Increased Physical Activity in High Risk Groups Reduces Incidence of Cardiovascular Disease and Mortality

Greater physical activity has been quite comprehensively demonstrated to correlate with reduced mortality in later life. The epidemiological study noted here shows that this relationship also holds up in people who have a higher risk of cardiovascular disease, due to factors such as type 2 diabetes or hypertension. The researchers examined outcomes in patients who improved their level of physical activity between two time points, finding a lower incidence of cardiovascular disease in comparison to those who did not improve. This is consistent with other studies of the role of physical activity in reducing the risk of cardiovascular disease and mortality.

The study included 88,320 individuals from the LifeLines Cohort Study. Participants underwent a physical examination and completed questionnaires about their medical history and lifestyle including exercise. The questionnaires were repeated after approximately four years. Study participants were divided into five groups according to activity levels at baseline and four years: large reduction, moderate reduction, no change, moderate improvement, and large improvement. Participants were followed-up for a median of seven years after the first assessment for the occurrence of cardiovascular disease or death.high cholesterol

A total of 18,502 (21%) individuals had high blood pressure, high cholesterol, and/or diabetes at the start of the study. The average age of this group was 55 years. After adjusting for age, sex, and baseline physical activity, the researchers found that those with a moderate to large improvement in physical activity were around 30% less likely to develop cardiovascular disease or die during follow-up compared to those who did not change their activity level.

The remaining 69,808 (79%) participants did not have high blood pressure, high cholesterol, or diabetes at the start of the study. The average age of this group was 43 years. After adjusting for age, sex, and baseline physical activity, the researchers found that those with large reductions in physical activity had a 40% higher risk of cardiovascular disease or death compared to those who did not change their activity level.

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Heart-patients-advised-to-move-more-to-avoid-heart-attacks-and-strokes

The EU Green Paper on Aging Ignores the Role of Medical Research in the Future of Aging

Governments and large international entities have in many cases published quite expensive and detailed positions on aging. They commonly urge individual and collective action based on the impending collapse of entitlement systems due to changing demographics. The growing number of older people relative to the size of the population as a whole makes pensions, government-run health systems, and the like, increasingly unsustainable in their present form. Something must change. That change must be the development and widespread deployment of therapies to treat the underlying mechanisms of aging, so as to slow and reverse the process of aging. Sadly that is the one approach to the challenge that never appears in these proposals, following the lead of the WHO's 2015 World Report on Aging and Health and 2020 Decade of Healthy Aging, which interventions to slow and reverse aging are not mentioned. The EU Green Paper on Aging discussed here is similarly entirely blind to the role of medical research in the future of aging.

"The Green Paper on Ageing highlights the importance of healthy and active ageing and lifelong learning as the two concepts that can enable a thriving ageing society. Active ageing necessitates promoting healthy lifestyles throughout our lives, including consumption and nutrition patterns, as well as encouraging physical and social activity. Lifelong learning means a constantly acquiring and updating of skills helping people to remain employable and succeed in job transitions."

Active ageing and lifelong learning are important, obvious, and attractive ideas but we would argue that without really addressing the underlying problem of accelerated biological aging and functional decline giving rise to the fundamental problem related to the demographic challenges promoting these ideas alone and proposing them as the remedy is akin to trying to build a house without a foundation.

The three biggest problems of the current Green Paper on Ageing are all rooted in the missed opportunity of learning from and applying the latest biomedical, scientific and technological results. This way the potential effect of this most decisive scientific and technological trend is rendered invisible concerning the changing demographics and hence actually and actively downplaying the role science and technology might play in the long term permanent solution.

1. The Green Paper on Ageing is missing the elephant in the room behind changing demographics affecting Europe (and the world): the real, life-compromising burden of accelerated biological aging in the second half of life, already present in middle age, and reaching its climax in older people.

2. The Green Paper on Ageing appears oblivious to science's current view on the malleability of the biological aging process, and the already mainstream translational geroscience paradigm that offers an interventionist approach to potentially slow, stop, reverse, or rejuvenate these aging processes in order to significantly increase healthy human lifespan.

3. Due to the previous 2 points the Green Paper on Ageing ignores the primary long-term policy solution of the demographic challenge: supporting the focused development and equitable access of science-intensive healthy longevity technologies for all EU citizens.

Link: https://www.longevity.technology/changing-demographics-warrant-solid-longevity-foundation/

Targeting the cGAS-STING pathway to Sabotage Chronic Inflammation

Chronic inflammation is a major issue in aging. The immune system reacts inappropriately to rising levels of molecular damage, spurred on by the pro-inflammatory signaling of growing numbers of senescent cells, and enters a state of continual overactivation. This broadly disrupts cell and tissue function throughout the body in many ways. Present approaches to reducing inflammation, largely deployed as treatments of autoimmune conditions, involve the brute force sabotage of important inflammatory signaling pathways such as those involving tumor necrosis factors. This can achieve the goal of reducing chronic inflammation, but at the cost of also sabotaging some of the vital work of the immune system in defending against pathogens and destroying errant cells.

Are there similar brute force approaches that can sabotage immune system signaling pathways that are less involved in vital work and more involved in inappropriate overactivation in old age and autoimmunity? That might be the case. The cGAS-STING pathway is attracting a great deal of research interest of late, and may prove to be a better option than tumor necrosis factor interactions, but it is still involved in the detection of pathogens and problematic cells. A better class of approach might be to instead address the causes of inflammation: the senescent cells, the cell damage, the reasons why the signaling environment shifts to be more inflammatory.

The cGAS-STING pathway as a therapeutic target in inflammatory diseases

The detection of foreign DNA serves as a crucial element of immunity in many organisms. In mammalian cells, this task is contributed in large part by the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which has emerged as a critical mechanism for coupling the sensing of DNA to the induction of powerful innate immune defence programmes. Within this pathway, the binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic activity and leads to the production of 2′3′ cyclic GMP-AMP (cGAMP), a second messenger molecule and potent agonist of STING.

A salient feature of the cGAS-STING pathway, which sets it apart from several other innate immune signalling mechanisms, is that its activation is triggered by a fundamental element of life (namely DNA) and, therefore, lacks any pathogen-specific attributes. For this reason, cGAS recognizes a broad repertoire of DNA species of both foreign and self origin. Today, our understanding of the diverse functions of the cGAS-STING pathway in host immunity has become clearer, and multiple examples highlight the protective effects of this pathway during infection. Recent studies showing that the cGAS-STING system arose from an ancient bacterial anti-phage mechanism underscore this notion.

Growing evidence has indicated, however, that dysregulation of this highly versatile innate immune sensing system can disrupt cellular and organismal homeostasis by fuelling aberrant innate immune responses associated with a number of pathologies. The parameters that dictate host-protective versus pathogenic activity are still being unfolded, but it appears that the intensity and chronicity of cGAS-STING signalling are major determinants in most cases. In light of this, efforts have been undertaken or are still under way to define strategies that allow selective modulation of cGAS-STING activity in various disease settings.

A critical aspect for the future will be to better understand the minimal level of inhibition required for therapeutic benefit. It is possible that strong reduction of the pathway provokes adverse effects in humans by increasing susceptibility to infection. This may be particularly relevant for the treatment of chronic conditions that require repetitive or continuous treatment regimens. Still, the direct targeting of cGAS-STING bears potential benefits over more non-specific and broadly acting anti-cytokine antibodies or compounds targeting key signalling molecules, such as JAK inhibitors or TBK1 inhibitors, as it leaves intact essential compensatory innate immune recognition pathways, most critically the TLR, RIG-like receptor, and inflammasome pathways.

Are Some Amyloid Plaques Protective in Old Age and Alzheimer's Disease?

Researchers here provide evidence to suggest that some of the amyloid-β deposits in the brain that are characteristic of Alzheimer's disease are in fact beneficial and protective, the efforts of immune cells to remove harmful amyloid-β from contact with cells and deposit it in elsewhere. This may or may not help to explain why amyloid clearance therapies have so far failed to produce benefits in patients: it is always hard to say just how large a contribution any one given mechanism has to disease progression. It seems likely that amyloid-β aggregates are either a moderately but not severely harmful side-effect of the real core disease processes - such as chronic infection and its consequences - or that amyloid-β aggregation is only relevant in the early stages of Alzheimer's disease. In the later stages of the condition, a feedback loop of inflammation, cellular senescence, and immune system dysfunction drives the condition.

Alzheimer's disease is a neurological condition that results in memory loss, impairment of thinking, and behavioral changes, which worsen as we age. The disease seems to be caused by abnormal proteins aggregating between brain cells to form the hallmark plaques, which interrupt activity that keeps the cells alive. There are numerous forms of plaque, but the two most prevalent are characterized as "diffuse" and "dense-core." Diffuse plaques are loosely organized, amorphous clouds. Dense-core plaques have a compact center surrounded by a halo. Scientists have generally believed that both types of plaque form spontaneously from excess production of a precursor molecule called amyloid precursor protein (APP).

But, according to a new study, it is actually microglia that form dense-core plaques from diffuse amyloid-beta fibrils, as part of their cellular cleanup. This builds on earlier research showing that when a brain cell dies, a fatty molecule flips from the inside to the outside of the cell, signaling, "I'm dead, eat me." Microglia, via surface proteins called TAM receptors, then engulf, or "eat" the dead cell, with the help of an intermediary molecule called Gas6. Without TAM receptors and Gas6, microglia cannot connect to dead cells and consume them.

The team's current work shows that it's not only dead cells that exhibit the eat-me signal and Gas6: So do the amyloid plaques prevalent in Alzheimer's disease. Using animal models, the researchers were able to demonstrate experimentally for the first time that microglia with TAM receptors eat amyloid plaques via the eat-me signal and Gas6. In mice engineered to lack TAM receptors, the microglia were unable to perform this function.

Digging deeper, they traced the dense-core plaques using live imaging. Much to their surprise, the team discovered that after a microglial cell eats a diffuse plaque, it transfers the engulfed amyloid-beta to a highly acidic compartment and converts it into a highly compacted aggregate that is then transferred to a dense-core plaque. The researchers propose that this is a beneficial mechanism, organizing diffuse into dense-core plaque and clearing the intercellular environment of debris.

"Some people are saying that the relative failure of trials that bust up dense-core plaques refutes the idea that amyloid-beta is a bad thing in the brain. But we argue that amyloid-beta is still clearly a bad thing; it's just that you've got to ask whether dense-core plaques are a bad thing." The researchers suggest that scientists looking for a cure for Alzheimer's should stop trying to focus on breaking up dense-core plaques and start looking at treatments that either reduce the production of amyloid-beta in the first place or therapies that facilitate transport of amyloid-beta out of the brain altogether.

Link: https://www.salk.edu/news-release/in-surprising-twist-some-alzheimers-plaques-may-be-protective-not-destructive/

A Nanomaterial Incorporating TNF Epitopes Reduces Inflammation

The inflammatory cytokine TNF is the target of many efforts to find ways to reduce inflammation in conditions characterized by excessive inflammatory activity of the immune system, such as autoimmune diseases. It is a blunt approach, as it reduces not only inappropriate activity, but also the needed activity of the immune system, such as defense against pathogens and destruction of potentially cancerous and senescent cells. The methods of targeting TNF are becoming ever more sophisticated, as this example demonstrates. It is nonetheless the case that better and different classes of treatment will be needed in order to avoid the issue of reducing the capacity of the immune system to carry out necessary tasks.

Researchers describe how novel nanomaterials could assemble into long nanofibers that include a specialized protein, called C3dg. These fibers then were able to activate immune system B-cells to generate antibodies. Due to the protein's ability to interface between different cells in the immune system and activate the creation of antibodies without causing inflammation, researchers have been exploring how C3dg could be used as a vaccine adjuvant, which is a protein that can help boost the immune response to a desired target or pathogen.

In their new nanomaterial, researchers were able put this idea to the test by weaving key fragments of the C3dg protein with epitopes of TNF into nanofibers. The C3dg protein would trigger the B-cells to create antibodies, while the TNF epitopes would provide a blueprint of what the antibodies need to seek out and destroy. "We saw that there was a strong B-cell response, which means there was an increased production of antibodies that targeted TNF. When we delivered the C3dg nanofibers into mice, it was highly protective, and the mice didn't experience an inflammatory response."

When the team tested their nanomaterial in a psoriasis mouse model, they found that the nanofibers carrying C3dg were as effective as a monoclonal antibody therapy targeting TNF. And because C3dg is normally found in the body, it wasn't flushed out of the system by anti-drug antibodies. After examining the psoriasis model, the team made a surprising discovery - C3dg wasn't just stimulating antibody production in the B-cells, it was also influencing the response of T-cells. For their next steps, the team hopes to further explore the mechanisms behind this beneficial T-cell activation. They'll also pursue additional experiments to explore the response to similar nanomaterials in rheumatoid arthritis models.

Link: https://pratt.duke.edu/about/news/self-assembling-nanofibers-prevent-damage-inflammation

Reducing Measured Epigenetic Age by a Few Years with Diet and Lifestyle Changes

Epigenetic clocks assess changing patterns of DNA methylation at CpG sites on the genome that correlate well with chronological age, and to some degree with biological age. People who age more rapidly, as judged by a range of factors such as presence or risk of age-related conditions, tend to have a higher assessed epigenetic age. It remains unclear as to which processes of aging are reflected by any given set of DNA methylation markers, however. For example, the early clocks are insensitive to exercise and fitness. Sedentary people and fit people at any given age tend to measure the same epigenetic age.

Today's open access paper is interesting as a further data point regarding lifestyle interventions for one of the early epigenetic clocks. It involves a small human study using changes in diet, including the use of probiotics, and exercise, which we can probably discount as a meaningful factor given earlier data. The results suggest that diet can make a modest difference of a few years in measured epigenetic age. Unfortunately this still doesn't tell us whether the clock does in fact reflect effects on human life expectancy for this class of lifestyle intervention. The next step on the road to robustly establishing that connection is to calibrate the clock against life span studies in mice using this approach to diet.

Overall, however, this is a taste of what the future holds: every class of intervention clearly and rapidly tested for its ability to affect biological aging. The world in which we can do this is a world in which the best interventions rise to the top of the pile and attract greater investment more rapidly. That is very much needed at the moment: too many resources are devoted to projects in the biology of aging and related medical research and development that cannot possibly produce meaningful gains to healthy human life span.

Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial

Manipulations to slow biological aging and extend healthspan are of interest given the societal and healthcare costs of our aging population. Herein we report on a randomized controlled clinical trial conducted among 43 healthy adult males between the ages of 50-72. The 8-week treatment program included diet, sleep, exercise and relaxation guidance, and supplemental probiotics and phytonutrients. The control group received no intervention.

Genome-wide DNA methylation analysis was conducted on saliva samples and DNAmAge was calculated using the online Horvath DNAmAge clock. The diet and lifestyle treatment was associated with a 3.23 years decrease in DNAmAge compared with controls. DNAmAge of those in the treatment group decreased by an average 1.96 years by the end of the program compared to the same individuals at the beginning with a strong trend towards significance. Changes in blood biomarkers were significant for mean serum 5-methyltetrahydrofolate (+15%) and mean triglycerides (-25%).

To our knowledge, this is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge epigenetic aging in healthy adult males. Larger-scale and longer duration clinical trials are needed to confirm these findings, as well as investigation in other human populations.

Reprogramming Astrocytes into Neurons Enhances Stroke Recovery in Mice

Reprogramming cells in order to change their cell type directly has shown some promise in animal studies as a way to generate new neurons in the brain, enabling regeneration. There are many more supporting cells in the brain, various types collectively known as glial cells, than there are neurons. These supporting cells are somewhat more fungible and replaceable, as they are not storing the data of the mind. A gene therapy that turns some small percentage of glial cells into neurons capable of integrating into existing neural circuits could prove to have numerous advantages over the cell therapy approach of growing patient-matched neurons and introducing them into the brain. Logistically, it should be considerable easier, for one. It may also turn out to be more effective, given the challenges inherent in keeping transplanted cells alive for any meaningful length of time following treatment.

Stem cell transplantation has emerged as a promising regenerative therapy for stroke due to its potential for repairing damaged brain structures and improving functional recovery. However, cell transplantation therapies face multiple obstacles including the hosts' immune systems, poor transplanted cell survival, inappropriate migration/homing and differentiation, and the lack of specificity or integration into endogenous brain networks. Some clinical trials have also reported inconsistent results in the efficacy of cell transplantation therapies.

Resident astrocytes in the brain remain mitotic throughout the lifespan and undergo rapid gliosis in response to injury. This characteristic response provides a rich source of cells adjacent to the site of injury. The idea of direct reprogramming of non-neuronal cells allows for the trans-differentiation of glial cells (astrocytes, microglia, and oligodendrocytes) into induced neurons (iNeurons) without passing through a stem cell stage. Theoretically, this is a more efficient way to obtain desirable endogenous neurons from a large cellular pool for "on-site" repair in the brain.

Based on the efficiency and efficacy of glial cell reprogramming, we and others experimented with several combinations of transcription factors and settled on the use of the single neural transcription factor NeuroD1 (ND1). Targeting astrocytes for neuronal reprogramming with different viral vectors has been tested in several animal models of neurodegenerative diseases including ischemic stroke with varying success. The exploration of this approach in animal disease models is at an early stage. The efficacy of neuronal conversion and its contribution to neuronal circuitry repair, the mechanisms involved in the regenerative process, and the functional benefits of this therapy have not been well defined.

Our investigation examined the viability of reprogramming of astrocytes in vitro and in vivo. Reprogramming therapy was tested in a focal ischemic stroke model of rats. After a stroke, we transduced ND1 using a lentivirus vector rather than other viral serotypes such as an adeno-associated virus (AAV) to preserve finer control over the scope of infection to study the mechanics of reprogramming on local circuitry and to limit the therapy to only the injured tissue. Neuronal network repair and functional recovery were confirmed using comprehensive assessments and behavioral tests up to 4 months after stroke. The present investigation presents compelling evidence for the feasibility and effectiveness of utilizing reactive astrocytes as an endogenous cellular source for the generation of neuronal cells to repair damaged brain structures.

Link: https://doi.org/10.3389/fnagi.2021.612856

Tabula Muris Senis: A Single Cell Transcriptome Database by Tissue and Age in Mice

Researchers here announce the publication of a database of 300,000 single cell transcriptomes across cell types, tissues, and ages in mice. This and similar vaults of data will no doubt keep factions within the research community busy for years to come, refining their efforts to produce useful, verified biomarkers of aging. The most important thing that can be achieved with such biomarkers of aging is the comparatively rapid assessment of different approaches to rejuvenation. At present all too much of the field is focused on projects that cannot possible do all that much good in terms of lengthening healthy life span. Redirecting researchers to better approaches much earlier in the development process is a desirable outcome.

Aging leads to the decline of major organs and is the main risk factor for many diseases, including cancer, cardiovascular and neurodegenerative diseases. While previous studies have highlighted different hallmarks of the aging process, the underlying molecular and cellular mechanisms remain unclear. To gain a better understanding of these mechanisms, the Tabula Muris Consortium created the single-cell transcriptomic dataset, called Tabula Muris Senis (TMS). The TMS contains over 300,000 annotated cells from 23 tissues and organs of male and female mice. "These cells were collected from mice of diverse ages, making the data a tremendous opportunity to study the genetic basis of aging across different tissues and cell types."

The original TMS study mainly explored the cell-centric effects of aging, aiming to characterise changes in the composition of cell types within different tissues. In the current gene-centric study, researchers focused on changes in gene expression that occur during the aging process across different cell types. Using the TMS data, they identified aging-dependent genes in 76 cell types from 23 tissues. They then characterised the aging behaviours of these genes that were both shared among all cell types ('globally') and specific to different tissue cells.

"We found that the cell-centric and gene-centric perspectives of the previous and current studies are complementary, as gene expression can change within the same cell type during aging, even if the composition of cells in the tissue does not vary over time. The identification of many shared aging genes suggests that there is a coordinated global aging behaviour in mice." The team then used this coordinated activity to develop a single-cell aging score based on the global aging genes. This new high-resolution aging score revealed that different tissue-cell types in the same animal can have a different aging status, shedding light on the diverse aging process across different types of cells.

Link: https://elifesciences.org/for-the-press/f0e7a8d9/researchers-reveal-aging-signatures-across-diverse-tissue-cells-in-mice

The Aged Bone Marrow Niche Impedes Hematopoietic Stem Cell Function

Stem cell activity declines with age for a variety of reasons. Damage in the stem cells, damage in the supporting cells of the stem cell niche, as well as altered behavior in stem cells and niche cells, a reaction to signaling changes such as increased inflammation. In some populations, such as muscle stem cells, the evidence suggests that reactions to signaling are a much more important factor than intrinsic damage. Those stem cells can in principle be put back to work in an aged individual. For hematopoietic stem cells, responsible for generating blood and the immune system, the evidence is less clear. In very late life it has been shown that these cells are very damaged, but it remains to be determined as to whether the majority of the problem is damage or reactions to signaling in earlier old age.

Given this, more research such as the work noted here is needed to better understand the aging of this vital stem cell population and its niche. The nature of this age-related decline determines which approaches to rejuvenation are more likely to work. The data here suggest that delivering new, replacement hematopoietic stem cells will be impeded by changes and damage in the aged stem cell niche. The niche is a sufficiently important determinant of function to require attention.

Aged bone marrow niche impedes function of rejuvenated hematopoietic stem cells

A new study shows that the youthful function of rejuvenated HSCs upon transplantation depends in part on a young bone marrow "niche," which is the microenvironment surrounding stem cells that interacts with them to regulate their fate. "The information revealed by our study tells us that the influence of this niche needs to be considered in approaches to rejuvenate old HSCs for treating aging-associated leukemia or immune remodeling."

Old HSCs exhibit a reduced reconstitution potential and other negative aspects such as altered gene expression profiles and an increase in a polar distribution of proteins. (Polarity is believed to be particularly important to fate decisions on stem cell division and for maintaining an HSC's interaction with its niche. Consequently, a failure to establish or regulate stem cell polarity might result in disease or tissue deterioration.) Aging of HSCs might even affect lifespan. Researchers already knew that increased activity of a protein called Cdc42, which controls cell division, leads to HSC aging, and that when old HSCs are treated ex vivo with CASIN, an inhibitor of Cdc42 activity, they stay rejuvenated upon transplantation into young recipients. The aim of this latest study was to learn what happens to these rejuvenated HSCs when they are transplanted into an aged niche.

Researchers transplanted rejuvenated aged HSCs into three groups of mice: young (8 to 10 weeks old), old (19 to 24 months old) and young cytokine osteopontin (OPN) knockout mice (8 to 12 weeks old). The team had recently demonstrated that a decrease in the level of secreted OPN in the aged bone marrow niche confers hallmarks of aging on young HSCs, and also that secreted OPN regulates HSC polarity. Old HSC and rejuvenated old HSCs were therefore transplanted into the OPN knockout recipients to test whether a lack of this protein in the niche affects the function of old rejuvenated HSCs. The results were then analyzed for up to 23 weeks after transplantation."They showed us that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of OPN found in aged niches. This tells us that in order to sustain the function of rejuvenated aged HSCs, we will likely need to address the influence of an aged niche on rejuvenated HSCs."

An aged bone marrow niche restrains rejuvenated hematopoietic stem cells

Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.

Hypertension Alters Artery Structure, Accelerating the Development of Atherosclerosis

The raised blood pressure of hypertension is well known to accelerate the progression of atherosclerosis. It certainly makes it more likely for blood vessels weakened by atherosclerotic lesions to rupture, or for the lesions themselves to fragment and cause blockages. Beyond that, however, mechanisms are at work in the environment of high blood pressure to accelerate the growth of these lesions. The major consequences of atherosclerosis, stroke and heart attack, are the cause of death for a sizable fraction of all people, and this is why blood pressure control produces a meaningful reduction in mortality risk, by slowing the progression towards those consequences.

Blood pressure-lowering drugs are routinely used to prevent the development of atherosclerosis and heart disease, but the mechanism of this effect is still unknown. People suffering from high blood pressure (hypertension) often have accompanying changes in the hormones that control blood pressure and it has been unclear whether the pressure itself or the hormonal changes are the driver of accelerated atherosclerosis. To investigate this, researchers analyzed the development of atherosclerosis in minipigs that were genetically engineered to have high blood cholesterol and develop atherosclerosis.

Minipigs have arteries that are very similar in structure to human arteries and like humans they develop atherosclerosis in the heart when exposed to high blood cholesterol. By manipulating blood pressure in the pigs and by analyzing the effects on arteries in the heart, the researchers found that the direct forces of pressure on arteries leads to structural changes that facilitate the development of atherosclerosis. "Arteries become denser and allow less passage of molecules from the blood. This includes the LDL particles that carry blood cholesterol, which instead accumulate in the innermost layer of arteries, where they drive the development of atherosclerosis."

This finding uncovers an intimate relationship between the most important risk factors for atherosclerosis, LDL cholesterol and high blood pressure. While it has been known for decades that accumulation of LDL particles in arteries lead to atherosclerosis, the new research shows that high blood pressure accelerates the accumulation of LDL. Therefore, high blood pressure aggravates the effect of having high LDL cholesterol in the blood.

Link: https://www.cnic.es/en/noticias/jacc-cnic-researchers-explain-how-high-blood-pressure-most-important-cause-disease

Neutrophils May Be Involved in the Transmission of Cellular Senescence in Aged Tissues

Researchers here provide evidence suggesting that one of the mechanisms by which senescent cells encourage nearby cells to also become senescent is via recruitment of neutrophil cells, a somewhat more complicated process than the direct signaling investigated to date. In its role as a suppressor of cancer, it makes sense for the state of cellular senescence to be transmissible to nearby cells, as that raises the chances of successfully preventing cancer from arising in a localized environment of cell damage. In aging, it makes things worse, however. Excessive numbers of lingering senescent cells cause harm to their surroundings and make that harm worse over time via the creation of yet more senescent cells.

The immune system is a collection of cells and proteins that works to keep the body healthy. But it's a balancing act. Tip in one direction and an infection might cause organ damage or lead to sepsis. Overbalance in the other and the cure might lead to an autoimmune disease. Neutrophils are a key part of immune system action. They help healing by clearing out cellular debris after an infection. They're also armed and can kill microbes. During infection, neutrophils release a short blast of unstable molecules called reactive oxygen species.

Another way the immune system keeps the body healthy is by telling damaged cells to perish. But not all cells die. Cells told to close down by the body sometime ignore that signal. Instead, they live in a sort of zombie state, undead but spewing toxic chemicals. These cells are senescent cells. They damage their neighbors through release of a toxic protein stew.

Researchers examined neutrophils' effect on human and mouse cell senescence. They co-cultured neutrophils with human cells and depleted neutrophils in mice to determine their role in encouraging senescence. "We asked if neutrophils could be drivers of cellular senescence in tissues and contribute to aging. We found that neutrophils can cause senescence in neighboring non-immune cells by damaging their telomeres via reactive oxygen species. We also found that if we deplete neutrophils in mice, we can prevent telomere damage and senescence. Our study suggests an evolutionary trade-off between having a good working immune system and age-related pathology. While neutrophils have evolved to play important roles in fighting infection, they may contribute to collateral damage and induction of cellular senescence which will be detrimental later in life."

Link: https://discoverysedge.mayo.edu/2021/03/25/balancing-damage-and-protection-neutrophils-may-lead-to-cell-aging/

Calorie Restriction as an Adjuvant Cancer Treatment

Calorie restriction and intermittent fasting have been extensively studied in the context of aging, and most of the age-slowing interventions so far tested in animal studies are derived in some way from a knowledge of the stress response mechanisms triggered by a lowered calorie intake. The long term effects of calorie restriction and fasting in short-lived species are quite different from those in long-lived species: only the short-lived species exhibit a meaningful extension of life span, as much as 40% in mice. Yet the short-term effects on metabolism and cellular mechanisms are very similar. The beneficial response to periods of low nutrient availability evolved very early in the development of life, likely because it increases the chance of living to replicate in the next period of abundance.

The short-term effects of calorie restriction are beneficial to normal cells, but harmful to cancer cells. Calorie restriction upregulates cell maintenance mechanisms likely to cause cancer cells to self-destruct. This is now well known, demonstrated in animal models and human trials. In recent years researchers have put considerable effort into codifying and quantifying fasting and fasting mimicking diets in the context of cancer treatment. Similarly, there is considerable interest in the application to cancer treatment of calorie restriction mimetic drugs, those that induce some fraction of the response to lowered calorie intake. An example is the class of mTOR inhibitors, known to slow aging and lower cancer incidence in mice.

Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy

Fasting and caloric restriction (CR) were shown in non-human primates to reduce the incidence of not only cancer but also metabolic diseases, arteriosclerosis, and neurodegeneration - thus extending the healthspan. Furthermore, fasting and CR were shown in yeast, plants, worms, flies, and rodents to prolong lifespan and reduce the incidence of a wide array of age-associated pathologies, notably malignant diseases. Fasting-mimicking-diets (FMDs) reproduce the effects of fasting while maintaining a food supply, yet with a limited number of calories and a particular macronutrient composition, frequently poor in proteins, enriched in unsaturated fats, and with low to moderate proportions of carbohydrates. FMDs were shown in pilot trials to reduce risk factors associated with aging, diabetes, cardiovascular disease, and cancer, without major adverse effects. In this review, when indistinctively referring to fasting, CR, and/or their mimetics, we will use the term "energy reduction" (ER).

It has been known for more than a decade that starvation protects normal but not transformed cells against chemotherapeutics and oxidative damage, in yeasts, cell cultures, and mice. This effect has been observed in several malignancies such as colon carcinomas, melanomas, gliomas, and breast cancers. Such phenomenon has been dubbed "differential stress resistance" (DSR; sometimes referred to as "differential stress sensitization"). DSR likely originates from the independence of malignant cells from growth signals and their insensitivity to anti-growth signals. These characteristics result from oncogenic gain-of-function mutations affecting the activity of AKT, mechanistic target of rapamycin (mTOR), RAS, and other pro-proliferative signaling factors, and/or of loss-of-function mutations in genes encoding tumor suppressors such as TP53. Consequently, cancer cells are unable to adapt to the lack of nutrients and maintain a sustained proliferation. On the contrary, normal cells switch to a maintenance program conferring resistance to stress.

One of the knock-on effects of ER is autophagy induction, which is triggered in response to cellular stress such as DNA damage, endoplasmic reticulum or mitochondrial stress, oxidative or metabolic stress. In cancer cells, autophagic activity helps to survive in the hypoxic and nutrient-deprived tumor microenvironment and has also been described as a drug resistance mechanism. Somewhat counter-intuitively, this knock-on autophagy induction is not detrimental to the general antitumoral effect of ER and helps explain DSR. As we have seen, cancer cells are more sensitive to metabolic stresses and, as we know, they are also more sensitive to genotoxic stress than most somatic cells. Thus, the concomitant amplification of these two stresses thanks to ER and chemotherapy can prove fatal to malignant cells, whereas ER-induced autophagy probably contributes to its observed protective effect against chemotherapy in healthy cells.

DSR is thus mediated in part by the different metabolic requirements of cancer and healthy cells, but also - and perhaps chiefly - by the cellular effects of ER, especially as it pertains to autophagy. We have known for a few years that autophagy promotes (i) cancer cell immunogenicity, (ii) tumor-bed immune infiltration, and (iii) depletion of tumor-infiltrating regulatory T cells, especially when autophagy is induced at the same time as immunogenic cell death (ICD)-inducing agents are administered. This points towards an immune mechanism that explains the capacity of ER to prevent - and probably even to treat - cancer. This has led us and others to propose ER as an adjuvant to immunotherapy, especially as ER is relatively well tolerated.

Tau Immunotherapy for Alzheimer's Disease is Proving to be as Challenging as Amyloid Immunotherapy

Alzheimer's disease is characterized by the aggregation of first amyloid-β and then tau protein in later stages. It took many years and many attempts to produce immunotherapies capable of clearing amyloid-β from the brain, only to find that this doesn't in fact help patients to any great degree. Amyloid-β may be a side-effect of the causative mechanisms - such as infection, or chronic inflammation - or only important in the earliest stages of the development of Alzheimer's. By the time tau aggregation happens, a different disease process has become dominant. One of the next options is to target tau protein with the same sorts of immunotherapy technologies. So far this is proceeding in much the same way, with the first attempts failing to achieve meaningful levels of clearance.

With anti-amyloid antibodies now consistently hitting their target, tau immunotherapy represents the next frontier. In Alzheimer's disease, tau tangles correlate far more closely with cognitive decline than plaques do, and tau aggregates are the main pathology in many related disorders. As with amyloid, however, initial trials of anti-tau antibodies have been beset by failures. Already, several antibodies that bind the N-terminus or C-terminus of tau have been scuttled after not doing recipients any good. Meanwhile, preclinical evidence suggests that antibodies that go after the protein's mid-section, particularly its microtubule-binding region (MTBR), may be better at preventing aggregates from spreading. Several such antibodies have now entered Phase 1 or 2.

At the 15th International Conference on Alzheimer's and Parkinson's Diseases, researchers discussed a number of these programs. Roche offered a first look at biomarker data from the negative Phase 2 trial of the N-terminal-targeting antibody semorinemab. Other speakers touted MTBR-binding antibodies. Pinteon Therapeutics showed preliminary Phase 1 findings for PNT001, while the Technical University of Munich presented on UCB's beprenemab, also in Phase 1. Prothena's MTBR-binder PRX005 is still preclinical, but the company offered mechanistic data on how it might inhibit the transfer of pathological tau.

Time will tell if this newest crop can perform in the clinic. Researchers believe the field is making progress in figuring out how to target the protein, and are encouraged by cerebrospinal fluid data that link cerebrospinal fluid MTBR tau with tangles, and specific tau phospho-species with plaques. "That's really exciting for us as a field. We're learning so much more about this target."

Link: https://www.alzforum.org/news/conference-coverage/n-terminal-tau-antibodies-fade-mid-domain-ones-push-fore

A Worse Oral Microbiome Correlates with Some Metrics Indicating Alzheimer's Risk

There has been some evidence for the oral microbiome, particularly the harmful bacterial species responsible for gingivitis, to contribute to systemic inflammation throughout the body. This in turn raises the risk of suffering from dementia, including Alzheimer's disease. The mechanisms look plausible, but the epidemiological evidence is mixed, suggesting that this is a small contribution to overall risk. Alzheimer's is a condition characterized by a long slow buildup of amyloid, and a later and more damaging aggregation of tau protein. Researchers here find that the presence of harmful microbial species in the oral microbiome correlates with a measure of amyloid aggregation, but not with tau aggregation in older patients. This suggests perhaps a contribution to the early establishment of the condition, but not to its later progression.

Alzheimer's disease is characterized by two hallmark proteins in the brain: amyloid beta, which clumps together to form plaques and is believed to be the first protein deposited in the brain as Alzheimer's develops, and tau, which builds up in nerve cells and forms tangles. "The mechanisms by which levels of brain amyloid accumulate and are associated with Alzheimer's pathology are complex and only partially understood. The present study adds support to the understanding that proinflammatory diseases disrupt the clearance of amyloid from the brain, as retention of amyloid in the brain can be estimated from cerebrospinal fluid (CSF) levels. Amyloid changes are often observed decades before tau pathology or the symptoms of Alzheimer's disease are detected."

The researchers studied 48 healthy, cognitively normal adults ages 65 and older. Participants underwent oral examinations to collect bacterial samples from under the gumline, and lumbar puncture was used to obtain CSF in order to determine the levels of amyloid beta and tau. To estimate the brain's expression of Alzheimer's proteins, the researchers looked for lower levels of amyloid beta (which translate to higher brain amyloid levels) and higher levels of tau (which reflect higher brain tangle accumulations) in the CSF.

Analyzing the bacterial DNA of the samples taken from beneath the gumline,the researchers quantified bacteria known to be harmful to oral health (e.g. Prevotella, Porphyromonas, Fretibacterium) and pro-oral health bacteria (e.g. Corynebacterium, Actinomyces, Capnocytophaga). The results showed that individuals with an imbalance in bacteria, with a ratio favoring harmful to healthy bacteria, were more likely to have the Alzheimer's signature of reduced CSF amyloid levels, indicating low clearance and greater amyloid in brain tissue. The researchers hypothesize that because high levels of healthy bacteria help maintain bacterial balance and decrease inflammation, they may be protective against Alzheimer's. The researchers did not find an association between gum bacteria and tau levels in this study, so it remains unknown whether tau lesions will develop later or if the subjects will develop the symptoms of Alzheimer's.

Link: https://www.eurekalert.org/pub_releases/2021-04/nyu-iig040721.php

It is Faintly Ridiculous to Propose that Human Life Span Cannot be Increased by Altering Metabolism

Today's open access commentary is, I think, an overreaction to present challenges in engineering greater longevity via metabolic manipulation. I would be the first to say that altering the operation of metabolism is not a good path forward, at least if the goal is to engineer greater healthy longevity in our species. Cellular metabolism and its intersection with aging is ferociously complex and poorly understood in detail. Those details matter greatly: there are many feedback loops and switches based on protein levels that will change from beneficial to harmful for reasons that only become apparent after years of painstaking research. The best-studied mechanisms that link cellular metabolism to individual and species longevity have been under investigation for decades, and are still at a point at which related interventions are haphazardly beneficial and poorly understood.

Further, those best studied mechanisms, linked to the response to calorie restriction and other stresses, cannot greatly increase life span in long-lived species. They work quite well in short-lived species. That is well demonstrated: calorie restriction itself boosts mouse life span by as much as 40%, and certainly does not do that in humans. Thus we should not be looking to altered metabolism as a path that can add decades to the healthy human life span in the foreseeable future.

Arguing that this line of development is hard, and that all of the specific approaches examined so far appear to be capable of producing only low yields at best, in terms of healthy years added, is one thing. Arguing that it is impossible to ever achieve meaningful gains via this line of development is quite another. It is ridiculous to argue that it is impossible in principle to engineer humans to be very long-lived by changing the operation of cellular metabolism. We only have to look at the wide range of life spans in mammals to note that some concrete collection of differences must be enabling naked mole-rats to live nine times as long as mice, or for whales to live for centuries. Making significantly longer-lived humans through the approach of altered cellular metabolism is scientifically plausible - it just isn't a viable project at this time, and probably won't be for a lifetime yet.

This is why many people who have looked into the field in detail support the damage repair approach to rejuvenation, as first put forward by Aubrey de Grey and presently championed by the SENS Research Foundation and its network of allies and researchers. This is explicitly a strategy to work around the inability to make near term progress in altering metabolism. Instead we keep the metabolism we have, and target the periodic elimination of the various well-described forms of cell and tissue damage that cause aging. Remove the damage, and rejuvenation results, as illustrated in animal studies in which senescent cells are selectively destroyed via senolytic therapies.

The Zugzwang Hypothesis: Why Human Lifespan Cannot Be Increased

Lifespan is one of the most variable life history traits in the animal kingdom, lasting from days to centuries. Despite intensive investigation, there are still many grey areas in our understanding of the factors which contribute to the variability of lifespan. Humans are among the fortunate animals which have an unusually long lifespan compared to their similar sized mammals. On the flip side, the long lifespan of humans and large genetic heterogeneity are important reasons why it is very difficult to use humans as models to study ageing or longevity or test the efficacy of anti-ageing interventions. Ageing studies on humans often require a very large cohort of people and can potentially be affected by many confounding factors. As a consequence, most studies involving ageing, lifespan, and anti-ageing interventions are based on model systems.

In the evolutionary history after divergence from the great apes, the most recent of our primate ancestors, humans have completed almost 300,000 generations. During this period, the lifespan of H. sapiens has almost doubled. The increased longevity of humans is, in part, attributable to environmental changes; improved food, water, and hygiene; reduced impact of infectious disease; and improved medical care at all ages. However, the above factors had an opportunity to play some role in increasing lifespan only in the last 2 centuries. The dramatic increase in human lifespan compared to our nearest ancestors, should, therefore, must have other valid explanations. It is highly conceivable that forces of natural selection may have played vital role in increasing the basic longevity of humans.

Zugzwang is a German word with the literal meaning "compulsion to move." This word is frequently used in chess to describe a situation when a player gets a disadvantage because it is his turn to play, but all the available moves are bad. In Zugzwang position, any move the player makes will clearly weaken his position. Here, I propose that at this stage of evolution, humans may face the Zugzwang problem. Scientific research and the understanding of the hallmarks of ageing now provide humans with more than a dream to extend lifespan. However, it must be taken into consideration that natural selection has already played its part in extending human lifespan much beyond the expectation. All possible mechanisms which can increase longevity in lower animals have already been exploited by natural selection to stretch human lifespan. Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.

Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum life­span, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.