Fight Aging!

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Contents

• Removal of Senescent Microglia Lowers α-synuclein in Cerebrospinal Fluid, Improves Parkinson's Symptoms in Mice
• The Complexities of Vascular Aging
• Does the Aging of the Gut Microbiome Contribute Meaningfully to Hearing Loss?
• DNA Damage is a Part of Neural Plasticity, Complicating the Study of Its Relevance to Aging in the Brain
• Whole Blood Exchange and the Peripheral Amyloid Sink Hypothesis
• Targeting Inflammatory Microglia in Alzheimer's Disease
• Cerebral Small Vessel Disease as a Consequence of Inflammation
• A Bacterial Species Involved in Gum Disease Provokes Neuroinflammation
• Compromised Circulation Contributes to One Variant of Macular Degeneration
• Microglia in the Aging Brain, Both Protective and Harmful
• Reducing the T Cell Exhaustion Caused by Cancer
• The Combination of Plaques and Tangles Indicates a Much Higher Risk of Dementia
• Launching the Longevity Prize
• Stem Cell Therapy - Are We There Yet?
• Glymphatic System Dysfunction Contributes to the Pathology of Cerebral Small Vessel Disease

Removal of Senescent Microglia Lowers α-synuclein in Cerebrospinal Fluid, Improves Parkinson's Symptoms in Mice
https://www.fightaging.org/archives/2022/07/removal-of-senescent-microglia-lowers-%ce%b1-synuclein-in-cerebrospinal-fluid-improves-parkinsons-symptoms-in-mice/

A growing body of evidence points to the role of senescent supporting cells in the brain as a meaningful cause of neurodegenerative conditions. In this context, a number of research groups have focused on microglia, the innate immune cells of the brain. Microglia become increasingly overactive and inflammatory with age, stimulated by features of the aged tissue environment that resemble the molecular signals of pathogens or cancerous cells. A significant number of microglia become senescent, and do so at a time when the immune system as a whole becomes less competent in its task of clearing senescent cells in a timely manner. Senescent cells secrete a pro-inflammatory mix of signals that is harmful to surrounding tissue.

Inflammation in the brain is coming to be seen as a central pillar of neurodegenerative conditions, and the research community is in the process of testing a broad range of approaches to suppression of inflammation. Most, however, involve interference in specific inflammatory signals that block both excessive and necessary inflammation, and thus reduce the efficacy of the immune response. Targeted removal of senescent cells via senolytic treatments is (more or less) the only present approach that can only eliminate the excessive and harmful inflammatory signaling. Given the animal evidence for senolytic therapies to greatly improve pathology in animal models, and the availability of cheap small molecule senolytics that cross the blood-brain barrier, far more human trials should be underway than is presently the case.

Photoinduced elimination of senescent microglia cells in vivo by chiral gold nanoparticles

Parkinson's disease (PD) is an age-related brain disease that is associated with motivation and cognitive disorders and the assembly of alpha-synuclein (α-syn); there is no effective therapeutic treatment for this condition. Along with tissue dysfunction, the typical senescence-associated secretory phenotype is significantly characterized by the generation of interleukin-6 (IL-6) and interleukin-1β (IL-1β). Indeed, the accumulation of senescent cells is associated with a range of age-related diseases as well as neurodegenerative diseases. However, it is still unclear how senescence in the brain contributes to PD and what role it might play in therapeutic strategies of PD.

It had been reported that senescent cells could give rise to local and systemic inflammation and contribute to neurodegeneration in neurodegeneration diseases like PD. In addition, direct exposure to amyloid-β (Aβ) was shown to cause senescence in oligodendrocyte precursor cells (OPCs), and the clearance of OPCs by senolytic therapy alleviated Aβ-associated inflammation and restored cognitive deficits in Alzheimer's disease mice, thus illustrating the potential for senescence clearance to be used in clinical practice. Moreover, senescent cells play a role in the initiation and progression of tau-mediated disease, and targeting of senescent cells may provide a therapeutic avenue for the treatment of such pathologies. Therefore, eliminating senescent cells may hold therapeutic promise for alleviating the symptoms of PD.

In this study, chiral gold nanoparticles (NPs) with different helical directions were synthesized to selectively induce the apoptosis of senescent cells under light illumination. By modifying anti-B2MG and anti-DCR2 antibodies, senescent microglia cells could be cleared by chiral NPs without damaging the activities of normal cells under illumination. Mechanistic studies revealed that the clearance of senescent cells was mediated by the activation of the Fas signaling pathway. The in vivo injection of chiral NPs successfully confirmed that the elimination of senescent microglia cells in the brain could further alleviate the symptoms of PD mice in which the alpha-synuclein (α-syn) in cerebrospinal fluid decreased from 83.83 ± 4.76 ng/mL to 8.66 ± 1.79 ng/mL and the pathological symptoms of the PD mice were greatly improved after two months of treatment.

The Complexities of Vascular Aging
https://www.fightaging.org/archives/2022/07/the-complexities-of-vascular-aging/

We are as old as our arteries, as the saying goes. The aging of the vasculature impacts all of the tissues in the body, and there are many distinct mechanisms by which this happens. The loss of capillary density reduces the supply of oxygen and nutrients to energy-hungry tissues such as muscles and the brain. The stiffening of vessels leads to hypertension and pressure damage to delicate tissues throughout the body. The leakage of the blood-brain barrier allows unwanted molecules and cells to provoke chronic inflammation in the brain. The fatty deposits of atherosclerosis narrow and weaken blood vessels, further reducing blood flow and allowing harmful rupture and blockage in vessels large and small.

A broad range of underlying mechanisms of aging contribute to the vascular dysfunction in old people. Effective repair and rejuvenation will not be achieved by just one therapy, or one class of therapies. Chronic inflammation, disruptive of vascular smooth muscle activity, must be addressed, such as via targeted destruction of senescent cells. The cross-linking that stiffens blood vessel walls must be reversed. The localized deposits of cholesterol characteristic of atherosclerosis must be cleared. And so on and so forth. Vascular aging is one of the better examples to clearly demonstrate that the manifestations of aging are the sum of many underlying processes. Incremental gains will be made by each new treatment that targets one of those processes, but all must be dealt with in order to achieve complete rejuvenation.

Aging of Vascular System Is a Complex Process: The Cornerstone Mechanisms

Changes in arterial structure and function accompanying aging lead to an increased risk of cardiovascular diseases (CVD). Thus, understanding the mechanisms by which age affects the vascular system can help to avoid altogether or to reduce the high risk of developing cardiovascular diseases in elderly people. Several new (preliminary) clinical studies have found that the most important vascular changes occur with aging and described 2 key traits: (1) generalized endothelial dysfunction and (2) stiffness of the central artery. As for generalized endothelial dysfunction, vascular aging alters the endothelium function and the cells that cover the lumen of blood vessels. Endothelial dysfunction includes a decrease in vasodilatory and antithrombotic properties, with an elevation in oxidative stress and inflammatory cytokines, which favor atherogenesis and thrombosis and predispose to cardiovascular diseases. Both human and experimental studies have proven a reduction in the bioavailability of nitric oxide (NO), a major mediator of vasorelaxation and antiatherogenic processes that are the foundation of age-related endothelial dysfunction.

With aging, the elasticity of arteries, especially the aorta, decreases. This leads to arterial stiffness, which is, at least in part, the result of gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers. The risk of hypertension and the range of various disorders are tightly linked to increased arterial stiffness. Vascular calcification is specific for aging and vascular stiffness. The development of calcification is accelerated in patients with hypertension, diabetes mellitus, and other disorders. However, an exact mechanism linking calcification with aging is still unclear.

During the process of aging, a shift towards the pro-inflammatory phenotype with elevated expression of inflammatory cytokines, adhesion molecules, and chemokines from endothelial cells (ECs) has been observed. These pro-inflammatory cytokines include interleukin (IL)-6, IL-1β, cellular adhesion molecules, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1. Prolonged exposure to TNF-α leads to early aging of the endothelium, which can be avoided by suppressing the activation of NF-KB. This fact gives rise to the hypothesis that inflammation leads to premature aging of the endothelium. Thus, human aging is a chronic, systemic and low-grade pro-inflammatory condition, and this phenomenon has been defined as "inflammaging".

All body systems age, lose their performance, and structural disorders accumulate. The cardiovascular system is no exception. And it is cardiovascular diseases that occupy a leading position as a cause of death, especially among the elderly. The aging of the cardiovascular system is well described from a mechanical point of view. Moreover, it is known that at the cellular level, a huge number of mechanisms are involved in this process, from mitochondrial dysfunction to inflammation. It is on these mechanisms, as well as the potential for taking control of the aging of the cardiovascular system, that we focused on in this review.

Does the Aging of the Gut Microbiome Contribute Meaningfully to Hearing Loss?
https://www.fightaging.org/archives/2022/07/does-the-aging-of-the-gut-microbiome-contribute-meaningfully-to-hearing-loss/

In today's open access paper, researchers discuss the link between the gut microbiome, chronic inflammation in aging, and the onset of age-related hearing loss due to hair cell death and destruction of axons connecting hair cells to the brain. It is definitively the case that changes in the balance of microbial populations in the intestine contributes to rising inflammation in older individuals. But how significant is this effect in comparison to other sources of chronic inflammation, such as excess visceral fat tissue, senescent cells, molecular waste and debris resulting from cell death and dysfunction due to other processes of aging, and so forth? It is very hard to answer that sort of question without fixing just the one contributing cause of inflammation in isolation, without affecting any of the others, and then see what happens. Identifying the mechanism is one thing, assessing its relative importance quite another.

That said, a study to determine whether or not the gut microbiome contributes significantly to age-related hearing loss could be started tomorrow, were there someone willing to put up the funds and manage the regulatory burden that attends even simple tests in humans. Gather a hundred aged volunteers in the early stages of age-related hearing loss, perform fecal microbiota transplants from young donors, and then assess the progression of their condition over the next five years or so. It is well established in animal models that fecal microbiota transplantation resets the gut microbiome to a youthful configuration for an extended period of time, reduces inflammation, improves health, and even extends life expectancy in short-lived species such as killifish. So why not try?

Age-Related Hearing Loss: The Link between Inflammaging, Immunosenescence, and Gut Dysbiosis

Age-related hearing loss (ARHL), or presbyacusis, is a type of sensorineural hearing loss that primarily affects the elderly. However, the age of onset, rate of decline, and severity of hearing loss vary widely. ARHL is the most common sensory disorder, with a high economic impact. The World Health Organization (WHO) estimates that by 2050, 2.5 billion people, predominantly over 60, will be living with some degree of hearing loss . Despite the high prevalence of this sensory disorder, there is a paucity of both preventative and treatment strategies other than prosthetic devices (hearing aids and cochlear implants).

Presbyacusis typically presents as bilateral, progressive, and irreversible. The increasing prevalence of presbyacusis may be attributable to environmental factors, notably noise exposure and the rise in metabolic diseases. This sensory disorder can be characterised by reduced hearing sensitivity and speech understanding in background noise, slowed central processing of acoustic information, and impaired localisation of sound sources. Hearing loss affects high frequencies initially and eventually spreads to lower frequencies involved in speech understanding. Untreated hearing impairment contributes to social isolation, loss of self-esteem, depression, and cognitive decline. Even mild levels of hearing loss increase the long-term risk of cognitive decline and dementia.

ARHL has a complex pathophysiology linked to genetic risk factors that determine the rate and extent of cochlear degeneration. However, the severity of the hearing loss is also influenced by previous otological diseases, chronic illnesses, cumulative noise exposure, use of ototoxic drugs, and lifestyle. Moreover, this condition has been associated with numerous comorbidities, including dementia, frailty, Alzheimer's disease, and type II diabetes. A common trait of these disorders is chronic inflammation in target organs.

Various stimuli can sustain inflammaging, including pathogens, cell debris, nutrients, and gut microbiota. As a result of ageing, the immune system can become defective, leading to the accumulation of unresolved inflammatory processes in the body. Gut microbiota plays a central role in inflammaging because it can release inflammatory mediators and crosstalk with other organ systems. A proinflammatory gut environment associated with ageing could result in a leaky gut and the translocation of bacterial metabolites and inflammatory mediators to distant organs via the systemic circulation. Here, we postulate that inflammaging, as a result of immunosenescence and gut dysbiosis, accelerates age-related cochlear degeneration, contributing to the development of ARHL. Age-dependent gut dysbiosis was included as a hypothetical link that should receive more attention in future studies.

DNA Damage is a Part of Neural Plasticity, Complicating the Study of Its Relevance to Aging in the Brain
https://www.fightaging.org/archives/2022/07/dna-damage-is-a-part-of-neural-plasticity-complicating-the-study-of-its-relevance-to-aging-in-the-brain/

As noted by the authors of today's open access paper, there is ample evidence to show that double strand breaks in DNA occur during the normal activity of neurons, such as during the synaptic remodeling necessary to learning and memory. Evolution loves reuse, and few possibilities are ignored! This process of utilitarian double strand breaks appears to be used to ensure that nuclear DNA is spatially reconfigured in such a way as to ensure that certain genes are expressed for a time; recall that the pattern of gene expression at any given moment is very much a function of how the mass of nuclear DNA is packaged, which parts of it, and hence which gene sequences, are accessible at any given time to the machinery of transcription.

This is all very interesting, as stochastic DNA damage, such as double strand breaks, is thought to have a role in degenerative aging. But if the process is taking place on a regular basis during the normal function of neurons, that makes it harder to study in the context of aging and neurodegeneration. On the one hand, DNA damage can spread through tissues from stem cells, and this happens in the brain even given the long-lived nature of neurons. On the other hand, recent research has suggested that the process of repairing repeated double strand breaks can produce some of the epigenetic change of aging as a side-effect, due to depletion of molecules needed to maintain a youthful configuration of nuclear DNA. More research is needed to fill out this presently sparse sketch; important details are missing, and the present understanding of DNA damage in the brain is incomplete.

The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration

DNA damage is now widely implicated in aging and the pathophysiology of age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). However, emerging evidence suggests that DNA damage and DNA repair are not only induced by pathological conditions. The same processes involved in neurodegeneration as we age are also involved in fundamental physiological functions of neurons that are related to neural plasticity. Hence, DNA damage and repair are associated with neural plasticity, implying an important role for these processes in neuronal function. Furthermore, in neurodegenerative diseases the selective death of specific groups of neurons is present. This suggests that the unique properties of neurons may contribute to selective neurodegeneration in pathophysiology.

Several studies have shown that neuronal activity generates double strand breaks (DSBs) in cultured neurons. A recent study concluded that DSBs are generated physiologically to resolve topological limitations to gene expression in neurons. Topoisomerase enzymes participate in the overwinding or underwinding of DNA and thus they manage DNA topological constraints. Neuronal activity produces DSBs at specific loci in vitro by topoisomerase IIβ (TopIIβ), in the promoters of early response genes (ERGs, also called immediate early genes, IEGs) that are crucial for experience-driven changes to synapses, learning, and memory. Interestingly, the expression patterns of ERGs in response to neuronal stimulation correlated well with the formation and repair of activity-induced DSBs, implying that generation of DSBs and their subsequent repair are essential steps for proper gene function. Furthermore, DSBs produced during neuronal excitation were repaired within 2 hours of the initial stimulus, suggesting that this process employs rapid DNA repair mechanisms such as non-homologous end joining (NHEJ).

Dysfunction in these processes of DNA damage and repair is also related to a decline in cognitive function and neuronal death in neurodegenerative diseases. However, human post-mortem tissues represent the end-point stage of the disease. Hence studies examining these tissues cannot be used to determine whether DNA damage has a primary or secondary role in pathogenesis. Future studies on the relationship between plasticity and DNA damage may provide a better understanding of the cellular processes that contribute to higher order brain functions.

Distinct groups of neurons are affected in different neurodegenerative diseases, such as motor neurons in ALS or neurons of the entorhinal cortex in AD, and these cells are specialized to perform specific functions. Given that DNA damage and repair are important for the unique functions of neurons, which in turn depend on their activation, it is possible that the interplay between DNA damage and neural plasticity is unique for specific groups of neurons. This could operate through the activation of specific genes by DNA damage, which would differ depending on the type of neurons involved and their associated functions. Therefore, a better understanding of the interplay between DNA damage and neural plasticity is required, as well as dysfunction in these processes in disease. In particular, the inclusion of specific neuronal types may reveal the causes of selective neuronal death in distinct neurodegenerative diseases.

To date, no previous studies have examined therapeutic strategies directed at DNA damage and repair in relation to aberrant neural plasticity. However, this approach has the potential to identify novel treatments for impaired cognitive functions in neurodegenerative diseases associated with excessive DNA damage.

Whole Blood Exchange and the Peripheral Amyloid Sink Hypothesis
https://www.fightaging.org/archives/2022/07/whole-blood-exchange-and-the-peripheral-amyloid-sink-hypothesis/

Today I'll point out an interesting study in mice that is based on the peripheral amyloid sink view of Alzheimer's disease. Researchers repeatedly replaced the blood in Alzheimer's model mice, that exhibit high levels of amyloid-β in the brain, with blood from normal mice. The result was less amyloid-β in the brain and better cognitive function. While one does always need to begin these discussions by noting that mouse models of Alzheimer's disease are very artificial constructs, in that mice do not naturally develop the condition, and thus the models are all some form of genetic dysfunction that generates a particular pathology that may or may not map well to why Alzheimer's is harmful in humans, this is nonetheless quite interesting.

The peripheral amyloid sink concept suggests that levels of amyloid-β in the circulation and vascular tissues, on the one hand, and in the brain, on the other hand, are in dynamic equilibrium. If amyloid-β is removed from the vasculature and circulation, such as via replacement of blood, then this will cause amyloid-β levels to drop in the brain. One can consider some form of balance being enacted at the blood-brain barrier, in which the barrier is sensitive to levels of amyloid-β on either side, or more simple diffusion processes. But either way, there is some evidence for this to actually work: a phase III trial in humans was successful in improving cognitive function, using replacement of blood.

However, it is entirely possible that this has absolutely nothing to do with redistribution of amyloid-β, and everything to do with the dilution of harmful factors in the old bloodstream and replacement of circulating age-damaged albumin, rife with modifications due to the age-damaged environment. Blood replacement treatments might be expected to reduce the chronic inflammation and tissue dysfunction that results from the presence of damage-associated molecular patterns and other harmful factors present in the bloodstream of an older individual - and thus perhaps reduction of amyloid-β and restoration of cognitive function has more to do with a modest improvement in the brain tissue environment, allowing greater clearance of amyloid-β by immune cells and less cellular dysfunction in general. Proving this one way or another is quite the different challenge from demonstrating that benefits occur, of course.

Whole blood exchange could offer disease-modifying therapy for Alzheimer's disease, study finds

Researchers have shown that the misfolding, aggregation, and buildup of amyloid beta proteins in the brain plays a central role in Alzheimer's disease. Therefore, preventing and removing misfolded protein aggregates is considered a promising treatment for the disease. After multiple blood transfusions, the researchers found that the development of cerebral amyloid plaques in a transgenic mice model of Alzheimer's disease was reduced by 40% to 80%. This reduction also resulted in improved spatial memory performance in aged mice with the amyloid pathology, and lowered the rates of plaque growth over time.

While the exact mechanism by which this blood exchange reduces amyloid pathology and improves memory is currently unknown, there are multiple possibilities. One possible explanation is that lowering amyloid beta proteins in the bloodstream may help facilitate the redistribution of the peptide from the brain to the periphery. Another theory is that blood exchange somehow prevents amyloid beta influx, or inhibits the re-uptake of cleared amyloid beta, among other potential explanations.

Preventive and therapeutic reduction of amyloid deposition and behavioral impairments in a model of Alzheimer's disease by whole blood exchange

Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD.

In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40-80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice. The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aβ in plasma soon after blood exchange suggest that mobilization of Aβ from the brain to blood may be implicated. Our results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD.

Targeting Inflammatory Microglia in Alzheimer's Disease
https://www.fightaging.org/archives/2022/07/targeting-inflammatory-microglia-in-alzheimers-disease/

It is becoming increasingly clear that chronic inflammation is important in the major neurodegenerative conditions, such as Alzheimer's disease. Animal studies suggest that a sizable portion of that inflammation is caused by the activities of activated and senescent microglia, innate immune cells of the brain. Both the use of CSF1R inhibitors (such as pexidartinib) to clear all microglia and the use of senolytics (such as the dasatinib and quercetin combination) to selectively destroy senescent microglia have shown benefits in animal models of neurodegeneration and brain injury. Interestingly, dasatinib is both a senolytic and a CSF1R inhibitor. Since these drugs are readily available and already used in human medicine, it would be quite feasible to run clinical trials, given the funding and the will to do so.

Alzheimer's disease (AD) is a common, progressive, and devastating neurodegenerative disorder that mainly affects the elderly. Microglial dysregulation, amyloid-beta (Aβ) plaques, and intracellular neurofibrillary tangles play crucial roles in the pathogenesis of AD. In the brain, microglia play roles as immune cells to provide protection against virus injuries and diseases. They have significant contributions in the development of the brain, cognition, homeostasis of the brain, and plasticity. Multiple studies have confirmed that uncontrolled microglial function can result in impaired microglial mitophagy, induced Aβ accumulation and tau pathology, and a chronic neuroinflammatory environment.

In the brain, most of the genes that are associated with AD risk are highly expressed by microglia. Although it was initially regarded that microglia reaction is incidental and induced by dystrophic neurites and Aβ plaques, nonetheless, it has been reported by genome-wide association studies that most of the risk loci for AD are located in genes that are occasionally uniquely and highly expressed in microglia. This finding further suggests that microglia play significant roles in early AD stages and they be targeted for the development of novel therapeutics.

In this review, we have summarized the molecular pathogenesis of AD, microglial activities in the adult brain, the role of microglia in the aging brain, and the role of microglia in AD. We have also particularly focused on the significance of targeting microglia for the treatment of AD.

Cerebral Small Vessel Disease as a Consequence of Inflammation
https://www.fightaging.org/archives/2022/07/cerebral-small-vessel-disease-as-a-consequence-of-inflammation/

Cerebral small vessel disease is the name given to the manifestation and consequences of a broad grab-bag of pathologies that affect the capillaries and other small blood vessels of the brain. That includes loss of elasticity, loss of capillary density, amyloid accumulation, leakage of the blood-brain barrier, and other similar problems leading to greater damage of tissues around blood vessels and a reduced blood supply to critical areas of the brain. Researchers here mount the argument that this is largely a consequence of the chronic inflammation of aging, a hypothesis that will be assessed in the years ahead by the widespread deployment of senolytic therapies, capable of removing senescent cells and their pro-inflammatory signaling from the body and brain.

Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an "inflammaging" condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD).

The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively.

Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.

A Bacterial Species Involved in Gum Disease Provokes Neuroinflammation
https://www.fightaging.org/archives/2022/07/a-bacterial-species-involved-in-gum-disease-provokes-neuroinflammation/

Researchers here provide evidence for one particular oral bacterial species associated with gum disease to provoke changes in microglia population in the brain, leading to chronic inflammation and acceleration of neurodegenerative conditions. The correlation between periodontal disease and neurodegenerative diseases such as Alzheimer's disease is well known, and there are established pathways and mechanisms for oral bacteria to deliver pro-inflammatory compounds into the body. However, some studies suggest that the contribution of gum disease to the incidence of neurodegenerative conditions is modest at best, in comparison to other factors.

Fusobacterium nucleatum (F. nucleatum) is a common type of bacteria that proliferates in periodontal disease. F. nucleatum can also generate severe generalized inflammation, which is a symptom of many chronic diseases including type 2 diabetes and Alzheimer's disease. The latest research, done in mice, shows that F. nucleatum results in an abnormal proliferation of microglial cells, which are immune cells in the brain that normally remove damaged neurons and infections and help maintain the overall health of the central nervous system. This over-supply of microglial cells also created an increased inflammatory response, the researchers found. Chronic inflammation or infection is believed to be a key determinant in the cognitive decline that occurs as Alzheimer's disease progresses.

Possible links between periodontal disease and Alzheimer's have been posited by scientists in the past. While the new research does not show that F. nucleatum-related periodontal disease leads directly to Alzheimer's disease, the new study suggests that periodontal disease caused by F. nucleatum and left untreated or poorly treated could exacerbate symptoms of Alzheimer's disease. Conversely, treating periodontal disease effectively in those who have early-stage Alzheimer's could potentially slow Alzheimer's progression.

Compromised Circulation Contributes to One Variant of Macular Degeneration
https://www.fightaging.org/archives/2022/07/compromised-circulation-contributes-to-one-variant-of-macular-degeneration/

While the destination is the same, blindness due to a breakdown of retinal structure and function, not all cases of age-related macular degeneration start in the same way. There are notable differences between patients in the early stages of the condition. Researchers here suggest that vascular dysfunction drives one form of macular degeneration, reduced blood flow to the retina leading to the aggregation of molecular waste and consequent cell death. This is one example of many: cardiovascular aging contributes indirectly to a great many of the common age-related conditions.

Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in people over 65 years old and is the result of damage to the central area of the retina called the macula, which is responsible for reading and driving vision. One major form of early AMD is called drusen, where small yellow cholesterol deposits form in a layer under the retina. They can deprive the retina of blood and oxygen, leading to vision loss. Drusen formation can be slowed by appropriate vitamin supplementation.

The other major form of early AMD is the presence of subretinal drusenoid deposits (SDD), which is lesser known, and requires high-tech retinal imaging to detect. These deposits are also made of fatty lipids and other materials, but form in a different layer beneath the light sensitive retina cells, where they are also associated with vision loss. Currently, there is no known treatment for SDD.

Researchers analyzed 126 patients with AMD and found that patients with cardiovascular disease or stroke were three times more likely to have SDD than patients without. The researchers suggested that the underlying heart and vascular disease likely compromises blood circulation in the eye, leading to the SDDs beneath the retina and ultimately causing vision loss and blindness. "We believe poor ocular circulation that causes SDDs is a manifestation of underlying vascular disease. This study further demonstrates that AMD is not a single condition or an isolated disease, but is often a signal of systemic malfunction which could benefit from targeted medical evaluation in addition to localized eye care."

Microglia in the Aging Brain, Both Protective and Harmful
https://www.fightaging.org/archives/2022/07/microglia-in-the-aging-brain-both-protective-and-harmful/

A growing body of evidence implicates the changing behavior of microglia in the aging of the brain and onset of neurodegeneration. Microglia are analogous to macrophages, innate immune cells unique to the central nervous system. They adopt different packages of behaviors, called polarizations, in response to circumstances. With age, microglia tend towards an inflammatory polarization, triggered by systemic inflammatory signaling and molecular debris characteristic of aged tissues. Further, an increasing number of microglia become senescent, producing pro-inflammatory signals that contribute further to the inflammation of brain tissue and dysfunction of other microglia. Yet for all this, microglia are also protective in function, at least until they are overwhelmed by the aged environment and begin contributing to its decline rather than fighting against it.

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development.

This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer's disease (AD), and Parkinson's disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

Reducing the T Cell Exhaustion Caused by Cancer
https://www.fightaging.org/archives/2022/07/reducing-the-t-cell-exhaustion-caused-by-cancer/

Cancers employ a range of mechanisms to subvert and suppress the activities of immune cells attempting to destroy cancerous cells. One issue that appears inherent to T cells of the adaptive immune system, however, is the exhaustion that sets in following repeated exposure to molecules present on cancerous cells or in the tumor environment that trigger T cell receptors. This is how T cells identify targets. Individual T cells are initially effective at killing cancerous cells after T cell receptor interactions, but then become increasingly less effective over time. Can this be prevented? Potentially yes, but the processes involved are not simple, as researchers here explain.

The T cells found in the human immune system are some of the front-line soldiers in recognizing, attacking, and directing the fight against foreign cells and molecules. They recognize their opponents-from pathogens to cancers-through unique receptors on their surfaces. When a molecule binds to one of these T cell receptors, it activates the T cell, which begins producing a variety of immune molecules. Scientists have long known, however, that this response diminishes over time. When a T cell receptor is activated continuously for weeks or months, the cell gradually produces fewer immune molecules and becomes less effective at destroying a cancer or pathogen.

Researchers long thought that T cell exhaustion might be driven by just a few genes that ended up permanently switched on or off after chronic receptor activation. But in recent years, studies on exhausted T cells began to hint that the cells undergo more major rewiring, with thousands of genes turned on or off. The genes found to be linked to T cell exhaustion helped support this idea; the most critical genes were epigenetic regulators, which remodel the physical structure of DNA to turn on or off hundreds of genes at once. These findings help explain how completely different an exhausted T cell is from other functional T cell states.

The researchers carried out detailed analyses of the epigenetic regulators identified in their screen to understand how they interacted with each other, and homed in on a few particularly important genes. Then, they used CRISPR/Cas9 gene editing to further study the effects of blocking individual genes in T cells that were delivered into living mice. They showed that in mice with tumors, blocking the gene Arid1a led to higher levels of T cells and smaller tumors after just 15 days. Moreover, at a molecular level, the T cells from those mice more closely resembled healthy, persistent immune cells than exhausted, less active T cells.

The Combination of Plaques and Tangles Indicates a Much Higher Risk of Dementia
https://www.fightaging.org/archives/2022/07/the-combination-of-plaques-and-tangles-indicates-a-much-higher-risk-of-dementia/

Medical imaging allows researchers to assess the burden of amyloid-β and tau deposits in the living brain. As noted here, it is the combination of both amyloid plaques and tau tangles that marks a greatly raised risk of the onset of cognitive decline and dementia, 20-fold higher in fact. This is a very large effect size, suggesting that the interaction of multiple mechanisms is the important driver of neurodegeneration in tauopathies such as Alzheimer's disease.

Do amyloid plaques and tau tangles destine a cognitively intact person to decline? Yes, according to researchers who report that cognitively normal older adults with plaques and tangles declined much faster than those without either pathology - and faster than those with only plaques. Over an average of 3.5 years of follow-up, people with plaques and tangles as measured by PET had a 15 to 20 times higher risk of developing mild cognitive impairment (MCI) or dementia. Other groups analyzing different cohorts appear to be finding the same thing; papers are under review. "This quick progression to MCI is clinically relevant because it tells us that amyloid and tau PET are predictive of imminent cognitive decline. To consider amyloid and tau PET positivity merely as a risk factor, and not manifest disease, may be an underestimation of its malignancy."

Researchers pooled data from 1,325 cognitively intact older adults from seven longitudinal research cohorts and divided them into groups based on their amyloid and tau PET scans: 843 had neither pathology, 328 had only amyloid (A+T-), 55 had amyloid with tau in the medial temporal lobe (A+T+MTL), and 65 had amyloid with tau in the neocortex as well (A+T+Neo). 80 percent of the neocortical-positive participants also had tangles in their MTL, as tau generally spreads from the MTL to the cortex. The researchers tracked scores on the modified preclinical Alzheimer cognitive composite 5 (mPACC5) and Mini-Mental State Exam (MMSE) for an average of 3.5 years after the PET scans. Biomarker-positive participants were an average of seven years older, and had slightly lower baseline MMSE scores, than their biomarker-negative counterparts. While controls held their ground on the mPACC5 and MMSE, A+T- participants slipped a tad and both A+T+ groups declined steeply.

People with plaques and tangles were likelier to develop MCI or dementia. Compared to controls, A+T- volunteers had a 2.5-fold higher risk of developing MCI, while people with A+T+MTL or A+T+Neo had 15 or 19 times higher risk, respectively. Twenty-one people progressed to all-cause dementia; half were A+T+Neo. They were a whopping 40 times likelier to develop dementia in this time frame than controls, while A+T+MTL people had a 5.5-fold higher risk. A+T- volunteers developed dementia at the same rate as controls.

Launching the Longevity Prize
https://www.fightaging.org/archives/2022/07/launching-the-longevity-prize/

The Longevity Prize initiative is, at least initially, a collaboration between VitaDAO, Foresight Institute, and the Methuselah Foundation. They are trying a different approach to the proven format of research prizes, a step by step progression in which smaller prizes are won in the process of defining concrete goals in medicine and biotechnology that will later receive larger prizes. It is an interesting and novel idea, like much of what orbits VitaDAO. The only way to see how well any novel idea works is to give it a try!

The longevity ecosystem is growing rapidly. But the problem is vast and we're running out of time. The longevity prize encourages novel approaches for turning back our aging clocks. You may be familiar with standard prize models that set a fixed amount to target a specific scientific goal with exact criteria. Those are great! This prize series is different. Its aim is to generate an avalanche of proposals, experiments, and collaborations on undervalued areas. This can include smaller bets growing into larger sums, innovating with novel prize voting mechanisms, or even a series of workshops or hackathons to develop promising ideas. Common to all these prize experiments is their goal to support a growing longevity ecosystem, connecting those who generate proposals for progress with those who want to help execute them, and drive high-trust collaboration toward solving them.

We love to collaborate. The first round of 180k in prizes was fundraised through Gitcoin, supported by community members, whose donations were matched by VitaDAO, Vitalik Buterin, and Stefan George.Thank you for your generous support! If you have an idea for a prize you'd like to sponsor, we'd love to hear from you!

One key problem with the prize model is that academics and biotechs will only perform experiments when they have the money in the bank. That's why our first round of prizes will be given out for hypothesis generation to define the second round of larger prizes. We would like to hear from you: what is the most promising but under-appreciated area of geroscience and longevity biotechnology that we should pursue? Review the literature (and you're welcome to include your own unpublished data), explain why this area is undervalued, generate a hypothesis for making progress, and propose an experiment to further investigate this approach. The more concrete, e.g. including people, resources, and time required for next steps, the better.

Up to 20,000 will be offered in prizes for this round! Finalists will be invited to present their proposal to the judges. Excellent proposals will be moved to the next phase, where they will be eligible for follow-on funding. The prize deadline is the end of 2022.

Stem Cell Therapy - Are We There Yet?
https://www.fightaging.org/archives/2022/07/stem-cell-therapy-are-we-there-yet/

The potential of stem cell therapy still lies ahead. The only outcome reliably achieved to date in human medicine is the reduction of chronic inflammation via transplantation of mesenchymal stem cells. The real goal for this field is, however, the replacement and enhanced performance of specific stem cell populations in order to produce regeneration that does not normally take place, or to restore youthful tissue maintenance in the old. That remains to be achieved in anything more than a preliminary way in even the most well studied stem cell populations, those of muscle, brain, and bone marrow.

In murine models, there have been some therapeutic successes reported when aged systems have an influx of stem cells with restored or robust function. One such study showed that ex-vivo treatment of aged muscle stem cells (MuSCs) with a small-molecule inhibitor and a culturing on a porous hydrogel substrate was able to restore potential to the aged MuSCs, and the improved potential was able to impart restored muscle repair when these cells were transplanted into injured, aged muscle. Another exciting study on aged MuSC rejuvenation recently reported that transplantation of aged MuSCs pulsed with transient expression of iPSC reprogramming factors was able to repair injured muscled from aged mice at a rate similar to young MuSCs. These data were also translated in human studies where aged human MuSCs were transiently reprogrammed and transplanted back to the aged donor and showed increased new tissue formation.

On the flip side of these very positive results of improved muscle repair from reprogrammed MuSCs in the aged environment, hematopoietic stem cell (HSC) transplants into aged mice did not have such promising results. In transplants of young, robust HSCs into aged recipient mice, studies report that the aged niche, where the donor stem cells home to in the bone marrow, have negative effects on the robust stem cells populations, altering the cell-intrinsic potential of the transplanted HSCs. Thus, in aged individuals, there may be complex interactions between intrinsic stem cell alterations and the systemic alterations that both need to be addressed for more effective stem cell therapies.

Harnessing the full potential of stem cells could lead to the mitigation of most aging phenotypes but, like most things worthwhile, we need to be patient to develop the most robust effects with these therapies. It will likely require the cooperation between multiple players-whether combinations of stem cell transplants or coordination between stem cell transplants and other pharmacological interventions. However, we may be just at the beginning of understanding these complex interplays.

Glymphatic System Dysfunction Contributes to the Pathology of Cerebral Small Vessel Disease
https://www.fightaging.org/archives/2022/07/glymphatic-system-dysfunction-contributes-to-the-pathology-of-cerebral-small-vessel-disease/

The vasculature becomes dysfunctional with age, and cerebral small vessel disease is a catch-all category that includes a variety of different malfunctions in the biology of smaller blood vessels that act to reduce blood flow to the brain or damage brain tissue. In recent years, attention has turned to the drainage of cerebrospinal fluid from the brain, with the idea that failure of drainage with age contributes to a buildup of molecular waste and consequent pathology in the brain. The glymphatic system is one of the major paths of drainage, and here researchers provide evidence for its dysfunction to be involved in the cognitive decline observed in patients with cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is common among older people. Cognitive impairment is one of the most important manifestations of CSVD. Vascular cognitive impairment and vascular dementia constitute the second most common cause of cognitive impairment. However, the factors causing cognitive impairment remain unknown. White matter lesions (WMLs) and lacunes, which are classical CSVD markers, are related to cognitive impairment in CSVD and could be used to predict cognitive impairment. However, in the clinic, some CSVD patients with mild WMLs have a severe cognitive impairment, which suggests that there are still some important factors that contribute to cognitive impairment in CSVD aside from traditional imaging markers and other imaging markers might enable predictions of cognitive impairment caused by CSVD.

Commonly, cognitive impairment in patients with CSVD occurs due to cerebral hypoperfusion or because other blood components permeate into the brain through a broken blood-brain barrier (BBB). Both of these situations are harmful to neurons and neuroglia. Recently, the glymphatic system was discovered. With the help of Aquaporin 4, cerebrospinal fluid (CSF) flow in the periarterial space enters the brain and becomes interstitial fluid (ISF). It was then drained orderly through the perivenous space, meningeal or olfactory mucosal lymphatics, cervical lymphatic vessel, and finally returned to the peripheral venous. This CSF-ISF exchange system is called the glymphatic system, and its main role includes metabolic product transportation and metabolic waste elimination.

In patients with Alzheimer's disease (AD) and animal models, dysfunction of the glymphatic system contributes to the deposition of amyloid-β and cognitive impairment. CSVD leads to arteriosclerosis and vascular pulsation, which are the driving forces of the glymphatic system. It is difficult to evaluate the glymphatic system in the human body directly. In 2017, based on diffusion tensor imaging (DTI), researchers proposed the DTI analysis along the perivascular space (ALPS) index to evaluate the glymphatic system function. To further explore the reason underlying cognitive impairment in patients with CSVD and identify other new imaging markers of cognitive impairment in patients with CSVD, we studied the relationship of the ALPS index and cognitive impairment in these patients.

We found that the ALPS index was independently linearly correlated with global cognitive function, executive function, attention function, and memory after adjusting for the aforementioned six risk factors or CSVD markers. Our results suggest that glymphatic system impairment is independently related to cognitive impairment in patients with CSVD.