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- Fecal Microbiota Transplantation from Young Mice Improves Function in Old Progeroid Mice
- Prevention of Microgliosis Reduces Early Progression of Alzheimer's Disease in Mice
- Growth Hormone Receptor Knockout in Adipose Tissue Extends Life in Mice
- Reviewing Approaches to Treating Transthyretin Amyloidosis
- What Has Omics Data Taught Us About Dementia?
- Reprogramming as an Approach to Reduce T Cell Exhaustion
- 10% of Older People Suffer Dementia, Another 20% Exhibit Mild Cognitive Impairment
- Clearing Microglia Reverses Age-Related Disruption of Sleeping Patterns in Mice
- Intermittent Fasting Promotes Initial Regeneration from Injury in Mice
- Alex Zhavoronkov's Longevity Pledge
- Control of Blood Pressure Reduces Dementia Risk
- BDNF-TrkB Interaction as a Potential Target for Novel Senolytic Therapies
- What is the Relationship Between Hearing Loss and Alzheimer's Disease?
- Cell Membrane Changes in Brain Aging
- Senescent Cells as a Contributing Cause of Inflammatory Gum Disease
Fecal Microbiota Transplantation from Young Mice Improves Function in Old Progeroid Mice
Scientists like to conduct studies using mouse lineages that exhibit forms of accelerated aging, as a faster study is a cheaper study. These mice do not exhibit accelerated aging per se, of course. Each lineage suffers from some sort of increased production of cell and tissue damage, leading to a faster onset of conditions akin to natural age-related diseases. Aging itself is a matter of damage accumulation, but it is usually the case that the types and mix of damage matters when it comes to drawing conclusions from an animal study. Not always, though. In today's open access paper, that the mice are damaged in ways that cause a faster onset of age-related disability and disease doesn't detract from the finding that resetting the aged gut microbiome to a more youthful state produces benefits to health.
As is now well known, the gut microbiome changes with age in ways that cause harm to long-term health. The reasons for this change are not fully understood, but the age-related decline of the immune system, responsible for gardening the gut microbiome, may be an important factor. Beneficial microbial populations, such as those that generate useful metabolites, decline in number. Harmful populations increase in number, provoking chronic inflammation. Numerous animal studies have demonstrated that fecal microbiota transplantation from young individual to old individuals can produce a lasting improvement in the state of the gut microbiome. That is accompanied by improved health and, in some studies, extension of life span.
Regular fecal microbiota transplantation to Senescence Accelerated Mouse-Prone 8 (SAMP8) mice delayed the aging of locomotor and exploration ability by rejuvenating the gut microbiota
Recent evidence points out the role of the gut microbiota in the aging process. However, the specific changes and relevant interventions remain unclear. In this study, Senescence Accelerated Mouse-Prone 8 (SAMP8) mice were divided into four groups; young-FMT-group transplanted fecal microbiota from young donors (2-3 months old) and old-FMT-group transplanted from old donors (10-11 months old); additionally, other two groups, either adult mice injected with saline solution or untreated mice, served as the saline and blank control groups, respectively. All mice were intervened from their 7-months-old until 13-months-old.
The open field test conducted at 9 and 11 months of age showed that the mice transplanted with gut microbiota from young donors had significantly better locomotor and exploration ability than those of transplanted with old-donors gut microbiota and those of saline control while was comparable with the blank control. 16S rRNA gene sequencing showed that the gut microbiome of recipient mice of young donors was altered at 11 months of age, whereas the alteration of the gut microbiome of old-donor recipient mice was at 9 months. For comparison, the recipient mice in the blank and saline control groups exhibited changes in the gut microbiome at 10 months of age.
The hallmark of aging-related gut microbiome change was an increase in the relative abundance of Akkermansia, which was significantly higher in the recipients transplanted with feces from older donors than younger donors at 9 months of age. This study shows that fecal microbiota transplantation from younger donors can delay aging-related declines in locomotor and exploration ability in mice by changing the gut microbiome.
Prevention of Microgliosis Reduces Early Progression of Alzheimer's Disease in Mice
Microglia are innate immune cells of the brain, akin to macrophages elsewhere in the body, but with a larger portfolio of tasks, extending beyond defense against pathogens and aiding in tissue repair to include assisting in neural function and maintenance of synaptic networks. A sizable body of evidence points to increasing inflammatory activation of microglia as an important factor in the development of age-related neurodegeneration. Microglia react to signals, such as DNA debris from stressed and dying cells, or the secreted cytokines produced by senescent cells, that become more common with advancing age. When this inflammatory reaction becomes chronic, it harms the brain, diverting microglia from necessary tasks and amplifying the state of inflammation and disruption of tissue function.
Therapies that selectively destroy senescent cells, particularly senescent microglia, and therapies that clear microglia are thus of considerable interest. They have been demonstrated to reduce inflammation and the progression of brain tissue dysfunction in mice engineered to exhibit features of human neurodegenerative conditions. Today's open access paper reports on a similar but less drastic approach, in which a small molecule drug is used to reduce the inflammatory reaction of microglia to their age-damaged environment. The result is a slowing of the early progression of neurodegenerative disease, again pointing to microglial dysfunction as an important factor in the aging of the brain.
Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease
Microglia are the main tissue-resident macrophages of the brain and are important players in Alzheimer's disease (AD). There is abundant evidence for the reactivity of microglia (microgliosis) in the pathogenesis of AD. In people with AD and in AD mice there is a clear change in microglia transcriptome, showing immune activation. Reactive microglia release cytokines causing damage to healthy brain structure. Via complement-dependent pathways, reactive microglia show increased pruning of synapses leading to excessive synapse loss early in AD and ultimately cognitive impairment.
Several recent studies on AD aimed to inhibit microgliosis, and associated AD pathology, using the tetracycline derivative minocycline. Minocycline decreases the inflammatory activation of microglia, and was shown to inhibit microgliosis and alleviate defects in synaptic plasticity and cognitive behavior in mouse models of AD. Although these studies applied minocycline treatment at a relative early pathological phase, gliosis, and amyloid-β (Aβ) plaques were already apparent. The efficacy of a preventive treatment with minocycline, before the onset of gliosis and amyloid pathology has not yet been determined. This is particularly relevant because a recent clinical study on patients with mild AD, showed that minocycline treatment was not successful in slowing disease progression. This implies that a too late treatment is not successful, but leaves the possibility that inhibition of microgliosis can be effective when targeted at an early AD stage, before microgliosis becomes apparent.
The APP/PS1 mouse is a transgenic model for increased amyloidosis, resulting from the introduction of human disease-related mutations, one in amyloid precursor protein (APP) and one in presenilin 1 (PSEN1). Whereas these transgenic mouse models do not reproduce the full spectrum of pathological and clinical symptoms observed in AD, they are useful in studying early pre-pathological memory and plasticity impairments due to increased amyloidosis. Here, we determined the temporal onset of microgliosis, in relation to other AD pathological parameters, in APP/PS1 mice. Subsequently, the outcome of preventive inhibition of microgliosis on AD-related disease progression was investigated.
We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline reduced gliosis, synaptic deficits, and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Our data establish that microglial reactivity is driving early-phase AD pathology and that early treatment is effective in preventing the resulting cognitive impairments.
Growth Hormone Receptor Knockout in Adipose Tissue Extends Life in Mice
The record for mouse life span is held by growth hormone receptor knockout lineages, approaching a 70% gain, but a lot of that increase is due to early life effects. These animals are very small in comparison to their peers. In comparison, growth hormone receptor knockout in adulthood has a greater impact on female mice than on male mice, and the gain in life span is much reduced. In today's open access paper, researchers demonstrate another approach, generating a lineage of mice in which growth hormone receptor is only disabled in fat tissue. Again, the outcomes are different in male and female mice, and smaller than those produced by full knockout.
While the effect size of full growth hormone knockout in mice is larger than that produced by most other interventions, this seems unlikely to be a viable approach to greatly extend human life span. The life span of short-lived species is more plastic in response to changes in environment and metabolism than is the case for long-lived species such as our own.
We can make direct comparisons between mice and humans for the practice of calorie restriction, and see that while mouse life span can be extended by up to 40%, adding more than a few years of human life span is just not in the cards. We can also directly compare interference in growth hormone receptor function, as a human lineage analogous to the growth hormone receptor knockout mice exists. Those individuals born with Laron syndrome inherit a loss-of-function mutation in growth hormone receptor. They may be resistant to some age-related conditions, but don't appear to live longer than the rest of us.
Disruption of Growth Hormone Receptor in Adipocytes Improves Insulin Sensitivity and Lifespan in Mice
Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the effect that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity.
To test the hypothesis that removal of GH action in adipocytes might partially replicate the increased lifespan and healthspan observed in global GHRKO mice, we assessed adiposity, cytokines/adipokines, glucose homeostasis, frailty, and lifespan in aging AdGHRKO mice of both sexes. Our results show that disrupting the GH receptor gene in adipocytes improved insulin sensitivity at advanced age and increased lifespan in male AdGHRKO mice. AdGHRKO mice also exhibited increased fat mass, reduced circulating levels of insulin, c-peptide, adiponectin, resistin, and improved frailty scores with increased grip strength at advanced ages.
Comparison of published mean lifespan data from GHRKO mice to that from AdGHRKO and muscle-specific GHRKO mice suggests that approximately 23% of lifespan extension in male GHRKO is due to GHR disruption in adipocytes vs approximately 19% in muscle. Females benefited less from GHR disruption in these two tissues with approximately 19% and approximately 0%, respectively. These data indicate that removal of GH's action, even in a single tissue, is sufficient for observable health benefits that promote long-term health, reduce frailty, and increase longevity.
Reviewing Approaches to Treating Transthyretin Amyloidosis
Transthyretin amyloidosis may be a primary component of the present limit on human longevity. Transthyretin is one of the few proteins in the human body that can misfold in ways that encourage other molecules of the same protein to misfold in the same way, joining together form solid aggregates that disrupt cell and tissue function. This is particularly an issue in the cardiovascular system, and while it is presently thought that transthyretin amyloidosis only contributes to a minority of fatal cardiovascular disease in younger old age, autopsies of supercentenarians suggested that it is the major cause of death in the oldest old.
Transthyretin amyloidosis has both normal and accelerated forms, the later resulting from inherited mutations. Most of the work done in developing therapies has focused on treating the rare mutant form of the condition, given the favorable incentives placed on therapies for rare diseases by regulators. Fortunately many of these treatments are also applicable to the age-related normal form of transthyretin amyloidosis. We might hope to see this condition better diagnosed and periodically reversed in its earlier stages, as this part of the industry progresses. Removal of this and other forms of amyloid should be a part of any comprehensive toolkit of rejuvenation therapies in order to prevent its contribution to degenerative aging.
A Review of Transthyretin Cardiac Amyloidosis
Transthyretin cardiac amyloidosis is a progressive disease known to cause heart failure, conduction anomalies, and arrythmias. Due to poor outcomes and mortality from severe cardiomyopathy, prevalence and incident rates are often underreported. As global longevity is increasing and rates of amyloidosis are also increasing, there is a need to improve diagnostic and therapeutic interventions. Previously, symptom management and transplantation were the mainstay of treatment for heart failure symptoms, but studies using RNAi and siRNA technologies have shifted the paradigm of therapeutic strategy in amyloid cardiomyopathy management.
Transthyretin (TTR) stabilizers are a new class of medication which function to selectively bind to TTR tetramers, stabilizer tetramer formation, and preventing dissociation of TTR into monomers, which happens to be the rate-limiting step in the formation of amyloidogenic protein deposits. Tafamidis is currently one of the few FDA-approved medications for cardiac amyloidosis that has shown promising results in clinical trials. Double-blind randomized control trials (n = 87) have shown increased quality of life, decreased or complete resolution of neuropathy, and reduction in all-cause mortality and hospitalization at 30 months. Tafamidis remains a very costly medication, estimated to cost 250,000 per year which may pose limitations for consumers.
Diflunisal, a non-steroidal anti-inflammatory, is another TTR stabilizer that has been FDA-approved for the treatment of musculoskeletal pathologies but is used for off-label purposes to treat cardiac amyloidosis. Like tafamidis, diflunisal also stabilizes the TTR tetramer but does so by binding specifically at the dimer-dimer interface and decreasing dissociation. Fewer studies have been conducted using diflunisal, but it has been shown to reduce progression of neuropathy by around 70% in the span of 24 months from the date of diagnosis.
TTR silencers work by inhibiting translation and reduction production of TTR protein. This can be accomplished either with the use of small-interfering RNA (siRNA) or antisense oligonucleotides (ASO). Patisiran is an siRNA that functions by binding to untranslated regions of TTR mRNA and effectively marking it for degradation to avoid protein production from mutated TTR genes. The Phase III APOLLO-A trial, a randomized placebo-controlled trial of 25 patients, investigated the use of patisiran in the treatment of systemic amyloidosis and showed improvements in polyneuropathy, global longitudinal heart strain, NT-proBNP levels, and numerous echocardiographic parameters. In fact, the study demonstrated a sustained 81% reduction in serum TTR levels after 18 months in patients treated with IV patisiran every 3 weeks.
Vutrisiran is a second-generation siRNA functions like patisiran but has the advantage of enhanced stabilization chemistry enabling longer binding to mRNA sequences and, as a result, infrequent dosing of the medication. Inotersen is also a TTR silencer but acts as an ASO, not an siRNA. This medication is a TTR-directed ASO which binds TTR mRNA, reduces these levels, and hereby reduces tissue deposition. The NEURO-TTR clinical trial, an international, randomized, double-blind, placebo-controlled trial of 172 patients, showed improved course of neurologic disease and quality of life. However, unlike the APOLLO study, it did not demonstrate improvement in echocardiographic parameters.
Kinetic stabilizers are yet another class of medications that have the potential to control cardiac amyloidosis disease progression. Acoramidis, which is currently under development, is an orally deliverable TTR designed to strengthen interactions between amyloid dimers and prevent tetramer dissociation. One Phase II randomized, double-blind, placebo-controlled trial with 49 patients is assessing the use of placebo versus 400 mg of acoramidis versus 800 mg of acoramidis and preliminary results have shown an increase in serum TTR with treatment, which is a marker for TTR stabilization. Tolcapone is another stabilizer which is typically used in the management of Parkinson's disease but has the potential to cross the blood brain barrier and treat systemic amyloidosis patients with leptomeningeal involvement. There is currently a Phase IIA proof-of-concept trial of two phases with 17 subjects showing significant stabilization of TTR with administration of tolcapone.
By targeting loose, floating pathogenic amyloid fibrils, fibril disruptors have the potential to prevent further deposition and tissue damage. Doxycycline, which belongs to the class of tetracycline antibiotics, is interestingly being considered as a fibril disruptor. Research has shown that, when combined with ambiphilic bile acid supplements like tauro-ursodeoxycholic acid (TUDCA), doxycycline can disrupt amyloid components. While studies thus far have shown decreased cardiac involvement, many study participants have voluntarily dropped out of studies due to poor tolerability and adverse effects like sun sensitivity. Currently, there is limited evidence supporting the use of doxycycline for the indication of cardiac amyloidosis, but it has shown some signs of effectiveness.
Numerous other avenues are being explored to treat TTR cardiac amyloidosis. Antibody therapies are being developed to target certain epitopes and have been increasingly studied for their role in removing ATTR amyloid or misfolded fibrils. Studies are now showing that the antibodies did not react with native tetramers in vivo but did appropriately react with TTR deposits in vivo and in vitro. In fact, a Phase I open-label three-phase clinical trial PRX004 involving 36 subjects has shown that antibodies targeting TTR89-97 residues improved neuropathy, reassuring drug tolerability, and favorable side effect profile at various dosages. There is a lot of promise in the science behind antibodies targeting amyloid genes.
The CRISPR-Cas9 system is a well-known gene editing treatment which has been engineered to identify and knock out TTR gene in a single administration. Pilot studies with less than 10 subjects have demonstrated reduced serum TTR by up to 87% in the span of just four weeks. Further studies are needed to assess tolerability and drug safety, but this system serves as an excellent example of translational science and the use of gene editing technologies to treat amyloidosis.
What Has Omics Data Taught Us About Dementia?
An enormous amount of biological data can now be obtained from any given study population, and at reasonable cost. The resulting databases have grown to become very large. The epigenome, transcriptome, proteome, metabolome, microbiome, and much more, are at the fingertips of every epidemiological researcher, at multiple time points, before and after interventions, and at different ages. It is easy enough to find differences in the data between more healthy subjects and patients suffering from one or more age-related conditions. It is a harder task to build upon that data in order to find useful therapies. Aging causes sweeping changes in all measures of cellular biochemistry, but few of those changes are connected to good points of intervention. Most are consequences, not causes.
In today's open access paper, the authors discuss this environment of near unlimited biological data in the context of age-related neurodegeneration. Examining the differences characteristic of disease and then laboriously working backwards in search of causes and points of intervention is the polar opposite strategy to that of the SENS vision for rejuvenation, which is to tackle the known root causes of aging and then see what happens as a result. The former involves a great deal more work than the latter before the production of therapies becomes viable.
What we have learned to date from the omics approach to non-Alzheimer's dementias
More than 50 million people live with dementia in worldwide, and due to the rapidly aging population, dementia cases are expected to increase at least five times in 2050. Dementia refers to a clinical syndrome characterized by the deterioration of this memory ability and, progressive cognitive decline that hinders an individual's ability to function. Dementia symptoms are persistent and progressive. Although 60%-70% of dementia cases that develop related are to Alzheimer's disease (AD), the remaining 30%-40% are diagnosed as non-Alzheimer's (non-AD) dementia.
The non-AD pathogenesis is still unknown. Despite advances in modern medicine, the developmental process of dementia is still not fully understood. Although some mechanisms have been defined, they still cannot fully explain the process that develops in all patients. In recent years, new molecular techniques that enable high throughput data to be obtained in laboratories, have created hope for many neurological diseases, such as AD. Thanks to the "omics" concept that has become part of neurological research, these techniques have enabled us to examine the unknown areas of biology, such as the genome, transcriptome, proteome, microbiome, and metabolome, thus providing a new perspective of the interactions between host and microorganisms.
From this point of view, preclinical and clinical data has demonstrated a bidirectional interaction between the host and the microorganism and led to the formation of the term "gut-brain axis" between the gastrointestinal system and the brain. This interaction is very important for the regulation of the neural, hormonal, and immunological balance of human beings. Our gut is therefore named our second brain. Indeed, based on this concept, new relationships between the gut microbiome and dementia have been identified. Alterations in the composition of the gut microbiome have also been shown to independently cause an increase in risk of dementia, along with other traditional risk factors.
The presence of microbiome-associated metabolites and bacterial products in the systemic circulation may increase, especially with the inflammatory process that can lead to dementia. Despite this information, it is not yet known how changes in the gut microbiome and microbiota-related metabolites affect cognitive functions. Confusion due to conflicting findings regarding this relationship between the gut microbiome and dementia also exist. Understanding this bidirectional interaction is essential for discovering the underlying molecular pathogenic mechanisms of many disorders, especially in the neuroscience field. Studies in this field will provide the means to develop personalized treatments and will reveal different biomarkers and help us consider new treatment options. This review highlights the progress that has been made in omics research while noting the gaps in our knowledge.
Reprogramming as an Approach to Reduce T Cell Exhaustion
T cell exhaustion occurs following repeated stimulation, such as when faced with a growing cancer or persistent viral infection. It manifests as a progressive loss of function, the T cells no longer attacking pathogens or errant cells. Finding a way to minimize this phenomenon would assist in a range of conditions, such as by improving the outcome of T cell immunotherapies targeting cancer, and might help improve the aged immune system, in which T cell exhaustion is also observed. Here, the use of partial reprogramming is suggested as an approach to achieve this goal. In partial reprogramming, cells are exposed to the factors that can change somatic cells into pluripotent stem cells, but only for a limited time. This exposure does not change cell type, but resets the epigenetic landscape - and thus cell behavior - to a more youthful, functional state.
Turn Biotechnologies, a cell rejuvenation company developing novel mRNA medicines to cure untreatable, age-related conditions, today presents interim pre-clinical data that demonstrates treating T cells with its proprietary technologies can significantly increase their ability to kill cancer. The data show that using Turn Bio's Epigenetic Reprogramming of Aging (ERA) technology in the manufacture of T cells can produce and deliver more effective therapies more efficiently. The findings promise to help reduce the cost of T-cell therapies and make them more accessible to cancer patients.
Turn Bio's technologies were applied concurrently with the CAR T-cell manufacturing process, which demonstrates that T-cell immunotherapy products can be enhanced without additional time or facilities beyond those already needed for manufacturing. The company's process can transfect immune cells with rates as high as industry-standard electroporation, but with no cytotoxicity while precisely controlling timing, duration and activation of the ERA factor cocktail while preserving cellular identity.
10% of Older People Suffer Dementia, Another 20% Exhibit Mild Cognitive Impairment
One in three people over 65 in the US exhibit either dementia or mild cognitive impairment. There is a great need for treatments that target the mechanisms of aging, particularly those that contribute to the environment of chronic inflammation that characterizes the aging brain. Neurodegenerative conditions are the outcome of so many different contributing mechanisms that success in the medical control of aging, finding ways to repair or work around the cell and tissue damage that causes aging, seems the most plausible path towards anything that resembles either a cure or absolute prevention.
Dementia is a highly prevalent condition characterized by cognitive difficulties that typically begin in adulthood and affect a person's ability to independently perform everyday activities. Alzheimer's disease is the most common cause of dementia, accounting for approximately 60% to 80% of all dementia cases. Mild cognitive impairment (MCI) is a clinical classification assigned to people who are thought to be transitioning between normal aging and dementia. Because age is the most potent risk factor for dementia and MCI, the number of adults with these conditions is projected to rise dramatically in the US and around the world due to demographic trends that have transformed populations from mostly young adults to mostly older adults.
Based on a community cohort of older adults in Chicago, Illinois, the prevalence of dementia due to Alzheimer's disease in the US in 2021 was estimated at 11.3% of those 65 years and older, which translates to about 6.2 million adults. Other recent estimates have been somewhat lower, likely related to differences in study methods. Similarly, different implementation of MCI criteria and cohort characteristics drive variability in MCI prevalence and rates of progression to dementia across cohorts. It is well established that annual progression rates of MCI to dementia in population- or community-based studies are lower (4% to 15%) than in clinic-based studies (12% to 17%).
The Health and Retirement Study (HRS) provides a core resource for researchers who require US population-level data on dementia and MCI prevalence and incidence. The Harmonized Cognitive Assessment Protocol (HCAP) was developed to update national estimates of the prevalence of MCI and dementia in the US. Of 9,972 age-eligible HRS participants, 4,425 were randomly selected for HCAP, and 3,496 completed a comprehensive neuropsychological test battery and informant interview, none of whom were excluded.
A total of 393 individuals (10%) were classified as having dementia and 804 (22%) as having MCI. Every 5-year increase in age was associated with higher risk of dementia (weighted odds ratio, OR, 1.95 per 5-year age difference) and MCI (OR 1.17 per 5-year age difference). Each additional year of education was associated with a decrease in risk of dementia (OR 0.93 per year of school) and MCI (OR 0.94 per year of school). In conclusion, the national prevalence of dementia and MCI in 2016 found in this cross-sectional study was similar to that of other US-based studies.
Clearing Microglia Reverses Age-Related Disruption of Sleeping Patterns in Mice
Microglia are innate immune cells of the central nervous system. They are analogous to macrophages in the rest of the body, but undertake additional duties relating to the function of neurons and in brain tissue. Microglia become overly active and inflammatory with age, reacting to the molecular damage of aging and growing numbers of senescent cells. Numerous lines of evidence suggest that this change in microglia behavior is a significant contributing cause of neurodegeneration. Fortunately, microglia can be near entirely cleared via CSF1R inhibitor drugs, triggering repopulation of the brain with new microglia that exhibit fewer issues, even in later life. This may be the basis for therapies for a range of issues in the aging brain, including sleep disruption, as noted here.
Changes in wake/sleep architecture have been observed in both aged human and animal models, presumably due to various functional decay throughout the aging body particularly in the brain. Microglia have emerged as a modulator for wake/sleep architecture in the adult brain, and displayed distinct morphology and activity in the aging brain. However, the link between microglia and age-related wake/sleep changes remains elusive. In this study, we systematically examined the brain vigilance and microglia morphology in aging mice (3, 6, 12, and 18 months old), and determined how microglia affect the aging-related wake/sleep alterations in mice.
We found that from young adult to aged mice there was a clear decline in stable wakefulness at nighttime, and a decrease of microglial processes length in various brain regions involved in wake/sleep regulation. The decreased stable wakefulness can be restored following the time course of microglia depletion and repopulation in the adult brain. Microglia repopulation in the aging brain restored age-related decline in stable wakefulness. Taken together, our findings suggest a link between aged microglia and deteriorated stable wakefulness in aged brains.
Intermittent Fasting Promotes Initial Regeneration from Injury in Mice
An interesting effect of intermittent fasting is here demonstrated in mice. Given a rotator cuff injury, mice undergoing intermittent fasting exhibit improved regeneration, but only in the early stages following injury. The researchers provide evidence for this effect to be mediated by changes in the gut microbiome. Various microbial populations generate metabolites that are connected to a range of cellular activities, so the microbiome is a reasonable place to search for mechanisms related to effects of fasting.
Mice underwent rotator cuff injury were treated with intermittent fasting or fed ad libitum. Fasting began one month before surgery and continued until euthanasia. Fresh feces were collected at 2 weeks before surgery, on the day of surgery, and 2, 4, 8 weeks postoperatively for 16S rRNA microbiome sequencing. Supraspinatus tendon-humerus (SSTH) complex was collected at 2, 4 and 8 weeks after surgery. Biomechanical, radiological and histological analysis indicated that intermittent fasting significantly promoted the repair of rotator cuff injury in the early postoperative period, but significantly inhibited the repair of rotator cuff injury at 4 weeks postoperatively.
16S rRNA microbiome sequencing result showed that P. distasonis was the species with the most obvious reduction in intestinal flora of mice after fasting. Then live P. distasonis was used for repair of rotator cuff injury, with equal amount of pasteurized P. distasonis (KPD) or sterile anaerobic phosphate buffer saline (PBS) as control. Biomechanical, radiological, histological analysis were used to assess the effect of rotator cuff repair. The results indicated that the live P. distasonis (LPD) significantly impaired the biomechanical properties, bone regeneration and fibrocartilage regeneration postoperatively.
Alex Zhavoronkov's Longevity Pledge
Alex Zhavoronkov founded one of the earlier companies in the now growing longevity industry, In Silico Medicine. There is a cycle in every industry, in which founders of successful companies tend to invest a fraction of their gains in new startups, either directly or via industry-focused funds, and act as philanthropists in support of relevant academic research. This reinforces and accelerates growth. The early longevity industry contains a good number of zealots willing to do more than invest only a fraction of their wealth. Thinking a great deal about health, aging, mortality, and medicine tends to focus the mind on what one truly gains from holding on to wealth in a world in which everyone becomes sick, aged, and dies.
What frustrates me is that most people do not pay enough attention to the inevitable decline, frailty, loss of function, diseases, and death that are associated with aging and choose to be distracted and spend their time on attention-grabbing causes that only provide a temporary reward. The problem is here, right now, and every individual contributor can make a difference. Like climate change or poverty, aging research requires everyone on the planet to become involved. But unlike climate change, aging is causing millions of casualties and suffering worldwide today and right now.
On the positive side, after two decades of hard work, my commercial ventures have started yielding financial returns. It would be logical to donate part of my wealth to charitable foundations focusing on aging research. Over the past two decades, I supported many projects in longevity, saw many failures, analyzed a massive number of grants, and learned how to evaluate the impact of the various longevity initiatives. In addition to capital, I can now bring years of experience, and multiple partner organizations to the most impactful projects. Therefore, I would like to pledge everything I have now, and what I will get in the future, to only one cause - extending healthy productive longevity for all human beings. Instead of donating just a portion of my wealth and energy to this cause, I would like to do more.
I pledge to spend 100% of my time and personal resources to accelerate research and clinical deployment of longevity technologies. At present, I do not plan to leave an inheritance, and I will invest everything I have into projects and companies that extend healthy, productive life for everyone on the planet.
Control of Blood Pressure Reduces Dementia Risk
Raised blood pressure produces damage to tissues throughout the body. That control of blood pressure via antihypertensive drugs, forcing better function without addressing any of the underlying causative damage of aging, does in fact reduce mortality in later life is a compelling indication of the degree to which raised blood pressure is directly harmful. In the brain, manifestations of this harm include an acceleration of the processes of atherosclerosis, disruption of the blood-brain barrier leading to brain inflammation, and an increase in the pace at which capillaries and other small vessels rupture, all of this damage contributing to the onset and progression of neurodegeneration and loss of cognitive function.
Dementia is fast becoming a global epidemic, currently affecting an estimated 50 million people worldwide. While many trials have looked at the health benefits of lowering blood pressure, not many included dementia outcomes and even fewer were placebo-controlled - considered to provide the best level of evidence. "Most trials were stopped early because of the significant impact of blood pressure lowering on cardiovascular events, which tend to occur earlier than signs of dementia."
To examine the relationship between blood pressure and dementia more closely, researchers analysed five double-blind placebo-controlled randomised trials that used different blood pressure lowering treatments and followed patients until the development of dementia. A total of 28,008 individuals with an average age of 69 and a history of high blood pressure from 20 countries were included. Across these studies, the mid-range of follow up was just over four years. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Regression analysis reported an adjusted odds ratio 0.87 in favour of antihypertensive treatment reducing risk of incident dementia with a mean blood pressure lowering of 10/4 mmHg.
"Our results imply a broadly linear relationship between blood pressure reduction and lower risk of dementia, regardless of which type of treatment was used. Our study provides the highest grade of available evidence to show that blood pressure lowering treatment over several years reduces the risk of dementia, and we did not see any evidence of harm. But what we still don't know is whether additional blood pressure lowering in people who already have it well-controlled or starting treatment earlier in life would reduce the long-term risk of dementia."
BDNF-TrkB Interaction as a Potential Target for Novel Senolytic Therapies
Researchers continue to investigate the fundamental biology of cellular senescence, and every so often they turn up new targets that might be the basis for development of novel senolytic therapies. First generation senolytic treatments, that provoke a sizable fraction of senescent cells in aged tissues into self-destruction, have produced impressive results in aged mice, extending life, but more importantly rapidly reversing many measures of aging and age-related disease. While many different forms of senolytic treatment are presently under preclinical and clinical development, there will always be room for more, given that every human much over the age of 50 is a potential repeat customer.
Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells.
Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.
What is the Relationship Between Hearing Loss and Alzheimer's Disease?
Age-related hearing loss correlates with the risk of onset and progression of neurodegenerative conditions such as Alzheimer's disease. There is some question as to whether this correlation exists because similar processes of neurodegeneration produce both outcomes, or whether one drives the other, or whether there is a bidirectional relationship. It seems plausible that reduced sensory input can accelerate decline of neural networks that run on a "use it or lose it" basis, though current thinking is also focused on reduced quality of sensory input causing functional issues in neural processing. Either way, the question remains as to whether that can account for a meaningful fraction of the loss of cognitive function and related issues, versus other more blunt mechanisms, such as the chronic inflammation in brain tissue that is characteristic of neurodegenerative diseases.
Evidence suggests that hearing loss (HL), even at mild levels, increases the long-term risk of cognitive decline and incident dementia. Hearing loss is one of the modifiable risk factors for dementia, with approximately 4 million of the 50 million cases of dementia worldwide possibly attributed to untreated HL. This paper describes four possible mechanisms that have been suggested for the relationship between age-related hearing loss (ARHL) and Alzheimer's disease (AD), which is the most common form of dementia.
The first mechanism suggests mitochondrial dysfunction and altered signal pathways due to aging as a possible link between ARHL and AD. The second mechanism proposes that sensory degradation in hearing impaired people could explain the relationship between ARHL and AD. The occupation of cognitive resource (third) mechanism indicates that the association between ARHL and AD is a result of increased cognitive processing that is required to compensate for the degraded sensory input. The fourth mechanism is an expansion of the third mechanism, i.e., the function and structure interaction involves both cognitive resource occupation (neural activity) and AD pathology as the link between ARHL and AD.
Exploring the specific mechanisms that provide the link between ARHL and AD has the potential to lead to innovative ideas for the diagnosis, prevention, and/or treatment of AD. This paper also provides insight into the current evidence for the use of hearing treatments as a possible treatment/prevention for AD, and if auditory assessments could provide an avenue for early detection of cognitive impairment associated with AD.
Cell Membrane Changes in Brain Aging
Researchers here discuss what is know of changes that take place with age in cell membranes in the brain, and how they might negatively affect cell function. Like many aspects of aging, connecting these changes to the set of underlying mechanisms that cause aging is a challenging prospect, yet to be accomplished. Everything changes with age, and drawing connections between any two of those changes in order to demonstrate causation is a hard task.
Aging affects the plasma membrane of all the cells of the body, not only its composition and structure but also the function of its different components. Any change in the lipid composition of the cell membranes will impact the function of membrane receptors and the way the cells sense the environment. Numerous studies have shown the existence of significant differences in the relative amounts of the different lipids in tissues of young and old individuals, and this is mainly evident in the brain, because the blood-brain barrier strictly controls the entrance of lipids to the central nervous system. In particular, an increase in saturated fatty acid content and a decrease in polyunsaturated fatty acid (PUFA) content was found with age starting from 50 years old.
Lipid changes in the old seems to be more pronounced in lipid raft fractions of the plasma membrane. Using lipid rafts isolated from human frontal cortex in nondemented subjects aged from 24 to 85 years, researchers showed that these lipid rafts undergo significant alterations of specific lipid classes with aging. Furthermore, lipid rafts seems to be particularly sensitive to aging and decreased arachidonic acid (AA) and docosahexaenoic acid (DHA) levels in lipid rafts may represent an early event during normal aging, at least in the brain. These results clearly show that lipid remodeling occurs at the plasma membrane with aging. In the brain, some of these changes seem to occur early, at the starting point of the aging process, supporting the hypothesis that reshaping of the plasma membrane may be a very early event in the development of cellular aging, responsible for the occurrence of some of the typical manifestations of aging.
Senescent Cells as a Contributing Cause of Inflammatory Gum Disease
Gum disease has bacterial causes, but the activities of senescent cells are implicated in the progression of the condition, as well as consequent bone loss and potential for oral cancer. When present in even comparatively small numbers, lingering senescent cells can disrupt tissue structure and function with their pro-growth, pro-inflammatory signaling. Many degenerative conditions characterized by chronic inflammation might be improved by the application of senolytic therapies capable of selectively destroying senescent cells.
The senescence-associated secretory phenotype (SASP), which accumulates over the course of normal aging and in age-related diseases, is a crucial driver of chronic inflammation and aging phenotypes. It is also responsible for the pathogenesis of multiple oral diseases. However, the pathogenic mechanism underlying SASP has not yet been fully elucidated.
Here, relevant articles on SASP published over the last five years (2017-2022) were retrieved and used for bibliometric analysis, for the first time, to examine SASP composition. More than half of the relevant articles focus on various cytokines (27.5%), growth factors (20.9%), and proteases (20.9%). In addition, lipid metabolites (13.1%) and extracellular vesicles (6.5%) have received increasing attention over the past five years, and have been recognized as novel SASP categories.
Based on this, we summarize the evidence demonstrating that SASP plays a pleiotropic role in oral immunity and propose a four-step hypothetical framework for the progression of SASP-related oral pathology - 1) oral SASP development, 2) SASP-related oral pathological alterations, 3) pathological changes leading to oral immune homeostasis disruption, and 4) SASP-mediated immune dysregulation escalating oral disease. By targeting specific SASP factors, potential therapies can be developed to treat oral and age-related diseases.