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- There is No One Universal Pro-Longevity Gut Microbiome
- Aducanumab Approved by FDA to Treat Alzheimer's Disease
- Inflammaging and Disruption of Coagulation as Contributions to High COVID-19 Mortality in the Old
- Trends in Human Healthspan versus Lifespan
- Progress on Understanding Why Human Growth Hormone Receptor Variants are Associated with Greater Longevity
- Glial Cell Senescence in the Aging Brainstem
- Reduced Oxygen Supply to the Brain as a Cause of Early Memory Symptoms in Alzheimer's Disease
- A Treatment to Rebuild Tooth Enamel
- A Mechanism by which Amyloid-β can Reduce Capillary Density in the Alzheimer's Brain
- A Less Well Explored Cdkn1a Transcript is a Marker of Aging and Cellular Senescence
- Distinctive Macrophage Signaling is Vital to Axolotl Limb and Organ Regeneration
- Assessing Sarcopenia and Dynapenia via Ultrasound
- Th17 Immunity and the Inflammation of Aging in Intestinal Barrier Dysfunction
- The Mainstream Media is Slowly Becoming Less Skeptical of Work to Extend the Healthy Human Life Span
- Athletes Undergoing Regular Strength Training Exhibit Slowed Aging of Bone Tissue
There is No One Universal Pro-Longevity Gut Microbiome
Evidence suggests that the gut microbiome is influential on long-term health and late life mortality, to perhaps a similar degree as exercise. The various populations of microbial life found in the gut change with age; microbes producing beneficial metabolites are lost, while microbes that provoke chronic inflammation or other issues increase in number. Experiments in short-lived species have shown that transplanting a youthful microbiome into an older individual results in improved health and extended life span. In principle, similar effects could be achieved by some sort of intensive oral probiotic treatment, but that has not yet been demonstrated in animal studies. Researchers have also shown that guiding the immune system to more aggressively attack problem gut microbes can improve the microbiome and its influence on health.
In today's open access paper, researchers propose that regional differences in diet mean that there is unlikely to be one optimal gut microbiome to promote longevity. This seems a reasonable prediction, given the degree to which human diet does vary around the world, and the way in which diet interacts with the gut microbiome. It still seems likely that there are universally beneficial changes that one can make to any aged microbiome, in humans or other species, such as enabling the immune system to better remove problem microbes. Early approaches to therapies are likely to involve such universal, narrow improvements; personalized medicine is more challenging problem.
Regional Diets Targeting Gut Microbial Dynamics to Support Prolonged Healthspan
Centenarians, who have escaped or survived lethal diseases earlier in life, may be considered a spontaneous model of healthy ageing. The gut microbial composition of centenarians has consistently been reported to differ in phylogenetic composition from that of younger people. Interestingly, within centenarian populations, species have been reported to display regional characteristics, further supporting that environmental and/or lifestyle factors including the diet, shape microbial composition.
For example, in an Italian cohort, the centenarian microbiome was found to be dominated by the same two microbial families as in the other age groups (<75 years old) of the population, namely Veillonellaceae and Ruminococcaceae (Firmicutes phylum), but was specifically enriched in the genera Akkermansia, Bifidobacterium, and Christensenella. In contrast, the Chinese Hainan Centenarian Cohort was dominated by Bacteroides (Bacteroidetes phylum) and Escherichia (Proteobacteria phylum). Long-term elderly care residents in the Irish ELDERMET Cohort also had a gut microbiome dominated by Bacteroidetes. Importantly, although the aggregate faecal microbiome in ELDERMET was dominated by Bacteroidetes, the residents showed extraordinary inter-individual variation with 3-92% Bacteroidetes and 7-94% Firmicutes, hinting at a long-term effect of their dietary habits.
The results of the Italian study are also in contrast to those of another Chinese Centenarian Cohort from the Guangxi region, who harboured significantly higher abundance of the genera Escherichia and Roseburia, and reduced abundance of Akkermansia, Lactobacillus, Faecalibacterium, Parabacteroides, Butyricimonas, Coprococcus, Megamonas, Mitsuokella, and Sutterella. A Korean centenarian study found trends similar to both Italian and Guangxi Chinese centenarians, with higher abundance of Akkermansia and Christensenella, and Escherichia, respectively. They also displayed increased abundance of Clostridium and Collinsella, and reduced abundance of Faecalibacterium and Prevotella compared to the general population.
At present, we do not have a good understanding to explain these geographical variations in the centenarian gut microbial composition or to unequivocally answer if there are certain microbial species globally associated with longevity. In the reviewed studies, some microbial genera associated with healthy elderly populations include Roseburia, Escherichia, Akkermansia, Christensenella, Bifidobacterium, and Clostridium, but they are all highly variable across populations. Based on these cross-sectional observations, it seems unlikely that a universal pro-longevity gut microbiome exists. Rather, the optimal microbiome for healthspan appears to be conditional on the microbial functionality acting on regional- and ethnicity-specific trends driven by cultural food context.
Aducanumab Approved by FDA to Treat Alzheimer's Disease
The underside of the approval of aducanumab, an immunotherapy that clears amyloid-β from the brain, is very much a textbook case of regulatory capture. While the treatment does clear amyloid-β, it doesn't help patients all that much. Benefits observed in trials were marginal to the point of non-existence. The arm-wrestling under the hood has nothing to do with the welfare of patients and everything to do with maintenance of bureaucracy and control for the sake of bureaucracy and control on one side versus rent seeking on the other. An ugly business.
The silver lining is that now it will be easier to work on combination therapies that remove amyloid-β and address other issues. Amyloid-β is either a side-effect of the development of Alzheimer's disease, or one of several important mechanisms, most or all of which must be meaningfully addressed in order to help patients. It is hard to make progress in this latter scenario if regulators insist on only testing one thing at a time, and also have an efficacy bar for approval.
The regulatory system is dramatically broken. Absent regulators, it would cost a tenth as much as it does now, or less, to prove out new therapies in human volunteers. For most medicines, there really isn't a sizable practical difference between the over the top rigor of GMP manufacture and ordinary, sensible quality control on a batch by batch basis. The enormous cost imposed by the the FDA process really isn't essential to producing safe medicines, or to testing efficacy. Yet here we are, in a world in which progress is glacial because the powers that be have decided that pursuing the unattainable goal of zero risk is worth any cost in lives and funding, and the population at large never sees the medical progress that would have taken place absent the regulators.
FDA's Decision to Approve New Treatment for Alzheimer's Disease
Today FDA approved Aduhelm (aducanumab) to treat patients with Alzheimer's disease using the Accelerated Approval pathway, under which the FDA approves a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug's clinical benefit.
We are well-aware of the attention surrounding this approval. We understand that Aduhelm has garnered the attention of the press, the Alzheimer's patient community, our elected officials, and other interested stakeholders. The late-stage development program for Aduhelm consisted of two phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.
We know that the Peripheral and Central Nervous System Drugs Advisory Committee, which convened in November 2020 to review the clinical trial data and discuss the evidence supporting the Aduhelm application, did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval. As mentioned above, treatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit. After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for Accelerated Approval.
The need for treatments is urgent: right now, more than 6 million Americans are living with Alzheimer's disease and this number is expected to grow as the population ages. Alzheimer's is the sixth leading cause of death in the United States. Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients.
Inflammaging and Disruption of Coagulation as Contributions to High COVID-19 Mortality in the Old
The burden of infectious disease falls most heavily upon the old. The attention given to COVID-19 has highlighted that point, though much of the media seems determined to avoid talking about the fact that near all mortality due to the condition occurs in the old and the cormorbid. It is nothing new, of course. Influenza kills tens of thousands of old people every year in the US alone, without much attention given to it. That the elderly suffer and die is old news. It is, however, old news that we should revisit in this era of revolutionary progress in medical biotechnology. The causes of aging and age-related mortality are amenable to treatment. The first rejuvenation therapies exist already, in the form of first generation senolytic treatments that destroy senescent cells.
COVID-19 mortality is strongly linked to inflammation. People with raised levels of chronic inflammation, such as the obese and the old, are much more vulnerable to suffering a runaway inflammatory event, a cytokine storm, and consequent severe illness and death. Today's open access paper is a novel consideration of this state of affairs that pulls in to this discussion what is known of the age-related dysfunction in coagulation. If a higher baseline inflammatory status leads to greater risk of severe inflammation due to infection, then, analogously, a greater baseline degree of dysfunction in mechanisms of coagulation leads to a greater risk of pathological disruption of coagulatory processes due to infection.
Do inflammaging and coagul-aging play a role as conditions contributing to the co-occurrence of the severe hyper-inflammatory state and deadly coagulopathy during COVID-19 in older people?
Older people with COVID-19 infection often suffer a severe form of interstitial pneumonia accompanied to an excessive human immune response with a hyper-inflammatory condition characterized by the increase of many plasma cytokines, including IL-6, interleukin 8 (IL-8), interferon (IFN), and tumor necrosis factor levels increase, particularly of IL-6 (the so-called "cytokine storm"). What drives such intense hyper-inflammation in COVID-19 is not yet known; however, the upregulation of IL-6 seems the pivotal pro-inflammatory function is contributing to COVID-19 severity.
Herein, we suggest that the preexisting upregulation of cytokine expression of inflammaging may trigger, and also support, the excessive hyper-inflammatory state in older people. Indeed, the superimposed SARS-CoV-2 infection in older adults may acutely exaggerate the already present pro-inflammatory background of inflammaging, predisposing older people to greater COVID-19 disease severity and mortality. The co-occurrence of the COVID-19 infection, constituting a second-hit to the preexisting pro-inflammatory condition of inflammaging, leading to a dysregulation of inflammation, which becomes harmful, reaching a severe pathological threshold.
We must also consider the impact of a pro-inflammatory state on coagulation because of the crosstalk between inflammation and coagulation. It is well established that the systemic inflammatory state of elderly people and coagulation disorder are closely linked, a phenomenon which here we refer to as "coagul-aging". Physiological aging is associated with increased plasma levels of many proteins of blood coagulation together with fibrinolysis impairment; this may be of great concern in view of the known association between vascular and thromboembolic diseases and aging, a condition which, here we suggest, may also contribute to the co-occurrence of the high incidence of coagulopathy in older COVID-19 patients.
In the future, we hope to carry out more studies on inflammaging and coagul-aging, which will enable us to understand the mechanism in-depth and find measures to intervene in the corresponding processes. More studies will not only help elderly patients with severe infections like COVID-19, but can also have the potential to intervene in the aging-associated pro-inflammatory state and the senescence process itself.
Trends in Human Healthspan versus Lifespan
Aging is damage, and the body fails in the same way that any complex, damaged machine fails. If one slows the pace of damage accumulation, as technological progress over the past century has achieved to a modest degree, albeit by accident rather than intent, both overall life span and the time spent in a period of damage and dysfunction at the end of life should extend. This is what we see happening, as is noted by the authors of today's open access paper. In order to extend healthy life and put off that period of damage and dysfunction, periodic repair of the underlying damage of aging is required. You make a machine last longer in a useful way by maintaining it.
This approach of repair, targeting the cell and tissue damage that causes aging, was not attempted by the scientific and medical communities until quite recently. The first repair based rejuvenation therapies worthy of the name are the various senolytic treatments that selectively remove senescent cells from aged tissues. Lingering senescent cells actively disrupt tissue maintenance and function, and eliminating them has been shown to reverse aspects of aging in mice. Senolytics emerged in the past decade, and are only now entering human clinical trials as a means of turning back selected conditions in which they are known to be a major component of pathology. There is still a lot more of aging to address if we want to change the past trend of increasing life span coupled to a longer period of damage and decline.
Trends in health expectancies: a systematic review of international evidence
Populations are ageing worldwide. Globally, the proportion of those aged 65 and over has increased by 9% in the last two decades, and is expected to grow by a further 16% by 2050. This demographic shift will require societies to adapt. If longer lives are spent in poor health, governments face the challenge of providing accessible, high quality and sustainable long-term care. The growth in life expectancy is a positive, but with this comes a responsibility to ensure people have the support they need as they age, and to facilitate ageing in place.
In 2019, the World Health Organisation (WHO) renewed its commitment to support countries to achieve longer and healthier lives with the Decade of Healthy Ageing 2020-2030 strategy. A critical part of achieving longevity is understanding whether longer lives are typified by more years spent in good health (compression of disability) or poor health (expansion of disability). This has important implications for the provision of health and care services to respond to the needs of people as they age. It is, therefore, crucial to keep abreast of trends, specifically how the growth in life expectancy is matched by a growth in years spent in good health.
Metrics to assess this most commonly include healthy life expectancy and disability-free life expectancy. Both provide an estimate of life expectancy spent in good health, but differ slightly with respect to their measurement. Healthy life expectancy tends to rely on single item questions of self-reported health, and is thus subject to fluctuations as expectations of health change over time. Disability-free life expectancy is often calculated from multiple items about activity limitations and/or dependencies, and therefore does not bear the same limitations as that of healthy life expectancy.
Previous reviews have summarised trends in total, healthy, and disability-free life expectancy, the most recently in 2016. Typically, such evidence shows that while people are living longer, gains in life expectancy are not consistently matched by a growth in the number of years lived in good health and free of disability. Nevertheless, this is an evolving evidence base requiring ongoing scrutiny.
This systematic review was undertaken to update our current understanding of trends in health expectancies in OECD high-income countries. The principal finding is that changes in health expectancies have not kept pace with the growth in life expectancy in a number of high-income countries. One clear exception was Sweden, where gains in women's disability-free life expectancy were greater than gains in life expectancy over a period of almost 20 years. In conclusion, a number of high-income countries, changes in health expectancies over time have not kept pace with the growth in life expectancy. That is, people are living longer but disability and poor health are occupying an increasing proportion of later life. Our findings suggest that countries still need to make significant progress to achieve the WHO's Decade of Healthy Ageing goal of healthier, longer lives for all.
Progress on Understanding Why Human Growth Hormone Receptor Variants are Associated with Greater Longevity
A few years back, researchers noted that a common growth hormone receptor gene variant was associated with greater life expectancy in humans. There was some theorizing as to possible mechanisms at the time, following the usual paths for anything that touches on growth hormone or its receptor. In short-lived mammals such as mice, loss of function in growth hormone or its receptor produces small body size and increased healthy longevity. The present record for mouse longevity is held by a growth hormone receptor knockout lineage. In humans, members of the small Laron syndrome population exhibit an analogous disruption of growth hormone metabolism, and while there are signs that they might be more resistant to some forms of age-related disease, they do not live notably longer than the rest of us. It is usually the case that metabolic alterations of this nature, in this part of metabolism, have large effects in short-lived species and much smaller effects in long-lived species.
Given the example of Laron syndome to suggest that the usual explanations regarding growth hormone metabolism may not be useful here, how might variants in the growth hormone receptor gene actually produce an effect on human longevity? Researchers have been working to answer that question, and in today's open access paper it is proposed that some variants reduce the negative impacts of raised blood pressure, or hypertension. Blood pressure is very influential on health and mortality in later life. Raised blood pressure causes damage to delicate tissues in organs throughout the body, and particularly in the brain. It also accelerates the progression of atherosclerosis, and makes it more likely that atherosclerotic vessels burst or become blocked. It also contributes to heart failure. Hypertension causes so many forms of downstream damage that control of raised blood pressure via current standards of medication, approaches that in no way address the underlying causes of the condition, can nonetheless reduce mortality risk by a sizable amount.
Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension
Growth hormone (GH) and its receptor (GHR) are not only important for regulating growth, they have many other important biological functions that include response to nutrients, regulation of metabolism, and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. Growth hormone signaling is an important regulator of aging. GH deficiency leads to slower growth, delayed maturation, reduced body size, and can result in attenuation of the rate of aging, increased health-span, and increased longevity. Key to this are evolutionarily conserved pathways of insulin/insulin-like growth factors and mechanistic target of rapamycin, where there are trade-offs between anabolic processes/growth and lifespan.
We have reported a significant negative association between height and longevity in our large cohort of American men of Japanese ancestry. More recently, in a case-control study of 13 single nucleotide polymorphisms (SNPs) of GHR in this cohort, SNP rs4130113 was associated with greater lifespan of nonagenarian men aged ≥ 95 years. In the present longitudinal study, we tested the hypothesis that genetic variation in GHR affects lifespan at least in part by protection against the detrimental effects of one or more aging-related diseases, namely diabetes, hypertension, coronary heart disease, and/or cancer.
The present study has found that the longevity-associated AA genotype (frequency 35.3%), but also the GG genotype (frequency 17.1%), of GHR SNP rs4130113 is associated with protection against risk of mortality in hypertensive elderly American men of Japanese ancestry. As a result, those individuals lived longer, whereas individuals with the AG genotype (frequency 47.6%) died sooner. Moreover, the survival curve for hypertensive AA/GG subjects did not differ significantly from the survival curve for normotensive subjects with the AA/GG genotype. This indicated that possession of the GHR longevity-associated genotype can mitigate the adverse effects on lifespan of having hypertension.
Glial Cell Senescence in the Aging Brainstem
A small but increasing fraction of the supporting glial cells of the brain become senescent in later life, and there is good evidence from animal studies for this to be an important contributing cause of neurodegeneration. Senescent cells secrete a mix of signals that provoke chronic inflammation, as well as detrimental changes to tissue structure and cell function. Inflammation in the brain is an important component of neurodegenerative disease, and researchers have proposed that the most common forms of dementia are driven in large part by cellular senescence and consequent inflammation in the brain.
Accumulating evidence suggests that the sympathetic nervous system (SNS) overactivity plays a crucial role in age-related increase in the risk for cardiovascular diseases such as hypertension, myocardial infarction, stroke, and heart diseases. Previous studies indicate that neuroinflammation in key brainstem regions that regulate sympathetic outflow plays a pathogenic role in aging-mediated sympathoexcitation. However, the molecular mechanisms underlying this phenomenon are not clear. While senescent cells and their secretory phenotype (SASP) have been implicated in the pathogenesis of several age-related diseases, their role in age-related neuroinflammation in the brainstem and SNS overactivity has not been investigated.
To test this, we isolated brainstems from young (2-4 months) and aged (24 months) male C57BL/6J mice and assessed senescence using a combination of RNA-in situ hybridization, PCR analysis, multiplex assay, and SA-β gal staining. Our results show significant increases in p16Ink4a expression, increased activity of SA-β gal and increases in SASP levels in the aged brainstem, suggesting age-induced senescence in the brainstem. Further, analysis of senescence markers in glial cells enriched fraction from fresh brainstem samples demonstrated that glial cells are more susceptible to senesce with age in the brainstem. In conclusion, our study suggests that aging induces glial senescence in the brainstem which likely causes inflammation and SNS overactivity.
Reduced Oxygen Supply to the Brain as a Cause of Early Memory Symptoms in Alzheimer's Disease
Researchers here hypothesize that the normal level of oxygen supply to the hippocampus, the area of the brain most involved in memory, is just barely adequate. As soon as any age-related decline in blood supply occurs, memory symptoms are the result, and hence memory symptoms occur early in the aging of the brain. There are numerous mechanisms by which the supply of blood to the brain can decline with age, such as a lack of physical fitness and the ability of the heart to pump blood uphill to the brain, or the loss of capillary density that occurs in tissues with age. One interesting point that is not brought up in the research materials here: it is known that physical exercise improves cerebral blood flow and memory function in the short term. This might be taken as supportive of the hypothesis that normal blood flow to the hippocampus is only just sufficient for correct function.
Researchers have studied brain activity and blood flow in the hippocampus of mice. The team used simulations to predict that the amount of oxygen supplied to hippocampal neurons furthest from blood vessels is only just enough for the cells to keep working normally. "These findings are an important step in the search for preventative measures and treatments for Alzheimer's, because they suggest that increasing blood flow in the hippocampus might be really effective at preventing damage from happening. If it's right that increasing blood flow in the hippocampus is important in protecting the brain from diseases like Alzheimer's, then it will throw further weight behind the importance of regular exercise and a low-cholesterol diet to long-term brain health."
"We think that the hippocampus exists at a watershed. It's just about OK normally, but when anything else happens to decrease brain blood flow, oxygen levels in the hippocampus reduce to levels that stop neurons working. We think that's probably why Alzheimer's disease first causes memory problems - because the early decrease in blood flow stops the hippocampus from working properly. The same factors that put you at risk of having a heart attack make you more likely to develop dementia. That's because our brains need enough blood flow to provide energy - in the form of oxygen and glucose - so brain cells can work properly, and because blood flow can clear away waste products such as the beta amyloid proteins that build up in Alzheimer's disease. Now we want to discover whether the lower blood flow and oxygen levels in the hippocampus are what causes beta amyloid to start to build up in Alzheimer's disease. Understanding what causes early damage will be really important to help us learn how to treat or prevent disease."
A Treatment to Rebuild Tooth Enamel
Rebuilding lost tooth enamel is an important goal in a world in which robust control over the bacteria responsible for producing cavities has not yet been achieved. In a welcome advance in this part of the field, researchers will soon conduct trials of a low cost approach to achieve reconstruction of enamel, slowly over time.
Researchers are preparing to launch clinical trials of a lozenge that contains an engineered peptide, or chain of amino acids, along with phosphorus and calcium ions, which are building blocks of tooth enamel. The peptide is derived from amelogenin, the key protein in the formation of tooth enamel, the tooth's crown. It is also key to the formation of cementum, which makes up the surface of the tooth root.
Each lozenge deposits several micrometers of new enamel on the teeth via the peptide, which is engineered to bind to the damaged enamel to repair it while not affecting the mouth's soft tissue. The new layer also integrates with dentin, the living tissue underneath the tooth's surface. Two lozenges a day can rebuild enamel, while one a day can maintain a healthy layer.
The lozenge produces new enamel that is whiter than what tooth-whitening strips or gels produce. It has another distinct advantage: Conventional whitening treatments rely on hydrogen peroxide, a bleaching agent that can weaken tooth enamel after prolonged use. Since tooth enamel can't regrow spontaneously, the underlying dentin can be exposed, with results ranging from hypersensitivity to cavities or even gum disease. The lozenge, on the other hand, strengthens, rebuilds, and protects teeth.
In addition, the researchers are investigating a gel or solution with the engineered peptide to treat hypersensitive teeth. This problem results from weakness in the enamel that makes the underlying dentin and nerves more vulnerable to heat or cold. Most common products currently on the market can put a layer of organic material on the tooth and numb nerve endings with potassium nitrate, but the relief is only temporary. The peptide, however, addresses the problem permanently at its source by strengthening the enamel.
A Mechanism by which Amyloid-β can Reduce Capillary Density in the Alzheimer's Brain
Aggregation of amyloid-β is a feature of the slow buildup towards Alzheimer's disease that takes place in later life, though it remains unclear as to whether this protein aggregation is a cause or a side-effect in the progression of the condition. Separately, loss of capillary density is a feature of aging in tissues throughout the body. In energy-hungry tissues such as the brain, this is a real problem, contributing to an insufficient supply of nutrients and consequent loss of function. The exact causes of this reduced capillary density are poorly understood. Here, researchers suggest that amyloid-β aggregation is one such cause, disrupting the balance of mechanisms needed to maintain capillary vessels in tissue.
Researchers have discovered a new mechanism of Alzheimer's disease that disorganises the blood vessels around amyloid plaques, one of the characteristic features of the disease. The mechanism put forward in this study is mediated by the dysfunction of a physiological process, angiogenesis. This mechanism is important during development to form the vessels of the brain and in adulthood to revert possible damage to pre-existing vessels. The study shows that Alzheimer's disease induces angiogenesis dysfunction that causes the loss of vessels instead of the formation of new ones, undoubtedly aggravating the pathology. By identifying the molecular pathways involved, new therapeutic strategies to alleviate the effects of this disease can be rationally designed.
A characteristic feature of Alzheimer's patients is the accumulation of highly toxic substances in their brains, known as senile plaques. The brain has the capacity to clean these toxic substances via transport through the blood. Thus the fact that the plaques cause the loss of the vessels constitutes a vicious circle: having fewer vessels reduces the ability to clean the brain thus allowing more toxic substances to accumulate, which in turn continue to destroy the vessels and worsen the situation. The brain consumes much of the body's oxygen and nutrients. Thus a local reduction in the supply of these substances through the blood represents an additional strain above and beyond the existing strain from the accumulation of toxic substances.
A Less Well Explored Cdkn1a Transcript is a Marker of Aging and Cellular Senescence
The gene Cdkn1a (or P21) generates two different RNA transcripts that both lead to the production of the same protein. Researchers here provide evidence to suggest that the less well explored second transcript is a good marker of aging and cellular senescence, at least in mice. The biochemistry of senescence seems to be well conserved across species, so with luck the same data will be replicated in humans in the near future. Better and less invasive approaches to robustly assess senescent cell burden, improvements on the the current standard of tissue samples and immunohistochemistry, are very much needed. A well-validated blood test, for example, would be a step forward in terms of speeding up the development of senolytic therapies to clear senescent cells.
Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16Ink4a and p21Cip1/Waf1. In mice, the p21Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues.
Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.
Distinctive Macrophage Signaling is Vital to Axolotl Limb and Organ Regeneration
Research into the comparative biology of regeneration suggests that mammals are in principle capable of proficient, full regeneration of complex tissues, but some critical difference in cell signaling and behavior leads instead to the formation of scar tissue in adults. In recent years, scientists have focused on the role of macrophages in coordinating the process of regeneration. In proficient regenerators like salamanders and zebrafish, the presence of macrophages is essential to the regenerative process. Absent macrophages, scar tissue forms in the same way as it does in mammals. Researchers now aim to understand exactly what is different in the behavior of macrophages in mammals and highly regenerative species.
The axolotl, a Mexican salamander that is now all but extinct in the wild, is a favorite model in regenerative medicine research because of its one-of-a-kind status as nature's champion of regeneration. While most salamanders have some regenerative capacity, the axolotl can regenerate almost any body part. Since mammalian embryos and juveniles have the ability to regenerate - for instance, human infants can regenerate heart tissue and children can regenerate fingertips - it's likely that adult mammals retain the genetic code for regeneration, raising the prospect that pharmaceutical therapies could be developed to encourage humans to regenerate tissues and organs lost to disease or injury instead of forming a scar.
Researchers compared immune cells called macrophages in the axolotl to those in the mouse with the goal of identifying the quality in axolotl macrophages that promotes regeneration. The research builds on earlier studies in which it was found that macrophages are critical to regeneration: when they are depleted, the axolotl forms a scar instead of regenerating, just like mammals. The recent research found that although macrophage signaling in the axolotl and in the mouse were similar when the organisms were exposed to pathogens, when it came to exposure to injury it was a different story: the macrophage signaling in the axolotl promoted the growth of new tissue while that in the mouse promoted scarring.
Specifically, the signaling response of a class of proteins called toll-like receptors (TLRs), which allow macrophages to recognize a threat such an infection or a tissue injury and induce a pro-inflammatory response, were unexpectedly divergent in response to injury in the axolotl and the mouse. The finding offers an intriguing window into the mechanisms governing regeneration in the axolotl. The discovery of an alternative signaling pathway that is compatible with regeneration could ultimately lead to regenerative medicine therapies for humans.
Assessing Sarcopenia and Dynapenia via Ultrasound
Researchers here propose an approach to measure the progression of sarcopenia, the loss of muscle mass and strength with aging, via ultrasound assessment of muscle structure. The present most widely practiced approaches involve assessment of muscle mass, grip strength, walking speed, ability to stand up from a chair, and the like. As understanding of the underlying mechanisms of the condition grow, a more rigorous form of assessment becomes desirable, one that can hopefully be extended into detecting the earliest stages of sarcopenia, with an eye towards prevention.
While the definition of sarcopenia is an evolving concept that started with a classification based on muscle mass alone, this has progressively moved to a more operational definition that includes the loss not only of muscle mass but also of muscle strength, with a risk of adverse outcomes such as physical disability, poor quality of life, and even death. However, as recognized by recent definitions of sarcopenia, low muscle mass or quality is a determinant factor for confirming sarcopenia in the presence of low muscle strength, otherwise known as dynapenia. Hence, the measurement of muscle mass remains a key requirement for the clinical diagnosis of sarcopenia. Typically, this has been achieved using dual X-ray absorptiometry (DXA), MRI, or bioelectrical impedance. The use of these methods has been widespread and has been instrumental for the diagnosis of sarcopenia in clinical settings.
In 2003, we reported for the first time that the loss of muscle mass associated with sarcopenia not only entails a decrease in muscle cross-sectional area and volume but also alterations in the spatial arrangement of muscle fibres within the muscle. Knowledge of the spatial arrangement of muscle fibres within a muscle is particularly important because muscle architecture is one of the most important determinants of muscle force and velocity. Using ultrasonography, we were able to show, for several locomotor muscles, that the key parameters of muscle architecture are significantly altered in sarcopenic muscle.
If changes in muscle architecture were to scale harmonically with the decrease in muscle volume due to sarcopenia, one would expect the ratio of fascicle length (Lf) to muscle thickness (Tm) to remain constant. However, muscle length (and thus fascicle length) is constrained by its connections into the proximal and distal tendons that insert into bony structures. Although fascicle length has been found to decrease with ageing, this effect should be limited by the proximal and distal tendon insertions into bone, unless tendons were to elongate, which is most unlikely. Hence, the reduction in muscle mass with ageing should be due more to a decrease in muscle thickness than in fascicle length, that is, it should involve a greater loss of sarcomeres in parallel than in series. Recent observations made in our laboratory in different populations of older individuals (active, sedentary, and mobility impaired) seem to confirm this assumption: with increasing degree of sarcopenia, the decrease in muscle thickness (Tm) exceeds that of fascicle length (Lf).
These findings prompted us to formulate the hypothesis that the Lf/Tm ratio, which we shall refer to as 'ultrasound sarcopenia index' (USI), may be used as a marker of the loss of muscle mass associated with sarcopenia. An important advantage of using a marker based on an anatomical ratio rather than on absolute values is its independence from gender and body dimensions. Further, there are several important advantages to be considered regarding the use of ultrasound for assessing muscle architecture, both for clinical and practical purposes. Ultrasound can be delivered at a fraction of the cost of MRI, and has a very good reliability and reproducibility when performed by properly trained personnel.
Th17 Immunity and the Inflammation of Aging in Intestinal Barrier Dysfunction
The immune system is a very complex network of many different cell types, signals, and layered responses. It is much more subdivided and varied than the broad distinction between innate and adaptive immune components might lead one to believe. As a whole the immune system runs awry in later life, becoming both overly active and incompetent at the same time. Chronic inflammation and an inability to adequately defend against pathogens is the result. Many researchers are engaged in picking apart the details of this failure state, and the work here is a representative example of this sort of work, with a narrow focus on one smaller portion of the immune system and its responsibilities.
Chronic sub-clinical inflammation of aging, resulting from lifetime exposures to pathogens in concert with impaired immune responses, poses an obstinate challenge to the health span of the growing elderly population. Several factors contribute to the increased morbidity/mortality of older adults, including loss of naïve lymphocytes, exhaustion of adaptive immunity, and a skew toward proinflammatory responses. Additionally, loss of intestinal homeostasis and perturbations in epithelial barrier protective immune functions have recently emerged as key factors underlying chronic inflammation and age-related comorbidities.
Defense of epithelial barriers against invading pathogens and maintenance of mucosal homeostasis mainly relies on the Th17-type immunity, also known as type-17 and Th3 immunity, which is characterized by IL-17/IL-22 cytokine production. IL-17 predominantly triggers the influx of neutrophils and tissue repair, while IL-22 stimulates proliferation of epithelial cells, and regulates epithelial permeability, production of mucus, antimicrobial proteins, and complement to help maintain barrier integrity.
Our laboratory has shown that systemic inflammation in older macaques was associated with reduced Th17-type cytokine functions of CD161+ immune cells. This correlated with circulating biomarkers of leaky gut and microbial translocation, suggesting a link between intestinal barrier dysfunction and inflammaging. There is significant evidence showing that Th17-type immunity and epithelial barrier functions have an important role in the immune response and inflammation of aging; however, the precise cellular and molecular mechanisms underlying altered Th17-type responses in aging humans remain to be elucidated.
The health and diversity of our microbiome and how it influences Th17-type responses should also be of value for mucosal immunity in the context of aging. A clear understanding of epithelial barrier protective Th17-type responses will aid the development of targeted therapies, specifically tailored for the elderly.
The Mainstream Media is Slowly Becoming Less Skeptical of Work to Extend the Healthy Human Life Span
One can't maintain dismissive skepticism forever in the face of scientific and medical development communities that are ever more engaged in the development of therapies to address the mechanisms of aging. To pick one example, senolytic treatments that clear senescent cells from aged tissues are producing consistently amazing data in mice: rejuvenation, extension of healthy life, reversal of measures of many specific age-related diseases. We'll soon know how well the more viable senolytics perform in human trials, as the preliminary data from the use of dasatinib and quercetin shows that it does selectively destroy senescent cells in humans as it does in mice. Given the serious prospect of living longer in good health, I would expect the previously doom and gloom crowd of naysayers to capitulate and admit that, yes, actually it would be pleasant to have more health, more life, and less pain, suffering, and death.
People are living longer, staying healthier longer and accomplishing things late in life that once seemed possible only at younger ages. And it's not just superstars. The fraction of over-85s in the U.S. classified as disabled dropped by a third between 1982 and 2005, while the share who were institutionalized fell nearly in half. As a whole, Americans seem to be aging more slowly than before. Researchers compared how men 60 to 79 years old aged in 1988 to 1994 and in 2007 to 2010. They found that in those later years, the men they studied had a biological age four years less than the men in the earlier years, in part because of improvements in lifestyle and medications. This suggests that not only are people living longer, they're also staying healthier longer.
On one level, greater health and longevity is an old story. In 1900, life expectancy in the U.S. was about 47 years and now it's about 78. But we may also be on the cusp of something new. Over the course of the 20th century, we primarily aided longevity by tackling disease. In the first half of the century vaccines and other innovations prevented people from dying young of communicable diseases. In the second half, improvements in lifestyle and other medical breakthroughs prevented many people from dying in middle age of things like heart attacks and cancer.
But while these improvements have made it more likely that people will live to be 65, after that, aging itself takes an inexorable toll. Even if you beat lung cancer or survive a heart attack, your body's deterioration will finish you off before too long. The average 80-year-old suffers from around five diseases. That's why even if we could totally cure cancer, it would add less than three years to average life expectancy. A total cure for heart disease would give us at best two extra years. To keep the longevity train rolling it may not be enough to cure diseases. We may also need to address the underlying condition of aging itself, which is, after all, the primary risk factor for late-life decline.
S. Jay Olshansky has said "While there are no documented interventions that have been proven safe and effective in slowing aging in humans today, we are on the verge of a breakthrough." For example, as we age, we build up more and more "senescent" cells, which secrete inflammatory molecules that can effectively accelerate aging. In 2011, researchers removed these cells from mice and extended their life spans. Clinical trials on people began in 2018. It's likely that all Americans could be living longer, healthier lives. I imagine an 80-year-old bounding from bed, biking in the morning and playing softball in the afternoon. We're all on borrowed time. More time is more life, and more of it will be sweet.
Athletes Undergoing Regular Strength Training Exhibit Slowed Aging of Bone Tissue
The mechanisms of aging produce a range of detrimental effects on bones, most evidently the progressive loss of density and resilience that becomes osteoporosis in its later and severe stages. It is known that strength training blunts the loss of muscle mass and strength that occurs with age, and reduces mortality risk in later life. Here, researchers show that it can also slow the aging of bone tissue. The effect size is small, but note that the researchers are comparing well trained athletes with adequately trained athletes, rather than with the general population.
Cross-sectional and interventional studies suggest that high-intensity strength and impact-type training provide a powerful osteogenic stimulus even in old age. However, longitudinal evidence on the ability of high-intensity training to attenuate age-related bone deterioration is currently lacking. This follow-up study assessed the role of continued strength and sprint training on bone aging in 40- to 85-year-old male sprinters (n = 69) with a long-term training background.
Peripheral quantitative computed tomography (pQCT)-derived bone structural, strength, and densitometric parameters of the distal tibia and tibia midshaft were assessed at baseline and 10 years later. The groups of well-trained (actively competing, sprint training including strength training ≥2 times/week; n = 36) and less-trained (less than 2 times/week, no strength training, switched to endurance training; n = 33) athletes were formed according to self-reports at follow-up. Longitudinal changes in bone traits in the two groups were examined.
Over the 10-year period, group-by-time interactions were found for distal tibia total bone mineral content (BMC), trabecular volumetric bone mineral density (vBMD), and compressive strength index, and for mid-tibia cortical cross-sectional area, medullary area, total BMC, and BMC at the anterior and posterior sites. These interactions reflected maintained (distal tibia) or improved (mid-tibia) bone properties in the well-trained and decreased bone properties in the less-trained athletes over the 10-year period. Depending on the bone variable, the difference in change in favor of the well-trained group ranged from 2% to 5%.
In conclusion, our longitudinal findings indicate that continued strength and sprint training is associated with maintained or even improved tibial properties in middle-aged and older male sprint athletes, suggesting that regular, intensive exercise counteracts bone aging.