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Fight Aging! Newsletter, August 3rd 2020

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#1 reason

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Posted 02 August 2020 - 12:56 PM

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,please visit:https://www.fightaging.org/newsletter/

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/


  • A Genomic Search for Longevity-Associated Genes Points to Iron Metabolism in Human Aging
  • Evidence for Oxytocin to Reverse Impairment of Synaptic Plasticity by Amyloid-β
  • Long Term Low Dose Ethanol Intake Modestly Extends Life in Mice
  • Bat Biochemistry Points to DNA Repair and Autophagy as Important Determinants of Mammalian Species Longevity
  • Combining Therapies as the Next Frontier for the Treatment of Aging
  • Age Related Hearing Loss is Caused by Damage to Hair Cells
  • Organoids Used to Identify NRG1 as a Regulator of Tissue Repair in the Intestine
  • Glycosylation Changes in Epidermal Stem Cells as a Biomarker of Aging
  • Glucosamine Supplementation Correlates with Lower All Cause Mortality
  • Naked Mole-Rat Senescent Cells are Unusually Vulnerable to Oxidative Stress
  • Cognitive Decline is Accelerated by Hypertension, Diabetes, and Smoking
  • Eating Ourselves into Shorter, Less Healthy Lives
  • An Age-Related Increase in CD47 Expression Impairs Vascular Function
  • Fitness in Humans Acts to Reduce Inflammation, But Does Not Reduce the Burden of Cellular Senescence in Muscle Tissue
  • Reviewing the Mechanisms of Alzheimer's Disease

A Genomic Search for Longevity-Associated Genes Points to Iron Metabolism in Human Aging

As a general rule, one should be skeptical about any and all single studies that identify longevity-associated genes from human data. Typically the results cannot be replicated in different study populations, and the effect sizes are in any case small. Identified gene variants confer only small changes in the odds of reaching a given age. Only a handful of gene variants show up reliably in multiple studies carried out in different human populations. So, unfortunately, however interesting or novel the data in a new study, such as the association of longevity with maintenance of normal iron levels noted in today's open access research paper, there is a good chance that it will remain unconfirmed.

Other approaches to determining the genetic contribution to longevity tend to indicate that genetic variants are much less important than lifestyle choices for near every individual. This all suggests that there exist a very large number of tiny, interacting, situational gene variants that influence longevity, but most likely nothing more promising than that. This isn't the road to greatly extended healthy human life spans; it is a road to better understanding the fine details of aging as it occurs today, very little influenced by medicine.

Multivariate genomic scan implicates novel loci and haem metabolism in human ageing

Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes.

The effects of loci of interest on male and female lifespan are largely the same, although their effect on survival may be slightly stronger in middle age (40-60 years) compared to old age (older than 80 years). We find these loci of interest colocalise with the expression of 28 cis-genes and 50 trans-genes, some of which are known to become differentially expressed with increasing age. Lastly, we find these genes are enriched for seven hallmark gene sets (particularly haem metabolism) and 32 largely overlapping biological pathways (including apoptosis and homeostasis), and in line with the highlighted pathways, we find a causal role for iron levels in healthy life.

Haem synthesis declines with age and its deficiency leads to iron accumulation, oxidative stress, and mitochondrial dysfunction. In turn, iron accumulation helps pathogens to sustain an infection, which is in line with the known increase in infection susceptibility with age. In the brain, abnormal iron homeostasis is commonly seen in neurodegenerative diseases such as Alzheimer's and Parkinson's disease and multiple sclerosis. Plasma ferritin concentration, a proxy for iron accumulation when unadjusted for plasma iron levels, has been associated with premature mortality in observational studies, and has been linked to liver disease, osteoarthritis, and systemic inflammation.

Evidence for Oxytocin to Reverse Impairment of Synaptic Plasticity by Amyloid-β

Today's research materials report on recently presented preliminary evidence, based on work in tissue slices from mouse brains, for oxytocin to dampen the harms done to the function of neurons by amyloid-β. Amyloid-β is one of the few proteins in the body capable of becoming altered in ways that encourage other molecules of amyloid-β to alter in the same way, aggregating into solid deposits in and around cells. This is disruptive to cell function when it occurs in the brain, and rising amyloid-β aggregation is widely thought to be the early, formative stage of Alzheimer's disease.

Oxytocin is one of the factors that diminishes with age in blood, identified as potentially interesting in parabiosis studies of recent years. This work was largely focused on the role of oxytocin in muscle regeneration via its influence on stem cell function, however. More recently, increasing oxytocin and lowering TGF-β in combination was shown to reverse measures of aging in numerous tissues in mice. That, again, seems to be a matter of effects on inflammation and stem cell function rather than something more specific such as an influence on cell mechanisms relevant to amyloid-β.

Oxytocin Could Be Used to Treat Cognitive Disorders Like Alzheimer's

Alzheimer's disease is a progressive disorder in which the nerve cells (neurons) in a person's brain and the connections among them degenerate slowly, causing severe memory loss, intellectual deficiencies, and deterioration in motor skills and communication. One of the main causes of Alzheimer's is the accumulation of a protein called amyloid β (Aβ) in clusters around neurons in the brain, which hampers their activity and triggers their degeneration.

Studies in animal models have found that increasing the aggregation of Aβ in the hippocampus - the brain's main learning and memory center - causes a decline in the signal transmission potential of the neurons therein. This degeneration affects a specific trait of the neurons, called synaptic plasticity, which is the ability of synapses (the site of signal exchange between neurons) to adapt to an increase or decrease in signaling activity over time. Synaptic plasticity is crucial to the development of learning and cognitive functions in the hippocampus. Thus, Aβ and its role in causing cognitive memory and deficits have been the focus of most research aimed at finding treatments for Alzheimer's.

Researchers first perfused slices of the mouse hippocampus with Aβ to confirm that Aβ causes the signaling abilities of neurons in the slices to decline, impairing synaptic plasticity. Upon additional perfusion with oxytocin, however, the signaling abilities increased, suggesting that oxytocin can reverse the impairment of synaptic plasticity that Aβ causes. In a normal brain, oxytocin acts by binding with special structures in the membranes of brain cells, called oxytocin receptors. Expectedly, when the receptors were blocked, oxytocin could not reverse the effect of Aβ, which shows that these receptors are essential for oxytocin to act.

Oxytocin is known to facilitate certain cellular chemical activities that are important in strengthening neuronal signaling potential and formation of memories, such as influx of calcium ions. Previous studies have suspected that Aβ suppresses some of these chemical activities. When the scientists artificially blocked these chemical activities, they found that addition of oxytocin addition to the hippocampal slices did not reverse the damage to synaptic plasticity caused by Aβ. Additionally, they found that oxytocin itself does not have any effect on synaptic plasticity in the hippocampus, but it is somehow able to reverse the ill-effects of Aβ.

Oxytocin reverses Aβ-induced impairment of hippocampal synaptic plasticity in mice

Oxytocin, a peptide hormone synthesized in the hypothalamic paraventricular nucleus, has been reported to participate in the regulation of learning and memory performance. However, no report has demonstrated the effect of oxytocin on the amyloid-beta (Aβ)-induced impairment of synaptic plasticity. In this study, we examined the effects of oxytocin on the Aβ-induced impairment of synaptic plasticity in mice.

To investigate the effect of oxytocin on synaptic plasticity, we prepared acute hippocampal slices for extracellular recording and assessed long-term potentiation (LTP) with perfusion of the Aβ active fragment (Aβ25-35) in the absence and presence of oxytocin. We found that oxytocin reversed the impairment of LTP induced by Aβ25-35 perfusion in the mouse hippocampus. These effects were blocked by pretreatment with the selective oxytocin receptor antagonist L-368,899. Furthermore, the treatment with the ERK inhibitor U0126 and selective Ca2+-permeable AMPA receptor antagonist NASPM completely antagonized the effects of oxytocin.

Long Term Low Dose Ethanol Intake Modestly Extends Life in Mice

As of the past few years, the long-standing debate over whether moderate alcohol intake has a protective effect on health had appeared to resolve to the conclusion that the observed epidemiology is explained by socioeconomic factors, not by the metabolic effects of molecules such as polyphenols present in wine or other alcoholic drinks. People who engage in more modest alcohol consumption tend to be in the wealthier sections of society, and thus are more health conscious, undertake lifestyle choices, and make better use of available medical technologies.

In that context, today's open access paper is quite interesting. The authors report on a study in which a 4.4% extension of mean lifespan and various improvements in metabolism take place in mice that are given drinking water that is 3.5% ethanol, that intervention starting at 8 weeks of age. The researchers suggest that this might be mediated by pathways involving AMPK and mitochondrial function, and note that there is a comparatively lack of research into alcohol intake at this low, sustained level. It will be interesting to see how this line of inquiry develops in the years ahead, although I'd be the first to say that the effect size here is far too small to be of more than academic interest.

Long-term low-dose ethanol intake improves healthspan and resists high-fat diet-induced obesity in mice

Previous studies on the protection of alcoholic beverages have been primarily focused on the polyphenols such as resveratrol, procyanidins and other substances like catechin and tannin. Ironically, the most important common component of all alcoholic beverages, alcohol or ethanol, has received much less attention. In this study, we use ethanol, the common substance in all kinds of alcoholic beverages, as a single variable to explore its effects in vivo. Our data showed that the long-term 3.5% ethanol substitution for drinking water had beneficial effects in mice, the daily performance of ethanol-fed mice was enhanced, the athletic ability and healthspan of ethanol-fed mice drastically improved. Furthermore, the ethanol-fed mice showed the resistance to high-fat diet (HFD). When supplemented with 3.5% ethanol, the HFD mice showed reduced multiple organ pathogenicity, increased insulin sensitivity, and decreased NF-kB activation and inflammatory cytokines. These changes caused by ethanol are astonishing and impressive.

It has been well accepted that acute and chronic excessive alcohol exposure is conducive to tissue injury. However, one should be mindful that the injuries caused by the excessive use of alcohol are dose-dependent. In our study, the long term 3.5% ethanol-fed mice did not show the common negative effects of alcohol. At this dose, we did not observe any pathological structural changes in the liver, the heart, or the kidneys; neither did we detect any impairments of learning, memory, and cognition by the water maze.

One of the pathophysiological mechanisms induced by alcohol abuse has been identified as mitochondrial dysfunction. On the other hand, the mitochondrial volume was associated with high levels of physical activity. The improved mitochondrial function of long-term low-dose ethanol-intake (LLE) mice may be due to their high level of daily physical activity and enhancement of athletic ability of LLE mice. In our experiments, we observed that the mitochondrial density in the liver and the skeletal muscles of the ethanol-fed group increased, and the morphology became stronger with more cristae, indicating improved mitochondrial function under the moderate ethanol feeding.

AMPK induces mitochondrial biogenesis and has emerging roles in the regulation of both mitochondrial metabolism and dynamics. Phosphorylation activity of AMPK, necessary for mitochondrial biogenesis via SIRT1 and PGC1a, was increased in the liver of the LLE mice. Considering the activation of AMPK by moderate ethanol intake, it seems reasonable to entertain the hypothesis that the rapid acetate metabolism following the ingestion of ethanol generates sufficient AMP to transiently activate AMPK, which in turn induces the synthesis of certain long-lived proteins that act to boost insulin sensitivity and possibly aid the efficiency of fat oxidation as well.

Bat Biochemistry Points to DNA Repair and Autophagy as Important Determinants of Mammalian Species Longevity

Investigation of the comparative biology of aging is one of many notable communities within the broader research community focused on aging and age-related disease. Scientists use comparisons between different species with very different life spans as a way to try to pin down the mechanisms that are most important in aging. Thus there is work on naked mole-rats versus mice, both similarly sized rodents. Whales capable of living for centuries are compared to smaller mammals that are not. Humans are compared to our nearest primate relatives, all of whom are less long-lived than we are. And so forth.

One of the more interesting comparisons to be made is between bats and other mammals. It is quite clear that flight requires considerable metabolic adaptation, and it seems plausible that these adaptations make individuals more resistant to some of the processes of aging. Both birds and bats tend to be long-lived for their size. Not all bats are long-lived, however, which means that perhaps there are things to be learned from a comparison of long-lived and short-lived bat species. That is the subject of today's open access paper.

It remains a question as to whether work on the comparative biology of aging will produce practical outcomes. It is one thing to identify a mechanism, or a different arrangement of cellular biochemistry, as likely important in aging. It is entirely another thing to try to build a therapy based on the way that bat, whale, or naked mole-rat cells function. There is no guarantee that any particular species difference is a practical basis for medical applications. Engineering a better human that ages more slowly by changing cellular metabolism into something that looks more like that of another species is more likely a product for later in the century, not now. Also, aging more slowly is of little use to people already old - we want rejuvenation and repair of damage, not ways to make damage accumulate more slowly.

Genetic variation between long-lived versus short-lived bats illuminates the molecular signatures of longevity

Natural selection has shaped a large variation of lifespan across mammals, with maximum lifespan ranging from a few months (e.g. short-lived shrews) to 211 years (e.g. bowhead whale). Although the bowhead whale is exceptionally long-lived, its lifespan is arguably not as extreme as that of a 30 years old naked mole-rat given their body sizes, as maximum lifespan (MLS) exhibits a positive correlation with body size within mammals. Thus, lifespan comparison across mammals requires body size correction. To resolve this, the longevity quotient (LQ) was introduced, which is defined as the ratio of observed lifespan to predicted lifespan for a non-flying mammal of the same body size. Using this approach bats are the longevity extremists, with some species living up to ten times longer than expected given their body size. The Brandt's bat (Myotis brandtii) holds the record for longevity, with a maximum lifespan of more than 40 years, living 8-10 times longer than expected given a body weight of ~7 grams. This renders bats as one of the most ideal taxa to explore the molecular basis of extraordinary longevity in mammals.

Although the majority of bat species are long-lived, especially within the Myotis genus, there are a few short-lived exceptions, such as the velvety free-tailed bat (Molossus molossus) and the evening bat (Nycticeius humeralis), living as long as would be expected given their body size. A recent study has suggested that the ancestral bat lived up to 2.6 times longer than expected given body size, indicating that the extreme longevity observed in the longest-lived bat genera may have evolved multiple times. This also suggests that short-lived bat species may have lost their longevity adaptations. Therefore, this wide range of lifespans observed in bats enables us to utilize comparative evolutionary approaches to search for genetic differences within closely-related long- and short-lived bat species.

In this study we performed a comparative genomic and transcriptomic analysis between long-lived Myotis myotis (MLS = 37.1 years; LQ = 5.71) and short-lived Molossus molossus (MLS = 5.6 years; LQ = 0.99) to ascertain the molecular signatures associated with longevity in bats. Based on the genome-wide alignments of single-copy orthologous genes between these two species, we detected and further investigated the genes that were fast-evolving and showed significant positive selection. We also deep sequenced blood transcriptomes from eight adult individuals for each species, and explored the genes and pathways that were differentially expressed. To ascertain if long-lived bats have evolved a transcriptomic signature of longevity, we further investigated the expression of 'pro'- and 'anti'-longevity genes in the blood transcriptomes of M. myotis and M. molossus. Although the majority of genes underwent purifying selection, we observed a significant transcriptional alteration between these two species.

Among 2,086 genes that exhibited large interspecific expression variation, the genes that showed higher expression in long-lived M. myotis were mainly enriched in DNA repair and autophagy. Further pathway analysis suggested that six biological processes, including autophagy, were differentially expressed between M. myotis and M. molossus. We also show that M. myotis had significantly lower expression levels of anti-longevity genes, suggestive of a transcriptomic signature of longevity naturally evolved in long-lived bats. Together with the previous findings in other long-lived mammals, our study implies that enhanced DNA repair and autophagy activity may represent a universal mechanism to achieve longevity in long-lived mammals.

Combining Therapies as the Next Frontier for the Treatment of Aging

There are two activities in medical science in which both the academic research community and clinical development industry are truly terrible at achieving results, or indeed even at getting started at all. The first is transfer of programs from academia to industry. The renowned valley of death in the development of new medical biotechnologies is very real; so very many programs languish undeveloped simply because neither side can effectively coordinate with the other. The second is the testing of synergies between multiple therapies that are applied at the same time to the same patient for the treatment of the same condition. We live in a world in which age-related conditions are the result of multiple distinct contributing mechanisms, so why is it that the exploration and application of combined therapies that target separate mechanisms is such a rare occurrence?

Firstly, different therapies tend to be owned by different groups (companies or universities) who have only limited incentives to collaborate with one another. Because the biotech field is governed in a very heavy-handed way by intellectual property and other forms of government regulation, setting up a collaboration is a costly matter. Thus in a world in which the expectation is that few efforts will be successful, as is the case for most initiatives in medical science, there is an unwillingness to explore. Secondly, the regulatory process for approval is very, very costly. Taking a candidate drug through to phase III trial success is at least a 150M proposition, and usually more. Companies do all they can to make clinical trials as simple as possible, and there is no incentive to roll the dice on a collaborative trial that depends on another drug outside the control of the company in question.

And yet, aging and all age-related diseases are the consequence of multiple underlying forms of molecular damage. They will require multiple very different therapies to achieve complete reversal or prevention. The perverse incentives in medical regulation and intellectual property are acting to close off the most promising strategy for the treatment of aging, which is to tackle all of its varied causes concurrently. Something must change here. As Aubrey de Grey points out in the short interview below, this is the next frontier for patient advocacy. Now that the first rejuvenation therapies are being actively developed, using them together is a logical next step.

Aubrey de Grey: "Damage repair is the future of longevity medicine"

Aubrey is a plain-speaking biomedical gerontologist who is committed to combating the aging process. We started by asking him about what he was up to at the moment.

SENS Research Foundation suffered a fair amount of slowdown as a result of the pandemic, but we're picking up now. I think the most exciting thing we're doing is continuing to strengthen the pipeline between the really early-stage translational work we do at SENS and the "just investable" stage work pursued by startups in our space, including our own spinouts. Basically, the appetite of some investors is increasingly emphasising projects that are so early that they would historically be viewed as pre-competitive; that boundary is now becoming very blurred.

What isn't getting sufficient exposure?

I would say that the single biggest elephant in the room is the simultaneous administration of multiple therapies. It is subliminally understood that damage repair is the future of longevity medicine, and also that the damage repair paradigm is inescapably a divide-and-conquer one that will entail combination therapies, but the medical industry is really not set up to develop and promote that way of working. At some point that has to change, and I'm hopeful that investors at the more courageous end of the spectrum will soon find ways to start that process in earnest.

Our survey found that most investors appear to prefer seed-to-early-stage investing, have you found this to be case in your networks?

Absolutely. At this point I don't see how things could be otherwise, actually, because the investment opportunities consist almost entirely of startups, which in turn is because the underlying technologies are so new.

We also saw that senolytics are a very popular category for investors - are you seeing an increased appetite from investors?

I do see that tendency too, and it's not surprising to me, because senolytics have two huge things going for them: they are bona fide rejuvenators (i.e. they repair a type of aging damage rather than just slowing down its accumulation), which is much more exciting to people old enough to have money to invest, and they are only just now going into clinical trials and showing impressive results, so they are opportunities for first movers.

Age Related Hearing Loss is Caused by Damage to Hair Cells

Researchers here provide evidence for age-related deafness to be caused by the loss of viable hair cells in the inner ear, rather than other possible mechanisms. As pointed out, this is perhaps the best outcome for such a study, given the numerous approaches to hair cell regeneration or hair cell replacement that are underway in the scientific community. While it is interesting to compare this result with earlier data suggesting that hair cells survive in old individuals, but are disconnected from the brain, it nonetheless boosts the prospects for near term reversal of age-related hearing loss.

Scientists have demonstrated that age-related hearing loss, also called presbycusis, is mainly caused by damage to hair cells, the sensory cells in the inner ear that transform sound-induced vibrations into the electrical signals that are relayed to the brain by the auditory nerve. Their research challenges the prevailing view of the last 60 years that age-related hearing loss is mainly driven by damage to the stria vascularis, the cellular "battery" that powers the hair cell's mechanical-to-electrical signal conversion.

Researchers examined 120 inner ears collected at autopsy. They compared data on the survival of hair cells, nerve fibers, and the stria vascularis with the patients' audiograms to uncover the main predictor of the hearing loss in this aging population. They found that the degree and location of hair cell death predicted the severity and pattern of the hearing loss, while stria vascularis damage did not. Previous studies examined fewer ears, rarely attempted to combine data across cases and typically applied less quantitative approaches. Most importantly, prior studies greatly underestimated the loss of hair cells, because they didn't use the state-of-the art microscopy techniques.

Previous animal studies suggested that presbycusis is caused by atrophy of the stria vascularis, a highly vascularized cluster of ion-pumping cells, located in the inner ear adjacent to the hair cells. The stria serves as a "battery" that powers the hair cells as they transform sound-evoked mechanical motions into electrical signals. In aging laboratory animals, such as gerbil, there is very little loss of hair cells, compared to humans, even at the end of life. However, there is prominent damage to the stria vascularis, and damage to the stria will, indeed, cause hearing loss. Prior to this new study, most scientists have assumed that the aging gerbil data also apply to human presbycusis.

The researchers say the new findings are good news given recent progress in the development of therapies to regenerate missing hair cells. If presbycusis were due primarily to strial damage, hair cell regeneration therapy would not be effective. This new study turns the tables, suggesting, that vast numbers of hearing impaired elderly patients could likely benefit from these new therapies as they come to the clinics, hopefully within the next decade.

Organoids Used to Identify NRG1 as a Regulator of Tissue Repair in the Intestine

The intestinal lining is an important tissue. Among its other functions, it protects the body from inflammation that can be generated by the actions of gut microbes. This barrier declines with age, and this is thought to be influential in the increased chronic inflammation observed in older people. Ways to spur greater maintenance and repair on the part of cell populations making up intestinal tissue would likely be of great benefit, given the importance of chronic inflammation as a driver of age-related disease.

A strong cellular lining is essential for a healthy gut as it provides a barrier to the billions of microbes and harmful toxins present in our intestinal tract. This barrier is often damaged by infection and inflammation, which causes many painful symptoms. Researchers investigated the environment that surrounds gut stem cells and used "mini gut" organoid methodology where tiny replicas of gut tissue were grown in a dish. The study defined key cells that reside in close proximity to stem cells in the gut that produce the biomolecule Neuregulin-1 (NRG1) that acts directly on stem cells to kick-start the repair process.

"Our really important discovery is that supplementation with additional Neuregulin-1 accelerates repair of the gut lining by activation of key growth pathways. Our findings open new avenues for the development of Neuregulin 1-based therapies for enhancing intestinal repair and supporting rapid restoration of the critical gut function."

Gastrointestinal disease, such as Crohn's disease and ulcerative colitis, is a major health issue worldwide and results in severe damage to the epithelial cell layer lining the gut. Under these conditions, the intestine has a limited capacity to repair efficiently to restore its main absorptive function and is associated with symptoms including diarrhoea, dehydration, loss of weight and malnutrition. Developing ways to support intestinal tissue repair will dramatically improve patient recovery.

Glycosylation Changes in Epidermal Stem Cells as a Biomarker of Aging

Researchers here analyze amounts and types of glycans in stem cells isolated from the skin of old and young mice. The differences observed might serve as a biomarker of aging, but also may be a contributing proximate cause of the age-related decline in skin stem cell function. As is usually the case, connecting downstream changes of this nature to the deeper causes of aging is a project yet to make any meaningful progress. It is also unclear as to whether glycan profile changes are a sizable cause of dysfunction versus all of the other possible proximate causes of stem cell functional decline.

Aging in the epidermis is marked by a gradual decline in barrier function, impaired wound healing, hair loss, and an increased risk of cancer. This could be due to age-related changes in the properties of epidermal stem cells and defective interactions with their microenvironment. Currently, no biochemical tools are available to detect and evaluate the aging of epidermal stem cells.

Cellular glycosylation is involved in cell-cell communications and cell-matrix adhesions in various physiological and pathological conditions. Here, we explored the changes of glycans in epidermal stem cells as a potential biomarker of aging. Using lectin microarray, we performed a comprehensive glycan profiling of freshly isolated epidermal stem cells from young and old mouse skin. Epidermal stem cells exhibited a significant difference in glycan profiles between young and old mice. In particular, the binding of a mannose-binder rHeltuba was decreased in old epidermal stem cells, whereas that of an α2-3Sia-binder rGal8N increased.

These glycan changes were accompanied by upregulation of sialyltransferase, St3gal2, and St6gal1 and mannosidase Man1a genes in old epidermal stem cells. The modification of cell surface glycans by overexpressing these glycogenes leads to a defect in the regenerative ability of epidermal stem cells in culture. Hence, our study suggests the age-related global alterations in cellular glycosylation patterns and its potential contribution to the stem cell function. These glycan modifications may serve as molecular markers for aging, and further functional studies will lead us to a better understanding of the process of skin aging.

Glucosamine Supplementation Correlates with Lower All Cause Mortality

An analysis of a large study population here shows that glucosamine supplementation results in about a 15% reduction in mortality, a sizable effect size in the context of what is known of the effects of lifestyle choices and supplementation on aging. Glucosamine is used as an anti-inflammatory intervention, but there is at best only mixed evidence for it to actually do much good as a treatment for specific inflammatory conditions such as arthritis. It is nonetheless widely used, hence the ability to see outcomes in sizable group of people. The effect on mortality is certainly an interesting outcome, given the lack of robust and compelling evidence for specific benefits.

Glucosamine is a non-vitamin, non-mineral specialty supplement commonly used to manage osteoarthritis and joint pain. Although the effectiveness of glucosamine supplementation for osteoarthritis and joint pain remains controversial, several human, animal, and laboratory studies have suggested that glucosamine may have anti-inflammatory properties, which could decrease the risk of multiple diseases. In this large-scale prospective cohort study of nearly half a million UK adults, we evaluated the association between regular glucosamine supplement use and mortality from all causes, cardiovascular disease (CVD), cancer, respiratory disease, and digestive disease.

At baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years, 19,882 all-cause deaths were recorded, including 3,802 CVD deaths, 8,090 cancer deaths, 3,380 respiratory disease deaths and 1,061 digestive disease deaths. The hazard ratios associated with glucosamine use were 0.85 for all-cause mortality, 0.82 for CVD mortality, 0.94 for cancer mortality, 0.73 for respiratory mortality and 0.74 for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers.

Glucosamine and chondroitin supplements are often taken together in a single daily supplements, and it is therefore possible that our observed associations are driven by either of these supplements. To address this issue, we performed sensitivity analyses examining the associations of glucosamine use alone (excluding participants who took chondroitin) with all-cause and cause-specific mortality. We found that the estimates did not change substantially. Therefore, it is likely that glucosamine use may reduce the risk of mortality, regardless of the co-administration of chondroitin.

Several potential mechanisms could explain the inverse association between glucosamine use and mortality. First, nuclear factor-κB (NF-κB) has been implicated in several diseases, such as inflammation-related CVD and cancers. Glucosamine use may affect inflammation by inhibiting the transcription factor NF-κB from translocating to the nucleus, reducing inflammation and thus lowering related mortality. Aside from reducing inflammation, an animal study reported that glucosamine use could trigger a mimic response of a low carbohydrate diet, via reducing glycolysis and increasing amino acid catabolism in mice. This could explain the linkage between glucosamine use and its protective effect, as population-based studies found that low carbohydrate diets are indeed related to a reduced risk of mortality.

Naked Mole-Rat Senescent Cells are Unusually Vulnerable to Oxidative Stress

This open access paper expands on earlier work on cellular senescence in long-lived naked mole-rats. Individuals of this species can live as much as nine times longer than equivalently sized rodents, and are near immune to cancer. In other mammals, senescent cells accumulate with age and disrupt tissue function via their inflammatory signaling. Evidence suggests that this is an important cause of degenerative aging, given that selective destruction of these errant cells produces rejuvenation and extended life span in mice.

In naked mole-rats, senescent cells exhibit very little of the harmful signaling that occurs in other mammals. These cells also also self-destruct more readily when stressed. That naked mole-rat senescent cells are more prone to self-destruction following oxidative stress is not just a benefit when it comes to getting rid of these harmful cells, but it also prevents damage to molecules caused by oxidative reactions - another important mechanism of aging - from causing further harm to tissues.

Naked mole-rats (NMRs) are the longest-lived rodents, showing minimal aging phenotypes. An unsolved paradox is that NMRs exhibit low intracellular anti-oxidant defence despite minimal aging. Here, we explained a link between these "contradicting" features by a phenomenon termed "senescent cell death" - senescence induced cell death in NMR cells due to their inherent vulnerability to reactive oxygen species and unique metabolic system.

Generally, the "free radical theory of aging", later modified to "mitochondrial free radical theory", is the well-known theory of aging mechanism. Intracellular reactive oxygen species (ROS), deriving especially from mitochondria, damages macromolecules such as lipids, DNA, and proteins, and the accumulated damages in tissues are assumed to contribute aging process. Indeed, the mitochondrial ROS production rate is negatively correlated with the maximal lifespan of animal species.

However, previous insights on responses of long-lived NMRs to ROS are puzzling: 1) Several reports suggested that NMRs have stronger anti-oxidant mechanisms. 2) However, many other reports suggested that NMRs exhibit low anti-oxidant defence. From young ages, NMR suffers greater oxidative damages in tissue DNA, protein, and lipids than mice. Nevertheless, the level of oxidative damage does not increase further and remains constant for more than 20 years. Thus, at least in part, NMR exhibits low intracellular anti-oxidant defence despite their delayed aging. These complex but interesting observations raise a possibility that NMR may have developed a unique system to remove damaged cellular components or the cells that suffered the oxidative damage during aging.

In mammalian cells, one of the typical "damaged" cellular status along with elevated oxidative damage is cellular senescence. Cellular senescence is an irreversible cell proliferation arrest induced in response to stresses such as DNA damage, oncogene activation, and telomere shortening. Cellular senescence contributes to avoidance of cancer formation by stopping proliferation of damaged cells. In addition, cellular senescence has important roles in tissue homeostasis, embryonic development, and wound healing. On the other hand, accumulation of senescent cells promotes age-related physiological deterioration and disorders, by secreting a bioactive "secretome" called senescence-associated secretory phenotype (SASP).

In NMR skin, we observed few senescent cells during aging or after ultraviolet irradiation, suggesting suppression of senescent cell accumulation in NMR tissue. We discovered that senescent NMR fibroblasts induce senescent cell death through retinoblastoma protein activation accompanied by autophagy dysregulation, increased oxidative damage, and accelerated H2O2-releasing metabolic pathways.

Cognitive Decline is Accelerated by Hypertension, Diabetes, and Smoking

The raised blood pressure of hypertension can be minimized with age by staying thin and active, type 2 diabetes is near entirely avoidable via much the same strategy, and smoking is just a bad idea. There is a mountain of evidence in each case for these outcomes to negatively impact health and lead to an earlier death. The work here is a reminder that if you want your mind to corrode somewhat more rapidly than would otherwise be the case, there exists a range of bad lifestyle choices that can achieve that goal.

A recent study involved 2,675 people with an average age of 50 who did not have dementia. Researchers measured their cardiovascular risk factors at the start of the study: 43% were considered obese, 31% had high blood pressure, 15% were smokers, 11% had diabetes, and 9% had high cholesterol. Participants were given thinking and memory tests at the beginning of the study and five years later. Then researchers estimated the association of the five cardiovascular risk factors with decline in their performance on the thinking and memory tests that was not defined as dementia, but was faster than what was seen in a group of adults of similar ages.

Five percent of the participants had accelerated cognitive decline over five years. A total of 7.5% of those with high blood pressure had faster decline, compared to 4.3% of those who did not have high blood pressure. And 10.3% of those with diabetes had faster decline, compared to 4.7% of those who did not have diabetes. A total of 7.7% of current smokers had faster decline, compared to 4.3% of those who never smoked.

After adjusting for age, race, education, and other factors that could affect the risk of cognitive decline, researchers found that people who smoked were 65% more likely to have accelerated cognitive decline, those with high blood pressure were 87% more likely and those with diabetes had a nearly three times as likely to have accelerated cognitive decline. People who had one or two of the risk factors were nearly twice as likely to have accelerated decline than people with no risk factors. People with three or more of the risk factors were nearly three times as likely to have faster decline than those with no risk factors.

Eating Ourselves into Shorter, Less Healthy Lives

We humans have not evolved for optimal function given a continually high calorie intake. We, and all other species, evolved in an environment characterized by periods of feast and famine: we desire food constantly, but nonetheless need some amount of hunger in order to be healthy. Periods of low calorie intake spur increased activity of tissue maintenance mechanisms throughout the body. A lower overall calorie intake minimizes excess visceral fat tissue that causes chronic inflammation and metabolic disease. In this modern society of comfort and cheap calories, all too many people are eating themselves into shorter, less healthy lives. This will continue until the advent of rejuvenation therapies that can meaningfully target the causes of aging, to a degree sufficient to outweight environmental influences on the pace of aging.

The global increase in food security due to modern long-term food storage coupled with the increase in worldwide global food transportation, and international marketing has reduced the cost of food, increasing its availability in the developed world. However, food commercialization and the shift toward production of processed and ultra-processed foods have revealed clear adverse effects, such as the identification of processed food as a major cause for over-eating and the increase in the risk of metabolic syndrome, obesity, and diabetes. As the brain is one of the primary energy-demanding organs in the human body, it comes with no surprise that the brain is highly affected by such metabolic disorders.

Worldwide, the life expectancy of males rose from 59.6 years in the 1980's to 69.0 years in 2015, whereas the life expectancy of females increased from 63.7 to 74.8 years, respectively. This increase in lifespan is correlated with multiple age-dependent pathologies which have also increased in prevalence, such as neurodegenerative disorders. It is plausible to argue that the combined effect of the continued increase in lifespan and life-long continuous food consumption leads to a dramatic increase in the prevalence of neurodegenerative disorders in the elderly population.

Studies in laboratory animals show that caloric restriction (decreased food intake or intermittent fasting) can extend lifespan in rodents and primates and delay the onset of age-related diseases such as hypertension and diabetes. Moreover, caloric restriction may protect neurons from degeneration and enhance adult neurogenesis and neuronal plasticity, which may protect the brain from a cognitive decline during aging and neurodegenerative diseases. One of the crucial processes that are adversely affected during aging is cellular autophagy, which is tasked with eliminating aggregated proteins, unhealthy organelles, and multiple intracellular components. Multiple mechanisms can explain the roles of fasting and caloric restriction in ameliorating neurodegeneration. One of the most studied mechanisms is the upregulation of autophagy via inhibiting mTOR activity.

The sobering statistics of one in three elderly people suffering from a type of age-related dementia call to devise a multi-pronged approach to targeting age-related neurodegenerative diseases. Synthesis of the current data indicates that not only age but also dietary lifestyles that changed dramatically during the twentieth century are at play. Many factors that are at play during aging have a role in promoting neurodegeneration, such as oxidative stress, accumulation of DNA damage, cell senescence, neuroinflammation, and decreased autophagic flux. Aging is also characterized by elevated levels of neuroinflammation that are transcriptionally regulated. Autophagy, however, is a cellular pathway that throughout life is predominantly regulated extrinsically in a nutrient-consumption mediated manner. This places food consumption as a major factor, along with aging itself, in promoting neurodegenerative disorders.

An Age-Related Increase in CD47 Expression Impairs Vascular Function

Researchers here provide evidence to indicate that increased expression of CD47 in aged blood vessels impairs a range of functions, from maintenance of these tissues to the generation of new blood vessels. The latter point is interesting given that capillary networks become less dense with age. This is thought to impair blood flow to tissues and thus contribute to age-related loss of function. The animal evidence here suggests that inhibition of CD47 may be a viable strategy to reduce the impact of aging on the vasculature, and thus also many of the consequences of vascular aging throughout the body.

The aged population is currently at its highest level in human history and is expected to increase further in the coming years. In humans, aging is accompanied by impaired angiogenesis, diminished blood flow, and altered metabolism, among others. A cellular mechanism that impinges upon these manifestations of aging can be a suitable target for therapeutic intervention. Here we identify cell surface receptor CD47 as a novel age-sensitive driver of vascular and metabolic dysfunction. With the natural aging process, CD47 and its ligand thrombospondin-1 were increased, concurrent with a reduction of self-renewal transcription factors OCT4, SOX2, KLF4, and cMYC in arteries from aged wild-type mice and older human subjects compared to younger controls.

These perturbations were prevented in arteries from aged CD47 knockout mice. Arterial endothelial cells isolated from aged wild-type mice displayed cellular exhaustion with decreased proliferation, migration, and tube formation compared to cells from aged CD47 knockout mice. CD47 suppressed ex vivo sprouting, in vivo angiogenesis and skeletal muscle blood flow in aged wild-type mice. Treatment of arteries from older humans with a CD47 blocking antibody mitigated the age-related deterioration in angiogenesis. Finally, aged CD47 knockout mice were resistant to age- and diet-associated weight gain, glucose intolerance, and insulin desensitizationipedia.org/wiki/Insulin_resistance">insulin desensitization.

These results indicate that the CD47-mediated signaling maladapts during aging to broadly impair endothelial self-renewal, angiogenesis, perfusion, and glucose homeostasis. Our findings provide a strong rationale for therapeutically targeting CD47 to minimize these dysfunctions during aging.

Fitness in Humans Acts to Reduce Inflammation, But Does Not Reduce the Burden of Cellular Senescence in Muscle Tissue

Fitness produced by training is here shown to correlate with reduced inflammatory signaling, but has no effect on the burden of senescent cells in old muscle tissue. This is interesting, as the accumulation of senescent cells with age is responsible for a sizable fraction of inflammatory signaling in tissues. Senescent cells secrete a potent mix of signals that cause chronic inflammation and tissue dysfunction, and are an important contributing cause of aging. The likely explanation here is that the cellular adaptations to exercise act to reduce harmful aspects of persistent senescent cell signaling. There is a good deal of research to show that senescent cell signaling can be muted to various degrees. This is probably not as a good a strategy for the development of new therapies as is the targeted destruction of senescent cells, but exercise is free.

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence and preserves telomeres health in skeletal muscle in older compared to younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies (n=34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS) and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence associated b-gal (SA-b-Gal) staining and qRT-PCR.

Independently of the endurance training status, TIF levels (+35%) and the percentage of SA-b-Gal positive cells (+30%) were higher in cultured satellite cells of older compared to younger subjects. p16 (4-5 fold) and p21 (2-fold) mRNA levels in skeletal muscle were higher with age but unchanged by the training status. Aging induced higher CD68 mRNA levels in human skeletal muscle (+102%). Independently of age, both trained groups had lower IL-8 mRNA levels (-70%) and tended to have lower TNF-alpha mRNA levels (-40%) compared with the sedentary subjects.

All together, we found that the endurance training status did not slow down senescence in skeletal muscle and satellite cells in older compared to younger subjects despite reduced inflammation in skeletal muscle. These findings highlight that the link between senescence and inflammation can be disrupted in skeletal muscle.

Reviewing the Mechanisms of Alzheimer's Disease

The present understanding of Alzheimer's disease is illustrative of a broader issue with aging in general, in that while there is considerable evidence to pin down specific pathological mechanisms in cells and tissues, it is hard to prove exactly how these mechanisms interact. What is cause, what is consequence. What is important, what is merely a side-effect of other, important processes. At present there is some upheaval in the Alzheimer's research community based on the failure of amyloid-β clearance to produce meaningful benefits in patients. This may or may not disrupt the present thinking on the condition, that early amyloid-β aggregation sets the stage for later neuroinflammation and tau aggregation. Amyloid-β may be a good early target, or it may turn out to be a side-effect of rising levels of chronic inflammation or persistent infection, and thus not a useful target at all.

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis.

AD pathogenesis involves pathogenic contributions from multiple components and alterations in behavior of various cell types within the central nervous system. Aβ is generated in neurons and then released to the extracellular space, where it can be degraded or cleared by microglia and astrocytes. Increased Aβ production or impaired Aβ degradation/clearance leads to Aβ accumulation. Tau is mainly expressed in neurons, and highly modulated through various post-translational modifications. Abnormal PTMs, liquid-liquid phase separation, and pathogenic tau seeds can cause tau aggregation and accumulation through different mechanisms. Tau pathology may be propagated during disease progression, and glial cells play an important role in the process of seeding and dispersion. Forms of Aβ aggregates, together with tau accumulation, can cause neuronal dysfunction and glial activation and the subsequent neuroinflammation; these events are regulated by various receptors expressed in neurons, microglia and astrocytes.

Genetic factors can cause or affect AD pathogenesis. Early-onset AD is mainly due to mutations in APP and PS1/PS2, which are involved in Aβ generation, while late-onset AD is largely associated with a group of genes enriched in glial cells, such as APOE and TREM2, which are important for Aβ clearance and glial function. Therefore, differential mechanisms may be involved in different forms of AD. In addition, other factors such as aging, metal ion, virus, and microbiota may also contribute to AD pathogenesis via various mechanisms. Mechanisms for late-onset AD are complex and subtypes of late-onset AD may exist. However, most of the available AD animal models carrying early-onset AD-associated mutations can only mimic early-onset AD. Development of animal models to recapitulate pathogenesis of late-onset AD may be beneficial to compare early and late stage forms of AD. This may uncover mechanisms specific to late-onset AD which represents over 90% of AD cases, and potentially provide new insights to therapeutic targets for treatment.

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