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Contents
- Michael Antonov Will Match the Next 600,000 of Donations to SENS Research Foundation in Support of their Important Work on Rejuvenation Therapies
- Inhibiting Protein Glycation as an Approach to Reduce the Contribution of AGEs to Aging
- Cellular Senescence and Immune System Aging as Causes of Chronic Kidney Disease
- Excessive Mitochondrial Point Mutations Do Not Lead to Obvious Metabolic Dysfunction
- An Overview of the Mechanisms of Transthyretin Amyloidosis
- Tsa1 in the Hormetic Response to Mild Oxidative Stress
- Changing Metabolite Production in the Aging Gut Microbiome Correlates with Presence of Amyloid-β in the Brain
- NeuroD1 Gene Therapy in Mice Transforms Glial Scars into Functional Neural Tissue
- Discussing the Evolution of Cellular Senescence
- Plasma Dilution Reduces Neuroinflammation and Improves Cognition in Old Mice
- Tau Pathology in Astrocytes in Alzheimer's Disease
- A Look at the Damage Done by Senescent T Cells in the Aged Immune System
- Investigating the Use of VEGF-B to Grow New Blood Vessels to Supply the Heart
- GrimAge Outperforms Other Epigenetic Clocks
- Towards a Retinal Assessment of Alzheimer's Risk, Years in Advance of Symptoms
Michael Antonov Will Match the Next 600,000 of Donations to SENS Research Foundation in Support of their Important Work on Rejuvenation Therapies
https://www.fightagi...tion-therapies/
Michael Antonov is one of a number of high net worth individuals who are interested in accelerating progress towards a first generation of comprehensive rejuvenation therapies, targeting all of the mechanisms of aging in order to cure age-related disease and extend healthy life spans. The SENS Research Foundation remains one of the most important organizations in this space, focused on the scientific advances needed in order to repair the molecular damage that causes aging. Degenerative aging and age-related disease exists because the normal operation of youthful metabolism produces forms of damage as a side-effect: varieties of molecular waste that are both toxic and hard to break down; mutational damage to DNA; accumulating senescent cells; cross-links in the extracellular matrix; and so forth.
Senescent cell accumulation can already be repaired to some degree, thanks to advances in science that led to senolytic drugs, the first class of rejuvenation therapy worthy of the name. The others will follow at a pace determined by how much funding goes into the necessary research programs.
SENS Research Foundation is delighted to announce a matching grant from the Antonov Foundation. The Antonov Foundation will match every donation between now and the end of the campaign on December 31, 2020 - up to a total of 600,000!
SENS Research Foundation is incredibly grateful for this generous investment in the future we all hope to create - a future where getting older brings wisdom and experience but not disease, suffering, and pain. Thank you, Michael Antonov, and thank you to all who have donated so far to our end of year campaign. And if you're still planning on donating, there's no better time to do it than on Giving Tuesday this December 1!
Michael Antonov said: "I've followed and supported SENS research over the last few years and am excited to up my commitment this year because their organized, practical approach to combating aspects of aging, such as breaking down of cross-links, rejuvenating the mitochondria, and clearance of senescent cells has potential to help human lives and achieve age reversal in the near future."
Over the past decade, thousands of visionary folk in our community have donated more than 10 million to the SENS Research Foundation. This support has produced clear progress towards the goal of rejuvenation. Neglected areas of research have been revived, companies created to start commercial development of therapies, and the field of rejuvenation research has gained legitimacy and support. There is still so much to accomplish yet, of course! So I am very pleased to see that Michael Antonov is stepping up to provide a sizable amount of funding to the SENS Research Foundation in the form of a matching grant for the 2020 year end fundraiser. It is Giving Tuesday soon, and we should all use that opportunity to support the future that we'd like to see, one in which aging is controlled by medical science, and there is no more suffering in old age.
Inhibiting Protein Glycation as an Approach to Reduce the Contribution of AGEs to Aging
https://www.fightagi...-ages-to-aging/
In today's open access paper, researchers propose the use of sodium 4-phenylbutyrate to inhibit protein glycation, reducing the creation of advanced glycation endproducts (AGEs) in the body, and thus limit the contribution of this class of compounds to aging and disease. AGEs are quite varied and comparatively poorly studied; it is still the case that new ones are being found, and there is considerable room for debate on which AGEs are more or less important to aging and outcomes of metabolic diseases such as diabetes. Short-lived AGEs, easily broken down, are inflammatory via the receptor for AGEs (RAGE), and this may be their primary contribution to aging and disease. Persistent AGEs, on the other hand, can form lasting cross-links that stiffen tissues such as blood vessel walls, causing conditions such as hypertension.
In studies like the one noted below, it is usually quite unclear as to whether or not a useful range of AGEs are being inhibited. In other words, whether the approach is better applied to treating metabolic disorders, to lower the large amounts of short-lived AGEs that are causing inflammation, or whether it might help to slow the progressive accumulation of cross-links with age. Further, the AGEs relevant to aging and disease are thought (and in some cases shown) to be different between mammalian species. This has been quite problematic in past attempts to produce drugs that can break down AGEs in order to produce therapeutic benefit. For example, this is why the development of the AGE-breaker drug alagebrium failed.
Ultimately, however, a therapy that has to be applied constantly in order to slow the accumulation of damage (such as persistent AGE cross-links in tissues) is a poor alternative to a therapy that can be applied intermittently to remove damage (such as by breaking down existing persistent AGE cross-links). Prevention of contributing causes of aging is not that helpful to those who are already old. That makes the class of approach here less interesting when compared with, say, the AGE-breaking enzymes under development at Revel Pharmaceuticals.
Sodium 4-phenylbutyrate inhibits protein glycation
Glycation is a non-enzymatic chemical reaction that occurs between a ketone or aldehyde group of fructose or glucose and an amino acid residue or the hydroxy-group of a protein or lipid, and is often referred to as the Maillard reaction. Protein glycation occurs through a complex series of very slow reactions in the body, including the formation of the stable Amadori-lysine products (Schiff bases). These give rise to advanced glycation end-products (AGEs).
It is hypothesized that the production and accumulation of AGEs have causal roles in the development of the complications associated with aging and lifestyle-related diseases, such as diabetes, atherosclerosis, and hyperlipidemia. Furthermore, the production and accumulation of AGEs are involved in the development of other diseases, such as cardiovascular diseases, cerebrovascular disorders, chronic renal failure, Alzheimer's disease, and Parkinson's disease. Therefore, the identification of safe treatments that can inhibit glycation is required, as they may exhibit anti-aging effects, or serve as a therapeutic option for prevention of diseases associated with glycation.
In the present study, the ability of sodium 4-phenylbutyrate (PBA) on inhibition of glycation was assessed. In vitro, PBA inhibited the glycation of albumin and collagen by up to 42.1% and 36.9%, respectively. Furthermore, when spontaneously diabetic KK mice were administered PBA (20 mg/day) or vehicle orally, glycosuria developed rapidly in the control mice, but after 6 weeks, only one treated mouse was glycosuric. In addition, the weight gain and HbA1c levels were significantly lower in the treated mice compared with the untreated mice. These results suggested that PBA also inhibited glycation in vivo. Further studies are required to determine whether PBA may be effective for the therapy or prevention of aging or lifestyle-related diseases caused by the accumulation of AGEs. The method of administration and the side-effects of PBA have already been established as PBA is already used clinically. Therefore, the repurposing of PBA for reducing AGE levels may be a potential option to reduce complications associated with aging.
Cellular Senescence and Immune System Aging as Causes of Chronic Kidney Disease
https://www.fightagi...kidney-disease/
There is a great deal of interest in cellular senescence these days. The accumulation of senescent cells in later life is robustly demonstrated to be an important mechanism of aging, and one that can be reversed via the application of what have come to be called senolytic therapies. In mice, the application of senolytics extends life and reverses the progression of numerous age-related conditions. Senescent cells are harmful, even though their numbers are never very large, because they secrete a mix of signals that provoke inflammation, tissue remodeling, and changes in cell activity. Sustained over the long term, this contributes meaningfully to age-related declines and diseases.
Chronic kidney disease is one such condition. Treatment options are limited, while the inexorable loss of kidney function in patients produces increasingly serious downstream issues throughout the body. Evidence has accumulated for cellular senescence to be a major contributing cause of chronic kidney disease. It is widely recognized in the research community that senolytic therapies are a promising new approach to treatment of the condition. An ongoing clinical trial, watched with interest, is using the senolytic combination of dasatinib and quercetin in chronic kidney disease patients, with preliminary results reported last year indicating that this does in fact remove senescent cells. We will have to wait and see for the rest of the data.
Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease
Age-related pathologies are a major global disease burden, with potentially half of all morbidities being attributable to aging. Inflammation (or "inflammaging") is one of the main causative factors contributing to disease progression, and has been described in various age-related pathologies, including type 2 diabetes (T2D) and cardiovascular disease. While being beneficial in the acute stages of an insult, inflammation increasingly fails to resolve with age, leading to changes in both cellular phenotypes and immune system composition. Senescence pathways are induced by, as well as potentiate, chronic inflammation, with increased cellular senescence being observed in various age-related diseases. Cellular senescence is characterized by a stable growth arrest and a proinflammatory secretome, which potentiates low grade chronic inflammation, thereby building a positive feedback loop, gradually exacerbating its effects on the body.
With a prevalence of approximately 44% in the elderly population (of 65 years and older), chronic kidney disease (CKD) presents a major disease burden in an aging population. Therapies for late stage CKD including dialysis and renal transplantation carry a significant burden for patients, and the outcome is often poor; therefore, there is a significant need for early diagnosis and novel therapies targeting mechanisms driving the disease. CKD is associated with chronic inflammation, elevated levels of cellular senescence, as well as immune system dysfunction.
Senescent cells may both be a phenotype of age-related inflammatory disease, as well as the cause for disease progression. Thereby two models of disease progression exist: One in which senescent cells arise from local tissue injury, promoting senescence in neighboring cells in a paracrine manner. Alternatively, immune clearance may be impaired, thereby allowing the accumulation of senescent cells. Distinguishing between these two models becomes pivotal when exploring potential new treatments of CKD.
Much of the immune dysregulation is governed by the presence of proinflammatory cytokines, and uremia, or by pre-existing comorbidities such as high blood pressure or diabetes. In addition to the levels of inflammatory markers, an elevated white blood cell count is predictive of CKD development. This suggests various modes of pathogenesis, with the immune system, senescence, and inflammation at its core. Cellular senescence and immunosurveillance occur in conjunction, increased cellular senescence due to chronic inflammation increases the demand for immune clearance; however, as described above, uremia and inflammation lead to dysfunction of the immune system, thereby establishing a positive feedback loop in which more senescent cells drive inflammation and immune dysregulation which, in turn, cause more senescence.
Excessive Mitochondrial Point Mutations Do Not Lead to Obvious Metabolic Dysfunction
https://www.fightagi...ic-dysfunction/
Every cell contains a herd of hundreds of mitochondria, organelles descended from ancient symbiotic bacteria. The primary purpose of mitochondria is to package the chemical energy store molecule adenosine triphosphate (ATP) that is needed to power cellular processes. Each mitochondrion contains one more copies of a small circular genome, the mitochondrial DNA. This mitochondrial DNA is unfortunately poorly protected and repaired in comparison to nuclear DNA. Accumulation of damage in the form of mutations is thought to be an important contributing cause of mitochondrial dysfunction in aging, leading to less ATP and thus disruption of cell and tissue function.
The data of recent years indicates that not all mutations in mitochondrial DNA are equal when it comes to causing problems. Point mutations seem to be quite well tolerated, as illustrated by the heterozygous PolG mutator mice. These mice exhibit very high levels of point mutations in mitochondrial DNA due to a loss of function mutation in one of the two copies of PolG, an enzyme involved in mitochondrial DNA replication and repair. Deletion mutations, on the other hand, are the path to sizable and detrimental changes, as they can remove or disable electron transport chain proteins. This can result in mitochondria that outcompete their undamaged peers in replication efficiency or resistance to the quality control mechanisms of mitophagy, take over a cell, render it dysfunctional, and export harmful reactive molecules into surrounding tissue.
Age-induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge
Mitochondria are essential for respiration and the regulation of diverse cellular processes; thus, mitochondrial dysfunction is believed to underlie a variety of metabolic and aging-related diseases. Mutations in the mitochondrial genome are thought to drive mitochondrial dysfunction and have been implicated in aging-related diseases; however, whether mtDNA mutations are causal or consequent of metabolic dysfunction remains unclear. The polymerase gamma (PolG) "mutator" mouse is a model of intrinsic mitochondrial dysfunction and was employed for this study to determine whether mtDNA mutations are sufficient to drive metabolic abnormalities and aging-associated insulin resistance and adiposity.
Mice harboring a homozygous PolG loss of proofreading 3′-5′ exonuclease function mutation (PolGmut/mut) develop mtDNA point mutations at a rate that far exceeds mutations observed in aged wild-type (WT) animals and humans. The mtDNA point mutations that accumulate in young PolGmut/mut mice (~136-fold increase versus WT mice) manifest a variety of preadolescent phenotypic abnormalities including progeroid-like symptoms throughout maturation as well as premature death (~12-16 months of age). Because of the complexity of the early-onset aging, we studied the PolG heterozygous (PolG+/mut) mouse, which lacks progeroid-like symptoms despite a supraphysiological mtDNA point mutation frequency (~30-fold greater mutation load in PolG+/mut versus WT mice). Furthermore, male and female PolG+/mut mice show no significant difference in lifespan versus WT animals (tested up to 800 days of age).
Based on previous reports, we hypothesized that an increased mtDNA point mutation frequency in PolG+/mut mice would promote mitochondrial dysfunction and accelerate the development of insulin resistance during aging. We examined specific aspects of metabolism in male PolG+/mut mice at 6 and 12 months of age under three dietary conditions: normal chow (NC) feeding, high-fat feeding (HFD), and 24-hr starvation. We performed mitochondrial proteomics and assessed dynamics and quality control signaling in muscle and liver to determine whether mitochondria respond to mtDNA point mutations by altering morphology and turnover. In the current study, we observed that the accumulation of mtDNA point mutations failed to disrupt metabolic homeostasis and insulin action in male mice, but with aging, metabolic health was likely preserved by countermeasures against oxidative stress and compensation by the mitochondrial proteome.
An Overview of the Mechanisms of Transthyretin Amyloidosis
https://www.fightagi...in-amyloidosis/
A score or so different types of amyloid can form in the human body, each a protein that can become altered or misfolded in a way that encourages other molecules of the same protein to also alter or misfold. These broken proteins aggregate together into sheets and fibrils, forming solid deposits in and around cells that interfere with the normal function of tissues, or are actively toxic. Transthyretin is one such protein, and transthyretin amyloidosis is present to some degree in all older people. Evidence of recent years suggests that it is a factor in 10% of heart failure cases in old people in general, and it may be the dominant cause of cardiac mortality in supercentenarians, those aged 110 or older.
The open access paper noted here is an interesting overview of the mechanisms by which amyloidosis occurs in the case of transthyretin, in the context of trying to predict who is most at risk and should therefore be treated. Eidos Therapeutics has a treatment in later stages of development that interfers enough with the mechanisms of transthyretin aggregation to be worth the effort, though as for most such lines of development it will initially be targeted at cases in which transthyretin is mutated in ways that accelerate amyloidosis, rather than as a preventative therapy for the entire population. More aggressive degradation of amyloid will likely be needed, such as via the use of catabodies, a line of work at an earlier stage of development at Covalent Bioscience, but nonetheless promising.
Proposing a minimal set of metrics and methods to predict probabilities of amyloidosis disease and onset age in individuals
The rate of synthesis of transthyretin (TTR) is constant. For proteostasis, the rate of removal of TTR must equal the rate of synthesis. TTR in plasma is largely in the tetrameric form, (TTR)4, but dissociates to give very low, but significant concentrations of dimers and monomers. Removal of TTR from plasma proceeds via monomers.
Monomers undergo two processes that remove them from solution, proteolysis or aggregation. The combined rates of these two pathways equals the total rate of monomer removal, which is also equal to the rate of production of monomer via dissociation of tetramer. Depending on the relative rates, either of the two reaction pathways could account for anywhere from 100% to 0% of the rate of monomer removal. The critical monomer concentration for aggregation is unknown, however the cause of aggregation develops slowly over time. Once amyloidosis begins, the rate of development of amyloidosis is determined by the rate of monomer incorporation into various aggregates that lead to fibrils and amyloids.
Destabilizing tetramer by pleiotropic mutations leads to greater dissociation of monomer and a higher, variant-dependent concentration of TTR monomer in plasma. Mutations are not required for TTR amyloidosis formation; point mutations only modify the equilibrium concentrations. Amyloidosis caused by wild-type TTR follows the same mechanism as amyloidosis caused by variants of TTR and thus should be considered as variants of the same disease for purposes of clinical studies.
Amyloidosis begins when the rate of TTR proteolysis decreases relative to the rate of amyloid formation and monomer concentration increases sufficiently to allow significant oligomerization into fibrils and amyloids. The cause of a decrease in the rate of proteolysis of TTR remains to be identified. When the tetramer is stabilized by drugs or stabilizing mutations, the concentration of tetramer will increase in plasma to a steady-state level determined by the rate of proteolysis.
Tsa1 in the Hormetic Response to Mild Oxidative Stress
https://www.fightagi...idative-stress/
Stressing cells a little leads to overall benefits, as maintenance mechanisms such as autophagy are upregulated to more than compensate for any damage. This is known as hormesis, and it is one of the reasons why exercise, calorie restriction, radiation, and heat can produce health benefits at appropriate dose levels. Researchers here explore one of the links between oxidative damage and the beneficial responses to that damage. In theory, a better view of these linking mechanisms may lead to better ways to mimic the effects of mild stress in order to improve long term health.
Researchers studied the enzyme Tsa1, which is part of a group of antioxidants called peroxiredoxins. Previous studies of these enzymes have shown that they participate in yeast cells' defences against harmful oxidants. But the peroxiredoxins also help extend the life span of cells when they are subjected to calorie restriction. The mechanisms behind these functions have not yet been fully understood.
It is already known that reduced calorie intake can significantly extend the life span of a variety of organisms, from yeast to monkeys. Several research groups have also shown that stimulation of peroxiredoxin activity in particular is what slows down the ageing of cells, in organisms such as yeast, flies, and worms, when they receive fewer calories than normal through their food. "Now we have found a new function of Tsa. Previously, we thought that this enzyme simply neutralises reactive oxygen species. But now we have shown that Tsa1 actually requires a certain amount of hydrogen peroxide to be triggered to participate in the process of slowing down the ageing of yeast cells."
Surprisingly, the study shows that Tsa1 does not affect the levels of hydrogen peroxide in aged yeast cells. On the contrary, Tsa1 uses small amounts of hydrogen peroxide to reduce the activity of a central signalling pathway when cells are getting fewer calories. The effects of this ultimately lead to a slowdown in cell division and processes linked to the formation of the cells' building blocks. The cells' defences against stress are also stimulated - which causes them to age more slowly.
Changing Metabolite Production in the Aging Gut Microbiome Correlates with Presence of Amyloid-β in the Brain
https://www.fightagi...β-in-the-brain/
The research materials here examine the age-related changes in metabolite production in the gut microbiome and correlate those changes with the presence of amyloid-β in the brain, a feature of Alzheimer's disease. It is a good companion piece to another recently published paper that links changes in microbial population abundance and Alzheimer's disease. The question of causation arises, as always, but it is plausible to think that the aging of the gut microbiome, influential on chronic inflammation in the body, contributes to the risk of Alzheimer's disease, which is a condition that appears to be driven in large part by chronic inflammation.
Intestinal bacteria can influence the functioning of the brain and promote neurodegeneration through several pathways: they can indeed influence the regulation of the immune system and, consequently, can modify the interaction between the immune system and the nervous system. Lipopolysaccharides, a protein located on the membrane of bacteria with pro-inflammatory properties, have been found in amyloid plaques and around vessels in the brains of people with Alzheimer's disease. In addition, the intestinal microbiota produces metabolites - in particular some short-chain fatty acids - which, having neuroprotective and anti-inflammatory properties, directly or indirectly affect brain function.
"To determine whether inflammation mediators and bacterial metabolites constitute a link between the gut microbiota and amyloid pathology in Alzheimer's disease, we studied a cohort of 89 people between 65 and 85 years of age. Some suffered from Alzheimer's disease or other neurodegenerative diseases causing similar memory problems, while others did not have any memory problems. Using PET imaging, we measured their amyloid deposition and then quantified the presence in their blood of various inflammation markers and proteins produced by intestinal bacteria, such as lipopolysaccharides and short-chain fatty acids."
This work thus provides proof of an association between certain proteins of the gut microbiota and cerebral amyloidosis through a blood inflammatory phenomenon. Scientists will now work to identify specific bacteria, or a group of bacteria, involved in this phenomenon. This discovery paves the way for potentially highly innovative protective strategies - through the administration of a bacterial cocktail, for example, or of prebiotics to feed the "good" bacteria in our intestine.
NeuroD1 Gene Therapy in Mice Transforms Glial Scars into Functional Neural Tissue
https://www.fightagi...-neural-tissue/
Glial scars made up of activated astrocyte cells form following injury to nervous system tissue in mammals, and while protective in some ways, this scarring blocks functional regeneration. It is an important mechanism that limits the degree to which nerves and brain tissue can regenerate, and thus a target for the regenerative medicine community. Researchers here demonstrate a gene therapy approach that causes glial scars in the brain to regenerate into functional neural tissue. This line of work seems well worth keeping an eye on.
Injuries in the central nervous system (CNS) often causes neuronal loss and glial scar formation. We have recently demonstrated NeuroD1-mediated direct conversion of reactive glial cells into functional neurons in adult mouse brains. Here, we further investigate whether such direct glia-to-neuron conversion technology can reverse glial scar back to neural tissue in a severe stab injury model of the mouse cortex. Using an adeno-associated virus (AAV)-based gene therapy approach, we ectopically expressed a single neural transcription factor NeuroD1 in reactive astrocytes in the injured areas.
We discovered that the reactive astrocytes were efficiently converted into neurons both before and after glial scar formation, and the remaining astrocytes proliferated to repopulate themselves. The astrocyte-converted neurons were highly functional, capable of firing action potentials and establishing synaptic connections with other neurons. Unexpectedly, the expression of NeuroD1 in reactive astrocytes resulted in a significant reduction of toxic A1 astrocytes, together with a significant decrease of reactive microglia and neuroinflammation. Furthermore, accompanying the regeneration of new neurons and repopulation of new astrocytes, new blood vessels emerged and blood-brain-barrier (BBB) was restored. These results demonstrate an innovative neuroregenerative gene therapy that can directly reverse glial scar back to neural tissue, opening a new avenue for brain repair after injury.
Discussing the Evolution of Cellular Senescence
https://www.fightagi...lar-senescence/
Cells become senescent in response to reaching the Hayflick limit on replication, suffering molecular damage, or in an environment of tissue injury. A senescent cell ceases replication and begins to secrete an inflammatory mix of cytokines and growth factors, the senescence-associated secretory phenotype (SASP), rousing the immune system and provoking changes in surrounding cell behavior. Near all senescent cells are quickly destroyed, but with age these cells linger. The signaling that is useful in the short term for cancer suppression (by removing damaged and potentially damaged cells in the earliest stages of cancer) or regeneration from injury (by provoking greater cell activity) becomes very harmful when sustained for the long-term. Senescent cell accumulation is an important contributing cause of aging and age-related disease.
Cellular senescence is a phenomenon that has been known about for a long time. During recent years, it has gained growing interest as its causal involvement in the aging process has been corroborated by several experimental findings. Because of this, several groups and companies are developing senolytic approaches that aim to remove senescent cells from aged animals in the hope of achieving a rejuvenation and life extension effect. However, at the same time, cellular senescence is also seen as an anti-cancer strategy, which raises the question why interfering with an anti-cancer mechanism should increase life span?
The argument that antagonistic pleiotropy explains the anti-tumorigenic as well as the pro-tumorigenic and inflammatory properties of senescent cells is problematic, since there are multiple ways imaginable to break the link between positive and negative effects. In this paper, we discussed an alternative idea for the evolution of cellular senescence that focuses on the involvement of senescent cells in the repair of cell and tissue damage. From such a viewpoint, many properties of the SASP make much more sense and are actually beneficial. Additionally, the recent finding that also post-mitotic cells can display characteristics of cellular senescence, agrees well with this idea. While post-mitotic cells benefit from triggering a healing and repair mechanism, they do not profit from an anti-cancer process.
According to our interpretation, the negative effects of cellular senescence only emerge because the clearance of senescent cells by the immune system, once the repair process has finished, is imperfect. Senescent cells represent a very heterogeneous population, depending on the original cell type and on how senescence was triggered. We therefore proposed that there is a continuum of turnover rates, since the immune system is more or less capable of recognizing this range of subtypes. A mathematical model, which for simplicity only uses two types of senescent cells (removable and non-removable), achieves an excellent fit to experimental data. Interestingly, our model also predicts a slowdown of senescent cell turnover with age, in our case explained by an accumulation of non-removable senescent cells relative to removable ones.
For obvious reasons, there are high hurdles for the destruction of body cells. We propose that for this reason, the optimal strategy is for the immune system to accept a small fraction of false negatives, leading to the slow accumulation of senescent cells in the body. This, in turn, then leads to life-threatening consequences like chronic inflammation (inflammaging), degenerative diseases, and cancer. In this interpretation of cellular senescence, there needs to be a balance between beneficial effects (i.e., wound healing and tissue repair) and negative consequences (i.e., accumulation of senescent cells with inflammation and diseases).
To see how this differs from the idea that cellular senescence is an anti-cancer strategy, we have to return to the questions that we posed earlier. Why did evolution not break the connection of the antagonistic effects and why do organisms not rely exclusively on apoptosis as anti-cancer strategy? The discussed proposal makes it more difficult to break the antagonistic effects, since there is always a trade-off between overlooking too many senescent cells (false negatives) and killing too many healthy body cells (false positives). However, the situation can be improved quantitatively by somehow enabling the immune system to better recognize senescent cells. Indeed, it may be that this has already happened during the evolution of long-lived species, which accumulate senescent cells at a slower pace than short-lived species.
If this outline of the evolution of cellular senescence is correct, it also follows that the removal of accumulated senescent cells is a good strategy, as long as it does not interfere with the primary function of this process. Thus, a brief senolytic treatment would be suitable, while a chronically administered drug might be problematic.
Plasma Dilution Reduces Neuroinflammation and Improves Cognition in Old Mice
https://www.fightagi...on-in-old-mice/
In heterochronic parabiosis, one joins the circulatory system of an old mouse and a young mouse. The old mouse exhibits reversal of manifestations of aging, and the young mouse exhibits an acceleration of manifestations of aging. Research initially focused on factors in young blood that might be producing benefits in older individuals, and work continues on GDF11 as one such factor, with Elevian heading towards human trials. More data has accumulated in recent years to suggest that the bulk of the effect is due to harmful factors in old blood, however, and benefits in old mice in parabiosis are simply a matter of diluting those factors.
A series of experiments run in recent years have results in ways to safely and simply dilute blood in old mice, using as few additional components as possible, in order to make the results quite clearly the outcome of dilution alone. As demonstrated here, diluting blood in old mice results in reduced inflammation and consequent improvement in tissue function. This reinforces the idea that the research community should focus on what makes old blood harmful, rather than on what might be making young blood beneficial.
Parabiosis studies have yielded a plethora of insights regarding mechanisms that underlie the aging of stem cell niches. It was shown that old partners have better health in multiple tissues when they shared blood with a younger animal. A prominent interpretation of heterochronic parabiosis is that aging is malleable and that the aging process can be slowed or even reversed. Brain aging in particular is associated with a progressive loss of functionality and is thought to be in large part the result of an excessive activation of microglia, the brain-resident myeloid cells. The age-related declines in brain function and cognition (among many other functions in the body) were once considered inevitable and permanent. Parabiosis studies, interestingly, have challenged this notion by illustrating the plasticity of brain maintenance and function after changing the age of the blood.
Several systemic proteins and young plasma infusions were suggested to influence the plasticity of brain aging, albeit with some controversy to the actual age-specific levels of some of these candidate factors, such as GDF11, B2M, CCL11, and TIMP2. There was also a lack of health span increase in young plasma infusion studies; and while safety trials were successful, the young blood approaches have not been demonstrated to be effective in improving the health of the brain or any other tissue in clinic. In concert, heterochronic blood transfusion exchange experiments have shown that in the absence of the organ sharing and environmental enrichment of parabiosis, young blood does not rejuvenate the old brain.
As we investigate and form an evolutionary conserved paradigm of systemic rejuvenation, our data demonstrated that young blood is not the primary determinant, and instead, dilution of old blood plasma yields a robust resetting of the systemic signaling milieu to youth and health, rejuvenating multiple tissues. The study of the brain in that report was limited to hippocampal neurogenesis; here we expand the work to other important facets of brain health: neuroinflammation and cognition. Our data demonstrate that neuroinflammation (specifically the activation of microglia), declines and the cognitive capacity of old mice, improves after a single treatment of blood dilution. Considering that therapeutic plasma exchange (TPE) is FDA approved, this study suggests a use of this procedure to prevent, attenuate, and possibly even reverse the degenerative and inflammatory diseases of the brain.
Tau Pathology in Astrocytes in Alzheimer's Disease
https://www.fightagi...eimers-disease/
Astrocytes are supporting cells in the brain, and contribute to the correct function of neurons in numerous ways. It is plausible that widespread disruption of astrocyte function could lead to cognitive issues. Researchers here offer evidence to suggest that tau pathology in Alzheimer's disease extends beyond neurofibrillary tangles made up of phosphorylated tau in neurons, and also includes excessive amounts of tau in astrocytes. This appears to change astrocyte behavior in ways that negatively affect memory, but as always in Alzheimer's disease, the animal models used to assess these effects are quite artificial and may or may not be relevant to the human condition.
Tau tangles are an integral part of Alzheimer's disease (AD) pathology, appearing in the hippocampus in early stage disease and then gradually spreading throughout the brain. Their accumulation closely mirrors cognitive decline. Researchers have focused on tau's role in neuron dysfunction and death. What about other cells? Researchers looked for tau tangles in different areas of the hippocampus in tissue samples from healthy controls and from people with AD. As expected, they found them in the AD samples, but the pathology was not equally distributed; there were hot spots in certain areas, including the hilus. "The hilus is seen as a highway between the dentate gyrus and CA3 region within the hippocampus, so most researchers do not pay much attention to what happens there. It turns out to be very important."
Zooming in on the astrocytes in the hilus, researchers saw they were packed with three-repeat (3R) tau in the AD tissue samples. This isoform contributes to the 3R/4R type of neurofibrillary tangles found in Alzheimer's. The amount of 3R tau in the astrocytes correlated with tau tangles and with amyloid-β plaques in the surrounding tissue, suggesting the 3R tau accumulation may be downstream of other AD pathologies. Oddly enough, researchers found no increase in phosphorylated forms of tau in the astrocytes or any evidence of tangles in these cells. He speculated that this might be because these hilar astrocytes cells do not phosphorylate the protein as easily as neurons do, or that tau is dephosphorylated by the astrocytes.
Does this 3R tau accumulation affect the astrocytes or their surrounding neurons? To test this idea in a mouse model, researchers overproduced tau in mouse hippocampi. Researchers injected lentiviruses carrying a gene for human 3R tau into the hippocampi of 3-month-old wild-type mice. Two weeks later, they verified that the human 3R tau was expressed only in hilar astrocytes. Within these astrocytes, mitochondria languished in the cell bodies, rather than travelling to the astrocyte arms that support neurons. Mitochondrial function also suffered; the organelles replenished less often, and they produced much less ATP than usual.
Still, neurons looked normal for the most part, with no signs of neuronal death. However, neurogenesis had faltered, and the treated mice had fewer parvalbumin-positive inhibitory neurons in the dentate gyrus than controls. The number of inhibitory synapses also collapsed. Parvalbumin-producing neurons are like the pacemakers of the brain, modulating γ-frequency oscillations, which is important for working memory. Indeed, the 3R mice had weaker γ activity in the hippocampus and had trouble finding a hidden platform in a water maze. Otherwise, they seemed to behave normally. Taken together, the results suggested that accumulation of tau in hilar astrocytes compromised the function of hippocampal inhibitory neurons.
A Look at the Damage Done by Senescent T Cells in the Aged Immune System
https://www.fightagi...-immune-system/
Cells become senescent and cease replication in response to damage, a toxic environment, or reaching the Hayflick limit. Such cells near all self-destruct or are destroyed by the immune system. In later life, however, they begin to linger and accumulate. This is an issue, as the secretions of senescent cells are quite harmful when sustained over the long term, producing chronic inflammation and disruption of tissue structure and function. The cells of the immune system are no less subject to the burden of cellular senescence than is the case for any other cell type, in fact arguably more so given that infection results in an aggressive replication of immune cells to meet the challenge, pushing those cells towards the Hayflick limit faster than they can be reinforced by newly created immune cells. Senescent immune cells are likely an important contributing cause of the systemic chronic inflammation of aging, as well as of many age-related conditions.
As we age, we accumulate cells in many organs that exhibit signs of DNA damage, have poor proliferative capacity, and are highly secretory. These cells are senescent, defined as being in a state of cell cycle arrest associated with phenotypic and functional changes. While transient senescence is a beneficial mechanism earlier in life, the accumulation of senescent cells with increasing age leads to organ dysfunction, driving inflammation and may underlie many age-related diseases such as atherosclerosis, osteoarthritis, neurodegenerative diseases, and cirrhosis.
While senescence was first discovered in fibroblasts and extensively worked on in other non-leukocytic cells, it has become increasingly clear that immune cells undergo senescence as well. Within the immune system, the existence of non-proliferative leukocyte populations that have high capacity for biologically active mediator secretion has been recognized for many decades, albeit under a different name. These are the effector T lymphocytes that secrete pro-inflammatory cytokines and cytotoxic granules but do not proliferate after activation. Recent studies show that these cells also harbour DNA damage, short telomeres, low telomerase activity, and engage signalling pathways associated with cellular senescence. Therefore, the terms effector T cells and senescent T cells may be synonymous and refer to the same T cell populations.
The extent of T cell proliferation the acute phase of a viral infection drives T cells to senescence. These cells are still susceptible to apotosis but can persist given sufficient antiapototic cytokines in tissue niches. It can be argued that senescent T cells derive from a subpopulation of effector T cells that do not undergo apoptosis, instead becoming senescent and lingering long term. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non-lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID-19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation.
Investigating the Use of VEGF-B to Grow New Blood Vessels to Supply the Heart
https://www.fightagi...pply-the-heart/
Researchers are interested in provoking the body into growing additional blood vessels that can bypass areas of damage. Most of this work is focused on restoring long term supply of blood to heart tissue following a heart attack, and thus on regrowth in an environment of damage and damage-related signaling. It would be perhaps more interesting to develop means of growing additional redundant blood vessels prior to that point, in the normal signaling environment. This could greatly reduce the damage done by a blockage that would ordinarily cause a heart attack, and slow the progression into heart failure caused by narrowing of blood vessels. This all compares poorly to developing means of prevention of atherosclerosis, the cause of blood vessel narrowing, rupture, and blockage, but even given a cure for atherosclerosis, there is a lot to be said for having redundant routes of blood supply to major organs.
Cardiovascular disease is the leading cause of mortality and ischemic heart disease is a major cause of death worldwide. Coronary vessels that nourish the heart develop from three main sources, the endocardium on the inner surface of the hearts blood-filled chambers being one of the major contributors. In normal conditions, the adult heart can no longer generate new blood vessels from the endocardium, because the endocardium-to-coronary vessel transition is blocked by a connective tissue wall beneath the endocardium.
In a recently published study researchers show that the VEGF-B growth factor can be used to activate the growth of vessels inside of the heart during cardiac ischemic damage. This novel finding opens the possibility that vessels emerging from the inner side of the heart could be further developed for the treatment of myocardial infarction, which results from insufficient delivery of oxygen to cardiac tissue. In normal conditions, blood nourishes the adult heart through coronary vessels.
VEGF-B (vascular endothelial growth factor) belongs to a family of growth factors that regulate the formation of blood- and lymphatic vessels. Earlier attempts to utilize another growth factor gene, VEGF-A, to grow new vessels in the heart have failed, mostly due to the leakiness of the vessels and increased inflammation caused by VEGF-A, but not by VEGF-B. Re-activation of the embryonic vessel growth program in adult endocardium could be a new therapeutic strategy for cardiac neovascularization after myocardial infarction. For possible future clinical use, the function of these vessels and their blood flow has to be further studied to ensure that they really increase transport of oxygen and nutrients into the cardiac muscle.
GrimAge Outperforms Other Epigenetic Clocks
https://www.fightagi...genetic-clocks/
There are now a variety of epigenetic clocks, weighted combinations of the methylation status of various CpG sites on the genome in various different tissues. The epigenetic marks of DNA methylation change constantly in response to circumstances and cell activities, but some of these changes are characteristic of the aged tissue environment, and thus correlate well with the burden of damage and dysfunction that causes manifestations of aging. A person more greatly damaged will tend to exhibit an epigenetic age higher than chronological age, a phenomenon referred to as age acceleration.
Epigenetic clocks are derived from the analysis of large amounts of epigenetic data obtained from study population of different ages, rather than from any understanding of how and why age-related epigenetic changes take place. Cell metabolism and epigenetics are very complex, and it remains unclear in near all cases as to why specific changes occur, and how those changes relate to the underlying processes of aging. Still, one can certainly run the numbers to decide which of the clocks are better or worse than others when it comes to assessing the burden of aging.
The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesised to represent a measure of biological ageing with a positive or negative residual signifying age acceleration or deceleration respectively.
The present study examines the associations of four epigenetic clocks - Horvath, Hannum, PhenoAge, GrimAge - with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA).
Horvath Age Acceleration (AA) and HannumAA were not predictive of health; PhenoAgeAA was associated with 4 of 9 outcomes (walking speed, frailty, MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8 of 9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.
Towards a Retinal Assessment of Alzheimer's Risk, Years in Advance of Symptoms
https://www.fightagi...ce-of-symptoms/
Researchers here report on progress towards non-invasive retinal scanning as an approach to determining Alzheimer's disease risk in the very early stages of progression towards the condition. The path to Alzheimer's is marked by years of a slow accumulation of amyloid-β, an antimicrobial peptide that can misfold to form solid aggregates. While the evidence suggests that amyloid-β can on its own cause mild cognitive impairment, it remains to be determined as to whether it also causes the later stages of Alzheimer's, the chronic inflammation and tau aggregation that kills large numbers of brain cells. It may be a side-effect of other processes, such as persistent viral infection, senescent cell accumulation, and the like. Fortunately, that present lack of knowledge may not matter when it comes to the use of amyloid-β as a marker of risk and progression towards Alzheimer's disease.
Researchers have identified certain regions in the retina - the lining found in the back of the eye - that are more affected by Alzheimer's disease than other areas. The findings were from a clinical trial involving people older than 40 who were showing signs of cognitive decline. In the trial, investigators used a noninvasive technique known as sectoral retinal amyloid imaging to capture retinal images in participants. The retina, which is directly connected to the brain, is the only central nervous system tissue accessible for patient-friendly, high-resolution and noninvasive imaging.
The images were then analyzed using a new process that could identify certain peripheral regions in the retina that corresponded better to brain damage and cognitive status. In studying the images, scientists could detect patients with an increased buildup of retinal amyloid protein, signifying a higher likelihood of developing Alzheimer's disease or cognitive impairments. These findings build upon pioneering research in 2010 in which researchers identified a pathological hallmark of Alzheimer's disease, amyloid beta-protein deposits, in retinal tissues from deceased patients. The team then developed a methodology to detect retinal amyloid beta-protein plaques in living patients suffering from the disease.
View the full article at FightAging
