Fight Aging! Newsletter, June 10th 2024

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.