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- Asking the Wrong Questions about Aging and Disease
- Another Study Assessing the Impact of Sitting on Life Expectancy
- Artificially Reduced LDL Cholesterol Levels Far Lower than those of Healthy, Young Individuals Appear to be Beneficial
- Senescent Cells May Disrupt Platelet Regulation while Generating Chronic Inflammation
- Cellular Biochemistry is Never Simple: an Example Involving Autophagy and Aging
- The Circular Relationship Between Senescent Cells and Chronic Kidney Disease
- Follicle-Stimulating Hormone in Long-Lived Mice
- Betterhumans Aims to Run Senolytic Trials
- Quantifying the Impact of Air Pollution on Life Expectancy
- Yes, Type 2 Diabetes is Reversible, as Soon as the Patient Chooses To Eat Less
- How Reversible is the Cellular Dysfunction Related to Amyloid-β?
- Calorie Restriction Slows Epigenetic Changes Associated with Aging
- Support for the "Bad Old Blood" rather than "Good Young Blood" View of what is Taking Place in Heterochronic Parabiosis
- Protein Posttranslational Modifications in Aging
- Can the Age-Related Harm Done by Fat Tissue be Prevented?
Asking the Wrong Questions about Aging and Disease
Age-related diseases began as a matter of taxonomy. Presented with the immensely complex, mysterious, varied, and inscrutable happenings at the end of life, the first scientists, before science was even much defined, began by trying to categorize their observations. Categorization is the first step towards making sense out of the unknown. Some forms of decline are obviously similar. Some are much worse than others in characteristic ways. Common manifestations are bucketed and given names: dementia, apoplexy, dropsy. These named facets of aging then became diseases just about as soon as people started to think that they could be treated - rightly or wrongly, and largely wrongly. The slow carving away of slivers of the inscrutable core of aging, making them known, and attempting to treat them, naturally gave rise to the idea that there existed aging, and separately there existed diseases of aging, states that were somehow distinct.
This mistaken belief has persisted into our era, in which the classification of age-related disease has become highly formal, regulated, and detailed. Aging is still not considered a medical condition to be treated, though the battle to change this state of affairs is progressing, and it requires years to create a new formal definition of age-related disease. The mainstream still proceeds by carving diseases from the bulk of aging, one by one, just as soon as mechanisms are understood to the point at which forms of therapy can be proposed. Sarcopenia is one of the most recently named diseases of aging, and it is still in undergoing formalization a decade after that process started. Without that formal, regulatory blessing, clinical development of therapies proceeds in only a limited fashion because it would be illegal to offer commercial therapies. There is so much inertia in this wasteful edifice of medical taxonomy that to break away to a better understanding and approach will require a major, long-running project of advocacy to reeducate the establishment.
There is such a thing as a wrong question: a question that arrives with a baggage of incorrect axioms, and to take it a face value is to be misdirected before even investigating a potential answer. To ask when the changes of aging become the pathology of disease is one such question. Yet that has been asked and answered for every formally defined age-related disease. It is built on a faulty view of aging, that the causative mechanisms of aging can be something other than pathological. But all aging is damage, even the damage that hasn't yet risen past minor inconvenience to the level of great pain, disability, and frailty. It is the same cell and tissue damage, and the current outcome is just a matter of degree. The most effective therapies will target that damage, but by drawing lines that don't exist between aging and disease, much of the research, medical, and regulatory communities have sabotaged and continue to sabotage their efforts to make a difference.
This paper is one example among many of researchers engaging with this model of thinking. It leads only to confusion - the inevitable destination for any attempt to split causation in aging into pathology and not-pathology, to find a definite transition from something innocuous to the malign cause of a disease state. At root it is all pathology: metabolism produces damage, damage produces aging, and the causes of aging start just as soon as metabolism starts. After that it is all just a matter of how damaged an individual happens to be. The more damage, the greater the disability, the higher the mortality rate. It is one unified, complex process, driven by the comparatively simple injection of molecular damage. Treating aging effectively can be as straightforward as working to address and reverse the damage, at any stage, however much of it there might be. The earlier the better.
Vascular aging and subclinical atherosclerosis: why such a "never ending" and challenging story in cardiology?
The true onset of atherosclerosis remains one of the biggest challenges for cardiologists. Is atheroma plaque development considered the earliest step of vascular aging? If so, when does it start? Before or after birth? If it starts before birth or early during childhood, it seems that Thomas Sydenham was right: "A man is as old as his arteries." Except disorganization of elastic fibers, less is known about the morphology of vascular aging and also about the molecular events influencing the age of arteries, arterial stiffness, and their role in the appearance of future complications. Cellular and molecular events responsible for the switch from physiologic to pathologic aging of human arteries are less known.
Vascular aging is described as a gradual process involving biochemical, enzymatic, and cellular events in vascular area combined with epigenetic and molecular alterations, and it is considered that arterial aging is a fundamental reflection of biological aging in general and a determinant of organ function. In the arterial wall, this is characterized by a decrease of elastin content, as well as by the production and accumulation of "bad" collagen and its cross-linkages, leading to increased arterial stiffness and elevated central blood pressure as well as brachial blood pressure, accompanied by increased variability in systolic blood pressure (SBP). A better understanding of these processes has led to the proposal of a condition named early vascular aging (EVA) in patients with increased arterial stiffness for their age and sex. This is a condition that could increase cardiovascular risk, and it is associated with various degrees of cognitive dysfunction, as well as other features of biological aging.
It is considered that vascular aging is found from several and sequential alterations that lead to the replacement of elastin fibers with collagen fibers in the vessel wall, which forms a less elastic structure due to the collagen bridges that prevent their elongation. This is the so-called physiological arterial stiffness. In time, there may be a pathological aging, consisting of various types of plaque deposition. There is no well-defined criteria that characterize EVA in this moment. What seems to be "early" for clinicians may be "too late" stages of vascular aging for vessel wall and also for the patient. "Early" microscopic changes in the structure of the arterial wall do not overlap with "early" vascular aging definition and assessment at all!
Data regarding the assessment of early steps of aortic wall changes and atheroma plaque formation are scattered for prenatal period, childhood, and teenage years. It is suggested that EVA starts in fetal life as stated by a few papers reporting perinatal atherosclerotic lesions in the fetal coronary arteries of babies of mothers who are smokers or by data suggesting the involvement of telomere length influencing arterial function and aging properties which could be programmed during fetal life or influenced by adverse growth patterns in early postnatal life.
The mechanism of vascular aging is associated with changes in the mechanical and structural properties of the arterial wall. These changes lead to the loss of arterial elasticity and reduced compliance because of the changes in the ratio between elastin and collagen fibers. Over time, destruction of elastin fibers with linear parallel structure takes place, due to the so-called fatigue phenomenon of the elastin. This leads to the breaking and fragmentation of elastin fibers which are replaced in a higher ratio with collagen fibers, resulting in a structure with increased rigidity.
The beginning of elastic fiber loss or damage remains a questionable issue for cardiologists. Our preliminary data showed that disorganization of elastic fibers appears early in human fetal aorta and continues during postnatal life, being extended immediately after birth. The process is not homogeneous along all length of the fetal or neonatal aorta, being mostly and easily detected on aortic arch level in prenatal life and immediately after birth. In this context, a big challenge is launched: how and when to define EVA related to detected microscopic changes which, for sure, anticipate the beginning of clinical vascular aging. Due to these facts, arterial stiffness may be seen as a complication of true, microscopic EVA.
If we would abruptly make a conclusion of the present review, we should go back to Thomas Sydenham who stated that "A man is as old as his arteries." This is definitely true but, unfortunately, it does not help patients to decrease vascular aging and to improve their life quality. Recently, it was suggested that the dissociation between chronologic and biologic age of large arteries represents the main reason for the failure of proper definition of EVA which overlaps clinical signs and patient prognosis. There are few studies regarding the molecular mechanisms of EVA with emphasis to the activation of pro-fibrotic, pro-inflammatory, redox-sensitive, and growth/apoptotic signaling pathways, but most of these studies were developed in mice and not yet validated in human subjects.
Another Study Assessing the Impact of Sitting on Life Expectancy
In the past few years, a number of epidemiological studies have suggested a correlation between more time spent sitting and a greater risk of mortality and age-related disease. Intriguingly, the claim is that this correlation persists even in people who do in fact exercise sufficiently. This should be considered in the context that statistical studies of human health and activities are notoriously challenging, given the degree to which data must be massaged into shape. Seemingly small differences in choice of metric can produce opposing outcomes: for example, differences in assessing the trajectory of weight over a lifetime, as well as whether to measure body mass index or waist circumference, have at times in the recent past produced quite distorted views of the degree to which excess fat tissue is harmful.
So the matter is far from settled as to whether lengthy periods of sedentary behavior - such as sitting - are a cause of harm even in people who meet guidelines for activity and exercise. There is no good mechanism, beyond that this might reflect an association with any number of other behaviors or conditions or choices or states of life that are themselves correlated with shorter life expectancy. Sitting time correlates with vascular calcification, for example, but that doesn't say anything about why this might be the case in people who do exercise in between their seated periods. The most obvious suggestion is that this is a question of overall activity levels in life, and length of time spent sitting is just a good proxy for overall activity levels. If the past fifty years are any guide, researchers will keep turning out this sort of study to argue subtle points of statistical interpretation well into the era of functional rejuvenation therapies - by which point the whole exercise becomes somewhat irrelevant.
Long Sitting Periods May Be Just as Harmful as Daily Total
A new study finds that it isn't just the amount of time spent sitting, but also the way in which sitting time is accumulated during the day that can affect risk of early death. Adults who sit for one to two hours at a time without moving have a higher mortality rate than adults who accrue the same amount of sedentary time in shorter bouts. "We tend to think of sedentary behavior as just the sheer volume of how much we sit around each day. But previous studies have suggested that sedentary patterns - whether an individual accrues sedentary time through several short stretches or fewer long stretches of time - may have an impact on health."
The researchers used hip-mounted activity monitors to objectively measure inactivity during waking time over a period of seven days in 7,985 black and white adults over age 45. (The participants were taking part in the REGARDS study, a national investigation of racial and regional disparities in stroke.) On average, sedentary behavior accounted for 77 percent of the participants' waking hours, equivalent to more than 12 hours per day. Over a median follow-up period of four years, 340 of the participants died. Mortality risk was calculated for those with various amounts of total sedentary time and various sedentary patterns. Those with the greatest amount of sedentary time - more than 13 hours per day - and who frequently had sedentary bouts of at least 60 to 90 consecutive minutes had a nearly two-fold increase in death risk compared with those who had the least total sedentary time and the shortest sedentary bouts.
Patterns of Sedentary Behavior and Mortality in U.S. Middle-Aged and Older Adults: A National Cohort Study
Excessive sedentary time is ubiquitous in Western societies. Previous studies have relied on self-reporting to evaluate the total volume of sedentary time as a prognostic risk factor for mortality and have not examined whether the manner in which sedentary time is accrued (in short or long bouts) carries prognostic relevance. Sedentary time was measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. Hazard ratios (HRs) were calculated comparing quartiles 2 through 4 to quartile 1 for each exposure (quartile cut points: 689.7, 746.5, and 799.4 min/d for total sedentary time; 7.7, 9.6, and 12.4 min/bout for sedentary bout duration) in models that included moderate to vigorous physical activity.
Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22; HR, 1.61; and HR, 2.63) and longer sedentary bout duration (HR, 1.03; HR, 1.22; and HR, 1.96) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [≥12.5 h/d] and high bout duration [≥10 min/bout]) had the greatest risk for death.
These findings highlight the importance of the total volume of sedentary time and its accumulation in prolonged bouts as important health risk behaviors. Meta-analyses have shown that total sedentary time is associated with cardiovascular disease and mortality, independent of moderate physical exercise. However, these findings are largely based on self-reported sedentary time, data that may underestimate the magnitude of the relationship between sedentariness and health risk. Use of accelerometers reduces potential biases and measurement error inherent in self-reported data. To our knowledge, this is the largest study to date with objective measures of sedentary behavior and prospective health outcomes. The magnitude of the association between total sedentary time and all-cause mortality (2.6-fold greater risk for quartile 4 vs. quartile 1) is notably higher than that reported in meta-analyses (HR 1.22).
A key finding of our study, which we believe is the first to report, is that patterns of sedentary time accumulation are associated with mortality. Previous cross-sectional studies have reported associations between the total number of breaks in sedentary time per day (the reciprocal to mean sedentary bout length) and cardiometabolic biomarkers. These findings led to the "prolonger" versus "breaker" hypothesis, which postulates that it is not only the amount of sedentary time that is important to cardiometabolic health, but also the manner in which it is accumulated.
Artificially Reduced LDL Cholesterol Levels Far Lower than those of Healthy, Young Individuals Appear to be Beneficial
Therapies such as statins, that aim to reduce circulating levels of low-density lipoprotein (LDL) cholesterol, are perhaps the most prevalent medical approach to cardiovascular disease. Indeed, when measured against the low bar set for past attempts to treat age-related conditions, they are one of the most successful forms of treatment to date. A sizable fraction of the reduction in cardiovascular mortality over the past few decades is attributed to the widespread use of statins and similar treatments. Still, this is only a delaying action, it is not a fix for the underlying problems.
How do reductions in LDL cholesterol slow the consequences of cardiovascular aging? The processes of interest involve damaged cholesterol molecules and cellular reactions to their presence. As the various causes of aging progress, there is ever greater inflammation and oxidative stress to produce damaged, oxidized cholesterols that find their way into the bloodstream. Once there, this mix of damaged molecules irritates blood vessel walls. In most cases unwanted metabolic waste of this sort is promptly cleaned up, consumed by the immune cells called macrophages, and disposed of. In some cases, however, there is an overreaction, or macrophages become overwhelmed by the damaged forms of cholesterol. A feedback loop is created in which the blood vessel wall becomes inflammatory, drawing in ever more macrophages that become dysfunction and die to add their mass to the creation of the characteristic fatty lesions of atherosclerosis. These masses narrow blood vessels and disrupt the structure of the blood vessel wall. They reduce critical blood flow, and eventually, as blood pressure rises due to other age-related issues, these fatty plaques rupture to kill or seriously injure the individual.
All of this can be slowed by interfering in any of the critical steps, even without preventing the underlying causes. It can't be reversed without forms of repair, however. So researchers could aim to make macrophages more resilient, could reduce the flux of damaged cholesterol by reducing the overall level of cholesterol, could dampen inflammation by attempting to adjust the regulation of the immune system, and so forth. All of these will slow down atherosclerosis to the degree that any particular implementation can produce change. But to turn it back, themedical community would need means of safely breaking down the problem compounds that irritate blood vessels and kill macrophages. Researchers associated with the SENS Research Foundation have investigated this class of treatment over the years, as their budget has permitted, and made some progress in targeting the problem compound of 7-ketocholesterol via adaptation of baterial enzymes.
Just how low can LDL cholesterol go, however? If less is consistently better, because it slows down atherosclerosis, does less ever stop being better? At some point, one has to presume that running out of LDL cholesterol has to be a bad thing, or else we wouldn't evolved to have it to begin with. With the advent of new and far more effective approaches such as PCSK9 inhibitors, a considerably more powerful intervention than statins, it is possible to reduce cholesterol levels to a fraction of what they would otherwise be. Normal healthy adults have LDL cholesterol measures somewhere below 100 mg/dL. The most severely impacted older people can be nearing or passing 200 mg/dL. The latest therapies can push LDL cholesterol in older people down below 10 mg/dL, far beneath that of normal, young, healthy individuals. The evidence suggests that this is beneficial, and for exactly the same reasons that smaller reductions are beneficial: it reduces the pace at which atherosclerosis progresses. This leads to a number of questions that researchers seem generally unwilling to state in print at this point in time, such as whether or not all adults should be lowering cholesterol throughout their lives, or whether to focus on gene therapies that can achieve this effect across the entire life span without the need for drugs.
How Low Should LDL Cholesterol Go?
A newer class of cholesterol lowering drugs known as PCSK9 inhibitors has emerged as an effective treatment for drastically lowering LDL cholesterol beyond current treatment targets. In a new analysis, researchers sought to explore whether there was "floor effect" in the lowering of LDL cholesterol - essentially, is there a threshold below which there would be no added clinical benefit? Additionally, researchers explored whether ultra-low LDL cholesterol levels would have any negative impact.
Using data from the FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk), which found that patients treated with the PCSK9 inhibitor evolocumab and statin therapy had a 20 percent reduction in the risk of cardiovascular death, myocardial infarction, or stroke, researchers examined the efficacy and safety of very low levels of LDL cholesterol among 25,982 patients per the degree of LDL-C reduction following one month of treatment. Researchers found that the risk for cardiovascular events (including cardiovascular death, heart attack, and stroke) over 2.2 years progressively declined as LDL cholesterol levels decreased to below 20 mg/dL (0.5 mmol/L), and participants who achieved an LDL-C of less than 10 mg/dL (0.26 mmol/L) had a more than 40 percent lower risk of cardiovascular events than those with an LDL cholesterol equal to or greater than 100 mg/dL (2.6 mmol/L).
"Our findings demonstrate that there is essentially no floor effect, and that lower levels translated to a greater reduction in risk. Among high-risk patients, achieving a LDL cholesterol level far below the most common treatment target of 70 mg/dL (1.8 mmol/L) can further reduce the risk for an adverse cardiovascular event, with no major safety concerns."
Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial
27,564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25,982 patients (94% of those randomly assigned) 13,013 were assigned evolocumab and 12,969 were assigned placebo. 2,669 (10%) of 25,982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8,003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3,444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4,395 (17%) patients achieved concentrations of 2.6 mmol/L or higher.
There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.
Senescent Cells May Disrupt Platelet Regulation while Generating Chronic Inflammation
If you spend much time scanning through papers of interest to the field of aging research, one of the things that may strike you about the past few years of work on senescent cells is the way in which it dovetails so well with past research of all sorts. A great deal of life science work in many parts of the broader field makes a whole lot more sense given the context of senescent cell accumulation as both (a) an important contributing cause of aging, and (b) an important source of chronic inflammation.
Yet this context wasn't missing a decade go or more - there was more than enough evidence to place senescent cell clearance into the first SENS rejuvenation research proposals, for example. It was there for anyone to recognize. But it wasn't given the weight it deserved, and too many researchers let the biochemistry of cellular senescence fade into the background, failing to consider it as a matter of importance for the mechanisms they happened to be focused upon. This is a problem, because, put simply, any condition or change in aging with a strong inflammatory component is fundamentally linked to cellular senescence. It cannot be ignored.
The paper noted here is a good example of this snug fit between older research and modern, more widespread realizations of the importance of cellular senescence. Researchers have long investigated links between cancer cells, inflammation, and platelet regulation. Platelets are a form of small cell-like structure that are primarily responsible for clotting as a way to control bleeding. They are manufactured by a fascinating process of shedding from cells known as megakaryocytes. But in this context, you might think of platelets as an abstract bundle of mechanisms by which cells can amplify inflammatory signaling to generate much larger effects on surrounding tissues and bodily systems, though that is perhaps an oversimplification.
Like all systems in cellular metabolism, the behavior of platelets runs awry in older people. Blood clotting can run amok or proceed incorrectly and fail to resolve. It turns out that the inflammatory signals from tumor cells and their relationship with platelets, categorized by interested cancer researchers over the years without giving all that much thought to cellular senescence, are probably very relevant to the activities of senescent cells as well. Senescent cells are the missing third leg for the stool portrayed in this picture, and platelets may be an important part of the bigger picture for cellular senescence and cancer risk in aging.
The Potential Role of Senescence as a Modulator of Platelets and Tumorigenesis
The functional connection between cancer and platelets has been recognized since the late nineteenth century, when an association between the occurrence of certain solid tumors and the development of venous thrombosis and blood hypercoagulability was first described. Accordingly, defects in platelet function or reduced platelet counts have both been associated with a reduced ability of tumors to metastasize. We now know that platelets may contribute to the establishment of various hallmarks of cancer, including the ability of cancer cells to sustain proliferation, to resist apoptosis and to promote angiogenesis and metastasis. It is presently unclear, however, to what extent these contributions are the result of a direct action of platelets on tumor cells or, alternatively, may be part of an underlying inflammatory process inherent to many tumors. Inflammatory cells and soluble mediators of inflammation are important constituents of the tumor microenvironment.
Typical hallmarks of physiological aging include impaired tissue regeneration and repair, a functional impairment of progenitor cellsalterations of the immune system. While the specific cellular changes associated with each one of these hallmarks will vary depending on the tissue analyzed, cellular senescence is rapidly emerging as an underlying process that may help explain some of these changes. In keeping with this idea, senescent cells accumulate in several tissues derived from aged animals. In addition to cell cycle arrest, the establishment of a mature senescent phenotype involves extensive metabolic reprograming, as well as the implementation of complex traits such as the senescence-associated secretory phenotype (SASP). The SASP refers to the almost universal capacity of senescent cells to produce and secrete a variety of soluble and insoluble factors, including extracellular proteases, cytokines, chemokines, and growth factors.
A common feature of aging and age-related diseases is chronic inflammation. The term "inflammaging" has been coined to describe a low-grade, chronic, and systemic inflammation associated with aging and aging phenotypes in the absence of evidence of infection. In line with this concept, many of the factors secreted by senescent cells are also well-known pro-inflammatory molecules with the potential to induce chronic inflammation in certain biological contexts. More recently, a unique type of inflammation triggered by senescent cells, the senescence-inflammatory response, has been identified.
Based on the emerging physiological and pathological processes in which the SASP might be involved, it is conceivable that senescent cells may also affect hemostasis through mechanisms that include, but are not limited to, changes in the production and functional status of platelets. As mentioned elsewhere in this review, IL-6 is one of the most prominent pro-inflammatory cytokines present in the SASP. Moreover, IL-6 upregulates the synthesis of hemostatic factors, such as fibrinogen, and may also directly activate platelets.
Thus, it is tempting to speculate that the high levels of IL-6 (and other pro-inflammatory factors, such as IL-1β and TNF-α) detected in aged individuals could reflect, at least in part, an increased rate of secretion of this cytokine by senescent cells - or by other cells responding to senescent cells - in the context of a senescence-induced chronic inflammation. An age-dependent increase of pro-inflammatory factors would, in turn, contribute to platelet activation and a higher proclivity to thrombus formation. Therefore, we postulate that cellular senescence (as a result of physiological aging or secondary to therapeutic stress) might play an important role in the regulation of platelet function. By regulating the activation of platelets, senescent cells could provide yet another mechanism contributing to the higher prevalence of chronic inflammation (and cancer) in aged individuals.
The functional interaction between cancer cells and platelets has been well established. Most of the efforts aimed to clarify these interactions have been focused on the ability of tumor cells (or tumor-associated stromal cells) to produce and secrete pro-inflammatory factors that can result in the activation of platelets. Active platelets - acting synergistically with other components of the tumor stroma - can then promote or enhance tumor progression and metastasis. Paradoxically, many of the factors secreted by tumor cells or tumor-associated inflammatory cells with a known effect on platelet activity are also produced and secreted by cells undergoing senescence, a process originally regarded as tumor suppressive. Indeed, the evidence indicates that cellular senescence may also play an active role in driving, rather than suppressing, tumor formation, a non-cell autonomous role that seems to be largely dependent on the SASP. Accordingly, factors released by senescent cells may help create a pro-tumorigenic microenvironment that enhances proliferation and migration of neighbor cells. Although still controversial, this model would be in line with the observation that the prevalence of most cancers increases with age.
Alterations in hemostasis involving platelet dysfunction or alterations in the process of fibrinolysis are at the core of thrombogenesis. As with cancer, thrombogenesis is most commonly observed in older individuals, who presumably harbor a higher proportion of senescent cells in their tissues. We, therefore, postulate that cellular senescence, either as a result of normal aging or secondary to stress, could play an important role in the regulation of platelet function. According to this model, senescent cells have the ability to modify the microenvironment in ways that may enhance tumorigenesis. Similarly, senescent cells might also regulate the activity of platelets, the process of fibrinolysis, or both. By regulating the activation of platelets, senescent cells may provide yet another mechanism to enhance tumorigenesis. Whether or not these circuits are relevant to tumorigenesis and/or thrombogenesis remains to be fully elucidated.
Cellular Biochemistry is Never Simple: an Example Involving Autophagy and Aging
Nothing in cellular biology is any way straightforward. All rules have exceptions, enormous complexity is the norm, and old understandings are consistently overturned with the arrival of new data: what was thought to be simple turns out to be anything but simple. Even something like the cellular maintenance processes of autophagy, universally demonstrated to be a good thing in laboratory species, to slow aging when more active, and to accelerate aging when disabled via genetic engineering, are no exception. As demonstrated here, researchers have found that selectively disabling autophagy can actually extend life in nematode worms, possibly because the operation of age-damaged autophagy in some important tissues is actually worse than the absence of running autophagy.
In the publicity materials, this is all wrapped in considerations of antagonistic pleiotropy in the evolution of aging, but I think the mechanics of the thing are more interesting in this case. In lower species like worms and flies there is a fair amount of evidence for some tissues to be especially influential over aging: the intestines, some groupings of neurons in the brain, for example. It is very unclear as to the degree to which this is still the case in mammals. Certainly most things demonstrated to slow aging in short-lived species have far less of an effect in long-lived species such as our own. Nonetheless, this research can be taken as an example of the importance of neurons in the pace of aging in nematodes.
Why we did not evolve to live forever: Unveiling the mystery of why we age
Natural selection results in the fittest individuals for a given environment surviving to breed and pass on their genes to the next generation. The more fruitful a trait is at promoting reproductive success, the stronger the selection for that trait will be. In theory, this should give rise to individuals with traits which prevent ageing as their genes could be passed on nearly continuously. Thus, despite the obvious facts to the contrary, from the point of evolution ageing should never have happened. This evolutionary contradiction has been debated and theorised on since the 1800s. It was only in 1953 with his hypothesis of antagonistic pleiotropy that George C. Williams gave us a rational explanation for how ageing can arise in a population through evolution.
Williams proposed that natural selection enriches genes promoting reproductive success but consequently ignores their negative effects on longevity. Importantly, this is only true when those negative effects occur after the onset of reproduction. Essentially, if a gene mutation results in more offspring but shortens life that's fine. This is because there can be more descendants carrying on the parent's genes in a shorter time to compensate. Accordingly, over time, these pro-fitness, pro-ageing mutations are actively selected for and the ageing process becomes hard-wired into our DNA. While this theory has been proven mathematically and its implications demonstrated in the real world, actual evidence for genes behaving in such as fashion has been lacking.
Now researchers have identified that genes belonging to a process called autophagy - one of the cells most critical survival processes - promote health and fitness in young worms but drive the process of ageing later in life. "These genes haven't been found before because it's incredibly difficult to work with already old animals, we were the first to figure out how to do this on a large scale. From a relatively small screen, we found a surprisingly large number of genes, 30, that seem to operate in an antagonistic fashion. Previous studies had found genes that encourage ageing while still being essential for development, but these 30 genes represent some of the first found promoting ageing specifically only in old worms. Considering we tested only 0.05% of all the genes in a worm this suggests there could be many more of these genes out there to find."
The researchers also found a series of genes involved in regulating autophagy which accelerate the ageing process. These results are surprising indeed, the process of autophagy is a critical recycling process in the cell, and is usually required to live a normal full lifetime. Autophagy is known to become slower with age and the authors of this paper show that it appears to completely deteriorate in older worms. They demonstrate that shutting down key genes in the initiation of the process allows the worms to live longer compared with leaving it running crippled. "Autophagy is nearly always thought of as beneficial even if it's barely working. We instead show that there are severe negative consequences when it breaks down and then you are better off bypassing it all together. It's classic antagonistic pleiotrophy. In young worms, autophagy is working properly and is essential to reach maturity but after reproduction, it starts to malfunction causing the worms to age."
In a final revelation, the team were able to track the source of the pro-longevity signals to a specific tissue, namely the neurons. By inactivating autophagy in the neurons of old worms they were not only able to prolong the worms life but they increased the total health of the worms dramatically. "We turn autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and we think this is what keeps the muscles and the rest of the body in good shape. The net result is a 50% extension of life."
Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans
Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen.
From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4. Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.
The Circular Relationship Between Senescent Cells and Chronic Kidney Disease
Growth in the number of senescent cells that linger in tissues is one of the root causes of aging. In this context, the open access paper noted here illustrates a couple of points that are worth bearing in mind while thinking about the biochemistry of aging, the first of which is that aging is a feedback loop of damage. Cell and tissue damage generates more cell and tissue damage, which is why aging accelerates as it progresses. The same rough structure of events is found in the age-related failure of any complex machinery.
The second point is that many of the mechanisms and relationships established in past research now make a lot more sense in the context of senescent cells as a driver of aging. The relationship partially outlined by the authors of this paper is an unusually compact feedback loop: senescent cells contribute to kidney dysfunction, for example through a disruption of normal tissue maintenance that produces fibrosis. Scar tissue forms in place of necessary small-scale structures, and in organs like the kidneys those structures are needed for normal function. Kidney dysfunction can in turn lead to stressful metabolic states such as hyperphosphatemia that encourage more cells to become senescent - and not just in the kidneys. It is a downward spiral, one repeated in many different ways through the aged body.
Hyperphosphatemia is a pathological condition related to chronic kidney disease (CKD) and more recently found on premature aging syndromes. High concentration of serum phosphate has profound effects on vascular cell behavior and on vascular function, and has been associated with cardiovascular disease in patients with CKD. Phosphate toxicity has been related with many other organ dysfunctions. However, less is known about the effect of hyperphosphatemia on vascular endothelial cells. A few works have described that a high extracellular phosphate level induces endothelial dysfunction via various mechanisms, including a decline in nitric oxide (NO) release due to oxidative stress.
Endothelium exerts multiple functions to preserve vascular homeostasis. Vasoactive endothelial factors such as NO or ET-1 are involved in this regulation. An unbalanced production of these bioactive mediators results in endothelial dysfunction, a critical event in the development of renal and cardiovascular damage in some diseases such as diabetes, hypertension, or atherosclerosis. On the other hand, vascular dysfunction has been related to endothelial senescence. Cellular senescence is considered one of the hallmarks of aging, and the presence of senescent cells in the tissue can induce or increase some pathologies. Senescent cells are not able to proliferate and present some morphological and biochemical changes, such as increased senescent activity of β-galactosidase (SA-β-GAL) and increased expression of cell cycle inhibitors such as p16 or p53 tumor suppressor genes.
Senescence can be promoted by the replicative life of cells, due to the progressive telomere shortening or prematurely in response to stressful stimuli, which result in DNA damage or oncogene activation. Recent studies from our group have demonstrated that hyperphosphatemia could be one of these stressful stimuli, as it induced cellular senescence in human aortic smooth muscle cells through the activation of IGF-1 receptor and integrin-linked kinase overexpression. The present work shows, for the first time, the key role of ET-1 in the senescence process induced by hyperphosphatemia. We show that a high extracellular phosphate concentration up-regulates the synthesis of ET-1 in endothelial cells, inducing cellular senescence through the modulation of ECE-1 via oxidative stress and AP-1 activation. Thus the hyperphosphatemia related to aging or aged diseases could increase senescent cells, which could be involved in the development of other pathologies.
Follicle-Stimulating Hormone in Long-Lived Mice
It has been quite a number of years since researchers first produced dwarf mice with disabled growth hormone or growth hormone receptors, some of which still hold the record for engineered mouse longevity. Using these mice as a point of comparison to further map metabolism and aging continues to be an ongoing process, as illustrated by this open access paper. In it, the authors discuss the role of just one of many regulatory genes that might be important in many of the methods that have been used to slow aging in mice.
Cellular biochemistry is enormously complex, and thus so are the details of the changes that occur with aging, even though the underlying root causes are comparatively simple. As an analogy, consider what happens when a complicated metal assembly rusts into structural failure: rust is very simple, and that the assembly can ultimately fall apart in any one of many different ways is a function of the complexity of the structure, not of the rust. This is why attempting to slow aging by altering metabolism is so very hard and expensive, while attempting to reverse aging by repairing the root causes is comparatively straightforward and cost-effective. You can see that dynamic at work by comparing the little that has been achieved in twenty years of attempts to replicate the metabolic response to calorie restriction versus the solid progress achieved over the past five years of work on clearance of senescent cells. The latter has required a fraction of the cost and far fewer researchers than the former, while the results are already far more impressive.
Recent evidence for extragonadal actions of follicle-stimulating hormone (FSH), including effects on the function of both brown and white adipose tissue, raises the intriguing possibility that FSH may be involved in the control of aging. If confirmed, this novel action of FSH would enhance our understanding of mechanisms and trade-offs involved in the control of healthspan and longevity of homeothermic organisms. Follicle-stimulating hormone is produced by the anterior pituitary gland and acts as one of the master regulators of reproductive functions in both females and males.
Recent work indicates that FSH also acts within nonreproductive tissues, including bone. Researchers provided elegant evidence that FSH also influences adipose tissue functions; specifically, blocking FSH actions with a specific antibody stimulated thermogenesis in both brown and white adipose tissues (BAT and WAT), reduced adiposity, and increased bone mass in laboratory mice. These findings imply that the well-documented postmenopausal increase in FSH secretion is likely among the causes for increased adiposity, reduction in bone mass, and alterations in energy metabolism at this stage of life history. One could also suspect that the gradual age-related increase in FSH levels in men has similar consequences.
We suggest that the physiological changes resembling the benefits of blocking FSH action may also occur in response to a modest reduction in FSH levels in animals genetically predisposed to extreme longevity. This would imply that FSH may have a role in the control of aging. Our hypothesis that FSH may have a role in the control of aging stems from observations in two types of mice in which reduction in FSH levels, activation of BAT, browning of WAT, and increased energy expenditure are associated with major extensions of healthspan and longevity.
In Prop1df (Ames dwarf) mutants with a genetic defect in the differentiation of somatotroph, lactotroph, and thyrotroph cell lineages in the anterior pituitary, the expression of the FSH-β subunit gene, the pituitary FSH content, and the plasma FSH levels are significantly reduced. A similar reduction in plasma FSH levels occurs in both sexes of mice with deletion of the growth hormone receptor (GHR) gene (Laron dwarf). In both Prop1df and GHR-/- mice, BAT is enlarged and highly active, subcutaneous WAT exhibits characteristics of 'beiging' and metabolic rate is increased. Moreover, their respiratory exchange ratio is reduced, implying a shift in mitochondrial function toward greater utilization of fatty acids as metabolic fuel. Both Ames dwarf and GHR-/- mice are remarkably long-lived, with increases in longevity ranging from some 20% to over 60% depending on the diet, gender, and genetic background of the animal.
We have previously proposed that the activation of BAT and increased metabolic rate in these long-lived mice represent responses to increased radiational heat loss in these diminutive animal. However, results of GH replacement therapy in Prop1df mice indicate that their metabolic characteristics and extended longevity can be at least partially uncoupled from body size. Extrapolating from the recent findings noted above, we now hypothesize that reduced FSH levels in these animals may produce (or contribute to) their unique metabolic profile, and also likely to their extended longevity.
If confirmed, the effects of reduced FSH levels in these animals would represent a novel mechanism of trade-offs between their fertility and longevity. Both sexes of GHR-/- mice and male Ames dwarfs are fertile, but their sexual maturation is delayed and fecundity is reduced. Important trade-offs between reproduction and aging have been studied and discussed for decades, but our understanding of the underlying mechanisms is very limited, and in mammals, virtually nonexistent. Thus, combining the results of FSH blockage with the available information on endocrine and metabolic characteristics of two types of long-lived mice produces a novel mechanistic insight into the complex interaction of sexual maturation, reproductive effort, fecundity, aging, and lifespan.
Betterhumans Aims to Run Senolytic Trials
Some of you may remember Betterhumans as one of a number of transhumanist community websites from years back, providing news and advocacy in service of efforts to improve the human condition. Extending healthy lifespan by engineering practical rejuvenation therapies has always been a core transhumanist goal. In one of the more interesting second acts in our community, the Betterhumans name is now hanging on the door of a medical research and development non-profit. This organization runs a supercentenarian study, and is now working on trials of senolytic therapies, starting with the dasatinib and quercetin combination that was first used in mice a few years ago. This is something that I would definitely like to see more of in our community. All of the pieces of the puzzle exist for people who want to work at assembling responsible, transparent, small human trials for the first candidate senolytic drugs. The drugs cost little, the animal studies are compelling, so why wait?
Betterhumans has a long history in the field of transhumanism. It was started as an educational website in mid-2001 and evolved to become a popular website presenting ideas and news about exponential technologies. It ceased operating as a website around late 2008, when h+ Magazine took over its functions. This new iteration of Betterhumans is the most aggressive yet. We will shortly be putting out new information about how ordinary people can modify their diet and lifestyle to take advantage of some of the latest findings in scientific research. Our research team is focused on bringing cutting-edge scientific discoveries from the lab to the clinic, so that humanity can take advantage of these breakthroughs in a safe and inexpensive manner, as quickly as possible.
Operating as a Florida non-profit corporation, the short-term goals of Betterhumans are extending healthy maximum human lifespan and greatly reducing the risk of disease. All discoveries will be offered under a Creative Commons Public Patent License, or equivalent. In 2015, Betterhumans received funding from the Methuselah Foundation to carry out stem cell research and gene-editing experiments, with the express intention of delaying aging and rejuvenating vital organs.
We intend to pursue many small scale human pilot studies to test the safety and efficacy of various FDA-approved drugs and therapies thought to have anti-aging effects. We will publish all results so that other researchers, physicians, and patients can have information which may aid their efforts. The question seeking to be answered by this Phase 0 pilot study is whether the senolytic compounds dasatinib and quercetin will significantly eliminate senescent cells contained in the muscle and fat tissue of elderly individuals who have metabolic syndrome and/or osteoarthritis, and will reduce levels of systemic inflammation, insulin resistance, improve their immunological responses, and in those having osteoarthritis, reverse the progression of this disease.
Quantifying the Impact of Air Pollution on Life Expectancy
Areas of China can act as a laboratory for the impact of particulate air pollution on long-term health. There are good reasons to think that the established correlations between air pollution and life expectancy are due to physical and biochemical mechanisms such as increased chronic inflammation. It has been equally possible to argue that that the relationship has more to do with relative wealth of populations, however, as wealthier regions tend to have lower levels of pollution. In this study, researchers put some numbers to the correlation, and improve on previous attempts to rule out wealth and other effects as significant contributing causes.
A study finds that a Chinese policy is unintentionally causing people in northern China to live 3.1 years less than people in the south, due to air pollution concentrations that are 46 percent higher. These findings imply that every additional 10 micrograms per cubic meter of particulate matter pollution reduces life expectancy by 0.6 years. The elevated mortality is entirely due to an increase in cardiorespiratory deaths, indicating that air pollution is the cause of reduced life expectancies to the north. "These results greatly strengthen the case that long-term exposure to particulates air pollution causes substantial reductions in life expectancy."
The study exploits China's Huai River policy, which provided free coal to power boilers for winter heating to people living north of the river and provided almost no resources toward heating south of the river. The policy's partial provision of heating was implemented because China did not have enough resources to provide free coal nationwide. Additionally, since migration was greatly restricted, people exposed to pollution were generally not able to migrate to less polluted areas. Together, the discrete change in policy at the river's edge and the migration restrictions provide the basis for a powerful natural experiment that offers an opportunity to isolate the impact of sustained exposure to particulates air pollution from other factors that affect health.
Overall, the study provides solutions to several challenges that have plagued previous research. In particular, prior studies rely on research designs that may be unlikely to isolate the causal effects of air pollution; measure the effect of pollution exposure for relatively short periods of time (e.g., weekly or annually), failing to shed light on the effect of sustained exposure; examine settings with much lower pollution concentrations than those currently faced by billions of people in countries, including China and India, leaving questions about their applicability unanswered; measure effects on mortality rates but leave the full loss of life expectancy unanswered.
The study follows on an earlier study, conducted by some of the same researchers, which also utilized the unique Huai River design. Despite using data from two separate time periods, both studies revealed the same basic relationship between pollution and life expectancy. However, the new study's more recent data covers a population eight times greater than the previous one. It also provides direct evidence on smaller pollution particles that are more often the subject of environmental regulations.
Yes, Type 2 Diabetes is Reversible, as Soon as the Patient Chooses To Eat Less
The evidence has been in place for some years to show that low calorie diets can reverse type 2 diabetes even in comparatively late stages. For the vast majority of patients, this is a disease of choice: they chose to become fat enough to suffer sufficient metabolic disruption to produce the condition, as well as to accelerate the aging process, and they choose to remain fat enough to maintain this level of damage. Yes, eating less and exercising more is harder than it used to be, in this environment of low-cost calories, comfort, and convenience, but "harder" is not "I have no choice in this."
A body of research putting people with type 2 diabetes on a low calorie diet has confirmed the underlying causes of the condition and established that it is reversible. Research has revealed that for people with type 2 diabetes: (a) excess calories leads to excess fat in the liver; (b) as a result, the liver responds poorly to insulin and produces too much glucose; (c) excess fat in the liver is passed on to the pancreas, causing the insulin producing cells to fail; (d) losing less than 1 gram of fat from the pancreas through diet can re-start the normal production of insulin, reversing type 2 diabetes; (e) this reversal of diabetes remains possible for at least 10 years after the onset of the condition.
"I think the real importance of this work is for the patients themselves. Many have described to me how embarking on the low calorie diet has been the only option to prevent what they thought - or had been told - was an inevitable decline into further medication and further ill health because of their diabetes. By studying the underlying mechanisms we have been able to demonstrate the simplicity of type 2 diabetes." A body of research now confirms the Twin Cycle Hypothesis - that Type 2 diabetes is caused by excess fat actually within both liver and pancreas. This causes the liver to respond poorly to insulin. As insulin controls the normal process of making glucose, the liver then produces too much glucose. Simultaneously, excess fat in the liver increases the normal process of export of fat to all tissues. In the pancreas, this excess fat causes the insulin producing cells to fail.
The Counterpoint study, which was published in 2011, confirmed that if excess food intake was sharply decreased through a very low calorie diet, all these abnormal factors would be reversed. The study showed a profound fall in liver fat content resulting in normalisation of hepatic insulin sensitivity within 7 days of starting a very low calorie diet in people with type 2 diabetes. Fasting plasma glucose became normal in 7 days. Over 8 weeks, the raised pancreas fat content fell and normal first phase insulin secretion became re-established, with normal plasma glucose control. "The good news for people with Type 2 diabetes is that our work shows that even if you have had the condition for 10 years, you are likely to be able to reverse it by moving that all-important tiny amount of fat out of the pancreas. At present, this can only be done through substantial weight loss." The Counterbalance study published in 2016, demonstrated that type 2 diabetes remains reversible for up to 10 years in most people, and also that the normal metabolism persists long term, as long as the person doesn't regain the weight.
How Reversible is the Cellular Dysfunction Related to Amyloid-β?
This is an interesting experiment, though note that the DOI link goes straight to a PDF at the time of writing. It is carried out in cell culture, so don't take the results too seriously: they would have to be replicated in at least an organoid tissue structure that better matched natural brain tissue. Nonetheless, the researchers show that brain cells in this more artificial environment are capable of recovering from some of the damage done by the presence of amyloid-β, the protein aggregate associated with Alzheimer's disease. The present consensus is that it isn't the amyloid itself that causes the harm, but rather the surrounding halo of related proteins and fragments. Still, get rid of the amyloid, and that halo vanishes as well.
Patients with Alzheimer's disease (AD) chiefly suffer from impairment of memory and other cognitive functions. AD is neuropathologically characterized by senile plaques and neurofibrillary tangles, which are composed of amyloid β-protein (Aβ) and phosphorylated tau proteins, respectively. Recently, a new concept has emerged: that soluble oligomeric forms of Aβ (Aβ oligomers), but not Aβ fibrils, play a primary pathogenic role in the pathological cascade of AD. This idea is based on findings that soluble forms of Aβ provoke neurotoxic effects, including tau abnormalities (especially hyperphosphorylation), functional and structural abnormalities of synapses, and induction of neuronal death. This concept is supported by numerous studies that have employed a variety of experimental systems, including cell culture, brain slices, and animal models, as well as the fact that Aβ oligomers are abundant in post-mortem AD brains. Thus, oligomeric Aβ is considered a major culprit in the molecular pathology of AD.
To investigate the pathological roles of Aβ oligomers, we have established a neuron culture model system, in which rat primary neurons are exposed to relatively low concentrations of Aβ42 oligomers (Aβ-O) for relatively long periods (2-3 days). We observed that Aβ-O induces neurotoxic insults with limited cell death under these conditions. Because these changes are reflective of characteristic pathological features of AD, this neuron model is considered a useful system for investigating the neurotoxic mechanisms triggered by Aβ oligomers.
We were interested in the question of whether the neurotoxicity of Aβ oligomers is reversible and abates upon their removal, an issue that has remained largely unexplored. To investigate this possibility, we designed the following experimental paradigm: Rat primary cultured neurons were treated with Aβ-O for 2 days, at which point cells were deprived of Aβ-O by replacing the medium with fresh medium lacking Aβ-O, or were re-provided Aβ-O and cultured for an additional 2 days; untreated neurons were used as controls. Neurons continuously treated with Aβ-O showed greater activation of caspase-3 and eIF2α, and exhibited persistent, abnormal alterations of tau and β-catenin. In contrast, upon Aβ deprivation, caspase-3 and eIF2α activation were considerably attenuated, aberrant phosphorylation and caspase-mediated cleavage of tau recovered for the most part, and abnormal alterations of β-catenin were partially reversed.
These results indicate that removal of extracellular Aβ-O can fully or partially reverse Aβ-O-induced neurotoxic and synaptotoxic alterations in our neuron model. Our findings suggest that Aβ oligomer-associated neurotoxicity is a reversible process in that neurons are capable of recovering from moderate neurotoxic insults. These data also support the idea that Aβ oligomers act on the cell surface of neurons to transmit aberrant signals, resulting in various abnormal cellular responses; upon Aβ oligomer removal, the aberrant signals subside, resulting in reversal of all abnormal responses.
Calorie Restriction Slows Epigenetic Changes Associated with Aging
The results noted here are unsurprising, a confirmation of what was expected by most in the field. The practice of calorie restriction has been shown to extend healthy life span and slow near all measures of aging in a range of species. Now that the research community has established a number of epigenetic clocks, characteristic patterns of DNA methylation that change in fairly predictable ways over the course of aging, it was only a matter of time before those too were shown to be slowed by calorie restriction. If, as is the consensus, calorie restriction does in fact slow the causes of aging, and slow aging as a process overall, then it should also slow all consequent measures of aging.
Where these publicity materials run awry is to paint epigenetic changes as a cause of aging. There is certainly a faction in the research community whose members consider aging to be a selected, evolved program, and place epigenetic changes as a root cause of aging. However I think they continue to have an uphill struggle to try to prove that case in the face of the overwhelming evidence for aging to be caused by accumulations of molecular damage, with epigenetic changes a downstream consequence of that damage: cells reacting to increased damage in the surrounding environment and themselves. The complexity of cellular biochemistry in a living individual means that this debate is unlikely be resolved through inspection before it is resolved by observing the results of different approaches to rejuvenation therapies. For example, clearance of senescent cells is a form of damage repair that extends life in mice: if that also turns back epigenetic changes of aging, something that has yet to be established in a published paper, then this would be strong evidence against epigenetic change as a cause of aging.
New research is the first to show that the speed at which the epigenome changes with age is associated with lifespan across species and that calorie restriction slows this process of change, potentially explaining its effects on longevity. "Our study shows that epigenetic drift, which is characterized by gains and losses in DNA methylation in the genome over time, occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans." The findings help to explain why mice live only about two to three years on average, rhesus monkeys about 25 years, and humans 70 or 80 years.
Chemical modifications such as DNA methylation control mammalian genes, serving as bookmarks for when a gene should be used - a phenomenon known as epigenetics. Previous studies had shown that these changes occur with age, but whether they were also related to lifespan was unknown. The researchers made their discovery after first examining methylation patterns on DNA in blood collected from individuals of different ages for each of three species - mouse, monkey, and human. Mice ranged in age from a few months to almost three years, monkeys from less than one year to 30 years, and humans from age zero to 86 years (cord blood was used to represent age zero). Age-related variations in DNA methylation were analyzed by deep sequencing technology, which revealed distinct patterns, with gains in methylation in older individuals occurring at genomic sites that were unmethylated in young individuals, and vice versa.
In subsequent analyses, striking losses in gene expression were observed in genomic regions that had become increasingly methylated with age, whereas regions that had become less methylated showed increases in gene expression. Investigation of a subset of genes affected by age-related changes in methylation revealed an inverse relationship between methylation drift and longevity. In other words, the greater the amount of epigenetic change - and the more quickly it occurred - the shorter the species' lifespan.
One of the strongest factors known to increase lifespan in animals is calorie restriction, in which calories in the diet are reduced while still maintaining intake of essential nutrients. To examine its effects, the researchers cut calorie intake by 40 percent in young mice and by 30 percent in middle-aged monkeys. In both species, significant reductions in epigenetic drift were observed, such that age-related changes in methylation in old animals on the calorie-restricted diets were comparable to those of young animals. With the latest findings, the researchers were able to propose a new mechanism - the slowing of epigenetic drift - to explain how calorie restriction prolongs life in animals. "The impacts of calorie restriction on lifespan have been known for decades, but thanks to modern quantitative techniques, we are able to show for the first time a striking slowing down of epigenetic drift as lifespan increases."
Support for the "Bad Old Blood" rather than "Good Young Blood" View of what is Taking Place in Heterochronic Parabiosis
Join the circulatory systems of two mice, one young and one old, a procedure known as heterochronic parabiosis, and the young one suffers some of the impact of aging while the old one loses some of that same impact. Regenerative capacity and stem cell activity are affected, for example. Researchers continue to search for factors in the blood that might explain this, but this work is still in its comparatively early stages. The question of the degree to which the mechanisms involve beneficial factors in young blood or harmful factors in old blood remains to be settled, with a range of interesting evidence on both sides. The "bad old blood" view seems to have the more compelling demonstration so far, I feel. If this is the case, benefits in the old mice are realized because the harmful factors in old blood are diluted by young blood, not because the young blood is providing beneficial signals.
Aging is a gradual biological process characterized by a decrease in cell and organism functions. Gingival wound healing is one of the impaired processes found in old rats. Here, we studied the in vivo wound healing process using a gingival repair rat model and an in vitro model using human gingival fibroblasts for cellular responses associated to wound healing. To do that, we evaluated cell proliferation of both epithelial and connective tissue cells in gingival wounds and found decreased of Ki67 nuclear staining in old rats when compared to their young counterparts.
We next evaluated cellular responses of primary gingival fibroblast obtained from young subjects in the presence of human blood serum of individuals of different ages. Eighteen to sixty five years old masculine donors were classified into 3 groups: "young" from 18 to 22 years old, "middle-aged" from 30 to 48 years old and "aged" over 50 years old. Cell proliferation, measured through immunofluorescence for Ki67 and flow cytometry for DNA content, was decreased when middle-aged and aged serum was added to gingival fibroblasts compared to young serum. Myofibroblastic differentiation, measured through alpha-smooth muscle actin (α-SMA), was stimulated with young but not middle-aged or aged serum both the protein levels and incorporation of α-SMA into actin stress fibers. High levels of PDGF, VEGF, IL-6R were detected in blood serum from young subjects when compared to middle-aged and aged donors. In addition, the pro-inflammatory cytokines MCP-1 and TNF were increased in the serum of aged donors.
In wounds in old rats there is an increased of staining for TNF compared to young rat wounds. Moreover, healthy gingiva (non injury) shows less staining compared to a wound site, suggesting a role in wound healing. Moreover, serum from middle-aged and aged donors was able to stimulate cellular senescence in young cells as determined by the expression of senescence associated beta-galactosidase and histone H2A.X phosphorylated at Ser139. Further, we detected an increased frequency of γ-H2A.X-positive cells in aged rat gingival tissues. The present study suggests that serum factors present in middle-aged and aged individuals may be responsible, at least in part, for the altered responses observed during wound healing in aging.
Protein Posttranslational Modifications in Aging
This very readable review paper walks through what is known of modifications to proteins that occur after their creation, and the role these modifications play in aging. If you are familiar with the SENS view of aging as an accumulation of damage, you'll recall that this damage includes the buildup of numerous forms of metabolic waste, and many of these items are modified proteins. Equally, the vast majority of other age-related changes in modified proteins are downstream consequences of the damage of aging or reactions to the damage of aging, not root causes - the details matter on a case by case, per-protein and per-modification basis.
From a biodemographic point of view, aging is defined as an exponential increase in mortality with time, sometimes accompanied by a deceleration or plateau at later ages. Although the changes that underlie aging are complex, it is characterized by the gradual accumulation of a wide variety of molecular and cellular damage throughout the lifespan. The nine proposed hallmarks of aging in mammals are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, the connections between these hallmarks, their contributions to aging, and their links with frailty and disease remain incompletely understood. In fact, uncovering the biological basis of aging is one of the greatest contemporary challenges in science.
Interestingly, epigenetics plays a crucial role in aging. While there are several different types of epigenetic mechanisms, protein posttranslational modifications (PTM) are intriguing contributors in regulating aging. Proteins are the basis of cellular and physiological functioning in living organisms, and the physical and chemical properties of proteins dictate their activities and functions. The primary sequence of a protein is a main determinant of protein folding and final conformation as well as biochemical activity, stability, and half-life. However, at any given moment in the life of an individual, its proteome is up to two or three orders of magnitude more complex than the encoding genomes would predict. One of the main routes of proteome expansion is through posttranslational modifications (PTM) of proteins.
Protein PTM results from enzymatic or nonenzymatic attachment of specific chemical groups to amino acid side chains. Such modifications occur either following protein translation or concomitant with translation. PTM influences both protein structure and physiological and cellular functions. Examples of enzymatic PTMs include phosphorylation, glycosylation, acetylation, methylation, sumoylation, palmitoylation, biotinylation, ubiquitination, nitration, chlorination, and oxidation/reduction. Nonenzymatic PTMs include glycation, nitrosylation, oxidation/reduction, acetylation, and succination. Some rare and unconventional PTMs, such as glypiation, neddylation, siderophorylation, AMPylation, and cholesteroylation, are also known to influence protein structure and function.
Generally, protein PTMs occur as a result of either modifying enzymes related to posttranslational processing (such as glycosylation) or signaling pathway activation (such as phosphorylation). Moreover, PTM patterns are known to be affected by disease conditions. Similarly, the dysregulation of PTM is associated with the aging process. In this context, both enzymatic and nonenzymatic PTMs can undergo age-related alterations. Alteration in the pattern of nonenzymatic PTMs depends mainly on the nature of the modifying substances, such as metabolites and free radicals. For instance, reactive oxygen species can lead to oxidation of amino acid side chains (oxidation of thiols to different forms, oxidation of methionine, formation of carbonyl groups, etc.), modification by-products of glycoxidation and lipoxidation, and formation of protein-protein cross-links as well as oxidation of the protein backbone, resulting in protein fragmentation. In contrast, changes in the nature of enzymatic PTMs rely primarily on the activities of modifying enzymes.
As awareness of the role of PTMs in aging and aging-related diseases grows, there is an urgent need for the development of methods to detect protein PTMs more rapidly and accurately. Furthermore, the recent finding of rare and unconventional modifications in age-related pathologies calls for the development of more specific and sensitive methods to detect such modifications. The recent rapid progress in large-scale genomics and proteomics technologies is likely to be a catalyzing factor for such studies. Drugs that target PTMs, such as phosphorylation, acetylation, methylation, and ubiquitination, will serve as useful tools in exploring the basic mechanism of PTM modulation and provide a pharmacological platform to combat the detrimental effects of aging.
Can the Age-Related Harm Done by Fat Tissue be Prevented?
The way to avoid the harms done to long-term health and life expectancy by excess visceral fat tissue is not to gain that fat, or to lose it if you have it. This is not the path pursued by that part of the research community interested following the large-scale funding associated with the metabolic diseases of obesity, of course. There is comparatively little profit to be made in telling people to lose weight, versus selling them compensatory pharmaceuticals for a lifetime. However, even with normal, healthy levels of fat tissue, as aging progresses that tissue starts to cause similar issues to those produced by excess fat in earlier life: chronic inflammation, metabolic disruption leading to type 2 diabetes, and so forth. The changes of aging include processes that introduce dysfunction into the relationship between fat and the immune system, one of which is examined here.
Adipose tissue inflammation has become widely accepted as a major contributor to metabolic dysfunction and disorders. Previous studies on diet induced obesity mice have shown that adipose tissue is primed for inflammatory changes prior to other metabolic organs. There is a plethora of research investigating factors in obese adipose tissue inflammation to identify valuable therapeutic targets for metabolic dysfunction. However, much less is understood about age-related adipose tissue inflammation and dysfunction. A better understanding of the cellular and molecular mechanisms of adipose tissue inflammation in aging will be crucial in the development of therapeutics for metabolic diseases beyond cases of diet-induced adipose tissue inflammation and insulin resistance.
Both age-related adiposity and diet-induced obesity are characterized by immune cell infiltration and a sustained inflammatory cycle. Among these various immune cells, adipose tissue macrophage (ATM) accumulation, proliferation, and polarization are major contributors to adipose tissue inflammation and dysfunction. Interestingly, recent studies suggest that changes in preadipocyte function during aging also lead to dysfunctional adipose tissue, eventually progressing to chronic inflammation. Our group have recently shown that elevated endoplasmic reticulum (ER) stress response in aging contributes to greater inflammatory responses, in part due to compromised autophagy activity in the aging adipose tissue. Recent studies have also indicated that with aging there is increased accumulation of senescent cells in many organs including fat depots, which contributes to aging pathologies. However, the detailed molecular mechanisms that lead to increased inflammation in aging adipose tissue are poorly defined.
During the last decade, major advances were made in identifying the molecular mechanisms by which lipid-derived products promote inflammation in different cell types. One type of lipid-derived product, non-esterified fatty acids (NEFA), elevates tissue inflammation through interaction with the pattern recognition receptor Toll-like receptor 4 (TLR4) via its endogenous ligand Fetuin-A (Fet A), a liver derived glycoprotein. Fet A is considered a biomarker of chronic inflammation due to its ability to stimulate the production of inflammatory mediators from both adipocytes and macrophages. Interestingly, Fet-A null mice were protected against obesity and insulin resistance with aging.
The involvement of Fet A-mediated activation of TLR4 pathway in adipose tissue inflammation in diet-induced obesity is well explored. However, the role of this pathway in age-associated adipose tissue inflammation is unknown. We undertook this study to test the hypothesis that age-related adipose tissue inflammation is dependent on the Fet A-mediated TLR4 signaling pathway. We first evaluated the expression of Tlr4 and Fet A gene products in adipose tissue, liver, and plasma samples derived from young and old mice. We then exploited the TLR4-deficient mice to investigate the role of TLR4 in age-associated adipose tissue inflammation, ER stress response, autophagy activity, cellular senescence, and metabolic status (glucose tolerance).
We found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced adipose tissue inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished cellular senescence. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced adipose tissue inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated adipose tissue inflammation that is distinct from diet-induced adipose tissue inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.