEs and pulmonary function in younger and elderly individuals. To this end, the present study aimed to evaluate the relationship between SAF and pulmonary function in younger and elderly people with normal spirometry results.
Two hundred and seventy-two males and females were enrolled in this study. Subjects underwent hematological examinations and additional assessments, such as the accumulation of AGEs in skin and pulmonary function. Subjects with an obstructive, restrictive, or mixed disorder pattern on the pulmonary function test were excluded. In addition, subjects with diseases that could influence pulmonary function (e.g., COPD, interstitial pneumonia, or asthma) or who received medications that could influence pulmonary function were excluded. Those with diabetes or hemoglobin A1c (HbA1c) higher than 6.5% were also excluded since diabetes and glycemic levels are known to be associated with both pulmonary function and level of SAF. The final study population consisted of 201 subjects (116 males).
We found that SAF is an independent factor negatively associated with the FEV1/FVC measure of pulmonary in elderly people with normal spirometry results, but not in younger people. Pack-years of smoking was a significant independent factor associated with FEV1/FVC in the elderly group. This study demonstrated that SAF is an independent factor associated with FEV1/FVC in the elderly group. According to other studies, AGEs in the blood and AGE accumulation in skin were higher in smokers than in non-smokers. AGEs can bind to and activate RAGE, which are present on cell surfaces in tissues, especially in the lung. Activation of RAGE increases inflammation via NF-κB. Therefore, the decrease in FEV1/FVC was likely accelerated by AGE accumulation.
With respect to the younger group, SAF was not associated with decreased FEV1/FVC. There are several potential explanations for the differences observed between the younger and elderly groups regarding factors associated with FEV1/FVC. First, the value of SAF is strongly related to age. In the present study, the value of SAF was significantly lower in the younger group compared to the elderly group. Therefore, inflammation resulting from AGEs might have been lower in younger subjects, resulting in the maintenance of FEV1/FVC. Second, the amount and/or activity of endogenous antioxidant enzymes between the two groups may have differed. It is well known that reactive oxygen species (ROS) can be buffered by endogenous antioxidant enzymes such as superoxide dismutase and catalase, and previous studies have demonstrated that levels of these antioxidant enzymes decrease with age.
No Sign of Benefits in a Study of Higher Protein Intake in Older Individuals
One of the many theories regarding the cause of sarcopenia, age-related loss of muscle mass and strength, is that impaired processing of the essential amino acid leucine is a significant cause. If this is the case, then leucine supplementation should help to some degree. Similar suggestions have been made for a few other aspects of aging - that we should assign a modest fraction of the blame to the typically lower protein intake observed in older people, as tissues find themselves lacking sufficient raw materials needed to maintain themselves. The study here suggests that this is not the case, or at least that the contribution of reduced protein intake is small in comparison to the other mechanisms of degenerative aging.
Regardless of whether an adult is young or old, male or female, their recommended dietary allowance (RDA) for protein is the same: 0.8g/kg/day. Many experts and national organizations recommend dietary protein intakes greater than the recommended allowance to maintain and promote muscle growth in older adults. However, few rigorous studies have evaluated whether higher protein intake among older adults provides meaningful benefit.
"It's amazing how little evidence there is around how much protein we need in our diet, especially the value of high-protein intake. Despite a lack of evidence, experts continue to recommend high-protein intake for older men. We wanted to test this rigorously and determine whether protein intake greater than the recommended dietary allowance is beneficial in increasing muscle mass, strength, and wellbeing."
The clinical trial, known as the Optimizing Protein Intake in Older Men (OPTIMen) Trial, was a randomized, placebo-controlled, double-blind, parallel group trial in which men aged 65 or older were randomized to receive a diet containing 0.8-g/kg/day protein and a placebo injection; 1.3-g/kg/day protein and a placebo injection; 0.8-g/kg/day protein and a weekly injection of testosterone; or 1.3-g/kg/day protein and a weekly injection of testosterone. All participants were given prepackaged meals with individualized protein and energy contents and supplements. Seventy-eight participants completed the six-month trial.
The team found that protein intake greater than the RDA had no significant effect on lean body mass, fat mass, muscle performance, physical function, fatigue or other well-being measures. "Our data highlight the need for re-evaluation of the protein recommended daily allowance in older adults, especially those with frailty and chronic disease."
Greater Aerobic Fitness Correlates with Better Memory Function in Later Life
This interesting open access paper reports on one of a number of efforts to map the details of the association between cardiovascular fitness and memory function over the course of aging. The brain is that the mercy of the vascular system in many ways. There is the age-related reduction in capillary formation cutting down the supply of nutrients and oxygen to the brain. Stiffening of blood vessels results in hypertension, and raised blood pressure pummels delicate tissue structures in the brain, kidney, and elsewhere. The structural decline of the vascular system, the weakening of blood vessels due to atherosclerotic lesions, combines with raised blood pressure to produce many ruptures of lesser blood vessels in the brain over the years, destroying small areas of functional tissue in silent, tiny strokes.
All of these processes are to some degree slowed by maintaining cardiovascular fitness - even capillary formation. Physical activity also adjusts many signaling processes related to tissue maintenance, such as the pace of neurogenesis in the brain, the production and integration of new neurons. To look at it the other way, in our modern age of comfort and indolence, most people fail to put in the necessary maintenance activity required to keep the declines of aging to the slowest possible rate. No-one can reliably add decades to life through exercise, but it is certainly possible to find oneself in one's sixties, unfit, overweight, encountering the first earnestly troubling signs of mental decline, and all the while regretting the path not taken.
Aging is associated with progressive changes in brain structure that gradually impair essential cognitive functions, including memory. Numerous mechanisms have been proposed to underlie memory decline, such as altered plasticity, connectivity, and excitability. One change of particular interest is the reduction of hippocampal neurogenesis and the observation that age-associated declines in neurogenesis and memory can be partly rescued in animals that engage in aerobic exercise. Aerobic exercise also increases hippocampal blood volume in humans. Critically, this suggests that physical activity in older humans may be associated with better memory performance. However, some aspects of memory processing may be more associated with aerobic fitness than others. The present study compared age-related differences for two critical memory processes: high-interference memory and general recognition memory.
High-interference memory represents the ability to discriminate between highly similar yet distinct items. In animal models, high-interference memory can be improved by stimulating neurogenesis and is impeded by interfering with neurogenesis. Younger adults (YA) have better high-interference memory than older adults (OA), therefore, the decline in hippocampal neurogenesis that occurs with aging may impact high-interference memory. General recognition is another aspect of memory that represents the ability to discriminate novel stimuli from those previously encountered. Unlike high-interference memory, general recognition memory may not be as dependent on hippocampal neurogenesis. The recruitment of a more distributed network for processing by general recognition may mean that this aspect of memory is less affected by the age-related decline. Indeed, YA and OA have been shown to have similar performance on general recognition memory tasks.
Individual differences influencing age-related decline of memory extend beyond biological aging to include lifestyle factors, such as physical activity. The present study investigated the effects of aging on high-interference memory and general recognition memory. Ninety-five YA and eighty-one OA performed the Mnemonic Similarity Task (MST). Age-related differences in high-interference memory were observed across the lifespan, with performance progressively worsening from young to old. In contrast, age-related differences in general recognition memory were not observed until after 60 years of age. Furthermore, OA with higher aerobic fitness had better high-interference memory, suggesting that exercise may be an important lifestyle factor influencing this aspect of memory. Overall, these findings suggest different trajectories of decline for high-interference and general recognition memory, with a selective role for physical activity in promoting high-interference memory.
A Marker for Cancer Stem Cells that Might Also Lead to a Cell-Killing Treatment
At least some forms of cancers are generated and supported by a small population of cancer stem cells, a malfunctioning, rapidly growing mirror of the healthy tissue environment in which large number of somatic cells are supported by a small number of stem cells. It is the presence of these cancer stem cells that makes it challenging to permanently clear cancer from a patient - if only a few such cells survive, the cancer will return, and the present generation of cancer treatments cannot reliably remove 100% of the targeted cells. Looking on the bright side, if a method of selectively targeting and destroying cancer stem cells could be developed, then this could be a very useful approach to cancer therapeutics. While it is still up for debate as to what degree of useful, exploitable similarity exists between the cancer stem cells that have been identified in cancers of various different types, the research here makes for interesting reading in this context. It strongly suggests that these similarities exist and are broadly present in many tissue types.
"Cancer stem cells", also known as tumor-initiating cells (TIC), appear to cause relapses after radiation and chemotherapy because a single surviving TIC can cause a new tumor to grow. In addition, they appear to be the main cause of metastasis. Effective tumor treatment must therefore aim to kill off TICs as extensively as possible. To this end, a "probe" that marks these cancer stem cells would be useful so that they become visible. Although there are markers that also recognize TICs associated with some types of cancer, no universal, selective probe for cancer stem cells has been found.
Researchers have now succeeded in finding such a probe. They were able to show that their new probe, a fluorescent dye, selectively stains TICs from a broad variety of cancers, including tumors of the lung, central nervous system, breast, kidney, ovary, colon, and prostate, as well as melanomas. Healthy cells and "ordinary" tumor cells were not marked. At high concentrations, the dye also demonstrates considerable cytotoxicity toward TIC, while other cells are barely affected.
The researchers discovered that their probe, named TiY (for tumor-initiating cell probe yellow), recognizes vimentin, which is a molecule in the cytoskeleton. Vimentin is more concentrated in epithelial cells when they transform into mesenchymal cells. Epithelial cells form the tissue that covers the inner and outer surfaces of the body, forming a boundary with the environment. The cells are polar, meaning that the side facing toward the underlying tissue and the side directed outward toward the lumen are different. The cells are also firmly integrated into the cell wall. When they transform into mesenchymal cells, they lose their polarity, are freed from the cell structure, and may wander. This process plays an important role in the development of embryos and healing of wounds. It is also involved in the metastasis of tumors.
Calorie Restriction Slows the Age-Related Accumulation of DNA Damage, Inflammation, and Cellular Senescence in Fat Tissue
The practice of calorie restriction slows near all measures of aging, slowing aging to a degree that appears to scale down with increased species life span. Calorie restricted mice live 40% longer, but calorie restricted humans are thought to at most gain five years or so - though a firm number has yet to be determined in our species. The short term changes to metabolism and benefits to health are nonetheless quite similar. As a companion piece to recent work on the effects of calorie restriction on cellular senescence, this open access paper makes for interesting reading. Senescent cells accumulate with age, and the damage they do to their environment via a potent mix of signal molecules is one of the root causes of aging and age-related disease. Unsurprisingly, calorie restriction slows this accumulation, just as it impacts all other processes of aging.
White adipose tissue (WAT) forms an endocrine organ with both positive and negative effects on metabolism. By secreting adipokines, adipocytes regulate metabolism, energy intake, and fat storage. Adipocytes are known to enlarge during obesity and the ageing process. In contrast, caloric restriction results in decreased body mass, and preferentially reduced the mass of different fat depots including up to 78% in visceral fat. Several studies demonstrated that increased fat cell size is a significant predictor of altered blood lipid profiles and glucose-insulin homeostasis. The contribution of visceral adiposity to these associations seems to be of particular importance.
Senescence and inflammation are two important mechanisms contributing to ageing and the metabolic consequences of obesity. Inflammation can result from accumulation of macrophages in adipose tissue via production of cytokines such as TNFα and IL-6. Increase in lipolysis has been shown to induce macrophage migration in vitro. Macrophage numbers in adipose tissue also increase with obesity and ageing where they scavenge dead or senescent adipocytes. However, inflammatory cytokines and chemokines are also characteristics of the senescence-associated secretory phenotype (SASP) in senescent cells. We have shown previously that reactive oxygen species (ROS), DNA damage, and mitochondrial dysfunction are instrumental to maintain cellular senescence.
Various treatments have been suggested to delay senescence in adipose tissues while obesity and short telomeres exacerbated senescence. A recent study showed that feeding a high-fat diet ad libitum induced senescence in mouse visceral adipose tissue which could be ameliorated by exercise. However, dietary restriction (DR) seems to regulate many more genes than exercise in subcutaneous fat in humans.
We have demonstrated previously that short-term dietary restriction in wild type mice decreased the amount of senescent cells in various tissues. We hypothesise that pro-inflammatory cytokines and senescence are also causally related in visceral WAT, increase together during ageing, and might be rescued during DR. We used visceral WAT from mice of different ages as well as mice on late-onset, short term DR to investigate the changes in adipocyte size, accumulation of DNA damage during ageing and DR, together with the expression of pro-inflammatory cytokines TNFα, IL-6, IL-1β, and senescence markers p16 and p21. We also analysed AMPK activity which is an important signal transduction pathway implicated in the regulation of physiological processes of DR. AMPK activation is thought to be able to inhibit inflammatory responses and plays a central role in the regulation of whole body energy homeostasis and functions as a key regulator of intracellular fatty acid metabolism.
Our results demonstrate increased senescence and inflammation during ageing in mouse visceral fat while DR was able to ameliorate several of these parameters. DR was able to significantly reduce adipocyte size and multiple markers of adipocyte senescence (significant for DNA damage, p21 and IL-6 expression). This indicates that DR acts as a senolytic treatment in visceral fat, similar to its effects in other tissues. This highlights the health benefits of a decreased nutritional intake over a relatively short period of time at middle age.
Better Understanding Why the Liver is a Highly Regenerative Organ
In adult mammals, the liver is the most regenerative organ, capable of significant regrowth following injury. Why is this the case? Researchers here point to a small subset of liver cells in mice that are distinguished by telomerase expression, and while mice and humans have quite different telomerase and telomere dynamics, indirect evidence suggests that a similar population may exist in our species. Significant telomerase expression is the characteristic of stem cells that allows for unlimited replication: telomerase acts lengthen telomeres, the caps at the ends of chromosomes that shorten with each cell division. When too short, cells enter senescence or destroy themselves. Lacking telomerase, the vast majority of cells can only divide a set number of times.
This segregation between a few privileged stem cells and the vast mass of restricted somatic cells is the primary strategy by which multicellular life keeps the incidence of cancer to a manageable level. Mutations occur constantly, and evolution requires mutation, even when harmful to individuals, but it is much harder for mutational damage to cause somatic cells to run amok, given their inherent limitations. Unsurprisingly then, researchers are interested in the source of the liver's regenerative capacity not just to improve on it, or to find ways to regenerate other organs, but also to gain insight into the origins and peculiarities of liver cancer.
A subset of liver cells with high levels of telomerase renews the organ during normal cell turnover and after injury, according to researchers. The cells are distributed throughout the liver's lobes, enabling it to quickly repair itself regardless of the location of the damage. Understanding the liver's remarkable capacity for repair and regeneration is a key step in understanding what happens when the organ ceases to function properly, such as in cases of cirrhosis or liver cancer. "It's critical to understand the cellular mechanism by which the liver renews itself. We've found that rare, proliferating cells are spread throughout the organ, and that they are necessary to enable the liver to replace damaged cells. We believe that it is also likely that these cells could give rise to liver cancers when their regulation goes awry."
The liver's cells, called hepatocytes, work to filter and remove toxins from the blood. The liver is unique among organs in its ability to fully regenerate from as little as 25 percent of its original mass. Stem cells and some cancer cells make enough telomerase to keep their telomeres from shortening. Mutations that block telomerase activity cause cirrhosis in mice and humans. Conversely, mutations that kick telomerase into high gear are frequently found in liver cancers. Telomerase is a protein complex that "tops off" the ends of chromosomes after DNA replication. Without its activity, protective chromosomal caps called telomeres would gradually shorten with each cell division. Most adult cells have little to no telomerase activity, and the progressive shortening of their telomeres serves as a kind of molecular clock that limits the cells' life span.
Researchers found that, in mice, about 3-5 percent of all liver cells express unusually high levels of telomerase. The cells, which also expressed lower levels of genes involved in normal cellular metabolism, were evenly distributed throughout the liver. During regular cell turnover or after the liver was damaged, these cells proliferate in place to make clumps of new liver cells. "These rare cells can be activated to divide and form clones throughout the liver. As mature hepatocytes die off, these clones replace the liver mass. But they are working in place; they are not being recruited away to other places in the liver. This may explain how the liver can quickly repair damage regardless of where it occurs in the organ. You could imagine developing drugs that protect these telomerase-expressing cells, or ways to use cell therapy approaches to renew livers. On the cancer side, I think that these cells are very strong candidates for cell of origin. We are finally beginning to understand how this organ works."
How Great is the Dormant Potential for Regeneration in Tissues?
Over the years numerous research groups have claimed the existence of novel stem cell or stem cell like populations in various tissues. Stem cells spend much of their time dormant, but with the right signals or other form of control, it is plausible that they could be directed to greater activity, enhancing tissue regeneration. This is a slow process of discovery, however, usually accompanied by debates over whether or not cells of a claimed type actually exist, whether the research methodologies used in published studies are sound, and so forth. It is wise not to become too excited over any specific claim, but the prevalence of this sort of research suggests that there may be something there. The results noted here are an example of the type, in this case for the central nervous system. The potential to induce regeneration of nerve tissue and the brain is a topic of great interest in the research community.
A major goal of regenerative research is to repair the brain efficiently following injury, for example due to stroke, Alzheimer's disease or head trauma, disease or ageing. The brain is poor at repairing itself; however, it may become possible to improve repair without surgery by targeting stem cells residing in patients' brains. Stem cells have the unique capacity to produce all of the cells in the brain but are normally kept inactive in a form of cellular 'sleep' known as quiescence. Quiescent cells do not proliferate or generate new cells. Thus, any regenerative therapy targeting stem cells must first awaken them from quiescence.
Researchers now report the discovery in the brain of a new type of quiescent stem cell (known as 'G2 quiescent stem cell') with higher regenerative potential than quiescent stem cells identified previously. Importantly, G2 quiescent stem cells awaken to make the key types of cell in the brain - neurons and glia - much faster than known quiescent stem cells, making them attractive targets for therapeutic design. "The brain is not good at repairing itself, but these newly-discovered stem cells suggest there may be a way to improve its ability. These stem cells are in a dormant state, but once awake, they have the ability to generate key brain cells."
By studying the fruit fly (Drosophila), the authors identified a gene known as tribbles that selectively regulates G2 quiescent stem cells. The DNA of fruit flies has many similarities with that of humans, making them a useful model to understand human biology, and 60% of human genes associated with disease are also found in Drosophila. The tribbles gene has counterparts in the mammalian genome that are expressed in stem cells in the brain. The researchers believe that drugs that target tribbles might be one route to awakening G2 quiescent stem cells. "We've found the gene that directs these cells to become quiescent. The next step is to identify potential drug-like molecules that block this gene and awaken a person's stem cells."