Fight Aging! Newsletter, June 10th 2024

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit:

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Why Does Hypertension Correlate with Age-Related Hearing Loss?

Age-related hearing loss is commonplace. It occurs due to loss of sensory hair cells in the inner ear, or due to the loss of axons connecting these cells to the brain. Evidence conflicts on which of these is the important mechanism. A good number of research programs aimed at reversing hearing loss are focused on generating more sensory hair cells, such as by reprogramming supporting cells of the inner ear to force transdifferentiation to the sensory hair cell fate. To the degree that new hair cells will forge new connections to the brain and correctly integrate into sensory processing circuits, this should fix both problems. Ensuring that this integration takes place sounds a more challenging than generating new hair cells, however.

Hearing loss correlates with a number of other aspects of aging, such as frailty, Alzheimer's disease, cognitive decline, and microstructural change in the brain. For brain aging one can at least consider that similar underlying mechanisms of neural and axonal damage are at work. For frailty, it is somewhat harder to guess at the shared cause. Similarly, researchers here note that the raised blood pressure of hypertension correlates with hearing loss, and once again it is not obvious as to where one should start looking for causation and shared mechanisms. Vascular damage is one of the evident consequences of hypertension, but it isn't clear as to how that interacts with sensory hair cells specifically.

Relationship Between Hypertension and Hearing Loss: Analysis of the Related Factors

This was a single-center population-based observational study, and clinical, biological, and hospital data were collected from the inpatient ward. In the present study, 517 patients (1034 ears) with or without hypertension were included, and the proportion of patients with hearing loss, mean pure-tone average hearing threshold, low-frequency pure-tone average hearing threshold (LFPTA), medium-frequency pure-tone average hearing threshold (MFPTA) and high-frequency pure-tone average hearing threshold (HFPTA) were evaluated. Risk factors related to hearing loss and hearing threshold were also estimated at different frequencies.

In this study, the hypertensive group exhibited more pronounced subclinical target organ damage and hearing impairment than the nonhypertensive group. Compared with the nonhypertensive group, the hypertensive group showed elevated albumin-to-creatinine ratio (ACR) levels, increased left ventricular mass index (LVMI) values, higher bilateral cardiovascular ankle index (CAVI) measurements, decreased bilateral ankle-brachial index (ABI) values, and a higher proportion of carotid intima-media thickening/plaque. Furthermore, the hypertension group demonstrated a higher prevalence of hearing loss at the mean pure-tone average hearing threshold and at individual frequencies.

Among these indicators, ABI and CAVI serve as markers of atherosclerosis and arterial stiffness, respectively, while ACR and LVMI indicate damage to the microvascular target organ in hypertension. These indicators have a significant clinical predictive value for subclinical target organ damage in hypertension. Therefore, the simultaneous appearance of hearing loss with these indicators may also be associated with early vascular damage caused by hypertension, which is consistent with previous studies. Although the exact mechanism underlying the influence of hypertension on the hearing threshold remains unclear, this study discovered that injuries to the vascular system can potentially contribute to hearing loss.

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Age-Related Frailty, a Case of All Too Little Prevention

One of the interesting points made in today's open access review paper is that there is a lack of research into the early manifestations and prevention of frailty. According to the authors, it was only recently the case that the research community established that meaningful levels of pre-frailty exist in middle-age. Further, while it is well established that resistance exercise is the best intervention for the treatment of pre-frailty and frailty at this time, the data is far less comprehensive when looking only at the question of early prevention in middle-age than, say, the evidence for statin use in atherosclerosis or other widely used pharmacological therapies.

A number of the small molecule therapies under development in the longevity industry are targeting components of frailty, particularly sarcopenia, the loss of muscle mass and strength. Some of these may be exploiting one or more of the many mechanisms making up the beneficial response to exercise, and quite likely so if the small molecules arose from unbiased screening exercises. It remains to be seen as to whether the treatments will match the benefits produced by resistance exercise. Calorie restriction mimetics perform less capably than the practice of calorie restriction, and we should probably expect the same to be true for exercise mimetics versus exercise.

Effectiveness of interventions to prevent or reverse pre-frailty and frailty in middle-aged community dwelling adults: A systematic review

While this review identified multicomponent and resistance exercise as the most effective interventions for preventing or reversing pre-frailty/frailty in 40-65-year-olds, significant evidence gaps, limited methodologies, and risk of bias were present in the literature. Previous reviews have demonstrated the benefits of resistance training in preventing or reversing pre-frailty and frailty in older adults. However, we found only one study which independently evaluated resistance training for middle-aged adults. In most instances resistance training was incorporated into multicomponent exercise programs (MEPs) making it difficult to understand the effectiveness of these interventions beyond standalone resistance training. This trend may stem from World Health Organisation (WHO) recommendations favouring multicomponent exercise for older adults. However, it's unclear if these complex interventions add sufficient benefit over resistance training alone.

Low-intensity and dynamic exercises have been shown to be less effective for preventing or reversing pre-frailty than other forms of exercise, though they do improve balance, an early frailty predictor. While these exercises benefit older adults, especially in balance, resistance training also enhances balance and offers additional benefits such as increased bone density. Nonetheless, the practicality of integrating low-intensity exercises like walking into daily routines for balance improvement shouldn't be underestimated.

There was insufficient evidence to recommend flavonoid supplementation or metformin prescription for preventing or reversing pre-frailty/frailty in middle-aged individuals. These findings are not surprising as similarly, in older adults, evidence is sparse or emerging. Unlike these less supported interventions, nutritional approaches like protein and/or creatine supplementation have strong evidence for frailty prevention/reversal in older adults. Specifically, in older adults, protein supplementation in conjunction with resistance training exercise is more effective than either intervention alone. Yet, in none of these studies was protein supplementation or any nutritional intervention included in conjunction with exercise. Considering the established benefits in older adults, future research in this younger age group is indicated.

The small number of studies in this review underscores the emerging nature of evidence for interventions targeting frailty in middle-aged adults. Notably, the high levels of detectable pre-frailty in middle age is an only recently discovered phenomenon, highlighting a research gap in this age range. The infrequent use of terms like 'pre-frailty' and 'frailty' in 40-65-year-olds suggests missed opportunities for research. Although previous studies have focused on related concepts such as functional decline or sarcopenia in older adults, their relevance to this younger group remains underexplored.

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Loss of TRIO Expression at Neuromuscular Junctions Precedes Age-Related Loss of Motor Function

Many mechanisms are thought to contribute to the age-related decline of muscle mass and strength, but there are the usual debates over which are more important, which are the primary causes, and how they relate to one another. Little of our biochemistry is as fully understood as we might like it to be, and in some senses even the very well understood regions are only sketches of a yet to be fully mapped environment. One hypothesis places degeneration of neuromuscular junctions as an early cause, leading to the other observed issues. A neuromuscular junction is the synaptic connection between a motor neuron and muscle fiber, allowing the muscle to contract. The degree to which muscles are innervated in this way appears to go a long way towards determining how well they are maintained and function.

Unfortunately, and like all complex small scale structures in the body, neuromuscular junctions are subject to the damage and disarray of aging. The expression of necessary genes changes, the surrounding signaling environment changes, nearby cell behavior changes. All of this is disruptive, leading to loss of neuromuscular junctions and a reduced ability to function where they remain more or less intact. Like all aspects of aging, researchers have yet to build a complete understanding of how exactly the identified low-level processes of aging give rise to these high-level manifestations. They have also yet to produce a complete map of the important alterations in the expression of genes in aging neuromuscular junctions, and the consequences of those alterations - but more attention is given to that layer of degenerative aging, for better or worse.

Trio preserves motor synapses and prolongs motor ability during aging

Across species, motor ability diminishes as aging progresses, and this curtailment is one of the most debilitating aspects of human aging. Concomitant with the age-dependent decline of motor ability are degenerative alterations of motor synaptic structures. These changes include the subdivision or fragmentation of neuromuscular junction (NMJ) synaptic terminals into smaller units in addition to a reduction in the size or number of terminals. These structural alterations are associated with a decline of neurotransmitter release, which may undermine motor ability during aging.

We have shown previously that Drosophila neuromuscular synapses undergo structural synaptic bouton fragmentation during aging, co-incident with the decline of motor ability. Here, investigating mechanisms that could contribute to age-dependent synaptic structural degeneration, we find that levels of Trio, an evolutionarily conserved guanine nucleotide exchange factor (GEF), decline at NMJ synapses with age. We discover that increasing Trio levels during aging has a remarkable ability to conserve synaptic structures and prevent bouton fragmentation, maintaining the capacity of synapses to sustain high intensities of neurotransmitter release and enabling a postponement of the age-dependent decline of motor ability. Enhanced Trio expression can also prevent accelerated synaptic structural degeneration induced by loss of miniature neurotransmission.

Our results support a paradigm where the structural dissolution of motor synapses precedes and promotes motor behavioral diminishment and where intervening in this process can postpone the decline of motor function during aging.

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SGLT2 Inhibition is Senolytic in Overweight Mice

SGLT2 inhibitors are a class of diabetes medication that falls within the broad present enthusiasm for pharmacological treatments that can reduce weight in obese individuals. In today's open access paper, researchers demonstrate that the SGLT2 inhibitor canagliflozin reduces the burden of senescent cells in obese mice fed a high fat diet. The researchers identify the mechanism as an increase in the efficiency with which immune cells clear senescent cells from tissues.

It is known that being overweight, specifically meaning a greater burden of metabolically active, inflammatory visceral fat tissue, increases the pace at which senescent cells accumulate. The consequent greater burden of senescent cells may contribute meaningfully to many of the negative consequences of visceral fat and excess weight. Given that cellular senescence is a hallmark of aging, it may be reasonable to say that being overweight accelerates aging.

However, it may well be the case that the senolytic effects of SGLT2 inhibitors will not occur to any great degree outside the context of obesity, a high fat diet, and their disruptions to normal metabolism. One would certainly want to see studies in aged mice of a normal weight before becoming too enthusiastic. While there is considerable interest in mining the panoply of diabetes drugs for compounds that might modestly slow aging, it remains to be seen as to whether benefits observed in overweight individuals with metabolic syndrome will also occur in individuals of normal weight and metabolism to any meaningful degree. One might suspect not, given the animal data.

SGLT2 inhibition eliminates senescent cells and alleviates pathological aging

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes.

In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age.

Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a metabolite well known to activate AMP-activated protein kinase (AMPK), enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1 (PD-L1). These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

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The Heart-Brain Axis, Cardiovascular Disease and Dementia

The aging of the cardiovascular system contributes to the aging of the brain. As the authors of today's open access review paper note, the relationship isn't straightforward and is mediated by a range of mechanisms that are far less direct than the pressure damage caused by hypertension, or the consequences of a reduced blood supply to the brain. One thing to consider about this relationship is that some fraction of cardiovascular disease in the wealthier regions of the world appears to be self-inflicted. Hunter-gatherers such as the Tismane exhibit little cardiovascular disease. To the degree that the brain declines because the vasculature declines, these populations are likely to also exhibit a lower incidence of dementia.

To restate in a more applicable way, maintaining the level of trim physical fitness needed to run an antelope to exhaustion every so often, and keeping that up into later life, is both possible and beneficial. Those of us seduced into an unhealthy lifestyle of excess fat and little exercise by the modern reality of cheap calories and readily available engines of transport are paying the price, slowly over time, and have charted a course for a worse old age with a greater level of cognitive decline.

Cardiovascular Disease and Alzheimer's Disease: The Heart-Brain Axis

A plethora of shared pathophysiological processes link the cardiovascular and the cerebrovascular system forming the heart-brain axis. Abnormalities in the heart-brain axis are likely associated with the incidence of cardiovascular disease (CVD) and Alzheimer's disease (AD), two of the leading aging-related chronic diseases. The precise mechanisms and molecular processes that modulate the heart-brain axis remain elusive. However, there are several common CVD risk factors that are increasingly linked with AD dementia and AD-related dementia incidence.

The links between CVD and AD have been confirmed in observational cohorts as well as experimental data. Although the pathophysiologic mechanisms for AD have not been fully elucidated, studies link AD with CVD manifested by hypertension and intracranial and extracranial atherosclerosis and arteriosclerosis. Both AD and CVD are progressive diseases with decades-long incubation periods before clinical manifestation. Although aging is the greatest risk factor, AD and CVD also share several modifiable risk factors, such as smoking, lack of physical exercise, hyperlipidemia, and hypertension. Furthermore, recent studies have suggested that subclinical CVD in midlife may be associated with incidence of dementia, including AD dementia, in late life.

Atherosclerosis is the deposition of fibrofatty lesions in the arterial walls, and arteriosclerosis is the stiffening of the media of the arterial wall as a result of degeneration of connective tissue, particularly elastin. Although both atherosclerosis and arteriosclerosis commonly occur together, they are thought to have differing causes and classical risk factors. The pathogenesis of atherosclerosis is centralized to the collection of lipoproteins (mainly low-density lipoprotein particles in the subendothelial intima). The smaller and cholesterol enriched lipoprotein particles easily cross the arterial wall and undergo modification via oxidation, acetylation, and aggregation. These modifications allow an easier capture by macrophages and smooth muscle cells, which then form foam cells inducing an inflammatory cascade response.

How exactly does atherosclerosis or arteriosclerosis lead to AD or AD-related dementias independently of ischemic brain lesions or neurodegenerative pathology? Atherosclerosis could contribute to brain dysfunction and axonal damage by a subtle reduction in microvascular perfusion without causing overt ischemic lesions. Blood-flow-independent aspects of neurovascular function, such as blood-brain barrier permeability, neurotrophic support by endothelial cells or neuroimmune modulation, could also be involved. Clinical events in arteriosclerosis are postulated to be secondary to the systolic hypertension that results from aortic stiffening as well as other adverse hemodynamic effects.

Arteriosclerosis, marked by measures of pulse wave velocity (among others), is associated with cognitive impairment. The brain, which is both a high flow and low impedance organ, is susceptible to damage from increased pulse pressures. Increased pulse pressure is also associated with cerebrospinal fluid amyloid-β (Aβ) and tau levels. Hypertension, a primary factor in arteriosclerosis formation, is associated with in vivo measures of Aβ deposition and Aβ interacts with vascular risk factors to increase cortical thinning.

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Continued Hype for Semaglutide Rather than Weight Loss

Drug sales efforts and research efforts merge at the boundary. Big, flashy, confirming trials of hot new drugs with already proven effects are more readily funded for all of the obvious reasons, primarily that the expected good results will help to sell more drugs. The hot new drugs of the past few years are GLP-1 receptor agonists, the first well-backed pharmaceutical answer to the widespread prevalence of obesity and its harmful consequences to health and longevity. The beneficial effects of losing excess weight (and specifically excess visceral fat tissue) are broad and sizable. Those who sell GLP-1 receptor agonists such as semaglutide are the first to lay these benefits at the feet of their drugs instead of loss of weight. As an example, the publicity materials noted here make no mention of weight loss whatsoever.

The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) study is a double-blind, randomised, placebo-controlled international trial comprising 3,533 patients, with a median follow-up period of 3.4 years. The trial was designed to assess the efficacy and safety of semaglutide, a once-weekly subcutaneous glucagon-like peptide 1 (GLP-1) receptor agonist, in preventing major kidney outcomes, specifically kidney failure, substantial loss of kidney function, and death from kidney or cardiovascular causes, in individuals with type 2 diabetes and chronic kidney disease. Patients either received semaglutide 1.0 mg once weekly or placebo.

Participants who received semaglutide had a 24% risk reduction for the composite primary endpoint, including kidney outcomes and death due to cardiovascular and kidney causes, compared to those who received placebo. This reduction risk was consistent across both kidney-specific and cardiovascular death outcomes. Secondary endpoints also showed significant improvements with semaglutide. Specifically, the total estimated glomerular filtration rate (eGFR) slope was 1.16 ml/min/1.73m2/year slower, the risk of major cardiovascular events was decreased by 18%, and the risk of all-cause mortality was reduced by 20%. This evidence of efficacy, combined with fewer serious adverse events in the semaglutide group, offers hope to millions of patients globally who face the daunting prospect of chronic kidney disease and type 2 diabetes, and their related complications.

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Astrocytes Restrict Access to Amyloid-β Plaques in the Aging Brain

Astrocytes react to the presence of extracellular amyloid-β aggregates in the aging brain by becoming more inflammatory and clustering around the aggregates of misfolded proteins. Researchers here show that this activity crowds out the microglia responsible for ingesting and breaking down these protein aggregates. The crowding can, however, be controlled to some degree by targeting plexin-B1, allowing microglia access to conduct greater clearance of amyloid-β. This is early stage research, so it remains to be seen as to whether it will actually offer a way to make forms of anti-amyloid therapies more effective, or can be the basis for such a therapy itself.

Researchers have made a significant breakthrough in Alzheimer's disease research by identifying a novel way to potentially slow down or even halt disease progression. The study, which focuses on the role of reactive astrocytes and the plexin-B1 protein in Alzheimer's pathophysiology, provides crucial insights into brain cell communication and opens the door to innovative treatment strategies.

This groundbreaking work is centered on the downregulation of the plexin-B1 protein to enhance the brain's ability to clear amyloid plaques, a hallmark of Alzheimer's disease. Reactive astrocytes, a type of brain cell that becomes activated in response to injury or disease, were found to play a crucial role in this process. They help control the spacing around amyloid plaques, affecting how other brain cells can access and clear these harmful deposits.

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Senolytic Effects of High Intensity Exercise

Here find a study assessing whether or not high intensity exercise can have transient senolytic effects, at least based on using P16 as a marker of senescence. The effects seem to be transient, but the underlying biochemistry might be of interest for the production of more lasting senolytic therapies. As a caution, there is some thought that this marker can also represent non-senescent populations of macrophages. Given the role of these innate immune cells in the muscle tissue response to small-scale damage resulting from high intensity exercise, a part of the overall beneficial response, one might want to see other measures of the burden of cellular senescence in addition to P16.

Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage.

In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 hours post-exercise (-82%), gradually recovering over the next 3-24 hours. A concurrent reduction pattern in CD11b mRNA (-87%) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA.

The strong correlation between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.

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More on P2Y6R Inhibition as a Strategy to Reduce Synaptic Loss in the Brain

Researchers recently found that inhibition of P2Y6R in microglia prevents these innate immune cells from excessively destroying synapses in the aging brain. The removal of synapses is just as important as their creation when it comes to the function of the brain, particularly memory. But with aging this removal process becomes too aggressive, for reasons yet to be fully understood. This short commentary offers a little more discussion on the topic. Work on P2Y6R inhibition remains at an early stage, some distance from compelling evidence for it to be a good basis for therapy. We shall see where it goes.

The brain shrinks with age, accompanied by a loss of synapses and memory. We outline here recent evidence in mice that this loss is due to microglial phagocytosis of the synapses, mediated by the microglial P2Y6 receptor (P2Y6R). Brain atrophy during aging appears to be partly due to brain cells, called microglia, eating bits of neurons and the connections between neurons, called synapses. Brain shrinkage and loss of synapses correlate with age-associated memory impairment.

There is evidence in mice that aging-induced loss of synapses and memory is due to the phagocytosis (i.e. eating) of synapses by microglia. Microglial phagocytosis is regulated by several factors, including the microglial P2Y6 receptor (P2Y6R) activated by extracellular UDP (uridine diphosphate). We recently reported that microglial phagocytosis of synapses during aging is mediated by P2Y6R. Inhibition or knockout of P2Y6R reduced microglial phagocytosis of synapses and synaptic loss in co-cultures of neurons and microglia. In vivo, microglial phagocytosis of synapses was increased in the brains of aged (17 months old) wild- type mice, compared to adult (4 months old) mice, but this increase was absent in P2Y6R knockout mice. P2Y6R knockout mice also had reduced aging-associated loss of synapses and memory.

What is inducing microglial phagocytosis of the brain in aging? We do not know for sure, but some factors that accumulate with age (such as amyloid-β aggregates, tau aggregates, or excess glutamate) stress neurons such that they expose so-called "eat-me" signals (such as UDP) that induce microglia to eat the neurons. Additionally, there is a general increase in inflammation within the brain with age that activates microglia and stimulates microglial phagocytosis, in part by the release of 'opsonins', such as complement factors C1q and C3, that bind to neurons and synapses, inducing microglia to phagocytose them. UDP activation of P2Y6R induces the engulfment phase of microglial phagocytosis, and expression of the receptor is increased by inflammation, while excitation of neurons and stress of other cells induces UDP release.

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ANGPTL3 Inhibition is the Newest Advance in Lipid-Lowering Therapies

The major therapies aimed at lowering lipid levels in the bloodstream all derive from the discovery of human mutants who exhibit low blood lipids and a lesser burden of atherosclerosis and cardiovascular mortality. The therapies aim at recapturing some of the effects of these mutations, which inevitably means that they confer smaller benefits than possessing the mutation over the full course of life. Over time these therapies have moved from small molecule drugs to the present approach of small interfering RNA to directly inhibit expression of specific genes. ANGPLT3 is the latest target, and here note the clinical trial performance of one of the ANGPLT3 inhibition therapies presently in development. It improves on statins in its effects on blood lipids, but the experience of PCKS9 inhibitors, also an improvement over statins, demonstrates that this approach of lowering circulating lipids can only slow the progression of atherosclerotic plaque, not reduce the size of existing plaques, no matter how much blood lipids are lowered.

A small interfering RNA (siRNA) investigational therapy that inhibits a gene involved in lipoprotein metabolism has been shown in a clinical trial to significantly reduce levels of different types of cholesterol and triglycerides in individuals with mixed hyperlipidemia, a condition in which fats build up in the blood. Researchers found the RNA interference (RNAi)-based therapy zodasiran to be a potentially promising option for substantially reducing a number of atherogenic lipoproteins while requiring less frequent dosing than conventional therapies.

Zodasiran (Arrowhead Pharmaceuticals) targets a specific gene expressed in hepatocytes known as angiopoietin-like protein 3 (ANGPTL3), which plays a role in regulating levels of low-density lipoprotein (LDL), non-HDL cholesterol (a measure of all the "bad" cholesterol in the blood including LDL), and triglycerides. Various research has identified these components as increasing risk of atherosclerotic cardiovascular disease.

In the phase 2b global trial (known as ARCHES-2) of 204 participants with mixed hyperlipidemia who received zodasiran (50, 100, and 200 mg) and background therapy of standard of care medications including statins, the researchers observed substantial reductions in all lipid level parameters monitored. These included lowering triglycerides by 54 to 74 percent compared to placebo, LDL cholesterol by up to 20 percent, non-HDL cholesterol by up to 36 percent, and remnant cholesterol by 73 to 82 percent. Remnant cholesterol measures the amount of "leftover" or remnant very-low-density lipoprotein (VLDL) particles. It is measured by adding up HDL and LDL and subtracting that sum from the individual's total cholesterol. Researchers suggested that based on prior genetic studies the magnitude of remnant cholesterol reduction evidenced by zodasiran in their study could translate into a 20 percent decrease in recurrent major cardiac events.

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Better Lifestyle Choices Correlate with a Lower Epigenetic Age

The more that researchers correlate epigenetic clock results with mortality in the context of specific interventions and lifestyle choices, the more useful those epigenetic clocks become. At present the challenge in using clocks to assess the results of any novel therapy is that it is entirely unclear as to whether the results are accurate, useful, or actionable, since there is no established connection between the epigenetic marks measured and specific underlying processes of aging. Only when someone has calibrated a clock against the use of a therapy or intervention across a large study population does it become trustworthy for that therapy or intervention. At present it is fair to say that the more modern epigenetic clocks are trustworthy when it comes to the benefits of common lifestyle choices. One interesting outcome of the study noted here is that people with high genetic risk for age-related disease benefit more from a healthy lifestyle than those with low genetic risk.

Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear. LE8 score was calculated for 5,682 Framingham Heart Study participants. We implemented 4 DNA methylation-based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD-specific mortality, and all-cause mortality.

We found that a 1 standard deviation increase in the LE8 score was associated with a 35% lower risk of incident CVD, a 36% lower risk of CVD-specific mortality, and a 29% lower risk of all-cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD-specific mortality, and all-cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score.

DNA methylation-based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD-specific mortality, and all-cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.

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A High Level Sketch of the State of Aging and its Treatment

At this point it seems an impossible task to write a review paper covering what is known of aging and avenues to treat aging as a medical condition. The only way forward is to do what the authors did here, which is to leave out nearly everything. Just focus on the high points, the areas of greatest study, to sketch an outline of a field in which, I would say, all of the truly transformative work is taking place in smaller programs, beneath the radar, less widely discussed, but poised to reshape the field of medicine.

The physiological characteristics of aging summarised in this article gradually accumulate over time and contribute to the aging process. Notably, antagonism of an organism's response to the characteristics of aging also plays a subtle role in the aging process. When the cumulative damage caused by primary and antagonistic markers is no longer compensated for by the complex markers of aging, it means that the rate of aging is accelerated. Furthermore, senescence also relies on the integration of cell-autonomous and non-cell-autonomous mechanisms, and mechanisms that promote senescence can be transmitted between different types of organs and cells.

In conclusion, aging is a gradual and complex process of decline in physiological function, and experiments in animal models have shown that certain interventions may not only extend lifespan, but also increase healthy longevity. However, in vitro models, tissue culture studies, and in vivo animal models, which are ultimately translated into human studies, are complex and diverse, and only a few models can be used to investigate these differences. There are also significant differences between physiological and pathological aging, and the scientific problem of slowing down aging and extending the healthy lifespan of humans involves a number of challenges, including inadequate regulation, barriers to clinical validation, failure to identify more biomarkers of human aging, and the unknown challenges of introducing new interventions to the market.

It is gratifying that years of basic research in the anti-aging field have laid the foundation for explosive biotechnology and industrial applications. Using modern biological techniques, including genetic manipulation or cell-based therapies with broad implementation prospects, to focus on the discovery of physiological mechanisms and interventions underlying the aging process will greatly advance anti-aging research, delay human aging to the maximum extent, maintain human physiological functions in later years, and mitigate the surge in age-related chronic diseases.

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Decreased Flow of Interstitial Fluid in the Brain After 50 Years of Age

A number of lines of evidence point to decreased fluid drainage from the brain into the body with aging. This drainage occurs through pathways such as the cribriform plate behind the nose and the comparatively recently discovered glymphatic system. Both of these fluid pathways are known to become dysfunctional with age. It is thought that the reduced drainage has a negative impact on the brain by allowing metabolic waste products to build up, such as the various forms of disruptive protein aggregates associated with neurodegenerative conditions.

Physiological age-related alterations in the interstitial flow in the brain, which plays an important role in waste product removal, remain unclear. Using [15O]H2O positron emission tomography (PET), water dynamics were evaluated in 63 healthy adult participants aged between 20 and 80 years. Interstitial flow was assessed by influx ratio (IR) and drain rate (DR), using time-activity concentration data.

Participants were divided into four age groups with 15-year ranges, to evaluate age-related functional alterations. At least one of the indices declined significantly with age across all groups. A significant linear negative correlation between age and both indicators was found in the scatter plots; both indicators were predominantly lower after age 50 years. These results suggest interstitial flow decreases with age, especially after 50 years. These important findings can contribute to devising therapeutic interventions for neurological diseases characterized by abnormal accumulation of waste products, and suggest the need for taking measures to maintain interstitial flow starting around the age of 50 years.

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Using Biomaterials to Modulate the Immune System to Heal Chronic Wounds

Non-healing wounds are a feature of aging and inflammatory metabolic diseases such as type 2 diabetes. To some meaningful degree these injuries are the result of dysfunction in the immune system, and thus strategies targeting the behavior of immune cells might prove to be useful, particularly if resolving excessive inflammatory signaling. The paper noted here focuses on the use of biomaterials, such as the scaffolding currently used in the development of cell therapies and tissue engineering approaches, to achieve this goal of immunomodulation.

Understanding the immune response in the context of chronic wound healing can inspire innovative strategies to enhance the efficacy of therapies by modulating immune cell behaviors. Thus, advances in this field require the convergence of multiple disciplines, including immunology, skin cell biology, biomaterial science, chemistry, and nanotechnology. Delving into the nuances of chronic wound healing from an immunology viewpoint reveals the complex interplay of the different immune cell types and their interactions between them and the extracellular matrix (ECM). By deciphering the dynamics of immune cell wound recruitment and leave and also the leucocyte polarization, we can devise strategies to optimize the healing process, minimizing inflammation and scarring, and also reducing the risk of infection.

Biomaterials, with their versatility, provide a platform for finely controlling immune cell behaviors. Thus, by carefully modulating their surface moieties, tuning their physical properties and combining them with bioactive agents or living entities, such as mesenchymal stem cells (MSCs), we can design therapies that can actively modulate the immune system. These modifications have been demonstrated to successfully facilitate different immune cells recruitment - polymorphonuclear neutrophils (PMNs), monocytes, macrophages, and lymphocytes - and activate and polarize macrophage and lymphocyte phenotypes.

Nonetheless, current research endeavors have primarily focused on understanding the behavior of macrophages, leaving a notable gap in the comprehension of the responses and interactions exhibited by mastocytes, lymphocytes, PMNs, and innate lymphoid cells (ILCs) in the context of varying biomaterial properties. In this regard, further investigation is needed to comprehensively understand the diverse immune responses elicited by biomaterial-based strategies, aiming to devise multifunctional therapeutic strategies for a precise modulation of distinct immune cell types.

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300-400 kDa Hyaluronic Acid is Processed by Gut Microbes to Reduce Inflammation

Researchers here note that specific species in the gut microbiome react to some forms of hyaluronic acid by increasing production of a metabolite that reduces inflammation in the body. This is likely one of many such discoveries waiting to be made, as researchers attempt to uncover specific mechanisms by which the gut microbiome can affect health. It remains the case that short-cuts exist for those who don't want to wait on a more complete understanding of these mechanisms. For example, resetting an aged gut microbiome to a more youthful configuration via fecal microbiota transplantation from a healthy young donor is one way to bypass a lack of specific knowledge as to what exactly has become less optimal in the aged gut microbiome.

In this study, the research team focused on investigating the effect of hyaluronic acid with various molecular weights. Utilizing a combination of multi-model and multi-omics technologies, the researchers established that hyaluronic acid with a specific molecular weight (300-400 kDa) can significantly mitigate inflammatory responses in mice. This effect is dependent on gut Bacteroides thetaiotaomicron and Bacteroides caccae, along with their crucial metabolite - myristic acid.

The research team found that hyaluronic acid stimulates Bacteroides to produce myristic acid, which in turn inhibits the NF-κB signaling pathway, thereby reducing cellular inflammation. This study identified the optimal molecular weight range of hyaluronic acid to improve host inflammation, elucidated the material basis and molecular mechanisms of gut effect strains, provided biomarkers for dietary polysaccharide strategies to alleviate host inflammation, and offered new strategies and insights for the efficient screening of microbiota-directed foods.

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