There is a certain mode of writing positively about aging, with the intent of opposing ageism, in which the author pretends that aging isn't a harmful process of decline in health and capabilities. It seems to me that the best practical solution for ageism is to build the medical technologies that enable older people to be just as physically and mentally capable as younger people. I'm not sure that anything else is likely to work, given the length of time over which all of the other forms of attempt have been made. While it is worthy goal to convince people that is inhumane to reject and persecute others simply because they are less capable, that undesirable aspect of human nature has persisted since prehistory, despite the best efforts of better individuals than you or I. Using technology to change the nature of the human condition seems more likely to succeed than any amount of persuasion and philosophy.

A report by the Royal Society For Public Health, "That Age Old Question," endeavors to expose ageism and help end discrimination against older people. While it does make a handful of valid points, however, it seems to suggest that sweeping the true nature of aging under the rug will help to end ageism. Everything in the report revolves around attitudes towards aging and how the authors think that these should change in order to eliminate age-related discrimination. There is no mention of aging as the chronic, progressive process of deterioration found in the scientific literature; there is not a word about medical research with the potential to prevent age-related diseases, nor is the importance of intervening on the root causes of aging to prevent diseases, and indirectly, ageism, even hinted at.

Quite frankly, if you were an alien who had never heard of aging before and you read this report, you'd likely get the impression that the ill health of humans in old age is just a myth fueled by stereotypes and negative perception of the phenomenon. The poor mental and physical health of old age are described as being merely "negative stereotypes" very early on in the report's foreword, yet later sections of the report suggest bringing together nursing homes and youth clubs to better integrate generations; however, if nursing homes for the elderly exist, age-related ill health is obviously not merely a stereotype.

Similarly, while individual elderly people may be able to make meaningful contributions to the economy before age-related disease takes their lives, the economic burden of an aging population is a real problem, not just a stereotype. It is hard to believe that any society would come up with retirement if elderly people's ability to work was mostly comparable to that of younger people; it is similarly hard to believe that governments and economists who worry about the expected surge in the elderly population of the next few decades, and about the consequences that they might have on our pension systems, are worrying about something that originates in prejudice rather than biology - or that they're not worrying at all but didn't go through the trouble of letting the rest of us know.

To be clear, the authors of the report don't openly oppose medical research against aging. Given that no mention of it was made, it's unclear whether they're even aware of the possibility and if they would endorse it or not. Their intent to undo age-based discrimination is genuine, if misguided. Ending ageism is nearly as important as ending aging; for one, if ageism wasn't a thing, rejuvenation advocates wouldn't have to spend time debating people who think that older people living too long would lead to cultural stagnation because of their alleged "old people mentality". However, ageism won't be defeated by sugarcoating aging, which only adds insult to injury.

Link: https://www.leafscience.org/sugarcoating-aging-wont-fight-ageism/

Researchers recently found that the size of pancreatic cells is inversely correlated with species longevity, given data obtained from a few dozen different types of mammal. Since this is an unexpected new discovery, the paper here contains little more than an initial educated guess at why this might be the case. At first glance this metric doesn't obviously relate to any of the usual mechanisms linking the operation of cellular metabolism with pace of aging, and thus I expect that we'll have to wait for some years of further investigation and theorizing to learn more.

How organs reach and maintain their proper size is a major question in biology. Organ size is the product of total cell number, average cell size, and volume of the extracellular space. Cell number is considered the main determinant of organ size, and differences in cell number explain much of the size difference between organisms, such as mice and humans. However, within a given species, different organs vary considerably in the relative contribution of cell number and cell size to total organ size. For example, the increase in the total mass of blood from birth to adult life results from larger cell numbers, while postnatal growth of cardiac and skeletal muscle largely relies on increased cell size.

Despite the major differences in final size among mammalian species, the molecular and cellular mechanisms underlying organ growth are usually thought to be highly similar. In the case of the pancreas, embryonic progenitor cells initially proliferate and differentiate to form a miniature organ. After birth, progenitor cells largely disappear. The current consensus is that postnatal growth of the pancreas, in mice and by extension also in humans, relies on simple duplication of differentiated cells, consistent with the classic description of the pancreas as an "expanding tissue."

The size of cells in the adult pancreas is recognized to be plastic. For example, acinar cells shrink when luminal nutrients are not available, and beta cell size increases transiently in pregnant rodents. However, increased cell size is not typically considered a significant contributor to normal postnatal pancreas growth. Here we report surprising differences in the mode of postnatal pancreas growth among different mammals. While the human pancreas grows by pure hyperplasia, the rodent pancreas grows mostly by cellular hypertrophy. Acinar cells of the salivary glands present a similar trend, namely larger cells in mice compared with humans. Finally, we identify a surprising negative correlation between acinar cell size and organismal lifespan, based on analysis of 24 mammalian species.

Our findings suggest that the associations of metabolic rate and body weight with lifespan are mediated by differences in cell size. This suggests that animals employing acinar hypertrophy live shorter lifespans. What might be the evolutionary advantage of hypertrophy as a mode of organ growth? We propose that the key is the speed of postnatal growth. Both humans and mice (and their organs, including the pancreas) grow approximately 15-fold from birth to reproductive age; however, this age is reached ∼100 times faster in mice. We hypothesize that cellular hypertrophy contributes to the rapid growth of short-lived mammals. Indeed, the rate of postnatal growth is negatively correlated with lifespan, and this correlation is eliminated when controlling for cell size. This result supports a model whereby cellular hypertrophy promotes rapid postnatal growth rate and earlier sexual maturity at the expense of lifespan.

Link: https://doi.org/10.1016/j.devcel.2018.05.024

The paper I'll point out today walks through the ways in which exercise is known to beneficially affect the Hallmarks of Aging. The Hallmarks are a list of the significant causes of aging that I disagree with about half of. The SENS catalog of root causes of aging, first published earnestly in the literature back in 2002, isn't cited anywhere near as much as the much later Hallmarks of Aging - which owes a great deal to its predecessor while failing to mention it in any way. There is some overlap between the two, but many of the Hallmarks are not causes of aging, but rather manifestations of aging, meaning secondary and later consequences of underlying molecular damage.

This question of whether not any specific manifestation of aging is or is not a root cause is important. The strategy adopted in the development of therapies to treat aging matters. Addressing root causes is far more effective than addressing downstream consequences. Near all medical technology employed to date to treat age-related diseases fails to touch on the root causes of aging, however, and this is why these therapies are only marginally effective at best. They modestly slow progression, or modestly ease suffering, but they cannot meaningfully turn back any aspect of the progression of aging. We can continue along that road, or we can choose to attempt a better strategy.

Exercise is beneficial, and the degree to which it is beneficial is fairly well defined. Knowing something about the molecular biology taking place under the hood won't make exercising any more or less beneficial, but it is an interesting topic. Exercise, like calorie restriction, modestly slows the impact of aging. Unlike calorie restriction it doesn't have a large impact on maximum life span in mice, but does raise the average life span. Both are just as reliable and just as cheap - even small effects are worth the effort when they cost little and are guaranteed. It is when we start to talk about the cost of research and development for new medical technologies to treat aging that we must think about the expected size of the outcome on human longevity. Why chase small, expensive gains? If the cost is significant, it only makes sense to pursue a strategy that can produce sizable gains in health and life span.

Aging Hallmarks: The Benefits of Physical Exercise

Traditionally, aging was not seen as an adaptation or genetically programmed phenomenon. More recently, biologic currents point to two main theories: the programmed aging and the damage or error-based theories. The first suggests an intrinsic biologic programmed deterioration of the structural and functional capacity of the human cells. The latter highlights the cumulative damage to living organisms leading to intrinsic aging. Nonetheless, a combination of these theories is usually preferred. In this sense, a state-of-the-art review, proposed nine cellular and molecular hallmarks that contribute to the process of aging, including (1) genomic instability, (2) telomere attrition, (3) epigenetic alterations, (4) loss of proteostasis, (5) deregulated nutrient sensing, (6) mitochondrial dysfunction, (7) cellular senescence, (8) stem cell exhaustion, and (9) altered intercellular communication. These hallmarks should be expressed during normal aging, with their experimental aggravation speeding up the aging process, and in contrast, their experimental amelioration retards the normal aging process, thus increasing a healthy life span.

Along with the nine cellular and molecular hallmarks stated above, aging is known to be correlated with several cardiovascular, cardiorespiratory, musculoskeletal, metabolic, and cognitive impairments. In this sense, regular physical activity in the older population - especially aerobic and resistance training - plays an important role at a multisystem level, preventing severe muscle atrophy, maintaining cardiorespiratory fitness and cognitive function, boosting metabolic activity, and improving or maintaining functional independence. In addition, physical exercise has a positive antiaging impact at the cellular level, and its specific role in each aging hallmark is described below.

Genomic Instability

In the face of genomic instability, the organism has developed a panoply of DNA repair mechanisms that skirmish altogether to overcome nuclear DNA damage. Exercise plays a role in maintaining genomic stability. In rodent models, aerobic exercise improves DNA repair mechanisms. It augments DNA repair and decreases the number of DNA adducts (up to 77%), related to aging and several risk factors for cardiovascular diseases. In addition, a six-month resistance training program in an institutionalized elderly population showed a tendency to reduce cell frequency with micronuclei (~15%) and the total number of micronuclei (~20%), leading to a higher resistance against genomic instability.

Telomere Attrition

Telomere shortening is described during normal aging in human and mice cells. The fact that telomere length decreases with aging, contributing to the normal cell senescence process, suggested that this could be a potential marker for biological aging. Although the potential mechanism is unclear, exercise exhibits a favorable impact on telomere length, especially on a chronic pattern and particularly in older individuals antagonizing the typical age-induced decrements in telomere attrition. Several potential mechanisms have been discussed linking exercise and telomere length decrements to changes in telomerase activity, inflammation, oxidative stress, and decreased skeletal muscle satellite cell content.

Epigenetic Alterations

The relationship between epigenetic regulation and aging is controversial and complex. A multiplicity of epigenetic modifications affects all tissues and cells throughout life. The literature clearly reveals that the epigenetic response is highly dynamic and influenced by different environmental and biological factors, such as aging, nutrient availability, and physical exercise. Regular aerobic exercise can change the human genome through DNA methylation. Thus, by using epigenetic mechanisms, aerobic exercise can induce the transcription of genes encoding telomere-stabilizing proteins and telomerase activity not only in animals but also in humans.

Loss of Proteostasis

Aging and some aging-related diseases are linked to impaired protein homeostasis, also known as proteostasis. The array of quality control is guaranteed through distinct quality control mechanisms that prevent the aggregation of damage components and ensure the continuous renewal of intracellular proteins, degrading altered proteins. Aerobic exercise induces autophagy, thus preventing the loss of strength and muscle mass through the modulation of signaling pathways. Chaperone associated functions, such as folding and protein stability, are impaired in aging. In animal models, the upregulation of co-chaperones of the heat-shock proteins (HSPs) was associated with prolonged life-span phenotypes. Despite limited comparison studies, evidence supports that acute endurance- and resistance-type exercise protocols are associated with increased HSPs transcription not only during activity but also immediately postexercise or several hours following exercise, which points out the possible favorable impact of physical activity on proteostasis.

Deregulated Nutrient Sensing

Exercise plays an important role in not only the glucose-sensing GH / IGF-1 somatotrophic axis but also other nutrient-sensing systems, promoting a beneficial anabolic cellular state. The effect of exercise on glucose metabolism through increased glucose transporter type 4 production is another well-known mechanism of improved insulin sensitivity associated with physical activity. Additionally, exercise-induced GH and IGF-1 levels are influenced by exercise intensity, duration, and type (higher in intense interval protocols and resistance exercise).

Mitochondrial Dysfunction

The clear causal relationship between mitochondrial dysfunction and aging has long been a target of great discussion. With increasing age comes a decline in mitochondrial integrity and biogenesis because of alterations in mitochondrial dynamics and mitophagy inhibition, impairing dysfunctional mitochondria removal. The regular practice of physical exercise has a positive impact in mitochondrial function. In this sense, endurance-trained humans presented higher levels of mitochondrial proteins expression. Regular physical exercise may maintain a pool of bioenergetically functional mitochondria that, by improving the systemic mitochondrial function, contribute to morbidity and mortality risk reduction throughout one's life span.

Cellular Senescence

Senescent cell accumulation in different tissues seems to be dependent, in one hand, on an increased rate of senescent cell generation and, in other hand, on a decreased rate of clearance. Exercise, specifically aerobic, induces the secretion of antitumorigenic myokines and greater natural killer cell activity, contributing to a decreased incidence of oncologic disease and improved cancer prognosis. This may also impact clearance of senescent cells. Aerobic exercise has been inversely correlated with p16INK4a mRNA levels in peripheral blood T lymphocytes, which might promote protective outcomes against age-dependent alterations. Aerobic exercise suppresses liver senescence markers and downregulates inflammatory mediators.

Stem Cell Exhaustion

For the long-term maintenance of the organism, the deficient proliferation of stem and progenitor cells is harmful, but an excessive proliferation can also be deleterious by speeding up the exhaustion of stem cell niches. Within this line, physical exercise is one of the most potent stimuli for the migration/proliferation of the stem cell subsets from their home tissue to impaired tissues for later engraftment and regeneration. In this sense, regular physical exercise attenuates age-associated reduction in the endothelium reparative capacity of endothelial progenitor cells. In addition, exercise activates pluripotent cells' progenitors, including mesenchymal and neural stem cells, which improve brain regenerative capacity and cognitive ability.

Altered Intercellular Communication

The physiological aging process implicates several alterations on intracellular communication mechanisms, namely, in neuroendocrine, endocrine, and neuronal levels. Inflammation plays a central role in this age-related alteration. Muscle contraction is traditionally associated with myokine secretion (proteins, growth factors, cytokines, or metallopeptidases) elevated during and after exercise. Interestingly, the muscle-released IL-6 creates a healthy influence, inducing the production of anti-inflammatory cytokines. Within these lines, several authors associated lifelong aerobic exercise training with lower inflammatory levels, particularly in advanced decades of life.

Chronic obstructive pulmonary disease (COPD) is caused by long-term inhalation of smoke or other particulate or chemical irritants. In wealthier parts of the world, that usually means smoking. In less wealthy parts of the world, cooking fires and industrial processes also contribute. The condition shares some mechanisms with aging, particularly the accumulation of senescent cells and the chronic inflammation produced by those cells. In some ways, it is possible to consider aspects of COPD to be accelerated lung aging. In other ways it is entirely different. This is generally true of the environmental contributions that make up secondary aging, the various exposures that cause harm and dysfunction by speeding up specific, narrow forms of cell and tissue damage. The open access paper here is interesting for the comparisons it draws between aging and smoking as causes of increased cellular senescence in the lungs.

Most parts of the body including the lungs experience progressive damage with aging as well as impaired function. Lung aging is associated with loss of elasticity, a decrease in pulmonary function, loss of structural integrity, and an increase in inflammation which are among the key characteristics of chronic obstructive pulmonary disease (COPD). COPD is the third leading cause of chronic morbidity and mortality on a global scale. Growing evidence suggest that age-associated structural and functional alterations enhance pathogenetic susceptibility to COPD.

Along with other toxic gases, the most common etiological factor that develops COPD is cigarette smoke (CS) which results in several pathophysiological changes in the lung. Recent reports suggest that CS induces oxidative stress-mediated DNA damage and triggers cellular senescence in the lungs. Cellular senescence is a process of complete and permanent cell cycle arrest. The accumulation of metabolically active senescent cells in tissues during aging impairs tissue repair and function. Pro-inflammatory mediators are secreted which give rise to a phenomenon known as senescence-associated secretory phenotype (SASP). Senescent cells increase the damage of neighboring cells by virtue of their SASP phenotype. Previous reports proposed a network of cellular senescence, inflammatory response, and premature lung aging in the pathogenesis of COPD.

We hypothesized that aging-associated changes in lungs worsen the COPD by CS exposure. Younger and older groups of C57BL/6J mice were exposed to chronic CS for 6 months with respective age-matched air-exposed controls. CS caused a decline in lung function and affected the lung structure of both groups of mice. No alterations were observed in the induction of inflammatory mediators between the air-exposed younger and older controls, but aging increased the severity of CS-induced lung inflammation. Aging per se increased lung cellular senescence. Thus our data suggest that normal aging and chronic CS exposure independently induce cellular senescence in the lungs.

Link: https://doi.org/10.1038/s41598-018-27209-3

Calcification of soft tissues occurs in the cardiovascular system with age, one of the processes that causes arterial stiffening and other pathogenic conditions such as aortic stenosis. Considered at a very high level, this happens because a fraction of cells in the blood vessel walls malfunction and begin to act in ways more appropriate to a bone environment, laying down deposits of minerals. The causes of this malfunction are incompletely understood, but evidence suggests that the presence of senescent cells and their inflammatory signaling is an important cause.

In this open access paper, researchers investigate cellular signals carried via exosomes in the context of vascular calcification. Exosomes are a class of extracellular vesicle, small membrane-bound packages of molecules that carry a sizable fraction of the signaling traffic between cells. In recent years, scientists have been paying a lot more attention to these packages, as they appear to carry most of the signals that are important in, for example, the beneficial effects of stem cell transplants. They are also probably a sizable part of the harmful signals produced by senescent cells. While the authors don't mention cellular senescence here, it is interesting to speculate on the overlap between this research and what is being discovered of the role of vesicles in senescent signaling.

Vascular calcification (VC) is caused by hydroxyapatite deposition in the intimal and medial layers of the vascular wall, leading to severe cardiovascular events in patients. Importantly, exosomes have been demonstrated to be involved in VC recently. Exosomes have up-regulated secretion from vascular smooth muscle cells (VSMCs) in vivo after pro-calcifying stimulation and become "calcifying" exosomes to induce VC. Calcium binds with phosphate to form hydroxyapatite nodes on the inner and outside of "calcifying" exosomes membranes, which further initializes mineral deposition. Although these studies did reveal that exosomes participated in the calcification procession through promoting mineral deposition sites formation, they did not discuss exosomes functioning as mediators for RNAs transportation, which is vital for exosome function.

Exosomes are secreted by diverse cells to mediate cell-to-cell communications. However, how exosomes regulate VC has been only preliminarily explored. It is found that exosomes with diverse origins mainly mediate microRNAs (miRs) transporting to VSMCs in coronary artery calcification. A bioinformatics analysis revealed that cultured in osteogenic medium, mesenchymal stem cells secreted exosomes with alterations of miRs, comparing with normal culturing. Such alterations were suggested to accelerate calcification in other mesenchymal stem cells to modulate osteogenic phenotype transition. Thus, it implies that besides heterogeneous mineral deposition inside vessel wall, exosomes can also promote VC by transporting messages among cells.

Link: https://doi.org/10.1111/jcmm.13692

Cellular senescence is one of the root causes of aging. Nonetheless, the study of cellular senescence used to be a comparative backwater in aging research, and as a topic it was mostly of interest to cancer researchers seeking ways to better shut down the replication of cancerous cells. But there is nothing quite like having a company raise $300 million in venture funding for rejuvenation therapies based on manipulation and destruction of senescent cells to bring a little excitement to this part of fundamental aging research. Who knows how many useful, exploitable mechanisms are yet to be found in senescent cells and the signals they generate? Each one is a potential lottery ticket for the discovering institution and research group.

This was in fact always the case, and for decades a compelling set of evidence has strongly suggested that the accumulation of senescent cells is a significant contribution to aging. Yet next to no-one was funding or working on it seriously until the high-profile proof of concept study in mice reported in 2011, in which senescent cells were eliminated and health and life span improved as a consequence. After that point, the avalanche started, leading to today's crop of first generation senolytic therapies capable of selectively destroying a fraction of the senescent cells present in older individuals.

Today I thought I'd point out a couple of examples of the sort of paper that results from an influx of funding and interest to the study of the fundamental biochemistry of senescent cells. The research community is mining for gold. The first explores the harmful signals secreted by senescent cells, the major way in which they cause tissue dysfunction in aging and age-related disease. A faction within the research community is more comfortable interfering in these signals rather than destroying senescent cells, despite it likely being a far worse and more challenging approach to therapy. The second paper is one of many in which researchers explore the role of mitochondrial activity in senescence, in search of approaches that might modulate the activity in beneficial ways. Both papers are quite different in focus, but they emerge from the same newfound interest in senescence as a cause of aging.

Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype

Senescent cells lose their cell type specific functionality and replicative potential required for tissue regeneration and acquire a senescence-associated secretory phenotype (SASP). The SASP is characterized by the secretion of growth factors, pro-inflammatory cytokines and chemokines, as well as extracellular matrix (ECM) remodeling enzymes. These SASP factors are considered to over-proportionally exert negative effects on tissue homeostasis and regeneration in vivo if chronically present by acting in a paracrine manner on the neighboring cells and ECM. Attenuation of the negative effects of the SASP have been shown to restore the formation of functional human skin equivalents and has been suggested as a putative target in preventing age-associated diseases and frailty.

Recently, extracellular vesicles (EVs) and their cargo have been reported to act in a similar manner as hormones or cytokines during intercellular communication. They are secreted by many, if not all cells, and by encapsulation of their cargo, they transport proteins, mRNAs, lipids, and non-coding RNAs, specifically miRNAs, over short or long distances. Thus, although many protein based SASP factors have been identified, miRNAs and EVs are under suspicion to be part of the SASP. However, a systematic catalogue of SASP-miRNAs has not yet been established and their selective secretion during senescence has not been studied so far. Here, we confirm that EVs and their miRNA cargo are indeed part of the SASP (EV-SASP) and identified a set of selectively retained and secreted miRNAs after the onset of senescence. In addition, senescent cell derived EVs might contribute to an anti-apoptotic environment in tissues where senescent cells have accumulated.

Mitochondrial peptides modulate mitochondrial function during cellular senescence

Mitochondria play important roles in cellular energy production, metabolism, and cellular signaling. These organelles have their own genomes, the mitochondrial DNA (mtDNA). Epigenetic modification of mitochondrial DNA, including DNA methylation, is still controversial. The overall mitochondrial DNA methylation occurs at a lower frequency compared to nuclear DNA, but specific locations have been found to be differentially methylated in certain cellular conditions or in different biological samples.

Humanin is a 24-amino acid peptide encoded within the mtDNA. It is secreted in response to cellular stress and has broad cytoprotective and neuroprotective effects. MOTS-c is a 16-amino acid peptide encoded within the mtDNA that improves metabolic functions. Among the basic processes that are known to drive aging phenotypes and pathology are genomic instability, epigenetic alterations, mitochondrial dysfunction, and cellular senescence. Although humanin and MOTS-c have protective roles in multiple age-associated diseases, the roles of these peptides in cellular senescence have not been explored.

Senescent cells are metabolically active, producing energy-consuming effectors of senescence, despite the loss of proliferative activity. Depending on the inducer, senescent cells show higher levels of glycolysis, fatty acid oxidation, and mitochondrial respiration. Manipulating bioenergetic status can induce senescence and a SASP, suggesting that bioenergetics play a role in the senescence phenotype. Thus, altering the metabolic status of senescence cells may be an important strategy for eliminating the deleterious effects of senescence. In this study, we investigate mitochondrial energetics and mtDNA methylation in senescent cells, and evaluate the potential of humanin and MOTS-c as novel senolytics or SASP modulators that can alleviate symptoms of frailty and extend health span by targeting mitochondrial bioenergetics.

It remains the case that a great deal of aging research these days is purely observational, which is, I think, unfortunate. This is an age in which more than mere observation of aging might be achieved; the first interventions likely to reliably slow or reverse aspects of aging are making their way out of the laboratory and into clinical development. There should be a lesser emphasis in the research community on watching what happens to a population of older individuals who lack effective treatments for aging, and a correspondingly greater emphasis on getting those treatments built and into the clinic.

Given this, does it really matter how frailty and cardiovascular disease interact? Would the world be changed by knowing, in detail, the exact relationship between the two? Both of these conditions will be banished in the wealthier half of the world fifty years from now, defeated and controlled by forms of regenerative medicine that are periodically applied to remove the root causes of these conditions. That will be achieved by focusing on those causes, ignoring the detailed end-stage mechanisms and relationships of the conditions that result.

Aging as it exists today will be a curio of the past given a further fifty years of development after that point. How much scientific work today goes towards considering how exactly different patient populations experienced the now extinct condition smallpox in the absence of effective treatments? How valuable was that sort of research during the years in which the first meaningful treatments were deployed? I'd say that, at that time, observational lines of research added very little to progress in defeating smallpox - and the situation will be much the same for aging.

In older adults both cardiovascular disease (CVD) and frailty are highly prevalent. Novel and advanced cardiovascular therapeutic treatments have improved life expectancy and consequently led to an increasing number of older adults suffering from chronic CVD. This presents an enormous clinical and public health burden. Frailty describes a state of vulnerability due to an age-related decline in many physiological systems and is associated with a considerably increased risk of falling, disability, hospitalisation, and mortality. According to cross-sectional data, CVD appears to be positively associated with frailty in community-dwelling older adults. However, cross-sectional studies do not clarify if CVD leads to frailty or if frailty precedes the development of CVD.

From a pathophysiological point of view, both directions are plausible. For example, exercise related symptoms in patients with CVD could lead to physical inactivity making them more likely to become frail. Additionally, comorbidities, as well as physical and cognitive decline are common in older adults with CVD. This could lead to a loss of homeostatic capability to withstand stressors and increase the risk of frailty. Yet, one could also argue that physical inactivity and its sequelae (e.g. obesity) due to frailty is a risk factor for development of CVD. Also, frailty is associated with a chronic state of low-grade inflammation which could trigger CVD.

The present study studied the bidirectional effect of CVD on frailty among community-dwelling older adults. First, we observed cross-sectional associations between CVD and frailty. Patients with CVD, especially those with peripheral arterial disease and heart failure, were more likely to be frail. Longitudinally, mainly HF was associated with incident frailty. These patients were at least twice as likely to become frail, which puts these patients at an equal or even higher risk of incident frailty than subjects with chronic lung disease, arthritis, or diabetes. Analyses studying the reverse association revealed that in this older population, frailty does not precede development of CVD during three years of follow-up.

Link: https://doi.org/10.14336/AD.2017.1125

Ilia Stambler, historian of our longevity science community, is in illustrious company in the author list for this open access position paper. Regular readers will recall that the World Health Organization (WHO) is among the most conservative and hidebound of institutions when it comes to the development of means to treat aging. The WHO positions on aging studiously avoid any mention of the idea that aging can be changed at all through medical science. This is somewhere between ridiculous and outrageous, given what is going on in the labs and clinical development today. More activist members of the scientific community have, accordingly, berated and advocated by turn in journal articles these past few years.

Should a broken system be changed from within, or should it be rejected entirely and worked around? In my experience, the latter approach is the one more likely to produce change, but as a general rule far more effort goes towards the first. We can speculate as why this might be the case. Perhaps because those people most able to identify and articulate the problem in question tend to be experienced with, embedded in, and thus invested in, the broken system. It is comparatively rare for outsiders to appear with sufficient knowledge to build viable alternatives; matters must usually decline for a long time before that happens. That is certainly happening elsewhere in the scientific and medical communities, but not yet here.

It can be confidently stated that global population aging is both the greatest success of global public health efforts of the past, as well as the greatest challenge for the further global public health efforts of the future. Over the past decades, life expectancy at birth has increased globally. Considering that both rising longevity and population aging are likely demographic events in the coming decades, by 2050 the proportion of people over 60 years is expected to double from about 13% to nearly 25%, which, in absolute terms, means an increase from 962 million to 2.1 billion people. Rising longevity during the last 150 years is a testament to human ingenuity, and there is reason to believe further advances are possible.

According to World Health Organization's data, "Noncommunicable diseases (NCDs) kill 40 million people each year, equivalent to 70% of all deaths globally. Cardiovascular diseases account for most NCD deaths. Each year, 15 million people die from a NCD between the ages of 30 and 69 years; over 80% of these premature deaths occur in low- and middle-income countries." In other words, of the 57 million deaths in the world each year, nearly 50% occur due to chronic non-communicable diseases in the world's oldest population (70+), and over 60% in the older population (60+), making the health of older persons the worst and most urgent global health problem.

In view of the urgency of the problem, it seems highly surprising that in the forthcoming draft 13th General Programme of Work of the World Health Organization for 2019-2023 the issue of aging and aging-related ill health is excluded completely! Beside a cursory mention of the word "aging," this work program does not contain any specific objectives, deliverables, and actions to improve the health of the aged. This means that, through 2023, according to this document, the World Health Organization is not obliged to provide any services to care for the health of older persons or to improve their health, not to mention conduct any research and development to create new therapies and technologies for improving the health of the aged. The issues of aged health are not in the WHO work program!

How can this exclusion coexist with the mission of WHO's division on Ageing and Life Course? How can it coexist with the recently adopted WHO's Global Strategy and Action Plan on Ageing and Health (GSAP) for 2016-2020, endorsed by all the WHO member states? According to its goal statement, the GSAP must prepare for the "Decade of Healthy Ageing from 2020 to 2030" which was also announced by WHO. The coordination and consultation between various arms and branches of the WHO must improve. The developers of the WHO Work Program must avail of the world expertise on ageing health, within the WHO and externally, to develop an effective, strategically-minded and inclusive global health program. We also urge the readers to make your voice heard, advocate and increase publicity about the need to include and implement concrete measures to improve aging health, including research and development for healthy longevity, as a priority in the WHO work program.

Link: https://doi.org/10.14336/AD.2017.1120

One of the many important points made by the advocacy community for rejuvenation research is that participants in the mainstream of medical science and medical regulation are not imbued with a great enough sense of urgency. We are all dying, and yet with each passing year the regulatory process moves ever more slowly, rejects an ever greater number of prospective therapies, becomes ever more expensive. The number of new therapies reaching the clinic falls. Regulators continue to reject the idea that treating aging is an acceptable goal in medicine. We live in an age of revolutionary progress in the capabilities of biotechnology, and yet patients must accept that new medicines are rare, and that fifteen years might pass between lab and clinic. This is not an industry moved by any sense of urgency.

Naturally, those who do see the urgency and are frustrated by the present state of medical development reach for different options. Some of those options are bad: cherry-picking research; testing interventions without evidence; self-experimentation without data or consideration of risk; building an industry to deliver supplements and other products that don't perform as advertised. Some of those options are sound: responsible development and medical tourism that takes place outside regions with the most onerous regulation; self-experimentation within a framework that encourages an understanding of risk and supporting research; advocacy to change the regulatory system.

Self-experimentation is the only way to obtain early access to new classes of medical technology, those described in research, manufactured in the marketplace, but not yet run through the regulatory process. Many will never even enter the regulatory process. The only way to provoke the sort of development needed to produce good data is for a community of self-experimenters to report on their experiences, obtaining a critical mass sufficient to attract research interest and funding. This is essentially what happened over the past few decades for the practice of calorie restriction. It isn't a medical technology, but proceeded through the same path of early research, adoption by self-experimenters, growth of a community, and that community then influenced the research community to pay greater attention. As a result we now have far better human data on calorie restriction, showing that the early research was essentially correct and it is a useful practice that modestly slows many of the consequences of aging.

Most people who self-experiment wouldn't call it that - and probably justifiably so. They rely on hope and how they feel rather than solid data, and are too readily swayed by hype and cherry-picked or misrepresented research. Many of those who went further than their own health to organize business ventures, such as the many members of the anti-aging marketplace, have built an industry that does at least as much harm as good. We cannot let the bad drive out the good when it comes to the frustration with the lack of urgency in medical development that leads people to choose to strike out on their own. It is possible to achieve meaningful gains through ventures in medical tourism, through responsible development, through self-experimentation with data and publication. Where this does happen, however, it is frequently the case that the people involved have a foot in both camps.

Such is the case for the principal subject of the popular science article here. I can't condone most of the activities of the Life Extension Foundation; the heart is absolutely in the right place, but so very much of the implementation is at best a waste, and at worse actively harmful to progress. Supplements as marketed over these past four decades do nothing for longevity, do nothing for aging, and participants in this market have used their advertising megaphone to convince the world that anti-aging is a sham, a joke: pills and potions that do nothing. It is an industry built on self-evidently false claims. Yet the Life Extension Foundation uses the proceeds from that business to fund some degree of meaningful, useful research into aging and means to treat aging and age-related disease. They also clearly support better paths forward in medical science. It is my hope that working rejuvenation therapies and biomarkers of aging will drive out the fraud and the lies and the nonsense in the years ahead, but don't ask me to approve of the state of this market today.

Bill Faloon has pursued immortality for decades. Now he's got lots of company. What does science have to say?

At 63, Bill Faloon is old enough to remember when talk of life extension labeled you a kook or charlatan. In the late 1970s, he co-founded the Life Extension Foundation, a nonprofit promoting the notion that people don't need to die - and later started a business to sell them the supplements and lab tests to help make that dream real. Nowadays he also distributes a magazine to 300,000 people nationwide and invites speakers to monthly gatherings at the Church of Perpetual Life, billed as a science-based, nondenominational meeting place where supporters learn about the latest developments in the battle against aging. Their faith is in human technologies that might one day end involuntary death.

After an hour of mixing, we all head to the second-­floor nave and fill the pews for the evening's event. Several rows back sits a beer scientist. Next to me, two women in dresses and heels. At the front, an elderly gentleman with hearing aids. Tonight's speaker is Aubrey de Grey, a biomedical gerontologist and chief science officer of SENS Research Foundation, a Mountain View, California, outfit that studies regenerative medicines that might cure diseases associated with old age.

Today, it is easy to locate university-affiliated labs at places such as Harvard and Stanford investigating their own interventions in the process of growing old. Since the National Institutes of Health established its Institute on Aging division in 1974, scientists have dedicated more and more resources to the challenge. Over the past dozen years, the NIA's budget has doubled to more than $2 billion. Faloon predates them all. These days, the several ­hundred people who regularly attend events at the church are personal validation for Faloon, who thinks that anyone his age and younger, given the proper physiological tweaking, could live to a healthy age of 130. The hope is that, by then, new solutions will make death truly optional. Yet no amount of self-tinkering can assure him and his followers that day will ever come.

Across all these potential aging interventions, there is one common denominator, and that is their fallibility. The medical community doesn't know what slows or reverses the process in humans, let alone what might cause harm. For that reason, researchers caution against the kind of self-experimentation Faloon practices. "We're playing with a new treatment paradigm," the Mayo Clinic's James Kirkland says of their research. "I've been around long enough to know there are going to be unpredictable things that happen as we get into people."

Faloon believes he faces a bigger risk from waiting than from being his own guinea pig. "I'm afraid that with aging research, some of the people don't have a sufficient sense of urgency," he says. He continually incorporates different interventions into his life-extension regimen. He restricts his calories to some 1,200 a day, about half what the average man consumes. He also ingests more than 50 medications daily, including metformin and Life Extension's own concoctions of nutraceuticals. "Anything that might work, I am doing," he says. Because he's impatient for clinical trials to yield ­conclusive results, Faloon gives about $5 million a year in profits from the buyers club to underwrite medical research. So far, the data from two recent studies on NAD+ and rapamycin that he backed are unpublished. "If we don't accelerate all these different projects, I'm not going to make it," Faloon says.

The heart is one of the least regenerative organs in mammals. Damage to heart tissue, such as that resulting from a heart attack, produces a harmful inflammatory response and the formation of scar tissue rather than regeneration. Scarring disrupts normal tissue function, whether in the heart or elsewhere. The research community would like to suppress the unhelpful inflammation and scarring following injury in all types of tissue, but this phenomenon is particular problematic in the heart. Here, researchers demonstrate that the source of this inflammation may be largely the activity of B cells.

In a heart attack, blood is cut off from an area of the heart that then often dies. If the person survives, the body tries to heal the dead muscle by forming scar tissue - but such tissue can further weaken the heart. Yet another wave of damage can occur when well-intentioned immune cells try to heal the injured heart but instead drive inflammation. Pirfenidone is approved to treat a lung condition called idiopathic pulmonary fibrosis, a scarring of the lungs that has no known cause. The drug also has been known for its heart-protective effects in a number of different animal models of heart attack. Researchers had assumed that pirfenidone's protective action in the heart paralleled the reason it helps in lung disease. In the lungs, the drug slows the formation of scar tissue.

"That this drug also protects the heart is not new. But in our studies, pirfenidone didn't physically reduce scar tissue in the heart. The scar tissue is still there, but somehow the heart works better than expected when exposed to this drug. It wasn't clear why. So we set out to reverse engineer the drug to pick apart how it may be working. Since scar tissue was still present, we suspected inflammation was the main culprit in poor heart function after a heart attack." Most immune studies of the heart have focused on other types of immune cells, including macrophages, T cell lymphocytes, neutrophils, and monocytes. But the researchers found no differences in the numbers of such immune cells in the injured hearts of mice that received pirfenidone versus those that didn't. When they serendipitously measured B cells, however, they were surprised to see a huge difference.

"Our results showing B cells driving heart inflammation was quite unexpected. We didn't know that B cells have a role in the type of heart damage we were studying until our data pushed us in that direction. We also found that there isn't just one type of B cell in the heart, but a whole family of different types that are closely related. And pirfenidone modulates these cells to have a protective effect on heart muscle after a heart attack." When the researchers removed these cells completely, not only was the heart not protected, the beneficial effect of the drug went away. So the B cells are not exclusively bad, according to the scientists. "The protective effects of pirfenidone hinge on the presence of B cells. The drug may be working on other cells as well, perhaps directly or perhaps through the B cells. We're continuing to investigate the details."

Link: https://medicine.wustl.edu/news/scientists-id-source-of-damaging-inflammation-after-heart-attack/

For various historical reasons, none of them justified, researchers seeking to intervene in the aging process have avoided talking about extending human life span. Until comparatively recently, and after a great deal of work on the part of advocates such as those of the Methuselah Foundation and SENS Research Foundation, the leaders of the research and funding communities actively suppressed efforts to discuss or work on the treatment of aging as medical condition. This environment gave rise to euphemisms such as "healthy aging" or "successful aging," and the goal of compression of morbidity: extend the period of health within the present human life span, but never, ever talk about trying to extend that life span. This has distorted the scientific endeavor, holding back efforts to develop meaningful rejuvenation therapies.

"Healthy aging" is a nonsense phrase. Aging is, by definition, the rise in mortality risk, the growth in systemic damage and failure of function. Aging is the opposite of health. Yet the phrase is well established and unlikely to go away any time soon, sadly. Any researcher or institution settling on the goal of healthy aging sets up for defeat before the work even starts. To pursue healthy aging is to accept aging rather than seek to defeat it. It is to aim at small modulations of the aging process, tiny adjustments here and there, rather than the sweeping change of rejuvenation. It is the assurance of failure, of missing the opportunity to change the world for the better.

Expressions such as "healthy aging" and "aging gracefully" signify that while the aging processes are making no exception for you, you're relatively healthy and/or the cosmetic signs of aging aren't as pronounced as they could be. This, of course, betrays the obvious reality that, in general, this kind of aging isn't the norm but rather a special case. If things were the other way around, you wouldn't find any articles stating the obvious fact that it's possible to age gracefully; rather, you'd find articles saying that disgraceful or unhealthy aging, however exceptionally, may happen too.

This choice of words is rather problematic, especially now that the dawn of rejuvenation is visible on the horizon. The terms "healthy aging" and "successful aging" really are sharp contradictions in terms. If you read the scientific literature on aging, most if not all papers giving general introductions to the phenomenon define it as a chronic process of damage accumulation or a progressive decline in health and functionality. If we try to replace these definitions in the two expressions above, the results are frankly hilarious: "a healthy chronic process of damage accumulation" and "a successful progressive decline in health and functionality". What's that even supposed to mean? Given that this progressive decline in health and functionality happens of its own accord and it invariably kills you, one would think that you really don't need to put any special effort in achieving it, and it appears to be "successful" enough without any need for external intervention.

It's of course good that healthy aging, as defined as a mitigated and relatively disease-free decay process, is actively promoted. However, this unfortunate terminological choice perpetuates the false dichotomy between aging and age-related disease; it reinforces the completely unsubstantiated belief that you can age biologically and yet retain your health. To put it bluntly, it's one of the reasons why you have people saying that when their grandfather died, at age 95, he was "perfectly healthy". If everything with him was in perfect working order, what did he die of, exactly? Some may think he just died of "old age", as if old age were a separate cause of death entirely, but that's not the case. Death by old age is just an expression to mean that he died of one of the many health issues that, in humans, generally manifest only after the seventh or eighth decade of life.

Just like the term "life extension" - albeit somewhat improper - has become a proxy for the application of regenerative medicine for the prevention of age-related diseases, so "healthy aging" and similar phrases have become synonymous with "being less sick than you could be", even though they really sound more like "getting sick in a healthy way". The only way to eradicate these misleading expressions is to successfully explain the true nature of aging to the public.

Link: https://www.leafscience.org/getting-sick-in-a-healthy-way/

Today's open access review looks over the evidence for senescent cells to contribute to the age-related loss of muscle mass and strength, leading to sarcopenia and frailty. Regular readers will know that the research community has found many mechanisms that are arguably important contribution to the characteristic weakness of old age. This part of the field is rife with competing evidence for processes ranging from the comparatively mundane, such as an inadequate dietary intake of protein in older people, to the highly complex, such as the biochemical disarray that causes loss of neuromuscular junctions, and the interactions between those junctions and mechanisms of muscle tissue maintenance. The most compelling evidence points to stem cell dysfunction as the primary cause of loss of muscle and strength with age. But then we might well ask which of the fundamental causes of aging produces that stem cell dysfunction?

The review here argues for cellular senescence to be an important cause. Senescent cells accumulate over time, a tiny fraction of the countless cells that become senescent every day managing to linger rather than self-destruct. The immune system clears out near all of those, but the immune system falters with age. Cancer is an age-related disease in large part because of this loss of capability in the portions of the immune system responsible for destroying errant cells, and the accumulation of senescent cells is no doubt in the same boat. Yet even in very old tissues, only a small percentage of cells are senescent. The harm they cause is not direct, but rather results from the potent mix of signals that they generate. Those signals produce chronic inflammation, destructively remodel tissue structure, and change the behavior of surrounding cells for the worse.

Just looking at chronic inflammation, it is known that this state can disrupt the normal processes of tissue maintenance and regeneration. But there are many other mechanisms worth surveying when it comes to the ways in which cellular senescence might be acting to suppress the activity of stem cell populations, thus leading to atrophy and loss of function in tissues such as skeletal muscle. What if these senescent cells could be removed, however? Might we expect some degree of rejuvenation of stem cell activity? That doesn't seem an unreasonable goal, based on the evidence to date. Senolytic therapies capable of clearing a fraction of senescent cells already exist, albeit not packaged up for the mass market, and not yet run through rigorous human trials. More effective therapies are entering the regulatory pipeline, under development in a number of young companies, and will arrive in the clinic over the years ahead.

Musculoskeletal senescence: a moving target ready to be eliminated

Aged individuals can deteriorate exceptionally fast after the onset of complications affecting the musculoskeletal system. Tissue erosion due to life-long mechanical and biological stress can ultimately result in pathologies such as osteoporosis, sarcopenia, and osteoarthritis, and contribute to frailty. While not all elderly people develop the same age-related diseases, virtually everyone will experience musculoskeletal complications sooner or later. To extend, and possibly even restore, healthy life expectancy in old age, it is essential to understand the cellular changes underlying musculoskeletal decline.

Tissue regeneration by stem-cell differentiation is critical in overcoming the relentless day-by-day damage to the musculoskeletal system. In young tissues, differentiation proceeds without much hindrance unless one exercises excessively or suffers undue levels of stress. However, during aging, the number and function of adult stem cells declines. For example, Pax7-expressing satellite stem cells, can replace damaged muscle fibers. Removing Pax7-positive cells from mice impairs muscle regeneration after injury, whereas increased availability of these cells enhances muscle repair.

In addition to cell-intrinsic regulation, muscle stem cell regenerative capacity also depends intimately on the microenvironment. During aging, the levels of inflammation chronically increase, an affect known as inflammaging. Evidence for this is provided by studies showing that muscle stem cells (satellite cells) from aged mice become more fibrogenic, a conversion mediated by factors from the aged systemic environment. In contrast, frailty is reduced by the JAK/STAT inhibitor Ruxolitinib, which reduces inflammation in naturally aged mice. Stem-cell impairing cues do not necessarily have to come from local sources but can travel over a distance. Therefore, there is a great interest in developing methods to interfere with the age-associated pro-inflammatory signaling profile. The question is how? To address this question, cellular senescence has recently gained attention as a potential candidate for intervention.

As we age, each cell in our body accumulates damage. Earlier in life, this damage is usually faithfully repaired, but over time more and more damage gets left behind. This can trigger a molecular chain of events, resulting in the entry of cells into a permanent state of cell-cycle arrest, called cellular senescence. Senescence can be invoked in healthy cells that experience a chronic damage response, either involving direct DNA damage or events that mimic the molecular response, such as telomere shortening or oncogenic mutations. As a consequence, these cells undergo an irreversible cell cycle arrest, effectively limiting the damage. So far, so good, except that senescent cells secrete a broad range of growth factors, pro-inflammatory proteins, and matrix proteinases that alter the microenvironment: the Senescence-Associated Secretory Phenotype (SASP).

Senescent cells persist for prolonged periods of time and eventually accumulate during aging. This also means there is a gradual and, importantly, ever-present build-up of deleterious molecules. Thus, senescence can have continuous detrimental effects on tissue homeostasis during aging. That senescent cells are a direct cause of aging was proven beyond a doubt in studies in which senescent cells were genetically or pharmacologically removed. In these studies, both rapidly and naturally aged mice maintained healthspan for much longer, or even showed signs of aging reversal.

Factors secreted by senescent cells can induce pluripotency in vivo. As such, these can impair normal stem cell function by forcing a constant state of reprogramming, something we dubbed a `senescence - stem lock'. Age-associated inflammation may thus deregulate normal stem cell function at different levels, for instance by preventing stem cells from producing differentiated daughter cells. Due to the constant secretion of SASP factors, senescent cells could thus impair local and distant stem cell function and differentiation in times of need. Here, we will highlight the interplay between senescence, the SASP and stemness in the individual musculoskeletal compartments: muscle, bone, and cartilage.

The research community continues to make progress, slow but steady, in understanding the low-level biochemistry of neurodegenerative conditions. It is a very complex area of study. You might compare the research here, focused on amyloid, with results noted yesterday, focused on α-synuclein. The aging of the brain is accompanied by the aggregation of a number of altered proteins, producing solid deposits and a halo of surrounding changes in cell biochemistry that damage or kill brain cells. Beyond that summary, each is very different in mechanisms and outcome. Regardless, the end result is cognitive decline, a disruption of function in the brain. Control of protein aggregation is a major focus of the research community, but achieving any meaningful progress towards that goal has proven to been far more challenging than was hoped when these projects began in earnest.

The accumulation of amyloid peptides in the form of plaques in the brain is one of the primary indicators of Alzheimer's disease. While the harmful effects of amyloid peptide aggregates are well established, the mechanism through which they act on brain cells remains ill-defined. Researchers knew, for instance, that amyloid peptides disrupt synapses - the area of contact and chemical communication between neurons - but did not understand how they did so. Now, new findings have revealed the molecular mechanism that links amyloid aggregates and deficient synaptic function observed in animal models of Alzheimer's disease: peptide oligomers interact with a key enzyme in synaptic balance, thereby preventing its normal mobilization.

The molecule, called CamKII, usually orchestrates synaptic plasticity, an aspect of neuronal adaptability that enables neurons to reinforce their responses to the signals they exchange. Groups of neurons that code for an information to be memorized are connected by synapses, which are themselves under the control of mechanisms of synaptic plasticity. When the connection between two neurons must be reinforced in order to memorize information, for instance during intense stimulation, CamKII is activated and leads to a chain of reactions that strengthen the capacity to transmit messages between these neurons.

Synaptic plasticity is central to memory and learning. Amyloid peptides prevent CamKII from participating in this process of synaptic plasticity, and this blockage eventually leads to the disappearance of the synapse. This discovery could find an application in early phases of Alzheimer's disease when initial cognitive deficiencies are observed, which could be linked to this synaptic malfunction. The goal for researchers now is to continue studying amyloid aggregates, especially by trying to prevent their interaction with CamKII and the loss of synapses observed during the disease.

Link: http://www2.cnrs.fr/en/3128.htm

A fair amount of research on raised blood pressure, hypertension, and its risks has been published of late. Hypertension is a downstream consequence of loss of elasticity in blood vessels. That loss of elasticity arises from the molecular damage at the root of aging, and the resulting hypertension is one of the more noteworthy mediating mechanisms by which that low-level biochemical damage is translated into structural damage to organs. Hypertension causes pressure damage to sensitive tissues, increasing the rate at which small blood vessels rupture, killing the nearby cells. This is particularly important in the brain, where regenerative capacity is limited. Individually, each tiny area of damage has little effect, but taken as a whole it adds up over time to contribute to cognitive decline.

A new study indicates that patients with high blood pressure are at a higher risk of developing dementia. This research also shows (for the first time) that an MRI can be used to detect very early signatures of neurological damage in people with high blood pressure, before any symptoms of dementia occur. High blood pressure is a chronic condition that causes progressive organ damage. It is well known that the vast majority of cases of Alzheimer's disease and related dementia are not due to genetic predisposition but rather to chronic exposure to vascular risk factors. The clinical approach to treatment of dementia patients usually starts only after symptoms are clearly evident. However, it has becoming increasingly clear that when signs of brain damage are manifest, it may be too late to reverse the neurodegenerative process. Physicians still lack procedures for assessing progression markers that could reveal pre-symptomatic alterations and identify patients at risk of developing dementia.

This work was conducted on patients with no sign of structural damage and no diagnosis of dementia. All patients underwent clinical examination to determine their hypertensive status and the related target organ damage. Additionally, patients were subjected to an MRI scan to identify microstructural damage. To gain insights in the neurocognitive profile of patients a specific group of tests was administered. As primary outcome of the study the researchers aimed at finding any specific signature of brain changes in white matter microstructure of hypertensive patients, associated with an impairment of the related cognitive functions.

The result indicated that hypertensive patients showed significant alterations in three specific white matter fiber-tracts. Hypertensive patients also scored significantly worse in the cognitive domains ascribable to brain regions connected through those fiber-tracts, showing decreased performances in executive functions, processing speed, memory and related learning tasks. Overall, white matter fiber-tracking on MRIs showed an early signature of damage in hypertensive patients when otherwise undetectable by conventional neuroimaging. As these changes can be detected before patients show symptoms, these patients could be targeted with medication earlier to prevent further deterioration in brain function. These findings are also widely applicable to other forms of neurovascular disease, where early intervention could be of marked therapeutic benefit.

Link: https://www.eurekalert.org/pub_releases/2018-06/oupu-dcb061218.php

The quality of the vasculature is an important determinant of the pace of aging in the brain. There are probably several distinct processes involved, all of which tend to correlate with one another as aging progresses. Firstly the brain is an energy-hungry organ, but the network of tiny capillaries in tissues becomes less dense with age. A consequently lower supply of nutrients to cells causes loss of function. The same result may also occur due to the age-related weakening of the muscles of the heart. Secondly, blood vessels lose their elasticity in later life, and this in turn causes a rise in blood pressure as feedback mechanisms run awry. Higher blood pressure causes damage to sensitive tissues in many organs through a variety of means, such as a greater rate of rupture or blockage of tiny blood vessels. The brain of an older individual is riddled with the minuscule scars left by these events, and that damage adds up.

Why do blood vessels grow stiff with age? A mix of underlying causes, not all of which are fully understood. Persistent cross-links that our biochemistry cannot break down glue together structural proteins of the extracellular matrix, altering the structural properties of tissue. Rising inflammation and signals from senescent cells contribute to both calcification of blood vessel walls and dysfunction in the smooth muscle cells responsible for contraction and dilation. The behavior of smooth muscle is more responsive to lifestyle circumstances than other factors; better diet, avoiding excess fat tissue, and greater fitness are thought to have an impact, either through reduced inflammation and or other mechanisms, whereas there isn't much that can be done about existing calcification or cross-linking given the tools to hand today.

Greater fitness and better lifestyle choices only slow the progression of aging to some degree - and only meaningfully impact a fraction of its mechanisms. But in an era of rapid progress in medical biotechnology, in which the research community is finally waking to the potential of treating aging and its causes, it makes sense to adopt lifestyle choices that reliably help long-term health, even if the outcome at the end of the day is just a few years gained. Those few years may make a sizable difference, between on the one hand living long enough and in good enough health to benefit from future technologies of rejuvenation, and on the other hand missing that boat.

Better Physical Fitness and Lower Aortic Stiffness Key to Slower Brain Ageing

The rate of decline in certain aspects of memory may be explained by a combination of overall physical fitness and the stiffness of the central arteries, researchers have found. "Exactly why this occurs is unclear, but research indicates that exercise and physical fitness are protective. A healthier, more elastic aorta is also theorised to protect cognitive function, by reducing the negative effects of excessive blood pressure on the brain."

One hundred and two people (73 females and 29 males), aged between 60 and 90 years, living independently in aged care communities, were recruited. Their fitness was assessed with the Six-Minute Walk test which involved participants walking back and forth between two markers placed 10 metres apart for six minutes. Only participants who completed the full six minutes were included in the analysis, which assessed the stiffness of their arteries and cognitive performance. The researchers found that (along with Body Mass Index and sex) the combination of fitness and aortic stiffness explained a third of the variation in performance in working memory in older people.

Interestingly, physical fitness did not seem to affect central arterial stiffness, however only current fitness was assessed - long term fitness may be a better predictor of central arterial stiffness, however this has yet to be investigated. "Unfortunately, there is currently no effective pharmacological intervention that has proven effective in the long term in staving off dementia. The results of this study indicate that remaining as physically fit as possible, and monitoring central arterial health, may well be an important, cost effective way to maintain our memory and other brain functions in older age."

Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People

Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. Our objective is to investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition.

Residents of independent living facilities, aged 60-90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation.

Thus greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline.