PGC-1α as a Target to Treat Age-Related Kidney Disease

Excellent Nutritional supplements to Support Nitric Oxide Health


Looking for state-of-the-art endorsed nutritional supplements?  Educate yourself about  these beneficial Medically Recognized Vitamins.

The research reviewed here is a great example of the presently dominant paradigm in efforts to treat age-related disease. Scientists analyze the disease state, find regulator proteins that are differently expressed in normal and diseased tissue, and look for ways to force expression in diseased tissue to look more like that of normal tissue. There is no consideration of trying to fix the underlying molecular damage that caused this change. It is a little like pressing the accelerator harder in a car with a failing engine. This strategy is why most efforts to treat age-related disease in the past have either failed or produce only minor benefits. Without fixing the underlying damage, it will continue to cause all of the downstream consequences that lead inexorably to failure of tissue function and death.


Aging is a progressive disruption of the homeostasis of physiological systems with age. It results in structural destruction, organ dysfunction, and increased susceptibility to injuries and diseases. The kidney is one of the most susceptible organs to aging. Aging-associated complications can lead to kidney dysfunction, including a decreased glomerular filtration rate, tubular dysfunction, and glomerulosclerosis. Furthermore, kidney aging has important implications for aging-associated comorbidities, especially cardiovascular diseases.

While the molecular mechanism underlying kidney aging remains unclear, chronic kidney disease (CKD) shares many phenotypic similarities with aging, including cellular senescence, fibrosis, vascular rarefaction, loss of glomeruli, and tubular dysfunction. The pathogenic mechanisms involved in CKD may thus provide insight into the molecular pathways leading to kidney aging. They might also provide potential targets against kidney aging.

Recent efforts to overcome aging have shifted from the identification of risk factors to the determination of endogenous protective factors that might neutralize the adverse effects of aging. Among the various endogenous protective factors reported are AMP-activated protein kinase (AMPK), fibroblast growth factor 21 (FGF21), insulin, and vascular endothelial growth factor (VEGF).

Recent studies have shown that aging-related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose metabolism and lipid metabolism. PGC-1α is abundant in tissues, including kidney proximal tubular epithelial cells, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC-1α by genetic or pharmacological intervention prevents telomere shortening and aging-related changes in the skeletal muscle, heart, and brain. The activation of PGC-1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC-1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

Link: https://doi.org/10.1111/acel.12994

Have a look at N.O. Supplements and Heart health.

Hippocampal Neurogenesis in Aging

Best Supplements needed for Nitric Oxide Health


Hunting for superb recognised health supplements?  Read about  these important Endorsed Vitamins.

In at least some portions of the brain, new neurons are created throughout life in a process called neurogenesis. This is vital to memory and learning, but declines with age. Faltering neurogenesis is arguably implicated in the development of some neurodegenerative conditions. As most of the evidence for neurogenesis in adult individuals has been established in mice, and in recent years there has been some debate over whether or not these same processes do in fact operate in humans. So far, the most recent evidence leans towards supporting the existence of human adult neurogenesis. Given this, the research community remains interested in developing means of increasing the pace of neurogenesis as a basis for therapies to enhance cognitive function in the old, but progress towards this goal remains slow.


Adult hippocampal neurogenesis has been proposed to be a key element in ensuring and maintaining functional hippocampal integrity in old age. Neurodegenerative diseases due to the age-dependent rapid and continuous loss of neurons (such as Parkinson’s disease and Huntington’s disease) have been suggested to reflect the contraposition of the neurogenic process such that under homoeostatic conditions a fine balance between neurodegeneration and neuroregeneration exists, and under pathological conditions, the balance is disturbed and a disease manifests. Even though little evidence has accumulated in support of this theory, if it proves correct, it in combination with findings regarding the high potential of stem-cell-based strategies for the treatment of age-related neurodegenerative disorders, make the hypothesis that adult neurogenesis holds a key to novel therapeutic approaches in the treatment of age-related neurodegenerative disorders rather attractive.

Decreased hippocampal neurogenesis is proposed as an important mechanism underlying age-related cognitive decline as well as neurodegenerative disorders such as Alzheimer’s disease (AD) and various types of dementia. Evidence in this regard was recently published in two separate recent studies examining hippocampal neurogenesis in human tissue from people suffering mild cognitive impairment and AD. Both studies demonstrated a dramatic decrease in the number of neural progenitor cells and neuroblasts in hippocampal tissue from AD patients which was related to the stage of the disease. Interestingly, a decrease in the number of newborn neurons was observed in AD patients at the very early stage of the disease when the characteristic neurofibrillary tangles and senile plaques had not become prevalent. This suggests a potential for using neurogenesis levels as an early biomarker of the disease.

The mechanisms underlying the age-related decline in hippocampal neurogenesis remain poorly understood. It has been proposed that within the senescent brain the neurogenic niche may be deprived of the extrinsic signals regulating the neurogenic process or that the aged neural progenitor cells are less responsive to normal signalling within the niche, or both. The evidence accumulated thus far points to changes in the properties of the neurogenic niche with age, rather than changes in the phenotype of the stem cells or progenitor cells themselves. For instance, it has been reported that the numbers of neural stem cells and neural progenitor cells as well as the proportion of astrocytes to neurons in the hippocampus of young and aged rats remained the same; however, there was a decrease in the number of cells actively undergoing mitosis in the aged animals.

Link: https://doi.org/10.1111/acel.13007

Study more about N.O. Supplements and Cardio fitness.

Fight Aging! Newsletter, July 22nd 2019

Top rated Supplements for Nitric Oxide Health


Searching for superior professional quality health supplements?  Educate yourself about  these special Medically Recognised Supplements.

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/

Contents

  • MitoCeption as a Method of Artificial Mitochondrial Transfer
  • Gene Therapy in Mice Alters the Balance of Macrophage Phenotypes to Slow Atherosclerosis Progression
  • Notes on the 2019 Ending Age-Related Diseases Conference in New York
  • Fibrates as a Potential Class of Senolytic Therapy to Clear Senescent Cells
  • The Infection-Senescence Hypothesis of Alzheimer’s Disease
  • Mtss1L Mediates Improvement in Synaptic Function Resulting from Exercise
  • Targeting Shelterin via TRF1 to Degrade Telomeres in Cancer Cells
  • Sabotaging a Mechanism of Decline in Age-Related Stem Cell Activity
  • Ghrelin Enhances Memory via the Vagus Nerve
  • Chromatin Stress Promotes Longevity in Yeast. Flies, and Nematodes
  • A Mainstream View of the Longevity Industry
  • Cellular Senescence in Mesenchymal Stem Cells
  • Dysfunctional Stem Cells Contribute to Impaired Fracture Repair in Old Age
  • Common Dietary Supplements Have Little to No Effect on Mortality
  • Diminished Estradiol Explains Faster Muscle Loss Following Menopause

MitoCeption as a Method of Artificial Mitochondrial Transfer

https://www.fightaging.org/archives/2019/07/mitoception-as-a-method-of-artificial-mitochondrial-transfer/

Mitochondria are the power plants of the cell, hundreds of bacteria-like organelles that divide like bacteria and are selectively destroyed when damaged by cellular quality control mechanisms. They carry out the energetic chemical reactions needed to package the chemical energy store molecule ATP that is used to power cellular processes. Some of the protein machinery vital to this function is encoded in mitochondrial DNA, a circular genome that resides in mitochondria themselves rather than in the cell nucleus with the majority of a cell’s DNA. It is this DNA that is the Achilles’ heel of mitochondria, as it is less well protected and repaired than is the case for nuclear DNA. It becomes damaged over time, and this damage leads to dysfunction in mitochondria and the cells that host them, particularly as cellular quality control mechanisms decline in efficiency with advancing age.

This mitochondrial dysfunction that manifests with age is an important component of age-related disease and disruption of normal tissue function. It is better studied in energy hungry tissues such as muscles and the brain, but it is a global phenomenon throughout the body. Evidence strongly implicates loss of mitochondrial function in sarcopenia, the loss of muscle mass and strength that occurs with age, and in all of the common age-related neurodegenerative conditions.

What can be done about this? The SENS approach is to create backups of mitochondrial genes in the cell nucleus, a process known as allotopic expression, with the challenge being that the resultant proteins have to be altered in ways that allow them to be delivered to mitochondria where they are needed. In principle this can eliminate the consequences of damage to mitochondrial DNA. This has been carried out as proof of principle at least for several mitochondrial genes. Other researchers have proposed the use of tools that can selectively destroy mutated mitochondrial DNA. Still others have suggested delivering new mitochondria into cells by exploiting one of a number of mechanisms by which this can happen naturally.

Of these approaches, only allotopic expression has made much progress towards realization, and even that line of work is arguably only at an advanced stage for one mitochondrial gene, via the work at Gensight Biologics. The open access paper here is illustrative of the present state of work on convincing cells to take up new mitochondria: the specific process used only works in cell cultures, and is thus only of potential near term use in rescuing the deteriorated function of cells from an aged patient prior to use in cell therapy. Even that might not be as useful a technique as induced pluripotency, which appears to clear out damaged mitochondria fairly effectively.

There is also the question of whether delivering new mitochondria without clearing out the old, damaged mitochondria will actually help in the long term. Damaged mitochondria can take over cells because their damage grants them either resistance to quality control mechanisms or the ability to replicate more readily than their undamaged peers. In that circumstance, new mitochondria will be quickly outcompeted by the existing damaged population, and whatever benefit is obtained will be short-lived.

Primary allogeneic mitochondrial mix (PAMM) transfer/transplant by MitoCeption to address damage in PBMCs caused by ultraviolet radiation


A substantial number of in vitro and in vivo assays have demonstrated the natural ability of cells to transfer mitochondria amongst each other. This phenomenon is most commonly observed in mitochondrial transfer from healthy mesenchymal stem/stromal cells (MSCs) to damaged cells. The transfer replaces or repairs damaged mitochondria and thereby reduces the percentage of dead cells and restores normal functions. In 1982, researchers introduced a type of artificial mitochondrial transfer or transplant (AMT/T) model using a co-incubation step between the recipient cell and exogenous mitochondria. Their pioneering study demonstrated for the first time that the mitochondrial DNA (mtDNA) of donor cells could be integrated into recipient cells and subsequently transmit hereditary traits and induce functional changes. AMT/T mimics the natural process of mitochondrial transfer, reprograms cellular metabolism, and induces proliferation. The introduction of this model elucidated the possible use of mitochondria as an active therapeutic agent.

Our study tests a modification of the original MitoCeption protocol which reduces the time and complexity of the protocol. We sought to determine if primary allogenic mitochondrial mix (PAMM) MitoCeption could be used to repair peripheral blood mononuclear cells (PBMCs) damaged by ultraviolet radiation (UVR). PAMM is composed of the PBMCs of at least three donors. Our results showed that when PBMCs are exposed to UVR, there is a decrease in metabolic activity, mitochondrial mass, and mtDNA sequence stability as well as an increase in p53 expression and the percentage of dead cells. When PAMM MitoCeption was used on UVR-damaged cells, it successfully transferred mitochondria from different donors to distinct PBMCs populations and repaired the observed UVR damage.

To our knowledge, this study is the first to demonstrate in-vitro that MitoCeption can be used to re-establish mitochondrial function loss caused by UVR exposure. Additionally, we successfully transferred a mix of different PBMC donors to one PAMM that was used to repair damaged cells. Other research groups have successfully transferred mitochondria from one cell donor type to others; however, none of them have mixed mitochondria isolated from different donors for the transfer/transplant. This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications.

Gene Therapy in Mice Alters the Balance of Macrophage Phenotypes to Slow Atherosclerosis Progression

https://www.fightaging.org/archives/2019/07/gene-therapy-in-mice-alters-the-balance-of-macrophage-phenotypes-to-slow-atherosclerosis-progression/

Atherosclerosis causes a sizable fraction of all deaths in our species. It is the generation of fatty deposits in blood vessel walls, distorting, narrowing, and weakening the blood vessels. This ultimately leads to the major structural failure of a stroke or heart attack, in which a vital blood vessel ruptures or is blocked. Lipids, such as cholesterols, are carried in the blood stream throughout life, associated with low-density lipoprotein (LDL) particles. The innate immune cells known as macrophages are responsible for removing cholesterol from blood vessel walls via the processes of reverse cholesterol transport: macrophages ingest the cholesterol and pass it on to high-density lipoprotein (HDL) particles, which carry it back to the liver for excretion.

In youth, reverse cholesterol transport keeps blood vessels in good shape. With age, however, an increasing fraction of lipids become oxidized and damaged. This is in part a consequence of mitochondrial dysfunction and increasing chronic inflammation, leading to more oxidizing molecules in the body. Oxidized lipids, even in comparatively small amounts, cause macrophages to become dysfunctional, inflammatory, and sometimes senescent. This degrades the effectiveness of their activities, and leads to macrophage death. The fatty atherosclerotic plaques in blood vessels are in large part the debris of dead macrophages, in addition to lipids and oxidized lipids.

The growth of atherosclerotic plaques is thus a feedback loop, in which macrophages are overwhelmed by oxidized cholesterol, and their struggles attract more macrophages that attempt (and fail) to assist in clearing up the issue. Any signaling or chronic inflammation that induces more macrophages into a pro-inflammatory state rather than a pro-regenerative state will tend to accelerate the progression of atherosclerosis, either by calling in more macrophages, or by making macrophages less effective at reverse cholesterol transport.

That the state of macrophages can influence aging and age-related disease has become a topic of great interest in the research community in recent years, and not just in the context of atherosclerosis. Many age-related conditions have a strong inflammatory component, and it is possible to argue that in all such cases, this inflammation detrimentally affects the activities of macrophages. Researchers divide macrophage populations into the M1, inflammatory and aggressive phenotype and M2, pro-regenerative phenotypes. Both are needed, but with age, the balance shifts too far towards M1, characteristic of the rising chronic inflammation that takes place in later life. A variety of potential therapeutic approaches have been developed in recent years that aim to shift macrophages into the M2 phenotype, to override the signaling that leads them to adopt the M1 phenotype. The example here is one of the more recent ones.

Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism


In recent years, different approaches have been developed to counteract the progression of vascular atherosclerosis, including cholesterol-level lowering and inflammation modulation. Owing to the large numbers of inflammatory molecular and cellular mediators, it is unlikely that blockade of a single cytokine will be therapeutically effective. Long-living individuals (LLIs) delay or escape atherosclerosis-related cardiovascular disease (CVD). We have previously found that LLIs are enriched for a longevity-associated variant (LAV) in BPI fold containing family B, member 4 (BPIFB4).

We report here new exciting results on the pleiotropic activity of LAV-BPIFB4 on different mechanisms of the atherogenic process. These benefits were not associated with changes in the lipid profile. In addition, we provide ex vivo and in vitro evidence that these beneficial actions may extend to human vasculature until to be inversely associated to subclinical index of atherosclerosis in selected patients. Mechanistically, the effects of LAV-BPIFB4 seem to be attributable to a CXCR4-dependent mechanism.

LAV-BPIFB4 gene therapy succeeded in the two primary endpoints, namely improving endothelial dysfunction and reducing adverse vascular effects in ApoE knockout mice fed a high-lipid diet. Interestingly, LAV-BPIFB4 gene therapy did not affect the serum cholesterol profile, but it did contrast the ability of oxidized cholesterol to induce endothelial dysfunction by positively modulating the inflammatory/immune background of atherosclerosis. In line with this, LAV-BPIFB4 redistributed the pool of monocyte subpopulations, redirecting them towards a pro-resolving phenotype.

This was reflected by the increased abundance of CXCR4+Ly6C-high monocytes in bone marrow and spleen, the two major tissue reservoirs of monocytes available to mobilize towards injured tissues. In the margination process, CXCR4 is considered the retention force in the vasculature. Therefore, we speculate that the higher level of CXCR4 in blood Ly6C-high monocytes after LAV-BPIFB4 treatment in mice may finely tune the transit time into the circulation, completing a protective intravascular differentiation process. Consistent with their functionally distinct immunological roles, newly recruited Ly6C-high but not Ly6C-low monocytes uniquely differentiate into pro-resolving M2 macrophages, driving murine atherosclerotic regression at the early stages of the disease. Accordingly, we documented an enrichment of M2 splenic macrophages, which can contribute to dampen T cell activation and proliferation in a CXCR4-dependent manner. This latter result is in keeping with the reported ability of CXCR4 to promote the acquisition of the M2 phenotype in healthy monocyte-derived macrophages.

Notes on the 2019 Ending Age-Related Diseases Conference in New York

https://www.fightaging.org/archives/2019/07/notes-on-the-2019-ending-age-related-diseases-conference-in-new-york/

I recently attended the second Ending Age-Related Diseases conference in New York, hosted by the Life Extension Advocacy Foundation (LEAF). The mix of attendees was much the same as last year: an even split between scientists, entrepreneurs, investors, patient advocates, and interested onlookers, all focused on the treatment of aging as a medical condition. The presentations were similarly a mix of scientists talking about their research programs, entrepreneurs presenting on the data produced by their companies, and investors discussing the state of the industry.

For my part, I have already presented several times this year on the work taking place at Repair Biotechnologies, while we were raising our seed round. So rather talk again on a familiar topic, I chose instead to discuss the terrible state of clinical translation in the life science industry – the institutional, widespread, ongoing failure to develop promising research programs into therapies. This is particularly the case for the treatment of aging, given that translational research in gerontology was actively suppressed by leading scientists for much of the last 40 years. This was an overreaction to the “anti-aging” industry of fraud, supplements, and false hope established in the 1970s, and probably set us back decades.

Even now there is a great gulf between academia and industry, into which projects vanish. This gulf is built of many factors: scientists rarely have good connections to the people who could carry forward their projects; academic funding tends to stop once projects get close to the point at which they could be translated; universities do far too little to nurture new companies, and instead focus on being toll collectors; most investors sit around waiting for companies to form and come to them, rather than devoting their resources to helping companies form; and so forth. The result is that the research community is littered with credible projects in a dormant state, just waiting for someone to champion their development.

A number of fellow entrepreneurs in the longevity industry presented their latest data at the conference. Doug Ethell of Leucadia Therapeutics noted the proof of principle of his thesis on the roots of Alzheimer’s disease, data obtained in ferrets. Partially occluding the cribriform plate in the skull, to mimic the process of ossification that occurs with age in humans, blocks drainage of cerebrospinal fluid, thus allowing amyloid and other molecular waste to build up in the brain and cause neurodegeneration and cognitive decline.

Greg Fahy of Intervene Immune presented quite a lot of data on what six to twelve months of treatment with growth hormone and DHEA does to the thymus and measures of immune system composition in older individuals. It makes for a compelling story, given their evidence for thymic regrowth and improvement in the immune system, for all that I remain dubious about growth hormone as a mode of treatment for aging. There is a lot of evidence to suggest that it isn’t such a great plan. But perhaps undergoing a year of such treatment to have a somewhat larger, somewhat more active thymus going forward is a sensible trade-off, should these results hold up in larger patient groups.

John Lewis of Entos Pharmaceuticals gave a great presentation on the lipid nanoparticle (LNP) platform used by Oisin Biotechnologies to destroy senescent cells and by OncoSenX to destroy cancer cells. This platform is one of the candidate technologies to power all of the next generation of gene therapies, ensuring that most implementations can just work, comparatively simply, and with far less effort than is presently required. The presentation included the final study results from the mouse lifespan study run by Oisin Biotechnologies in which LNPs were set to target cells that expressed p16, p53, or both p16 and p53. That last group lived significantly longer, and had their first death at the point at which half of the control group had died.

Kelsey Moody presented on LysoClear, one of the ever growing number of subsidiary companies generated by the Ichor Therapeutics team. The company is developing an approach to treat macular degeneration by using compounds derived from bacterial enzymes to break down molecular waste that builds up in the lysosome, impairing cell function. His emphasis was on the need to be careful, conservative, and methodical in preclinical development, using LysoClear development as an example of always proving each step before moving on, building on well-proven existing work.

From the scientific community, Maria Blasco discussed at length her work on telomeres and telomerase gene therapy in mouse models. Her group sees loss of telomere length in tissues as a significant contributing cause of aging, with wide-ranging downstream effects, rather than a marker of aging that results from loss of stem cell function. Amutha Boominathan presented on her work at the SENS Research Foundation, moving mitochondrial genes into the cell nucleus in order to prevent the consequences of damage to mitochondrial DNA. In principle this can stop inevitable mitochondrial DNA damage from causing aging. Morgan Levine discussed epigenetic clocks based on DNA methylation, and what lies ahead in getting them to be useful to speed up development of rejuvenation therapies. The clocks and the therapies must develop in parallel, and many different clocks will likely be needed. The biggest task ahead is to understand exactly what it is that these epigenetic clocks are measuring.

From the investment community, Joe Betts-Lacroix noted that of the 1000 or so biotech startups out there, maybe 70 or so are credibly involved in working on aging and longevity. This industry is in its very earliest stages. One of the worthies in our community is presently assembling a database of those aging-focused startups, which I hope will be made publicly available fairly soon. There is a lot more that our community needs to do in order to help newly arriving entrepreneurs and investors become knowledgeable and productive quickly, and a database of companies is a good idea in this context.

Both James Peyer of the newly founded Kronos BioVentures and Sree Kant of Life Biosciences discussed how to invest in longevity, given the nature of the industry and its present constraints and peculiarities. James Peyer, as always, brought a very interesting set of ideas to the conference, and Life Biosciences is itself a sensible strategic response to the twin challenges of (a) a lack of entrepreneurs and (b) researchers who really don’t want to leave academia. Life Biosciences wraps subsidiary companies around research teams, providing an environment that still feels like academia, and in which much of the trouble of running a company is abstracted away into the larger parent organization.

I have of course omitted mention of a number of other presentations and panels, and no offense is intended to the speakers. The above is really just a list of things that caught my attention, or that I happened to be there for rather than being caught up in meetings. All in all it was a good event, as was the case last year. The LEAF volunteers did a great job, and I encourage you to add this conference series to your 2020 agenda.

Fibrates as a Potential Class of Senolytic Therapy to Clear Senescent Cells

https://www.fightaging.org/archives/2019/07/fibrates-as-a-potential-class-of-senolytic-therapy-to-clear-senescent-cells/

Accumulation of senescent cells with age is one of the causes of aging. In recent years, the broader scientific community has become convinced of this point, and thus funding is now directed towards many varied investigations of cellular senescence and what to do about it. A young industry has emerged, made up of biotech companies focused on the selective destruction of senescent cells, mostly using small molecule drugs. Since these drugs operate through different mechanisms, tend to be tissue specific, only clear a fraction of senescent cells that varies by tissue, and will thus probably be more effective when combined together, research continues to find ever more senolytic compounds.

Senescent cells are created constantly, either in response to damage or a toxic local environment, or more commonly as the result of a somatic cell reaching the Hayflick limit on cell replication. Senescence is an irreversible state in which cell replication shuts down, and a potent mix of inflammatory signals is secreted. This can be useful in the short term, such as during wound healing, or to put a halt to potentially cancerous cells. Near all senescent cells either self-destruct or are destroyed by the immune system quite quickly. It is the tiny minority to linger that contribute to the aging process, such as by generating an environment of chronic inflammation.

The open access paper here is representative of numerous projects presently underway in the research and development communities, performing screening of small molecules from established databases in search of new senolytics. Some of these searches are more informed by prior investigation of plausible mechanisms than others, but at the end of the day the output is compounds that are then evaluated in detail for their ability to selectively destroy senescent cells. The best of the compounds noted here, fenofibrate, is on a par with navitoclax for selectivity, which is about at the lower level of what might be tolerable as a human therapy. The more off-target cells that are destroyed, the worse the side-effects. This is a starting point, however: other compounds in this category will no doubt be better, or might be engineered to be better.

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy


Increasing evidence about the molecular mechanisms of ageing suggests that many chronic diseases such as osteoarthritis (OA) are associated with the hallmarks of ageing, including cellular senescence and defective autophagy. Accumulation of senescent cells in tissues contributes to age-related diseases. Articular cartilage of patients with OA shows features of senescence. Senescence-associated secretory phenotype (SASP) factors released from chondrocytes, such as pro-inflammatory cytokines and extracellular matrix degrading enzymes, have been identified as major mediators contributing to the development and progression of OA. Similarly, intra-articular injection of senescent cells in mice results in OA-like pathology.

Cartilage ageing can be modified by selective elimination of senescent chondrocytes to prevent the detrimental microenvironment changes occurring in joint dysfunction. A major step into the translation of senolytic treatments for OA was demonstrated by the beneficial effects of selective clearance of senescence chondrocytes using the Bcl-2 family inhibitor Navitoclax in animal models. The broad impact of senolytic treatment is also highlighted by the efficacy of dasatinib and quercetin combination in several models of age-related disease, which results in an extension of healthspan and lifespan in mice.

Cellular senescence and autophagy are not only essential for homeostasis but are potential therapeutic targets for age-related diseases. We aim to test this therapeutic hypothesis in preclinical models of OA, where senescence and autophagy play a relevant role. A novel cell-based dual imaging screening assay was developed to identify both senotherapeutics, able to either suppress markers of senescence (senomorphics) or to induce apoptosis of senescent cells (senolytics), and autophagy modulators.

Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients.

Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. Blood from the PROspective Osteoarthritis Cohort of A Coruña (PROCOAC) and human cartilage from non-OA and knee OA patients were employed. Levels of PPARα were lower in OA patients compared to non-OA controls. The potential efficacy of PPARα agonists was also evaluated using the Osteoarthritis Initiative (OAI) Cohort. In this cohort, there were 35 fibrate users and 3322 participants not taking fibrates in the selected sample. Using a genetic matching, 35 fibrate users were matched to 35 participants in the control group. Interestingly, the results indicate that fibrate use by time interaction was associated with a statistically significant improvement of self-reported Western Ontario McMaster Osteoarthritis Index (WOMAC) function and WOMAC total scores. There was also a trend towards a decrease in WOMAC pain score. The results suggest that the fibrate use, when compared with non-use, was associated with a yearly decrease in WOMAC.

The Infection-Senescence Hypothesis of Alzheimer’s Disease

https://www.fightaging.org/archives/2019/07/the-infection-senescence-hypothesis-of-alzheimers-disease/

With the continued failure of clinical trials of therapies for Alzheimer’s disease, largely immunotherapies, that aim to clear amyloid-β, a growing faction of researchers are rejecting the amyloid hypothesis. In that mainstream view of the condition, the accumulation of amyloid-β causes the early stages of Alzheimer’s, but in addition to disrupting the function of neurons, it also causes immune cells in the brain to become inflammatory, dysfunctional, and senescent. This in turn sets the stage for the aggregation of tau protein into neurofibrillary tangles, which causes widespread cell death and the much more severe manifestations of later stage Alzheimer’s disease.

Why do only some old people exhibit the condition? In the mainstream view, this is equivalent to asking why only some old people have significantly raised levels of amyloid-β in the brain. This might be due to different rates at which drainage of cerebrospinal fluid becomes impaired with aging, preventing molecular waste from leaving the brain. But many researchers are starting to consider that infectious pathogens are the most important cause, as amyloid-β has now been shown to be an antimicrobial peptide, a part of the innate immune system. The more infection, the more amyloid-β. There is good evidence for persistent infections such as forms of herpesvirus to be associated with Alzheimer’s risk.

In today’s open access paper, the infection hypothesis is extended further to bypass amyloid-β. The authors suggest that infection leads directly to the stage of chronic inflammation and senescent immune cells in the brain. Amyloid-β accumulation is not necessary for the progression of Alzheimer’s in this view of the condition, and may be just a side-effect. As is usually the case in such matters, the best way to find out what is actually going on is to repair or block one mechanism in isolation of all of the others and see what happens. This is quite challenging in the case of Alzheimer’s disease, as the animal models are all highly artificial: mice don’t naturally suffer Alzheimer’s or any similar condition. Thus one can reverse a mechanism or pathology that was introduced into the model, but that doesn’t say much about what happens in the human condition, as it has quite different origins and progression.

The Post-amyloid Era in Alzheimer’s Disease: Trust Your Gut Feeling


Advanced age is a major Alzheimer’s disease (AD) risk factor; therefore, understanding cellular senescence and its impact on endothelial cells (ECs), neurons, glia, and immune cells is an essential prerequisite for elucidating the pathogenesis of this condition. Brain accumulation of extracellular β-amyloid and intracellular hyperphosphorylated tau are the pathological hallmarks of AD. Both neurons and astrocytes synthesize β-amyloid from amyloid precursor protein (APP), while phagocytic microglia prevent its accumulation by removing it via the triggering receptor expressed on myeloid cells-2 (TREM-2).

The amyloid hypothesis postulates that accumulation and deposition of β-amyloid are the primary causes of AD, which promotes tau aggregation into neurofibrillary tangles (NFTs), ultimately triggering neuronal death. Although never universally accepted, the amyloid hypothesis drove AD research for at least two decades. Lately, however, many researchers and clinicians have questioned this model as amyloid removal failed to improve memory in numerous clinical trials. With the same token, neuroimaging studies detected significant β-amyloid deposits in 20-30% of healthy older individuals, while in many AD patients, this marker was not observed.

Moreover, β-amyloid was recently characterized as an antimicrobial peptide (AMP), and its accumulation in AD brains may be a reflection of increased microbial burden. AMPs are defensive biomolecules secreted by the innate immune system, including microglia and astrocytes, in response to a variety of microorganisms and malignant cells. The β-amyloid-AMP connection is further supported by the observation that central nervous system (CNS) infections were diagnosed in some clinical trials, following the administration of anti-amyloid vaccines.

Recent studies have reported co-localization of microorganisms with senescent neurons and glial cells in the brains of both AD patients and healthy older individuals, reviving the infectious hypothesis. CNS infectious agents have been detected previously in AD patients; however, it was difficult to assess if they represented the cause or effect of this condition. A recent study may have settled this issue as it detected gingipain, a Porphyromonas gingivalis antigen, linked to AD, in the brains of healthy older persons, suggesting that they would have developed the disease if they lived longer. As P. gingivalis is a major cause of gum disease and a modifiable AD risk factor, treatment of periodontal infection must be considered a clinical priority.

It has been well-established that inflammation and cellular senescence are closely related, but the role of pathogens in this process has been less emphasized. Astrocytes are the most numerous brain cells. Recent studies report that astrocytes are innate immune cells that, along with microglia, play a key role in the phagocytic removal of molecular waste, dead, or dying cells. Preclinical studies have reported that astrocytes undergo both replicative senescence and stress-induced senescence, however, the difference between senescent and reactive astrocytes is not entirely clear at this time. Recent studies seem to indicate that these phenotypes may be closely related or even identical as upregulated inflammatory and synapse-eliminating genes were found in both senescent and reactive astrocytes.

Dystrophic microglia with growth arrest and senescent markers have been demonstrated in AD patients, but the difference between the reactive and dystrophic phenotype is unclear at this time. Taken together, senescent microglia, incapable of proper immunosurveillance and phagocytosis, contribute to the accumulation of molecular waste, dead or dying cells, inducing inflammaging and immunosenescence. Astrocytes may respond to these microenvironmental changes by converting to a phenotype marked by aberrant elimination of healthy synapses and neurons, a possible pathogenetic mechanism of AD.

Thus, microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer’s disease brains associated with senescent neurons, glia, and endothelial cells. We take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. Commensal gut microbes live in symbiosis with the human host as long as they reside in the GI tract where they can be kept under control. Cellular senescence alters the integrity of biological barriers, allowing translocation and dissemination of gut microorganisms throughout the body tissues, including the brain. Operating “behind enemy lines,” pathogens can gain control of host immune defenses and metabolism, triggering senescence and neurodegenerative pathology.

Mtss1L Mediates Improvement in Synaptic Function Resulting from Exercise

https://www.fightaging.org/archives/2019/07/mtss1l-mediates-improvement-in-synaptic-function-resulting-from-exercise/

Exercise is known to improve cognitive function, and researchers here delve into one of the mechanisms that may be responsible for this effect. Specifically, this work relates to synaptic plasticity in the brain, the ability of neurons to restructure their connections. This is important for learning and memory function. The work here is not the only project to have picked out specific genes and proteins relating to the regulation of brain function. It remains to be seen whether this can lead to some form of enhancement therapy at the end of the day, as may be the case for klotho and its effects on cognitive function.


The beneficial cognitive effects of physical exercise cross the lifespan as well as disease boundaries. Exercise alters neural activity in local hippocampal circuits, presumably by enhancing learning and memory through short and long-term changes in synaptic plasticity. The dentate gyrus is uniquely important in learning and memory, acting as an input stage for encoding contextual and spatial information from multiple brain regions. This circuit is well suited to its biological function because of its sparse coding design, with only a few dentate granule cells active at any one time. These properties also provide an ideal network to investigate how exercise-induced changes in activity-dependent gene expression affect hippocampal structural and synaptic plasticity in vivo.

While exercise is a potent enhancer of learning and memory, we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked the activated mature dentate granule cells of the hippocampus using conditional Fos-TRAP mice. Exercise-activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity.

Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied I-BAR domain-containing gene, which we hypothesized could be involved in membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses.

Targeting Shelterin via TRF1 to Degrade Telomeres in Cancer Cells

https://www.fightaging.org/archives/2019/07/targeting-shelterin-via-trf1-to-degrade-telomeres-in-cancer-cells/

Cancer cells depend on lengthening their telomeres, usually via telomerase activity. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little length is lost with each cell division, and when short a cell either self-destructs or becomes senescent and ceases replication. Cancer cells can only replicate continually if telomeres are extended continually. Thus some research groups are looking into sabotage of telomerase or the alternative lengthening of telomeres (ALT) processes as the basis for a truly universal cancer therapy. Others, as here, are investigating ways to interfere in mechanisms that protect telomeres from degradation, hopefully obtaining much the same result in the end.


In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: on one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers.

In human cells, telomeric chromatin is organized into a terminal loop (t-loop), nucleosomes, the non-coding RNA TERRA, the protein complex shelterin, and a network of nuclear factors. The shelterin complex is essential for telomere protection and comprises six subunits: Three subunits bind telomeric DNA (TRF1, TRF2, and POT1), while the three others establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1, TRF2, and TPP1 with TIN2 and POT1. Each shelterin subunit has a specific role in telomere protection, i.e., TRF1 prevents replication stress, TRF2 blocks ataxia telangiectasia-mutated (ATM) signaling and non-homologous end joining (NHEJ), while POT1 blocks ataxia telangiectasia and Rad3-related (ATR) signaling.

A wealth of recent findings points toward shelterin as a valuable alternative to telomerase to fight cancer. Researchers have identified small molecule compounds targeting TRF1 using an FDA-approved library to screen for TRF1 expression and localization. Several of the drugs downregulating TRF1 expression interfere with common cancer signaling pathways. Treatment of lung cancer and glioblastoma cells with these compounds triggered DDR activation at telomeres and telomere replication defects. In patient-derived glioblastoma stem cells (GSC), these TRF1 inhibitors reduced stemness in vitro.

Sabotaging a Mechanism of Decline in Age-Related Stem Cell Activity

https://www.fightaging.org/archives/2019/07/sabotaging-a-mechanism-of-decline-in-age-related-stem-cell-activity/

Stem cells are responsible for maintaining surrounding tissue function via generation of daughter cells to make up losses. Stem cell activity declines with age, and research of the past twenty years suggests that a sizable fraction of this decline is a reaction to rising levels of cell and tissue damage, rather than being due to intrinsic damage to the stem cells themselves. Thus researchers are searching for the signals that influence stem cell activity, with the intent of interfering in order to boost stem cell activity in old tissues. This seems a worse strategy than repairing the underlying damage that causes stem cell decline, but it is nonetheless a popular field of research, and there is plenty of evidence for it to be possible to produce some degree of benefits via this approach.


Researchers have discovered how regenerative capacity of intestinal epithelium declines when we age. Targeting of an enzyme that inhibits stem cell maintaining signaling rejuvenates the regenerative potential of an aged intestine. This finding may open ways to alleviate age-related gastrointestinal problems, reduce side-effects of cancer treatments, and reduce healthcare costs in the ageing society by promoting recovery.

The age-induced reduction in tissue renewal makes dosing of many common drugs challenging. Targeting of an inhibitor called Notum may provide a new way to increase the therapeutic window and to promote recovery in societies with the aging population. Researchers believe that in addition to direct targeting of Notum, lifestyle factors such as diet may also provide means to reduce Notum, and thus improve tissue renewal and repair.

Using organoid culture methods, researchers understood that poor function of tissue repairing stem cells in old intestine was due to aberrant signals from the neighboring cells, known as Paneth cells. “Modern techniques allowed us to examine tissue maintenance at a single cell level, and revealed which cell types contribute to the decline in tissue function. We were surprised to find that even young stem cells lost their capacity to renew tissue when placed next to old neighbors.”

Normally intestinal epithelium is renewed by stem cells that rely on activity of Wnt-signaling pathway. Surrounding cells produce molecules that activate this pathway. The study shows that during ageing, Paneth cells begin to express a secreted Wnt-inhibitor called Notum. Notum enzymatically inactivates Wnt-ligands in the stem cell niche, decreasing regenerative potential of intestinal stem cells. However, pharmacologic inhibition of Notum rejuvenated stem cell activity and promoted the recovery of old animals after treatment with a commonly used chemotherapeutic drug with severe side-effects in the gut.

Ghrelin Enhances Memory via the Vagus Nerve

https://www.fightaging.org/archives/2019/07/ghrelin-enhances-memory-via-the-vagus-nerve/

It is reasonable to hypothesize that the mechanisms of hunger might mediate some fraction of the short-term and long-term benefits to health and life span noted to occur as a result of calorie restriction. Which in turn suggests that strategies for the practice of calorie restriction that suppress hunger might be counterproductive. The hormone ghrelin is involved in the response to hunger, and like most proteins it is involved in a range of processes in metabolism. Evolution tends to result in reuse of protein machinery in many mechanisms. Researchers here report on the connection between ghrelin and memory function, which, like many of the interactions between body and brain, is quite indirect.


Ghrelin is produced in the stomach and secreted in anticipation of eating, and is known for its role to increase hunger. For example, ghrelin levels would be high if you were at a restaurant, looking forward to a delicious dinner that was going to be served shortly. Once it is secreted, ghrelin binds to specialized receptors on the vagus nerve – a nerve that communicates a variety of signals from the gut to the brain. Researchers recently discovered that in addition to influencing the amount of food consumed during a meal, the vagus nerve also influences memory function. The team hypothesized that ghrelin is a key molecule that helps the vagus nerve promote memory.

Using an approach called RNA interference to reduce the amount of ghrelin receptor, the researchers blocked ghrelin signaling in the vagus nerve of laboratory rats. When given a series of memory tasks, animals with reduced vagal ghrelin signaling were impaired in a test of episodic memory, a type of memory that involves remembering what, when, and where something occurred, such as recalling your first day of school. For the rats, this required remembering a specific object in a specific location.

The team also investigated whether vagal ghrelin signaling influences feeding behavior. They found that when the vagus nerve could not receive the ghrelin signal, the animals ate more frequently, yet consumed smaller amounts at each meal. Researchers think that these results may be related to the episodic memory problems. “Deciding to eat or not to eat is influenced by the memory of the previous meal. Ghrelin signaling to the vagus nerve may be a shared molecular link between remembering a past meal and the hunger signals that are generated in anticipation of the next meal.”

Chromatin Stress Promotes Longevity in Yeast. Flies, and Nematodes

https://www.fightaging.org/archives/2019/07/chromatin-stress-promotes-longevity-in-yeast-flies-and-nematodes/

Researchers here report on the finding that modest impairment of the histones responsible for packaging nuclear DNA into chromatin leads to slowed aging in short-lived laboratory species. This adds to the sizable number of existing forms of stress that can somewhat slow aging via hormetic processes, such as heat, lack of nutrients, and so forth. A little damage induces greater cellular maintenance activities, which on balance leads to more efficient, less damaged cells and tissues over the long term. Unfortunately, effects on life span are very much smaller in long-lived species such as our own, when compared with effects in short-lived species such as flies, worms, and mice.


In the nucleus of cells, DNA wraps itself around histone proteins forming a ‘beads-on-a-string’ structure called chromatin. Other proteins bind along chromatin and the structure folds further into more complicated configurations. Everything involving DNA would have to deal with this chromatin structure. For example, when a particular gene is expressed, certain enzymes interact with the chromatin structure to negotiate access to the gene and translate it into proteins. When chromatin stress happens, disruption of the chromatin structure can lead to unwanted changes in gene expression, such as expression of genes when they are not supposed to or lack of gene expression when it should occur.

In this study, researchers worked in the lab with the yeast Saccharomyces cerevisiae to investigate how the dosage of histone genes would affect longevity. They expected that yeast genetically engineered to carry fewer copies of certain histone genes than normal or control yeast would have chromatin changes that would result in the yeast living less than controls. “Unexpectedly, we found that yeast with fewer copies of histone genes lived longer than the controls.” Yeast with a moderately low dose of histone genes showed a moderate reduction of histone gene expression and significant chromatin stress. Their response to chromatin disruption was changes in the activation of a number of genes that eventually promoted longevity.

“We have identified a previously unrecognized and unexpected form of stress that triggers a response that benefits the organism. The mechanism underlying the chromatin stress response generated by moderate reduction of histone dosage is different from the one triggered by histone overexpression we had previously described, as shown by their different profiles of protein expression responses.” The researchers found that chromatin stress also occurs in other organisms such as the laboratory worm C. elegans, the fruit fly, and mouse embryonic stem cells, and in yeast and C. elegans the chromatin stress response promotes longevity. “Our findings suggest that the chromatin stress response may also be present in other organisms. If present in humans, it would offer new possibilities to intervene in the aging process.”

A Mainstream View of the Longevity Industry

https://www.fightaging.org/archives/2019/07/a-mainstream-view-of-the-longevity-industry/

This popular science article from the AARP is representative of the sort of outsider’s view of the longevity industry that is presently dominant. On the one hand, it is good that the media and advocacy organizations such as AARP are finally talking seriously about treating aging as a medical condition. On the other hand, the author looks at two of the most popular areas of development, mTOR inhibitors and senolytics, in a way that makes them seem more or less equivalent, and then further adds diet and exercise as another equivalent strategy. This will be continuing issue, I fear. People, as a rule, don’t think about size of effect and quality of therapy when discussing present initiatives.

These strategies are in fact very different, and the differences are important. Clearance of senescent cells via senolytic treatments is a radically different and better class of therapy than mTOR inhibition. Senolytics remove a cause of aging in one treatment, improving all aspects of health in later life in consequence, while mTOR inhibitors must be taken continually and only encourage the aging metabolism into a state that is somewhat more resistant to the underlying damage that causes aging. Tackling underlying causes will always be more effective than trying to cope with those causes without repairing them.


“We’ve reached the perfect storm in aging science,” says physician Nir Barzilai. “Everything is happening. We have the foundation from decades of animal studies. We’re ready to move on to people.” The ultimate goal: to put the brakes on aging itself – preventing the pileup of chronic health problems, dementia and frailty that slam most of us late in life. “I want 85 to be the new 65,” says Joan Mannick, the chief medical officer and cofounder of resTORbio.

The need is enormous. In a decade, nearly 1 in 5 Americans will be 65 or older. Three out of 4 will have two or more serious health conditions. At least 1 in 4 can expect memory lapses and fuzzy thinking, while 1 in 10 will develop dementia. “Right now doctors play whack-a-mole with chronic diseases in older adults. You treat one, another pops up. The goal instead is to tackle aging itself, the major risk factor for almost every major disease. Our society, our drug companies and medical profession aren’t addressing all this suffering that happens as people grow old. But the older people in my life are beloved to me. If we can do something about aging, we shouldn’t ignore it.”

Older people who took the mTOR inhibitor RAD001, a similar drug to resTORbo’s RTB101, had a stronger response to a flu vaccine. Their immune systems looked younger, with fewer exhausted T cells – a depressingly common feature of aging called immunosenescence. “This was the first evidence that if you target a pathway in humans, you may actually impact how we age.” The results of a trial of RTB101 were particularly strong for people 85 and older; they had 67 percent fewer infections. That’s good news, because – in part due to an age-related weakening of the immune system – respiratory infections are the fourth-leading reason older U.S. adults wind up in the hospital and their eighth-leading cause of death.

Alas, there’s more going wrong in older cells than on-the-fritz mTOR. Among these issues: inflammation; out-of-whack metabolism; inactive stem cells that can’t repair body tissues; damage from stress, environmental toxins and free radicals; reduced “quality control,” which can’t eliminate rogue cells. These glitches boost the risk for everything from heart disease and stroke to diabetes, osteoarthritis, Alzheimer’s disease, Parkinson’s and cancer. If these and other cellular issues are the underlying causes of so many diseases, preventing cells from succumbing to them as they age is a key to preventing disease. That’s why resTORbio, other biotech start-ups and university aging labs across the U.S. are launching an unprecedented number of human clinical trials with experimental compounds aimed at these mechanisms.

One big target: senescent cells that refuse to die, instead glomming up in joints and other body tissues. They pump out dozens of inflammatory compounds and other chemicals that contribute to age-related diseases. In a raft of mouse studies, clearing out these senescent cells boosted health – easing arthritis pain, improving kidney and lung function, increasing fitness, extending life and even making fur thicker. In January, the first-ever human study of a treatment to kill senescent cells in the lungs was published. Fourteen people with the fatal lung disease idiopathic pulmonary fibrosis took a mix of the drugs dasatinib and quercetin for three weeks. The verdict: The drug combo was safe, triggered just one serious side effect (pneumonia), and seemed to improve study volunteers’ basic ability to stand up and walk. There were also hints it may have reduced senescent-cell activity, but the researchers say bigger, longer studies are needed.

Right now, simply staying healthy into our 80s, 90s and beyond is a lot like hitting the lottery jackpot. In a survey of 55,000 Americans age 65-plus, just 48 percent rated their health as very good or excellent. No wonder drugstores, the internet, and human history are littered with unproven rejuvenation come-ons. Meanwhile, as researchers slowly test these more legitimate drugs, what can we do today if we wish to retain good health longer? That answer has been with us all along. Not smoking, eating healthy, getting exercise, managing stress and sleep.

Cellular Senescence in Mesenchymal Stem Cells

https://www.fightaging.org/archives/2019/07/cellular-senescence-in-mesenchymal-stem-cells/

Cellular senescence is a cause of aging. Cells become senescent in response to a variety of circumstances: damage, a toxic environment, reaching the Hayflick limit on replication, and so forth. In all cell populations, older individuals exhibit increasing numbers of senescent cells, perhaps largely due to the progressive decline of the immune system and its growing failure to clear out unwanted or harmful cells. Lingering senescent cells secrete a potent mix of signals that rouse the immune system into a state of chronic inflammation, and degrade tissue function and structure. The more of them there are, the worse the outcome.


Mesenchymal stem cells (MSCs) are located in specific areas of tissues, called “niches”, and are characterized as being in a state of relative quietness, from which they can exit under the proper conditions to obtain the proliferative potential necessary for tissue regeneration. MSCs have sustained interest among researchers by contributing to tissue homeostasis and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors, because their paracrine action is the main mechanism explaining their effects, regardless of source.

Senescence is defined as a mechanism for limiting the regenerative potential of stem cells. It is now evident that senescent cells secrete dozens of molecules, for which the terms “senescence-associated secretory phenotype (SASP)” and “senescence-messaging secretome (SMS) factors” have been proposed. The secreted factors contribute to cellular proliferative arrest through autocrine/paracrine pathways as well as in vivo and in vitro. SMS factors released by senescent cells play a key role in cellular senescence and physiological aging by activation of cytoplasmic signalling circuitry.

The population of mesenchymal stem cells, also known as mesenchymal stromal cells, contributes directly to the homeostatic maintenance of organs; hence, their senescence could be very deleterious for human bodily functions. The milestone in MSC investigation will be discovering senescence markers to determine the quality of the in vitro cells for cell-based therapies. Researchers have proposed TRAIL receptor CD264 as the first cellular senescence mesenchymal marker in bone marrow-derived MSCs, because it has the same expression profile of p21 during culture passage.

Dysfunctional Stem Cells Contribute to Impaired Fracture Repair in Old Age

https://www.fightaging.org/archives/2019/07/dysfunctional-stem-cells-contribute-to-impaired-fracture-repair-in-old-age/

Stem cells perform the vital function of supporting surrounding tissue by providing new daughter somatic cells to make up losses and take their place to maintain tissue function. This stem cell activity declines with age, however, due to a combination of intrinsic damage to these cell populations, and increasing inactivity. The latter is an evolved reaction to rising levels of damage, one that serves to reduce cancer risk in earlier old age, but at the cost of a lengthy decline into incapacity. Pick near any dysfunction of aging and it is likely that loss of stem cell activity is to some degree contributing to the outcome.


Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells.

MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs.

Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. The causes of cellular aging and the concomitant decline in functionality are wide-ranging, but provide some intriguing indications of potential targets for speeding fracture healing in older individuals. In the future, cell therapies that supplement the inadequate native cellular response with MSCs or endothelial colony forming cells (ECFCs); bone anabolic pharmacological agents, particularly in combination with strategies to localize their delivery to the bone fracture; drugs that reduce oxidative stress, cellular senescence, or activate SIRT1; and/or physical therapeutics may prove effective in promoting fracture healing in the elderly.

Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.

Common Dietary Supplements Have Little to No Effect on Mortality

https://www.fightaging.org/archives/2019/07/common-dietary-supplements-have-little-to-no-effect-on-mortality/

Yet another sizable study has shown that common dietary supplements have little to no effect on late life mortality. This finding of course has to compete with the wall to wall marketing deployed by the supplement market. Researchers have been presenting data on the ineffectiveness of near all supplements of years, but it doesn’t seem to reduce the enthusiasm for these products. In the past it was fairly easy to dismiss all supplements as nonsense, or at the very least causing only marginal effects that were in no way comparable to the benefits of exercise and calorie restriction, but matters are now becoming more complex. New supplements based on altered mitochondrial biochemistry or senolytic activity, such as nicotinamide riboside, mitoQ, and fisetin, might well have effect sizes that are worth it as an addition to calorie restriction and exercise; we shall see as human studies progress.


In a massive new analysis of findings from 277 clinical trials using 24 different interventions, researchers say they have found that almost all vitamin, mineral, and other nutrient supplements or diets cannot be linked to longer life or protection from heart disease. Although they found that most of the supplements or diets were not associated with any harm, the analysis showed possible health benefits only from a low-salt diet, omega-3 fatty acid supplements and possibly folic acid supplements for some people. Researchers also found that supplements combining calcium and vitamin D may in fact be linked to a slightly increased stroke risk.

Surveys show that 52% of Americans take a least one vitamin or other dietary/nutritional supplement daily. An increasing number of studies have failed to prove health benefits from most of them. “The panacea or magic bullet that people keep searching for in dietary supplements isn’t there. People should focus on getting their nutrients from a heart-healthy diet, because the data increasingly show that the majority of healthy adults don’t need to take supplements.”

The vitamin and other supplements reviewed included: antioxidants, β-carotene, vitamin B-complex, multivitamins, selenium, vitamin A, vitamin B3/niacin, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, calcium and vitamin D together, folic acid, iron and omega-3 fatty acid (fish oil). The diets reviewed were a Mediterranean diet, a reduced saturated fat (less fats from meat and dairy) diet, modified dietary fat intake (less saturated fat or replacing calories with more unsaturated fats or carbohydrates), a reduced fat diet, a reduced salt diet in healthy people and those with high blood pressure, increased alpha linolenic acid (ALA) diet (nuts, seeds and vegetable oils), and increased omega-6 fatty acid diet (nuts, seeds and vegetable oils). Each intervention was also ranked by the strength of the evidence as high, moderate, low or very low risk impact.

The majority of the supplements including multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone and iron showed no link to increased or decreased risk of death or heart health. “Our analysis carries a simple message that although there may be some evidence that a few interventions have an impact on death and cardiovascular health, the vast majority of multivitamins, minerals and different types of diets had no measurable effect on survival or cardiovascular disease risk reduction.”

Diminished Estradiol Explains Faster Muscle Loss Following Menopause

https://www.fightaging.org/archives/2019/07/diminished-estradiol-explains-faster-muscle-loss-following-menopause/

Both genders lose muscle mass and strength with age, leading to sarcopenia and frailty. Why do women undergo age-related muscle loss more rapidly following menopause, however? Researchers here suggest that the sex hormone estradiol is necessary to support the activity of muscle stem cells, and thus falling levels of estrogen following menopause is the mechanism driving this outcome. Loss of stem cell function in muscle tissue is also the most credible cause for the onset of sarcopenia without considering gender, so this all fits together quite nicely.


Over the course of an individual’s life, skeletal muscle undergoes numerous injurious insults that require repairs in order for function to be maintained. The maintenance and injury repair of skeletal muscle is dependent on its resident stem cell (i.e., the satellite cell). With proliferation, satellite cells undergo asymmetric division through which a subpopulation of the daughter satellite cells do not differentiate, but instead return to quiescence, repopulating the satellite cell pool (i.e., self-renewal). The balance of this asymmetric division process is critical and necessary to ensure the life-long preservation of satellite cells in skeletal muscle.

Aging diminishes the satellite cell pool and, as a result, the regenerative capacity of skeletal muscle in aged males is impaired compared to that of younger males, but such age-induced impairments in females is less studied. Similarly, age-associated changes in the satellite cell environment, in combination with cell-intrinsic alterations, disrupt quiescence and the balance of asymmetric division, ultimately impacting satellite cell maintenance and muscle regenerative potential. Such results support the concept that circulatory factors, including hormones that differ between the young and old systemic environments and the activity of their subsequent signaling pathways, contribute to age-associated decrements in satellite cell maintenance and overall muscle regenerative capacity.

A well-known hormone that changes with age is estradiol, the main circulating sex hormone in adult females. Serum estradiol concentration declines dramatically at the average age of 51 in women, corresponding to the time of menopause. Estradiol deficiency reduces skeletal muscle mass and force generation in women and prevents the recovery of strength following contraction-induced muscle injury and traumatic muscle injury in female mice. However, evidence that this regenerative phenotype involves effects of estradiol directly on satellite cells is lacking.

In this study, we use rigorous and unbiased approaches to demonstrate the in vivo necessity of estradiol to maintain the satellite cell number in females. Further, we use mouse genetics to show that the molecular mechanism of estradiol action is cell-autonomous signaling through estrogen receptor α (ERα). Specifically, we show the functional consequence of estradiol-ERα ablated signaling in satellite cells including impaired self-renewal, engraftment, and muscle regeneration, and the activation of satellite cell mitochondrial caspase-dependent apoptosis. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females.

Discover more about Nitric Oxide Supplement and Cardiovascular fitness.

Vitamin D is essential for your heart

The best Nutritional supplements designed for Nitric Oxide Health


Browsing for superb certified nutritional supplements?  Read and learn about  Cardio Cocktail Endorsed Products.

Vitamin D plays a significant role in several health conditions. It might be one of the simplest solutions to a wide range of problems. Despite the name, vitamin D belongs to a group of steroid molecules that are metabolized by the body in the liver and kidneys.1

According to the Vitamin D Council, your body undergoes numerous turns this molecule into a hormone that undergoes numerous changes during that process before it’s actually put to work managing calcium in your blood, bones and gut, and in helping your body’s cells communicate with each other.2

Vitamin D is optimally obtained through sun exposure, a small amount of food sources and supplementation. Since many dermatologists,3,4 other doctors and health care agencies like the CDC5 began telling people to avoid the sun and to use liberal amounts of sunscreen before going outside, deficiency in vitamin D has reached epidemic proportions.6,7,8,9,10

While the justification for avoiding the sun is it may reduce your risk of skin cancer, vitamin D deficiency raises your risk for many other cancers,11,12,13 including skin cancer.14

We now understand more about vitamin D than ever before in history. Many people are realizing that several of the long-held recommendations on sun exposure and vitamin D are not accurate and have contributed to declining health.

One condition recently linked to low levels of vitamin D is high blood pressure in children. In a study published in the American Heart Association journal Hypertension, researchers found that deficiency in infancy may lead to high blood pressure in later childhood and teen years.15

Childhood vitamin D deficiency predicts high blood pressure

A study from the Centers for Disease Control and Prevention16 showed 4% of those between 12 and 19 years had high blood pressure and another 10% had elevated blood pressure. An analysis of more than 12,000 participants led to these results using the 2017 clinical practice guidelines for high blood pressure.

Application of the new guidelines resulted in a net increase in the number of children and teens between 12 and 19 years with high blood pressure.17 High blood pressure may damage your heart and your health in many ways, including increasing your risk of heart failure and heart attack, stroke and kidney disease.18

Past research has demonstrated that low vitamin D levels in adults increases the risk of high blood pressure,19 but the degree to which it may affect children was unknown until a new study conducted at Boston Medical Center was published.20

In this study, researchers followed 775 children in ages ranging from birth to age 18 from 2005 to 2012 to investigate the effect vitamin D had on the development of high systolic blood pressure. For the purposes of the study,21 low vitamin D status was defined as less than 11 nanograms per milliliter (ng/mL) at birth and less than 25 ng/mL during early childhood.

The researchers22 compared those with low levels of vitamin D to children who were born with adequate levels. They found that children with low levels had about a 60% higher risk of elevated systolic blood pressure from ages 6 to 18.

Children who experienced persistently low levels throughout childhood were at double the risk of elevated systolic blood pressure between ages 3 and 18.23 Lead author Guoying Wang, Ph.D.,24 an assistant scientist at Johns Hopkins University, commented on the implications:25

“Currently, there are no recommendations from the American Academy of Pediatrics to screen all pregnant women and young children for vitamin D levels. Our findings raise the possibility that screening and treatment of vitamin D deficiency with supplementation during pregnancy and early childhood might be an effective approach to reduce high blood pressure later in life.”

Vitamin D and estrogen may reduce metabolic syndrome

Metabolic syndrome is a cluster of physiological symptoms associated with the development of cardiovascular disease and Type 2 diabetes. And, according to the Mayo Clinic, these symptoms include high blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol or triglyceride levels.26

While having just one of these symptoms does not mean you have metabolic syndrome, it might mean you have a greater risk of serious disease. Metabolic syndrome also goes by the terms dysmetabolic syndrome, insulin resistance syndrome, obesity syndrome and Syndrome X.27

The prevalence of metabolic syndrome increases as women reach menopause, which may somewhat explain accelerated levels of heart disease after menopause.28 Scientists have theorized that these changes may be related to ovarian failure or the redistribution of fat to the stomach area, which is associated with estrogen deficiency.29

The combination of adequate vitamin D levels and normal estrogen levels have been well-documented as improving bone health.30 In a recent study,31 researchers found data to suggest that the same combination may help prevent metabolic syndrome.

They wrote that metabolic syndrome affects 30% to 60% of postmenopausal women globally. This has led some to recommend estradiol treatments for the first six years after menopause, to help prevent heart disease.

In that study,32 researchers looked at a cross-section of 616 postmenopausal women who were 49 to 86 years old and not taking estrogen, vitamin D or calcium supplements. At the end of the data collection period, they took blood samples to measure estrogen and vitamin D levels.

They found that higher levels of vitamin D were positively correlated with healthier blood pressure measurements, glucose levels and lipid profiles. The data also revealed that low estrogen levels increased the risk of metabolic syndrome in those who also had low vitamin D. They believe the results suggest33 a synergistic role between vitamin D and estrogen deficiencies in postmenopausal metabolic syndrome.

Vitamin D insufficiency may affect more than 75%

A simple math error accounts for one reason there are inaccuracies in the amount of vitamin D that is believed to be necessary to maintain good health. As pointed out in a 2014 paper,34 the then Institute of Medicine (which underwent a name change to the National Academy of Medicine in 2015)35 underestimated the need by a factor of 10 due to a miscalculation.

If corrected, the official recommendation would become 6,000 IUs a day for adults, not 600; however, the Vitamin D Council recommends 5,000.36 According to data published in the Archives of Internal Medicine,37 75% of American adults and teens are deficient in vitamin D, based on a sufficiency level of 30 ng/mL.

Insufficiency affects an estimated 1 billion people worldwide38 and may be attributed to lifestyle activities, such as a reduced number of hours spent outside in the sun. Environmental factors are also at play, relating to air pollution reducing our exposure to sunlight. A low vitamin D level is an independent risk factor for various chronic diseases.

The only way to definitively identify a vitamin D deficiency is through blood testing. However, some general signs and symptoms may tell you it’s time to be proactive. You’ll find a discussion in my past article, “Top 5 Signs of Vitamin D Deficiency.”

Risk factors for low vitamin D levels include rarely spending time outdoors or always wearing sunscreen when you are, having dark skin pigmentation, being older than 50, being obese and having gastrointestinal problems. While regular, sensible sun exposure is the best way to optimize your vitamin D status, those in northern climates may need an oral supplement, especially during the winter months.

The only way to gauge how much supplement you need is to have your levels tested, ideally twice a year. Test once in the early spring, after the winter months to ensure you took enough supplement throughout the winter, and again in the early fall when your level is at its peak. You are aiming for a level between 60 and 80 ng/mL, with 40 ng/mL being the lowest cutoff for sufficiency.39,40 In fact, new research in 2018 showed that the optimal levels for cancer prevention are between 60 and 80.

Deficiency increases the risk of cancer and mortality

Although some may struggle with the concept that just one vitamin may have a significant impact on your health, wellness and longevity,41 or that vitamin D deficiency is problematic,42 there is ample research with evidence to the contrary. As I mentioned earlier, low levels of vitamin D have been associated with an increased risk for some cancers,43,44,45 bowel conditions,46,47 and skin conditions48 It also has a negative impact on your immune system.49

Vitamin D insufficiency is strongly associated with increased mortality. An epigenetic mortality risk score, developed based on whole blood DNA methylation, was used in one study50 aimed at determining whether vitamin D status was associated with this risk.

Another aim of the study was also to see if vitamin D and the mortality risk score could be used together to predict all-cause mortality in a general population of older adults. The researchers measured 1,467 participants whose ages ranged from 50 to 75. They found the combination was in fact a good indicator of the likelihood of all-cause mortality.51

Although a number of anticancer properties for vitamin D have been proposed, data suggest the metabolism and function of vitamin D is dysregulated in many types of cancers. Researchers believe this contributes to the development and progression of cancer. This means that understanding this dysregulation and function of vitamin D in cancer is of great importance.52

In addition to affecting cancers and all-cause mortality, low levels of vitamin D may also trigger dry eye syndrome53 and macular degeneration.54 I also believe vitamin D can have a beneficial impact on all autoimmune diseases. Many studies55,56,57 have found a strong link between multiple sclerosis and vitamin D deficiency.

Vitamin D plays a role in inflammatory rheumatic diseases,58 such as rheumatoid arthritis. According to one study,59 many with systemic lupus erythematosus (SLE) have presented with some level of vitamin D deficiency, defined in the study as a level of 10 ng/mL or less, or insufficiency defined between 10 and 30 ng/mL.

As reported in another study, an elderly person who has a low vitamin D level may have “a substantially increased risk of all-cause dementia and Alzheimer’s.”60 Some scientists have also found links between depression and vitamin D deficiency61 and the impact low levels have on insulin resistance leading to Type 2 diabetes.62

D3 and K2 protect your arteries from calcification

While vitamin D is essential for good health and is best obtained from sensible sun exposure, if your levels are not high enough, you may need a supplement. However, it’s vital you take vitamin D with sufficient amounts of vitamin K2 (MK7) as both are required to slow the progression of arterial calcification.63

Vitamin D improves bone development by helping you absorb calcium, while vitamin K2 directs the calcium to the skeleton and prevents it from being deposited in the arteries. There are two forms of vitamin K: K1 and K2. Vitamin K164 is primarily involved in blood coagulation while K2 has a more diverse range of functions.65

In one long-term study66 of 36,629 participants, researchers found vitamin K2 reduced the risk of peripheral artery disease in those with high blood pressure, but K1 had no effect. Other67 data suggest that the body absorbs vitamin K 10 times more when it is in the form of MK-7.

Vitamin K2 in the MK-7 form has been found to be bioactive. It regulates atherosclerosis, cancer, inflammatory diseases and osteoporosis.68 Vitamin K2 may lower the risk of damage to the cardiovascular system by activating a protein that prevents calcium from depositing in the walls of your blood vessels.69

If you consider supplementation, it is important to know that vitamin D2 and D3 are not interchangeable. In one study of 335 South Asian and white European women,70,71 researchers found that those taking vitamin D3 experienced twice the effectiveness in raising vitamin D levels in the body as compared to vitamin D2.

According to another data collection72 and analysis of 50 randomized controlled studies in the Cochrane database, researchers found vitamin D3 decreased mortality in elderly women who were in institutions and dependent care. Vitamin D2 did not have any solid effects on mortality.

Astaxanthin: Your internal sunscreen

Maintaining optimal levels of vitamin D through sensible sun exposure is the best way. However, too much sun may be just as much of a problem as too little. You may also want to avoid certain commercial sunscreens because they contain harmful chemicals that are easily absorbed through the skin. When this happens, you are exposed to a range of risks that outweigh the benefits.73,74

One option to consider is the use of astaxanthin, commonly called the “King of the Carotenoids.”75 The carotenoid found in astaxanthin is naturally occurring in a specific type of microalgae and in certain seafoods. The seafood with the highest amount of astaxanthin consume the microalgae, including wild-caught Alaskan salmon and krill.76

One of the benefits of this nutrient is its ability to protect your skin from the sun and to reduce the signs of aging. In one clinical trial77 involving 21 individuals, researchers found that after taking 4 mg of astaxanthin each day for just two weeks, the participants had an average 20% increase in the amount of time needed for UV radiation to redden their skin.

One study78 set out to evaluate the effects of supplementation with astaxanthin on UV-induced skin deterioration. Using 23 healthy Japanese participants in a 10-week, double-blind, placebo-controlled investigation, the researchers found those taking astaxanthin had a reduction in loss of moisture. They also had improved skin texture and appeared to experience protective effects against UV skin deterioration.

In another study79 evaluating the effects of radiation on hairless mice, researchers found dietary supplementation with astaxanthin significantly lowered wrinkle formation and water loss. They suggested that the results point to dietary supplementation with astaxanthin as being helpful for protecting the skin and slowing skin aging.

Optimize your vitamin D levels

Remember, it’s best to optimize your vitamin D levels with sunshine rather than oral supplements. Before considering supplementation with vitamins D3 and K2 MK-7 form, first get tested since you can’t know your levels by looking in the mirror. GrassrootsHealth offers a simple combined test for vitamin D and omega-3, which are both important for maintaining optimal health.

While many labs and physicians use 40 ng/mL as a cutoff for vitamin D deficiency, please remember that an ideal level for health and disease prevention is between 60 and 80 ng/mL.80 Once you know your level consider using a simple tool from GrassrootsHealth to estimate the additional amount you need to take to reach your targeted level.

Check out N.O. Supplements and Cardiovascular health.

Oxidative Stress in the Aging Brain Accelerates the Spread of α-synuclein

Excellent Supplements designed for Heart


Hunting for unsurpassed endorsed health supplements?  Read and learn about  these Medically Recognised Vitamins.

Parkinson’s disease, like many neurodegenerative conditions, is associated with the age-related aggregation of a specific protein, in this case α-synuclein. The protein aggregates have a halo of harmful biochemistry, causing dysfunction and cell death in neurons. Researchers here propose that the increased levels of oxidative stress observed in old tissues spur the spread of α-synuclein protein aggregates from cell to cell as the disease progresses. Oxidative stress can arise from mitochondrial dysfunction, as mitochondria produce oxidative molecules as a byproduct of their normal operation, but is also associated with chronic inflammation. Both are also features of aging and thought to be important in the progression of neurodegenerative conditions.


At the microscopic and pathological levels, Parkinson’s disease is characterized by accumulation of abnormal intraneuronal inclusions. They are formed as a result of aggregation of a protein called α-synuclein. In the course of the disease, these inclusions progressively appear in various brain regions, contributing to the gradual exacerbation of disease severity. The mechanisms behind this advancing pathology are poorly understood. Research now indicates that oxidative stress, i.e. an excessive and uncontrolled production of reactive oxygen species, could play an important role in the pathological spreading of α-synuclein.

In a series of experiments, researchers studied mice that overproduced α-synuclein in a specific brain region, namely the dorsal medulla oblongata, known to be a primary target of α-synuclein pathology in Parkinson’s disease. Under this condition, the researchers were able to show oxidative stress, formation of small α-synuclein aggregates (so called oligomers) and neuronal damage. Increased production of α-synuclein also led to its “jump” from donor neurons in the medulla oblongata into recipient neurons in neighboring brain regions that became affected by progressive α-synuclein accumulation and aggregation.

Interestingly, treatment of mice with paraquat, a chemical agent that generates substantial amounts of reactive oxygen species and thus triggers an oxidative stress, exacerbated α-synuclein pathology and resulted in its more pronounced spreading throughout the brain. “Our findings support the hypothesis that a vicious cycle may be triggered by increased alpha-synuclein burden and oxidative stress. Oxidative stress could promote the formation of alpha-synuclein aggregates which, in turn, may exacerbate oxidative stress. Jumping from neuron to neuron, this toxic process could affect more and more brain regions and contribute to progressive pathology and neuronal demise.”

Link: https://www.dzne.de/en/news/public-relations/press-releases/press/detail/parkinsons-a-new-study-associates-oxidative-stress-with-the-spreading-of-aberrant-proteins/

Check out Nitric Oxide and Cardio health and fitness.

Myeloid Skew Arises from Age-Related Changes in Bone Marrow Niches

Best Dietary supplements for Cardiovascular Health


Shopping for unsurpassed recognised health supplements?  Educate yourself about  these Recognised Products.

Hematopoietic stem cells (HSCs) resident in bone marrow generate immune cells, and their activity is thus vital to the correct function of the immune system. Like all stem cell populations, HSCs are sustained by a niche of supporting cells. One of the interesting questions relating to the aging of stem cells and the decline of stem cell activity in later life is whether this is a problem inherent to the stem cells themselves, or it arises from change and damage in the niche. There is evidence for both to be the case, but it is possible to argue that, until extreme old age, the loss of activity is more a matter of the niche than actual incapacity on the part of stem cells.

One of the ways in which HSC behavior changes with age, and that alters the immune system for the worse, is that ever more myeloid and ever fewer lymphoid daughter cells are created. This myeloid skew is a well studied phenomenon, but as for all complex systems in the body, the causes and their relations to one another are much debated. Here, researchers discuss some specific mechanisms in the HSC niches in the bone marrow that may contribute to this phenomenon.


Hematopoietic aging is characterized by expansion of hematopoietic stem cells (HSCs) with impaired function, such as reduced engraftment, quiescence, self-renewal, unfolded protein response, and lymphoid differentiation potential, leading to myeloid-biased output both in mice and humans. Myeloid malignancies are more frequent in the elderly, but whether changes in the aged HSCs and/or their microenvironment predispose to these malignancies remains unclear.

Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological or natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the bone marrow microenvironment promotes myelopoiesis in premature and physiological aging.

During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased bone marrow noradrenergic innervation promotes β2-adrenergic-receptor(AR)interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal or premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.

Link: https://doi.org/10.1016/j.stem.2019.06.007

Read nore about Nitric Oxide Supplements and Cardio health and fitness.

What happens to your body when you’re dehydrated

Best Supplements regarding Cardiovascular Health


Wanting to find top quality authorised quality nutritional supplements?  Learn about  these Approved Supplements.

Dehydration is a health concern that should never be ignored. Anyone can become dehydrated for various reasons, so it is important that you always hydrate yourself with filtered water. Read on to learn more about symptoms of dehydration and how you can prevent it.

What is dehydration?

Dehydration happens when you’ve lost too much water without replacing it, preventing your body from performing its normal functions.1 Remember that water makes up nearly 50% to 60% of your body, depending on your gender.2 It plays a large part in many bodily functions, such as lubricating your joints and retaining moisture in your eyes, keeping your skin healthy, eliminating toxins and facilitating proper digestion.

Proper intake of fluids is also vital for kidney function3 so, every time your body loses water, you need to replace those fluids to maintain balance between the salts, glucose and other minerals in your system.4

If you become dehydrated, drastic changes in your body can immediately occur. Research has shown that even mild dehydration can decrease brain tissue fluid, which can result in changes in brain volume.5 Your blood becomes more viscous as well, straining your cardiovascular system and putting you at risk of health issues like thrombogenesis.6 Dehydration also compromises your body’s ability to regulate your temperature.7

Losing just 1% to 2% of your entire water content can cause thirstiness, a sign that you need to replenish the lost liquids.8 Mild dehydration can easily be treated but if it reaches extreme levels, it can be life-threatening and will require immediate medical attention.

Signs and symptoms of dehydration

Here are the mild and severe symptoms of dehydration, according to the Mayo Clinic:9

Mild to moderate dehydration

  • Dry, sticky mouth
  • Sleepiness or tiredness
  • Dry skin
  • Headache
  • Constipation
  • Dizziness or lightheadedness
  • Few or no tears when crying
  • Minimal urine
  • Dry, cool skin10
  • Muscle cramps

Severe dehydration

  • Extreme thirst
  • Irritability and confusion
  • Sunken eyes
  • Dry skin that doesn’t bounce back when you pinch it
  • Low blood pressure
  • Rapid heartbeat
  • Rapid breathing
  • No tears when crying
  • Fever
  • Little or no urination, and any urine color that is darker than usual
  • In serious cases, delirium or unconsciousness

Infants and children are more vulnerable to dehydration. HealthyChildren.org notes that immediate attention must be given to these age groups if they exhibit the following symptoms:11

Mild to moderate dehydration

  • Urinates less frequently (for infants, fewer than six wet diapers per day)
  • Plays less than usual
  • Parched, dry mouth
  • Fewer tears when crying
  • Sunken soft spot on the head (fontanelle)
  • Loose stools (if dehydration is caused by diarrhea). If dehydration is due to fluid loss, there will be fewer bowel movements

Severe dehydration

  • Very fussy
  • Excessively sleepy
  • Sunken eyes
  • Cool, discolored hands and feet
  • Wrinkled skin
  • Urinates only once or twice a day

Chronic dehydration can affect your organs and lead to kidney stones,12 constipation13 and electrolyte imbalances that may result in seizures.14 Whether it is mild, moderate or severe dehydration, the liquids lost from your body must be immediately replaced. If you become dehydrated and begin experiencing symptoms like those mentioned here, get professional treatment as soon as possible.

What causes dehydration?

There are various reasons why dehydration occurs, and the causes can be a result of both losing too many fluids and not taking in enough. For example, intense physical activity can cause you to sweat profusely and lose substantial amounts of water, so proper hydration is necessary to replenish what you’ve lost. Medical News Today says other causes of dehydration include:15

  • Diarrhea — This condition prevents your intestinal tract from absorbing water from the foods that you eat, making it the most common cause of dehydration.
  • Vomiting — Common causes include foodborne illnesses, nausea and alcohol poisoning.
  • Sweating — Vigorous sweating may occur for various reasons, such as if you have a fever, work in hot environments or engage in intense physical activity.
  • Diabetes Having high blood sugar levels can cause frequent urination and, subsequently, extreme loss of fluids in your cells, leading to dehydration.
  • Frequent urination — Nondiabetics may urinate frequently because of alcohol intake or from taking certain drugs like antihistamines, blood pressure medications and antipsychotics. Too much caffeine intake can cause you to urinate more frequently, too.16

Who is at risk of dehydration?

Everyone is prone to dehydration, but some people have a higher risk for it, such as those who engage in strenuous exercise. One example is mountain climbing. It is especially hard for hikers to stay hydrated because the pressure at high altitudes makes them sweat more and breathe harder.17

Professional athletes, particularly those who compete in marathons, triathlons and cycling tournaments, are also predisposed to dehydration. Research suggests that even low levels of dehydration can impair athletes’ cardiovascular and thermoregulatory response.18

One study even revealed that dehydration can impair basketball players’ performance. The study focused on 17 males ranging from 17 to 28 years old, and determined their performance based on different dehydration levels of up to 4%. The result showed that when there’s an increase in dehydration, skill performance decreases.19

Infants are especially prone to dehydration since their bodies are composed of 78% water at birth, dropping to about 65% by age 1.20 Since their bodies are more vulnerable to water depletion, their need for water is greater than adults.

Elderly people are also at risk for dehydration since the thirst mechanism weakens as a person grows older. According to a 2016 study,21 20% of seniors are not getting enough water every day due to several causes, ranging from forgetfulness to a desire to fight incontinence by consuming fewer fluids, to simply being too frail to care for their personal needs.

Those who have chronic diseases that cause frequent urination such as diabetes or kidney problems have an increased risk of dehydration.22 If you have a chronic illness that causes dehydration, make sure to take the necessary steps to hydrate yourself at all times to protect your health.

How to prevent dehydration

Water plays such an immense role in your bodily functions, making it an essential part of your everyday life. Since dehydration can be life-threatening, it is important that you replenish your body with water immediately if you feel yourself becoming dehydrated.

Always bring water with you during exercise or any physical activity, especially when the temperature’s too hot. One good rule of thumb to prevent dehydration is to drink as much water as it takes for your urine to turn light yellow. Dark urine means that your kidneys are retaining liquids in an effort to have enough for your body to perform its normal functions.

It is especially important to pay attention if you are sick with fever, are vomiting or have diarrhea, so you don’t become dehydrated. Be sure to drink enough water to replace the liquids that you’ve lost. If you are vomiting or have diarrhea to the point that you can’t drink enough to stay hydrated, you may need to visit an emergency department for help in maintaining hydration.

Sports drinks and other sweetened beverages will not keep you hydrated

Sports drinks are one of the most commercialized beverages today — from TV advertisements to popular athlete endorsers, mainstream media make it look like sports drinks are the answer to keeping you healthy and well-hydrated.

Beverage companies advertise that these drinks will help replenish the electrolytes in your body during exercise or outdoor activities, but the truth is the drinks with actual science studies behind them were created for high-performance athletes who deplete their water stores quickly, not for the average person looking to address thirst issues.

Indeed, downing too many of these drinks may even be detrimental to your health — particularly if they fall in a class of beverages known as “energy” drinks.23

A typical sports or energy drink contains high amounts of citric acid. According to a 2017 study from The Science Journal of the Lander College of Arts and Sciences, drinking sports or energy drinks that have citric acid can chip away the enamel in your teeth faster, leading to dental erosion.24 Sports drinks like Powerade and Gatorade also come loaded with sugar — a BMJ study25 reported 19 grams and 30 grams, respectively, for a 500 mL (about 17 ounces) bottle of these two beverages.

Aside from sports drinks, there are other sweetened beverages that won’t give you any benefit, like sodas. These are equally unhealthy for you, as a 20-ounce bottle of cola gives you 16 teaspoons of sugar, usually in the form of high-fructose corn syrup.26

Energy drinks come with their own set of problems: Consumed by 30% to 50% of adolescents and young adults, these drinks are supplemented with ingredients hyped as energy boosters. From dangerous levels of caffeine to taurine to herbs and various sugars, what’s in these drinks can cause “seizures, mania, stroke and sudden death” when consumed, and are a risk especially for anyone who is diabetic, has a heart, thyroid or kidney disease, or is taking certain medications.27

Commercial fruit juices are another group of heavily processed sweetened drinks that have too many sugars and not enough value to make them useful for hydrating purposes. For example, a 12-ounce can of Minute Maid’s 100% Apple Juice contains 37 grams of sugar,28 which can put you at risk of diabetes, weight gain and obesity.

Choose to drink living water

If you’re on a community water system, don’t just turn on the tap and fill a glass or water bottle, as it may very well contain fluoride, as well as heavy metals and disinfection byproducts that can have ill effects on your health. Installing a water filter in your home, both at the tap and preferably also at the point of entrance, can help eliminate these harmful contaminants.

If you want the best water for you and your family, I suggest drinking structured or “living” water, such as deep spring water. According to Gerald Pollack, one of the world’s leading research scientists on the physics of water, structured water or EZ “exclusion zone” water is the same type of water found in your body’s cells. It has a negative charge, and works just like a battery by holding and delivering energy.

Since distilled water is too acidic and alkaline water is too alkaline, you should nourish your body only with structured water, as it contains the ideal PH range of 6.5 to 7.5, which enables your body to maintain a balanced and whole state.

I personally drink vortexed water since I became a fan of Viktor Schauberger, who did so much work regarding vortexing many years ago.29 By creating a vortex in your glass of water, you are putting energy into it and increasing EZ as well.

Ideal EZ water can be found in glacial melt, but since it is practically inaccessible for almost everyone, natural deep spring water is a good source. When storing water, use glass jugs and avoid plastic bottles since they contain bisphenol A and phthalates, which are linked to health issues, such as sexual dysfunction and disruption of thyroid hormone levels.30,31

Other natural thirst-quenchers for preventing dehydration

If you want to drink something more flavorful than water, you can opt for raw, organic green juice made from fresh vegetables. However, I recommend refraining from drinking juice with too many fruits as it will have high amounts of sugar and calories. Go for a green juice recipe that combines one or two fruits only and larger amounts of greens like spinach, celery or kale. That way, you can minimize your sugar intake and still get all the nutrients from the fruits and vegetables in their purest forms.

I advise keeping your fructose consumption below 25 grams per day. If you have Type 2 diabetes, insulin resistance or heart disease, it is wise to minimize your total fructose to 15 grams daily, including that from fruits.

Coconut water serves as a great replacement for sports drinks. It provides optimal health benefits due to its anti-inflammatory32 and antioxidant33 effects. A word of caution: Coconut water also contains sugar, albeit in smaller amounts compared to other fruits, so drink it in moderation, preferably after a cardio workout, when you need to replace minerals and fluids.

The key to avoiding dehydration: Listen to your body

No one but you can determine if you are hydrated enough. If you feel thirsty or you’re sweating profusely, this is a signal that you need to replenish your body with water immediately. Don’t wait for severe dehydration symptoms to occur before you take action, since this can be life-threatening.

Since anyone can become dehydrated even without any physical activity, keeping a bottle of filtered water nearby can help keep you hydrated. Remember that a healthy person should urinate seven to eight times each day, so if you’re not urinating frequently it means you’re not drinking enough water.

Remember: Nothing feels more refreshing than drinking cool water to replace the liquids that you’ve lost. It’s also important to always listen to your body. Once you feel that urge to drink, opt for structured or filtered water rather than artificially sweetened beverages, which can have negative effects on your health.

Discover more about Nitric Oxide Supplement and Cardio physical health.

Common Dietary Supplements Have Little to No Effect on Mortality

Ideal Dietary supplements regarding Heart


Looking for quality professional quality health supplements?  Read and learn about  these special Endorsed Products.

Yet another sizable study has shown that common dietary supplements have little to no effect on late life mortality. This finding of course has to compete with the wall to wall marketing deployed by the supplement market. Researchers have been presenting data on the ineffectiveness of near all supplements of years, but it doesn’t seem to reduce the enthusiasm for these products. In the past it was fairly easy to dismiss all supplements as nonsense, or at the very least causing only marginal effects that were in no way comparable to the benefits of exercise and calorie restriction, but matters are now becoming more complex. New supplements based on altered mitochondrial biochemistry or senolytic activity, such as nicotinamide riboside, mitoQ, and fisetin, might well have effect sizes that are worth it as an addition to calorie restriction and exercise; we shall see as human studies progress.


In a massive new analysis of findings from 277 clinical trials using 24 different interventions, researchers say they have found that almost all vitamin, mineral, and other nutrient supplements or diets cannot be linked to longer life or protection from heart disease. Although they found that most of the supplements or diets were not associated with any harm, the analysis showed possible health benefits only from a low-salt diet, omega-3 fatty acid supplements and possibly folic acid supplements for some people. Researchers also found that supplements combining calcium and vitamin D may in fact be linked to a slightly increased stroke risk.

Surveys show that 52% of Americans take a least one vitamin or other dietary/nutritional supplement daily. An increasing number of studies have failed to prove health benefits from most of them. “The panacea or magic bullet that people keep searching for in dietary supplements isn’t there. People should focus on getting their nutrients from a heart-healthy diet, because the data increasingly show that the majority of healthy adults don’t need to take supplements.”

The vitamin and other supplements reviewed included: antioxidants, β-carotene, vitamin B-complex, multivitamins, selenium, vitamin A, vitamin B3/niacin, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, calcium and vitamin D together, folic acid, iron and omega-3 fatty acid (fish oil). The diets reviewed were a Mediterranean diet, a reduced saturated fat (less fats from meat and dairy) diet, modified dietary fat intake (less saturated fat or replacing calories with more unsaturated fats or carbohydrates), a reduced fat diet, a reduced salt diet in healthy people and those with high blood pressure, increased alpha linolenic acid (ALA) diet (nuts, seeds and vegetable oils), and increased omega-6 fatty acid diet (nuts, seeds and vegetable oils). Each intervention was also ranked by the strength of the evidence as high, moderate, low or very low risk impact.

The majority of the supplements including multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone and iron showed no link to increased or decreased risk of death or heart health. “Our analysis carries a simple message that although there may be some evidence that a few interventions have an impact on death and cardiovascular health, the vast majority of multivitamins, minerals and different types of diets had no measurable effect on survival or cardiovascular disease risk reduction.”

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/save-your-money-vast-majority-of-dietary-supplements-dont-improve-heart-health-or-put-off-death

Know more about Nitric Oxide Supplements and Cardio health.

Diminished Estradiol Explains Faster Muscle Loss Following Menopause

Very best Nutritional supplements designed for Nitric Oxide Health


Shopping for superb endorsed quality health products?  Educate yourself about  Cardio Cocktail Medically Certified Products.

Both genders lose muscle mass and strength with age, leading to sarcopenia and frailty. Why do women undergo age-related muscle loss more rapidly following menopause, however? Researchers here suggest that the sex hormone estradiol is necessary to support the activity of muscle stem cells, and thus falling levels of estrogen following menopause is the mechanism driving this outcome. Loss of stem cell function in muscle tissue is also the most credible cause for the onset of sarcopenia without considering gender, so this all fits together quite nicely.


Over the course of an individual’s life, skeletal muscle undergoes numerous injurious insults that require repairs in order for function to be maintained. The maintenance and injury repair of skeletal muscle is dependent on its resident stem cell (i.e., the satellite cell). With proliferation, satellite cells undergo asymmetric division through which a subpopulation of the daughter satellite cells do not differentiate, but instead return to quiescence, repopulating the satellite cell pool (i.e., self-renewal). The balance of this asymmetric division process is critical and necessary to ensure the life-long preservation of satellite cells in skeletal muscle.

Aging diminishes the satellite cell pool and, as a result, the regenerative capacity of skeletal muscle in aged males is impaired compared to that of younger males, but such age-induced impairments in females is less studied. Similarly, age-associated changes in the satellite cell environment, in combination with cell-intrinsic alterations, disrupt quiescence and the balance of asymmetric division, ultimately impacting satellite cell maintenance and muscle regenerative potential. Such results support the concept that circulatory factors, including hormones that differ between the young and old systemic environments and the activity of their subsequent signaling pathways, contribute to age-associated decrements in satellite cell maintenance and overall muscle regenerative capacity.

A well-known hormone that changes with age is estradiol, the main circulating sex hormone in adult females. Serum estradiol concentration declines dramatically at the average age of 51 in women, corresponding to the time of menopause. Estradiol deficiency reduces skeletal muscle mass and force generation in women and prevents the recovery of strength following contraction-induced muscle injury and traumatic muscle injury in female mice. However, evidence that this regenerative phenotype involves effects of estradiol directly on satellite cells is lacking.

In this study, we use rigorous and unbiased approaches to demonstrate the in vivo necessity of estradiol to maintain the satellite cell number in females. Further, we use mouse genetics to show that the molecular mechanism of estradiol action is cell-autonomous signaling through estrogen receptor α (ERα). Specifically, we show the functional consequence of estradiol-ERα ablated signaling in satellite cells including impaired self-renewal, engraftment, and muscle regeneration, and the activation of satellite cell mitochondrial caspase-dependent apoptosis. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females.

Link: https://doi.org/10.1016/j.celrep.2019.06.025

Check out Nitric Oxide and Cardiovascular fitness.

The Infection-Senescence Hypothesis of Alzheimer's Disease

Top Health supplements to Support Heart


Hunting for top-quality certified supplements?  Read about  these quality Approved Supplements.

With the continued failure of clinical trials of therapies for Alzheimer’s disease, largely immunotherapies, that aim to clear amyloid-β, a growing faction of researchers are rejecting the amyloid hypothesis. In that mainstream view of the condition, the accumulation of amyloid-β causes the early stages of Alzheimer’s, but in addition to disrupting the function of neurons, it also causes immune cells in the brain to become inflammatory, dysfunctional, and senescent. This in turn sets the stage for the aggregation of tau protein into neurofibrillary tangles, which causes widespread cell death and the much more severe manifestations of later stage Alzheimer’s disease.

Why do only some old people exhibit the condition? In the mainstream view, this is equivalent to asking why only some old people have significantly raised levels of amyloid-β in the brain. This might be due to different rates at which drainage of cerebrospinal fluid becomes impaired with aging, preventing molecular waste from leaving the brain. But many researchers are starting to consider that infectious pathogens are the most important cause, as amyloid-β has now been shown to be an antimicrobial peptide, a part of the innate immune system. The more infection, the more amyloid-β. There is good evidence for persistent infections such as forms of herpesvirus to be associated with Alzheimer’s risk.

In today’s open access paper, the infection hypothesis is extended further to bypass amyloid-β. The authors suggest that infection leads directly to the stage of chronic inflammation and senescent immune cells in the brain. Amyloid-β accumulation is not necessary for the progression of Alzheimer’s in this view of the condition, and may be just a side-effect. As is usually the case in such matters, the best way to find out what is actually going on is to repair or block one mechanism in isolation of all of the others and see what happens. This is quite challenging in the case of Alzheimer’s disease, as the animal models are all highly artificial: mice don’t naturally suffer Alzheimer’s or any similar condition. Thus one can reverse a mechanism or pathology that was introduced into the model, but that doesn’t say much about what happens in the human condition, as it has quite different origins and progression.

The Post-amyloid Era in Alzheimer’s Disease: Trust Your Gut Feeling


Advanced age is a major Alzheimer’s disease (AD) risk factor; therefore, understanding cellular senescence and its impact on endothelial cells (ECs), neurons, glia, and immune cells is an essential prerequisite for elucidating the pathogenesis of this condition. Brain accumulation of extracellular β-amyloid and intracellular hyperphosphorylated tau are the pathological hallmarks of AD. Both neurons and astrocytes synthesize β-amyloid from amyloid precursor protein (APP), while phagocytic microglia prevent its accumulation by removing it via the triggering receptor expressed on myeloid cells-2 (TREM-2).

The amyloid hypothesis postulates that accumulation and deposition of β-amyloid are the primary causes of AD, which promotes tau aggregation into neurofibrillary tangles (NFTs), ultimately triggering neuronal death. Although never universally accepted, the amyloid hypothesis drove AD research for at least two decades. Lately, however, many researchers and clinicians have questioned this model as amyloid removal failed to improve memory in numerous clinical trials. With the same token, neuroimaging studies detected significant β-amyloid deposits in 20-30% of healthy older individuals, while in many AD patients, this marker was not observed.

Moreover, β-amyloid was recently characterized as an antimicrobial peptide (AMP), and its accumulation in AD brains may be a reflection of increased microbial burden. AMPs are defensive biomolecules secreted by the innate immune system, including microglia and astrocytes, in response to a variety of microorganisms and malignant cells. The β-amyloid-AMP connection is further supported by the observation that central nervous system (CNS) infections were diagnosed in some clinical trials, following the administration of anti-amyloid vaccines.

Recent studies have reported co-localization of microorganisms with senescent neurons and glial cells in the brains of both AD patients and healthy older individuals, reviving the infectious hypothesis. CNS infectious agents have been detected previously in AD patients; however, it was difficult to assess if they represented the cause or effect of this condition. A recent study may have settled this issue as it detected gingipain, a Porphyromonas gingivalis antigen, linked to AD, in the brains of healthy older persons, suggesting that they would have developed the disease if they lived longer. As P. gingivalis is a major cause of gum disease and a modifiable AD risk factor, treatment of periodontal infection must be considered a clinical priority.

It has been well-established that inflammation and cellular senescence are closely related, but the role of pathogens in this process has been less emphasized. Astrocytes are the most numerous brain cells. Recent studies report that astrocytes are innate immune cells that, along with microglia, play a key role in the phagocytic removal of molecular waste, dead, or dying cells. Preclinical studies have reported that astrocytes undergo both replicative senescence and stress-induced senescence, however, the difference between senescent and reactive astrocytes is not entirely clear at this time. Recent studies seem to indicate that these phenotypes may be closely related or even identical as upregulated inflammatory and synapse-eliminating genes were found in both senescent and reactive astrocytes.

Dystrophic microglia with growth arrest and senescent markers have been demonstrated in AD patients, but the difference between the reactive and dystrophic phenotype is unclear at this time. Taken together, senescent microglia, incapable of proper immunosurveillance and phagocytosis, contribute to the accumulation of molecular waste, dead or dying cells, inducing inflammaging and immunosenescence. Astrocytes may respond to these microenvironmental changes by converting to a phenotype marked by aberrant elimination of healthy synapses and neurons, a possible pathogenetic mechanism of AD.

Thus, microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer’s disease brains associated with senescent neurons, glia, and endothelial cells. We take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. Commensal gut microbes live in symbiosis with the human host as long as they reside in the GI tract where they can be kept under control. Cellular senescence alters the integrity of biological barriers, allowing translocation and dissemination of gut microorganisms throughout the body tissues, including the brain. Operating “behind enemy lines,” pathogens can gain control of host immune defenses and metabolism, triggering senescence and neurodegenerative pathology.

Study more about Nitric Oxide Supplements and Cardiovascular health and fitness.