Fight Aging! Newsletter, August 12th 2024

The insulin/IGF/mTORC1/Ras nutrient-sensing network is highly conserved in evolution and is implicated in the aetiology of many age-related diseases. There is therefore growing interest in the possibility of repurposing existing drugs with targets in this signalling network as geroprotectors to improve human health during ageing. One such example is inhibition of mTORC1 by rapamycin (sirolimus). Rapamycin robustly extends lifespan in multiple model organisms, ranging from worms and flies to mice, where rapamycin administration later in life at 600 days of age increases median and maximal lifespan in both sexes.

Reduced signalling through the phosphatidylinositol 3-kinase (PI3K) node of the nutrient-sensing network can extend lifespan in C. elegans and Drosophila, and was for long viewed as the primary route by which the anti-ageing effects of reduced upstream insulin/IGF signalling are mediated. However, Ras signalling plays a role in ageing in yeast, while in Drosophila the Ras-MEK-ERK pathway is as important a mediator as the PI3K pathway of the effects of reduced upstream insulin/Igf signalling on lifespan. Indirect inhibition of Ras in mice is associated with increased lifespan and enhanced motor function in old age. These findings suggest that inhibition of Ras pathway signalling may have an evolutionarily conserved, geroprotective effect.

Trametinib (also known as Mekinist) is a potent and highly specific small molecule inhibitor of MEK, and is an FDA-approved drug for the treatment of specific melanomas. Oral administration of trametinib increases Drosophila lifespan, even when started later in life. However, it is yet to be determined whether the lifespan-extending effects of trametinib are evolutionarily conserved. To examine whether trametinib is geroprotective in mice, we orally dosed female and male mice and assessed their ageing phenotypes.

In the present study, we investigated whether administration of trametinib alone or in combination with rapamycin can extend lifespan and improve health at old age in mice. We orally treated male and female mice with trametinib, or rapamycin, or with both drugs at the same doses as in the single drug treatments. We assessed their survival, fitness, brain metabolism, and organismal health. Single administration of trametinib or rapamycin significantly increased male and female mouse lifespan, while the combined treatment produced an additive further increase in both. Additionally, the double combination of trametinib and rapamycin significantly reduced liver tumours in both sexes and spleen tumours in males at old age, and alleviated the age-related increased glucose uptake in the brain. Combination treatment also caused a marked reduction of age-related inflammation in brain, kidney, spleen, and muscle, accompanied by reduced levels of circulating pro-inflammatory cytokines.

As previously shown, intermittent rapamycin treatment can extend lifespan in both sexes with an increase in median and maximum lifespan of 17.4% and 16.5% respectively in females and 16.6% and 18.3% respectively in males. Combined treatment caused a larger increase compared to the single treatment in both sexes, with median and maximum lifespan increased by 34.9% and 32.4%, respectively, in females and by 27.4% and 26.1%, respectively, in males.

Gut dysfunction is a prevalent, frequently premotor symptom in Parkinson disease (PD) and associated with faster progression. Gut microbiota (GMB) impacts PD pathology and symptoms, and GMB composition is linked to motor and nonmotor symptoms as well as disease progression. Interventions targeting GMB, such as fecal microbiota transplantation (FMT), have shown promising symptomatic and potentially neuroprotective effects in PD animal models. The underlying mechanisms are incompletely understood, but could involve changes in metabolism and immune activation. While several randomized clinical trials have suggested efficacy of probiotics for constipation in PD, with respect to FMT, only small and mostly uncontrolled studies are published suggesting safety and improvement of motor and nonmotor symptoms irrespective of the method of application. This study aimed to assess safety and symptomatic efficacy of FMT in PD.

In the FMT group in this randomized clinical trial, neither clinically meaningful improvement of PD symptoms vs placebo nor major safety concerns were observed. Donor FMT achieved a sustained GMB change close to what is observed between individuals. In the placebo group, dissimilarity remained somewhat higher than observed longitudinally in healthy individuals, indicating a persistent moderate alteration of GMB composition in the placebo group. However, the GMB alterations did not translate into observable clinical or biomarker improvements. This apparent futility or, for some readouts even worsening, is in contrast to previously published reports. Several studies showed improved motor function, increased striatal dopamine and serotonin, and reduced dopaminergic neuron loss, neuroinflammation, and gut inflammation in PD rodent models after FMT. Mostly uncontrolled or small clinical studies suggested safety of FMT in PD irrespective of the method of application and the potential for improvement of motor and nonmotor symptoms.

This negative trial may give important insights to design future improved and hopefully successful trials of this intervention. There is no consensus on many practical aspects of FMT, such as selection of donors and recipients, preparation of the fecal material (e.g., aerobic or anaerobic conditions, concentration of cryoprotectant, and transferred amount), pretreatment with antibiotics, and method of application (eg, upper vs lower gastrointestinal tract and single vs multiple dosing). Also, for clinical trials, there is no consensus about the best comparator (e.g., inert placebo vs autotransplant). Encouraging results from the probiotics field suggest that impact on motor and nonmotor PD symptoms through GMB manipulation is possible, however.

The aging process differs from tissue to tissue. The primary feature of aging in most tissues is the accumulation of senescent cells. Cellular senescence is a state of permanent cell cycle arrest triggered in response to numerous stressors, aiming to inhibit the proliferation of aged and/or damaged cells. Despite this, senescent cells are metabolically active and secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases. These factors are commonly referred to as the senescence-associated secretory phenotype (SASP). The SASP allows senescent cells to modulate pathways in neighboring and distant cells and tissues and has been widely used as a marker of cellular senescence. The SASP recruits immune cells, thereby creating a pro-inflammatory microenvironment in injured or aging tissues. The chronic accumulation of senescent cells with advancing age results in detrimental effects on health, increasing age-related diseases.

There is limited data on senescence cell accumulation and their function in the ovary. Although there is no well-defined panel of biomarkers for cellular senescence, some have been widely used in the ovary, including markers of pro-inflammatory stress, double-strand DNA breaks, and lipofuscin. Corresponding with reduced ovarian function, there is also a significant increase in markers related to senescence in the ovaries of mice between 3 and 12 months of age, along with the accumulation of lipofuscin aggregates. Similar accumulation of senescent cells in other organs is observed much later in life, around 18-20 months of age. Additionally, the ovarian transcriptomic profile indicates a positive regulation of genes related to pro-inflammatory stress and cell cycle inhibition, while genes involved in cell cycle progression were negatively regulated, which is characteristic of senescent cells. Increased SA-β-Gal and p21 levels were detected in the ovarian stroma of mice at 8-10 months of age, indicating senescent cell accumulation. Thus markers of senescence in ovarian tissue can be observed before 12 months of age in mice. Similar observations were made in human tissue. Expression of p21 was elevated in ovarian of middle-aged women (older than 37 years) compared to young controls (younger than 33 years). Other senescence and fibrosis related genes were also up-regulated in stromal cells of middle aged compared to younger women.

There are few studies using senolytics in young reproductive age mice available in the literature, which suggest that the compounds currently used have few beneficial systemic benefits at this age window. Even fewer studies evaluated the effects of senolytics in the ovary. These suggest that senolytics may prevent ovarian reserve loss, but cannot reverse the damage to the ovarian reserve after senescence is established. The activation of primordial follicles is an irreversible process, which means that the damage promoted by senescent cells in the ovarian reserve would not be able to be reverted by senolytics. This may indicate the direction for future studies, focusing on preventing accumulation of senescent cells in the ovaries in order to prevent declines in fertility. Additionally, the inflammation generated by senescent cells through the SASP itself can contribute to irreversible follicular activation. Therefore, it is possible that other senolytic compounds with greater efficacy in the ovary need to be tested. Compounds with senomorphic activity, i.e. able to decrease SASP secretion, may be considered to prevent the negative pro-inflammatory environment generated by senescent cells in the ovary. Therefore, the path to validating the use of senotherapies in female reproductive aging is still open. A better understanding of ovarian senescence biomarkers and the role of senescent cells on female fertility is still necessary in order to define how to promote targeted elimination of these cells without negative impact on other organs in young females.

While certain animals like planarians and hydras possess the remarkable ability to regenerate their entire body from a small fragment, other groups with more complex body structures, such as mammals and insects, exhibit a diminished regenerative potential and can only regenerate specific tissues and/or organs to a limited extent. Several cellular and molecular factors have been identified as determinants of regeneration capacity. Highly regenerative animals such as planarians and cnidarian polyps rely on pluripotent adult stem cells, called neoblasts and interstitial cells (i-cells), respectively. These stem cells migrate to the injury sites and contribute to the formation of a blastema, an undifferentiated cellular mass, enabling the restoration of amputated body structures. Some vertebrates like salamanders and fish, which do not possess adult pluripotent stem cells, can regenerate organs after injury by recruiting blastema cells through dedifferentiation and/or the activation of quiescent lineage-restricted stem cells. At the molecular level, the evolutionary conserved WNT signaling pathway promotes a wide range of regenerative events across species, including blastema formation in newts and Hydra.

In contrast to the conserved regulators of regeneration, several genes are specific to highly regenerative animal groups and species. For instance, the newt gene Prod1 regulates re-patterning during limb regeneration, and viropana family (viropana 1-5) is upregulated during lens regeneration. These species/group-specific genes might explain differences in regeneration capacity between species. Remarkably, ectopic expression of viropana 1-5 can enhance regeneration of the primordium of Drosophila eyes that maintain regenerative capacity during development. This finding raises the possibility that heterologous induction of regenerative genes may accelerate tissue regeneration, at least in developing animals, and potentially provide a cue for developing novel regenerative therapies.

Notably, given that basal metazoans such as Porifera, Ctenophore, Placozoa, and Cnidaria all exhibit robust regenerative abilities, it is conceivable that a common ancestor of all metazoans once possessed a high regenerative potential and independently lost genes related to high regenerative capacity in multiple phyla. Building upon this hypothesis, bioinformatics analysis has identified genes that are common among species with high regenerative abilities and absent in species with limited regenerative capacities. The highly regenerative species-specific JmjC domain-encoding genes (HRJDs) are a group of such genes (with typically two or three orthologs per species) characterized by their JmjC domain, yet their molecular functions remain unknown. Given their potential influence on the regenerative process, HRJDs may contribute to the high regeneration potential of highly regenerative animals. With this in mind, a question arises: what would happen if a low regenerative species, which has lost HRJDs, were to acquire them again?

Here, we express HRJDs in the fruit fly Drosophila melanogaster and evaluate their impact in vivo, especially by focusing on two epithelial tissues: developing wing discs and post-developmental adult midguts, both of which exhibit regeneration potential and can replenish damaged epithelial cells. In contrast to the predicted contribution of HRJDs in regeneration as observed in planarian, ectopic HRJD induction impedes regenerative responses and decreases organismal survival upon injury in Drosophila. Surprisingly, however, HRJD expression in the stem/progenitor population of the adult midguts extends organismal lifespan under the non-regenerative condition. Further investigations reveal that HRJDs enhance the proliferative activity of intestinal stem cells while keeping their differentiation fidelity in aged guts, ameliorating age-related decline in gut barrier functions. These findings provide evidence that genes specific to highly-regenerative animals can improve stem cell function as well as increase healthy lifespan upon heterologous expression in aging animals.

Chronic liver disease (CLD) is a debilitating proinflammatory 'scarring' condition that often results in the development of age-associated comorbidities (especially physical frailty), leading to reduced quality of life and ultimately increased mortality. Increased systemic inflammation is recognized as a key driver of the aging phenotype, which increases the risk of multiple life-limiting diseases. The present study investigated whether CLD increases the rate of biological aging in skeletal muscle and in the immune system. These biological systems with known hallmark mechanisms of aging were also investigated to help explain the increased incidence of sarcopenia and reduced immunity in this patient population.

Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years). Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge, DunedinPACE, or Hannum epigenetic clocks, with no difference using the Horvath clock. The present findings provide the first evidence of increased biological aging in patients with CLD across these two biological systems utilizing epigenetic and immune phenotype-based measures. Clinically, the identification of a divergence of biological age from chronological age, or the presence of a negative aging trajectory, may highlight CLD patients at greatest risk of disease progression, allowing early therapeutic intervention, including medicines that directly modulate aging processes.

It has previously been reported that patients with CLD display hallmarks of aging, including reduced telomere length in liver tissue, hepatocytes, and leukocytes, and this telomere attrition is positively associated with mortality risk and hepatic fibrosis. In line with this, the present study identified greater epigenetic age acceleration in the skeletal muscle tissue of CLD patients, suggesting that epigenetic muscle aging may be a contributing factor to the development of muscle dysfunction, which has been reported in up to 70% of patients with CLD. Aging is also associated with a chronic increase in circulating proinflammatory cytokines and a decrease in the level of anti-inflammatory cytokines, a process referred to as 'inflammageing'.

Although the mechanisms that drive age-related epigenetic changes are not fully understood, elevated levels of circulating factors, including proinflammatory cytokines, such as TNFα, IL-6, and IL-12, may play a role in modulating epigenetic modifications of DNA. Similarly, increased adiposity, which is also strongly associated with chronic low-grade inflammation, has been reported to drive epigenetic age acceleration in other tissues, including the liver. Therefore, it is possible that alterations in circulating factors, such as increased levels of proinflammatory cytokines or ammonia following primary liver dysfunction, may drive epigenetic changes in secondary tissues, such as skeletal muscle, negatively impacting their aging trajectory. However, it will be important to elucidate key factors that drive epigenetic aging and those that become elevated secondary to age-associated changes in cellular function.

Alzheimer's disease (AD) and related dementias feature a prolonged preclinical stage spanning decades, with the transition from midlife to late life marking the critical period for the onset and accumulation of pathological brain changes. Plasma biomarkers have shown great promise in becoming a cost-effective and noninvasive screening tool for AD pathology and neurodegeneration in symptomatic persons, but their presymptomatic trajectories are not well understood.

Using the well-established community-based Atherosclerosis Risk in Communities study, we characterized temporal changes in plasma biomarkers, identified factors associated with changes in plasma biomarkers over time, and evaluated the prospective associations of plasma biomarkers with late-life all-cause dementia. Analyses were conducted overall and stratified by demographics (sex, race), apolipoprotein E epsilon 4 (APOE ε4) allele status, and cognitive diagnosis.

In this retrospective analysis of prospectively collected plasma biomarkers from 1,525 adults from the Atherosclerosis Risk in Communities study, only Alzheimer disease (AD)-specific (Aβ42:Aβ40 ratio and p-Tau181) biomarkers in midlife demonstrated significant long-term associations with late-life dementia. In late life, each of the biomarkers and their change from midlife were significantly associated with incident all-cause dementia.

The complement system, best known as a key arm of innate immunity, has gained attention as a major player in healthy central nervous system (CNS) biology based on its contributions to normal neuronal development, but also for its involvement in inflammatory processes within the CNS. Studies have revealed dysregulation of complement activation in various neurodegenerative and inflammatory conditions, including Alzheimer's disease and multiple sclerosis. Interestingly, both beneficial and pathological activities of complement in the brain or spinal cord are majorly dependent on locally produced complement with limited involvement from the liver-derived circulating complement. This observation is in line with recent adjustments in our understanding of the complement system.

Initially, complement was thought to be a circulation- or vessel-operative system with only a simple role in mediating the detection and removal of bloodborne pathogens. Today, we acknowledge that the complement system is operative at different locations that span the vasculature, the extracellular space in tissues where it is critical in mediating protective tissue immunity, and within cells where it regulates basic cellular processes. The functional reach of complement allows it to directly modulate innate and adaptive immune responses and the behavior of non-immune cells, both during homeostasis and in response to danger-associated molecular patterns (DAMPs) and other noxious triggers. Furthermore, complement has emerged as a key mediator of tissue homeostasis, repair, and regeneration and as such is also involved in the molecular pathways underlying resolution of CNS inflammation and remyelination of neurons after myelin sheath loss, for example, in multiple sclerosis.

Here, we will give a condensed overview of the known sources and roles of complement components in normal CNS function, such as neuronal development and nerve pruning, as well as in disease pathologies contributing to neurodegenerative or neuroinflammatory pathogeneses, and processes that may aid in the resolution or repair of CNS tissue injury. We will conclude with a summary on emerging areas of new complement locations and activities that we suggest could be important in CNS pathologies, such as the intracellularly active complement system and its tight association with the control of single cell physiology and a potential connection between viral infections, complement, and neuroinflammation.

MAG200 is a single injection of donor stem cells into the joint (an intra-articular injection). It's considered an 'off-the-shelf' therapy because it uses donor, or allogeneic, stem cells rather than the patient's own, the surgical harvesting of which is labor-intensive. Importantly, because the treatment uses mesenchymal stem cells - adult stem cells that can differentiate into other cell types - from adipose tissue or body fat, it doesn't trigger an immune response.

For the first-in-human Phase I/II trial of MAG200, the researchers randomized 40 participants with moderate knee osteoarthritis to receive either an intra-articular injection of the stem cell therapy or a placebo. All the participants had attempted to manage their osteoarthritis conservatively and had an average pain score of equal to or more than five on a scale of zero to 10. Measures of the impact of their osteoarthritis on function - performing the activities of daily living - were taken using a subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS). KOOS scores go from zero, indicating the worst possible knee symptoms, to 100, indicating no symptoms.

The primary efficacy objective of the study was clinically meaningful differences in pain (a decrease in pain score by two or more points) and function (an eight or more point increase in KOOS score) at 12 months. The researchers found that 75% of participants who'd received MAG200 exhibited clinically relevant and statistically significant improvement in pain and function, reporting improvement or complete recovery. There was sustained pain improvement of 58% at 12 months. MRI scans of the participants' knees indicated that, at 12 months, those who'd received MAG200 had improvements in cartilage volume and quality.

Epigenetic clocks are a common group of tools used to measure biological aging - the progressive deterioration of cells, tissues and organs. Epigenetic clocks have been trained almost exclusively using blood-based tissues but there is growing interest in estimating epigenetic age using less-invasive oral-based tissues (i.e., buccal or saliva) in both research and commercial settings. However, differentiated cell types across body tissues exhibit unique DNA methylation landscapes and age-related alterations to the DNA methylome. Applying epigenetic clocks derived from blood-based tissues to estimate epigenetic age of oral-based tissues may introduce biases.

We tested the within-person comparability of common epigenetic clocks across five tissue types: buccal epithelial, saliva, dry blood spots, buffy coat (i.e., leukocytes), and peripheral blood mononuclear cells. We tested 284 distinct tissue samples from 83 individuals aged 9-70 years. Overall, there were significant within-person differences in epigenetic clock estimates from oral-based versus blood-based tissues, with average differences of almost 30 years observed in some age clocks. In addition, most epigenetic clock estimates of blood-based tissues exhibited low correlation with estimates from oral-based tissues despite controlling for cellular proportions and other technical factors.

Our findings indicate that application of blood-derived epigenetic clocks in oral-based tissues may not yield comparable estimates of epigenetic age, highlighting the need for careful consideration of tissue type when estimating epigenetic age.

In recent years, the intricate pathogenesis and potential interventions for ischemic stroke (IS) have been an intriguing area of research. Although there are some feasible treatments for IS, more effective treatments are still urgently needed. More and more evidence has indicated the vital roles of vascular aging in the pathology of IS with the involvement of oxidative stress and inflammatory response. Therefore, the identification of novel targets and the development of effective interventions that can modulate vascular aging by regulating oxidative stress and inflammatory response are worth continued research efforts. Only by unraveling the intricate pathogenesis and exploring more accurate targets can light be shed on how the risk of IS can be mitigated and the patient's quality of life improved with the innovation of more effective therapies.

Vascular aging is critically involved in the pathology of IS. Cellular senescence refers to a stress-induced, permanent cessation of the cell cycle, which leads to adverse functional and structural changes. Increased senescent cells in blood vessels tend to induce vascular aging within aging organisms, which brings about a gradual deterioration in oxidative stress and inflammatory response. This deterioration usually results in endothelial dysfunction and vascular remodeling, which increases the susceptibility and exacerbates the pathology of IS. Further uncovering the underlying mechanisms of vascular aging and IS holds significant implications for advancing our understanding and therapeutic strategies. In this review, we conclude that vascular aging is a multifaceted contributor to IS. It promotes endothelial dysfunction and drives vascular remodeling, which is marked by both oxidative stress and inflammatory response. These interconnected factors collectively amplify the susceptibility and pathological severity of IS.

In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as β-amyloid (Aβ) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function.

Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear.

Here, we discuss these issues from a viewpoint of amyloidogenic evolvability (aEVO), a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.

Reproduction and ageing tightly interact with each other. It has been shown in various organisms that the absence of germline significantly extends lifespan. Studies in the nematode Caenorhabditis elegans indicate that the somatic gonad generates an unknown signal to trigger a complex signalling network in other tissues to promote longevity when the germline is removed. Downstream of the somatic gonad-derived signal lies a complex genetic network. For example, daf-16/FOXO controls gonadal longevity. The biosynthesis of dafachronic acids (DAs) and the subsequent activation of the nuclear hormone receptor DAF-12/FXR is another critical pathway driving gonadal longevity. Intriguingly, the gonadal longevity signalling shares components with developmental timing machinery. In particular, the DA synthesis and DAF-12 activation are initiated at the end of germline development, implying that gonadal longevity could be from a checkpoint for germline integrity.

Despite the extensive understanding of the molecules controlling ageing upon germline ablation, the longevity signal from the somatic gonad remains poorly understood. Within the germline, the somatic gonad constitutes the niche of germ cells and regulates their development. It is the germline stem cells (GSCs) but not the oocytes or sperms that influence ageing. Therefore, we hypothesize that the gonadal longevity signal originates from the somatic gonadal cells neighbouring GSCs because these cells have intensive interactions with GSCs as their niche and should be the first to sense their absence.

In this study, we found that removing worm germline disrupts the cell adhesions between GSC and its niche, the distal tip cell (DTC), causing a significant transcriptomic change in DTC through the translocation of two GATA transcription factors, elt-3 and pqm-1, and the translocation of hmp-2/β-catenin. This, in turn, extends the lifespan of worms. Moreover, we further identified the TGF-β ligand, tig-2, as the cytokine from DTC upon germline ablation, which evokes the downstream longevity pathways throughout the body. Our findings thus reveal the origin of the longevity signalling in response to germline ablation, underscoring the interaction of stem cells and their niche in metazoan ageing.

A key protein that helps assemble the brain early in life also appears to protect the organ from Alzheimer's and other diseases of aging. A trio of studies published in the past year all suggest that the protein Reelin helps maintain thinking and memory in ailing brains, though precisely how it does this remains uncertain. The studies also show that when Reelin levels fall, neurons become more vulnerable. The research has inspired efforts to develop a drug that boosts Reelin or helps it function better, as a way to stave off cognitive decline.

Reelin became something of a scientific celebrity in 2023, thanks to a study of a man who should have developed Alzheimer's in middle age but didn't. The man was part of a large family that carries a very rare gene variant known as Paisa. Family members who inherit this variant are all but certain to develop Alzheimer's in middle age. But this man, despite having the variant, remained cognitively intact into his late 60s and wasn't diagnosed with dementia until he was in his 70s. After he died at 74, an autopsy revealed that the man's brain was riddled with sticky amyloid plaques, a hallmark of Alzheimer's. Scientists also found another sign of Alzheimer's - tangled fibers called tau, which can impair neurons. But oddly, these tangles were mostly absent in a brain region called the entorhinal cortex, which is involved in memory. That's important because this region is usually one of the first to be affected by Alzheimer's

The researchers studied the man's genome. And they found something that might explain why his brain had been protected. He carried a rare variant of the gene that makes the protein Reelin. A study in mice found that the variant enhances the protein's ability to reduce tau tangles. Another team published an analysis of the brains of 427 people. It found that those who maintained higher cognitive function as they aged tended to have more of a kind of neuron that produces Reelin.

A more recent study included a highly detailed analysis of post-mortem brains from 48 people. "The neurons that are most vulnerable to Alzheimer's neurodegeneration in the entorhinal cortex, they share one feature. They highly express Reelin." In other words, Alzheimer's appears to be selectively damaging the neurons that make Reelin, the protein needed to protect the brain from disease. As a result, Reelin levels decline and the brain becomes more vulnerable. The finding dovetails with what scientists learned from the man whose brain defied Alzheimer's. He had carried a variant of the Reelin gene that seemed to make the protein more potent. So that might have offset any Reelin deficiency caused by Alzheimer's.

Uncontrolled hypertension is a major risk factor for stroke and myocardial infarction. Health providers should be aware that uncontrolled hypertension is one of the most common, serious and increasing conditions in their patients. Nationally, adults over the age of 18 include 249.2 million people of which 119.9 have hypertension. Myocardial infarction accounts for 25% of all deaths and stroke about 16.5%.

Hypertension has long been deemed "the silent killer" as most patients affected were unaware of their condition until its first presenting symptom was the myocardial infarction or stroke. Sudden cardiac death accounts for 50% of deaths from cardiovascular disease and is the first symptomatic event in ≥25% of cases. In addition, for 76% of stroke patients, the initial presenting symptom is the stroke itself.

Control of hypertension is effective and, at least in theory, is straightforward. Before the Hypertension Detection and Follow Up Program only about 50% of patients were aware of their hypertension, and of those, only 50% were actively treated. Of that group, only 50% received effective treatment. Thus, 1/8 of all patients were effectively treated. Today these figures are 54% aware of their hypertension, 40% actively treated, and 21% adequately controlled, respectively.

Bone homeostasis in physiology depends on the balance between bone formation and resorption, and in pathology, this homeostasis is susceptible to disruption by different influences, especially under ageing condition. Gut microbiota has been recognized as a crucial factor in regulating host health. Numerous studies have demonstrated a significant association between gut microbiota and bone metabolism through host-microbiota crosstalk, and gut microbiota is even an important factor in the pathogenesis of bone metabolism-related diseases that cannot be ignored. This review explores the interplay between gut microbiota and bone metabolism.

Given the increasing recognition of the involvement of the gut microbiota in bone health, various investigations have explored the potential interventions in the gut microbiota for the treatment or prevention of bone diseases by inhibiting the inflammatory response in the senescent microenvironment or directly promoting the osteogenic process.

Probiotic therapy represents a feasible approach. Supplementation with Lactobacillus animalis has been documented to offer benefits in averting osteonecrosis of the femoral head via an extracellular vesicular mechanism. Lactobacillus helveticus HY7801 has demonstrated prophylactic and therapeutic properties in a murine arthritis model by increasing IL-10 expression in CD4+ T cells. Moreover, the administration of Bifidobacterium longum was found to suppress post-fracture weight reduction and lumbar spine bone density loss in a model of fractures in elderly female mice.

Fecal microbiota transplantation (FMT) involves transferring functional gut amicrobiota from the feces of a healthy individual into the gastrointestinal tract of a patient to restore normal intestinal function. This approach has demonstrated effectiveness in manageing systemic conditions like multiple sclerosis and cancer. While there is currently no research on the use of FMT for degenerative bone diseases, this paper highlights the substantial evidence linking intestinal dysbiosis to these conditions. Therefore, FMT has the potential to restore a healthy gut microbiota and may be a promising strategy for treating degenerative bone diseases.