Summary: Researchers have discovered that the enzyme ATP-citrate lyase (ACLY) plays a critical role in driving the inflammatory process linked to aging, known as the senescence-associated secretory phenotype (SASP). The study shows that blocking ACLY can reduce the expression of inflammation-related genes in aging cells, opening the door for potential therapies to combat age-related diseases like dementia and atherosclerosis.
By inhibiting ACLY, researchers were able to suppress chronic inflammation in aged mice, offering a promising new strategy for extending healthy lifespans. This breakthrough could lead to treatments that specifically target the damaging aspects of aging without eliminating aging cells.
Key Facts:
Source: Kumamoto University
A team at Kumamoto University has made a groundbreaking discovery in the field of aging and inflammation. Japan’s aging population is growing at an unprecedented rate, making it crucial to extend healthy lifespans rather than just lifespans.
The research focuses on “cellular senescence,” a process where cells stop dividing and enter a state associated with chronic inflammation and aging.
This cellular state, known as the senescence-associated secretory phenotype (SASP), involves the secretion of inflammatory proteins that accelerate aging and disease, such as dementia, diabetes, and atherosclerosis.
The researchers found that ATP-citrate lyase (ACLY), an enzyme involved in converting citrate to acetyl-CoA, plays a critical role in activating SASP. This discovery was made using advanced sequencing and bioinformatics analyses on human fibroblasts, a type of cell found throughout the body.
They demonstrated that blocking ACLY activity, either genetically or with inhibitors, significantly reduced the expression of inflammation-related genes in aging cells. This suggests that ACLY is a crucial factor in maintaining the pro-inflammatory environment in aged tissues.
Furthermore, the study revealed that ACLY-derived acetyl-CoA modifies histones, proteins that DNA wraps around, allowing the chromatin reader BRD4 to activate inflammatory genes.
By targeting the ACLY-BRD4 pathway, the researchers were able to suppress inflammation responses in aged mice, highlighting the potential of ACLY inhibitors in controlling chronic inflammation while maintaining healthy aging.
This discovery opens new avenues for developing treatments that specifically target the harmful aspects of aging cells without removing them, offering a promising strategy for managing aging and age-related diseases.
The research provides a stepping stone toward therapies that can control cellular aging, promoting longer, healthier lives.
Author: Nuo LI
Source: Kumamoto University
Contact: Nuo LI – Kumamoto University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers” by Kan Etoh et al. Cell Reports
A new study provides more evidence that sildenafil (Viagra) which is used to treat erectile dysfunction (ED) may help protect against Alzheimer's disease (AD).
The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in AD among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.
This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).
"Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer's, which is in great need of new therapies," Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release.
"We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil's potential against this devastating neurological disease," Cheng noted.
The study was published online on March 1, 2024, in the Journal of Alzheimer's Disease.
Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities.
They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of AD relative to the control drugs.
For example, sildenafil use was associated with a 54% reduced incidence of AD in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of AD in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.
The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on AD risk, as previously reported by Medscape Medical News.
However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced AD risk.
The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient induced pluripotent stem cell (iPSC)-derived neurons.
They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD.
"We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer's disease," Cheng said.
The study was primarily
supported by the National Institute on Aging (NIA) and the National
Institute of Neurological Disorders and Stroke (NINDS). Cheng had no
relevant disclosures.
Erectile dysfunction drugs were associated with reduced risk of Alzheimer's disease, electronic health record (EHR) data from 270,000 men in the U.K. suggested.
Over a median follow-up of about 5 years, men who started taking phosphodiesterase type 5 (PDE5) inhibitors were less likely to have an Alzheimer's diagnosis than nonusers (adjusted HR 0.82, 95% CI 0.72-0.93), reported Ruth Brauer, PhD, of the University College London, and co-authors.
Alzheimer's risk dropped further for men who had more than 20 prescriptions for PDE5 inhibitors, the researchers wrote in Neurology. For those issued 21-50 prescriptions, the HR was 0.56; for those with more than 50 prescriptions, the HR was 0.65.
PDE5 inhibitors are anti-hypertensive agents. Four -- sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra) -- are approved to treat erectile dysfunction because of their vasodilatory effects on the corpus cavernosum. Sildenafil also is approved to treat pulmonary arterial hypertension (PAH).
In rodents, sildenafil has been shown to improve memory and cognitive function, help synaptic plasticity and learning, and reduce amyloid burden. Tadalafil also has improved memory and lowered amyloid in animal studies. "However, evidence of neuroprotective effects in humans is not conclusive," Brauer and colleagues wrote.
The findings conflict with ones reported from a recent NIH DREAM study, which showed no difference in Alzheimer's and dementia diagnosis rates with PDE5 inhibitors compared with other PAH drugs among Medicare recipients.
But they're in line with a previous case-control analysis of insurance claims data that suggested sildenafil users were 69% less likely to develop Alzheimer's disease than non-users, noted Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, both of the Johns Hopkins University School of Medicine in Baltimore, in an accompanying editorial.
"One major limitation of all three studies is that they have all used insurance claims or EHR data, which relies heavily on diagnosis by providers, which may lead to underdiagnosis or misdiagnosis of dementia, thus leading to misclassification bias," Yasar and Nidadavolu wrote.
Brauer and colleagues studied 269,725 men in U.K. primary care records with a new diagnosis of erectile dysfunction between 2000 and 2017. Patients with a history of cognitive impairment or dementia were excluded. Those who had a prescription for a PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or avanafil) were compared with those who didn't.
The mean age at cohort entry was 58.5 years. Median follow-up was 5.1 years, during which 1,119 men were newly diagnosed with Alzheimer's disease.
Overall, 749 men exposed to PDE5 inhibitors developed Alzheimer's, which corresponded to a crude incident rate of 8.1 per 10,000 person-years at risk. Among unexposed men, 370 developed Alzheimer's, corresponding to a crude incident rate of 9.7 per 10,000 person-years.
The primary result was consistent in a sensitivity analysis that included a 1-year lag period to partly account for prodromal Alzheimer's, but not one with a 3-year lag.
In subgroup analyses, Alzheimer's risk was lower than those who started on sildenafil compared with men who didn't use PDE5 inhibitors (adjusted HR 0.81, 95% CI 0.71-0.93). PDE5 inhibitor exposure in men ages 70 and older, and in those with a history of hypertension or diabetes, also was associated with a lower risk of Alzheimer's.
Additional data from in vitro and in vivo studies could strengthen analyses that examine links between PDE5 inhibitors and Alzheimer's, the editorialists noted. "These include in vitro studies exploring the role of inflammation and clearance of beta-amyloid," Yasar and Nidadavolu wrote. Blood and cerebrospinal fluid biomarkers of inflammation and endothelial function or imaging to assess neuroinflammation and vascular changes also could help evaluate potential mechanisms associated with PDE5 inhibitor use.
"In the end, however, further observational studies exploring mechanisms will not prove a causal association," they emphasized. "A well-designed randomized controlled trial is needed before [PDE5 inhibitors] can be prescribed for Alzheimer's disease prevention."
Disclosures
This study had no targeted funding.
Brauer and co-authors reported no disclosures.
The editorialists had no disclosures.
Primary Source
Neurology
Source Reference: Adesuyan M, et al "Phosphodiesterase type 5 inhibitors in men with erectile dysfunction and the risk of Alzheimer disease: a cohort study" Neurology 2024; DOI: 10.1212/WNL.0000000000209131.
Secondary Source
Neurology
Source Reference: Yasar S, Nidadavolu L "Repurposing erectile dysfunction medication for Alzheimer disease prevention" Neurology 2024; DOI: 10.1212/WNL.0000000000209180.
Objective:
Investigate the potential of krill oil (KO), a marine-based, long chain, omega-3 (n-3) polyunsaturated fatty acid (PUFA), to negate the deleterious effects of high fat diet and aging on spatial learning, microglia migration and neurogenesis. Hypothesis: KO exhibits beneficial, anti-inflammatory properties comparable to other sources of n-3 PUFA, but with several biochemical advantages. KO contains phospholipid-bound fatty acids, improving bioavailability when compared to triacylglyceride bound n-3 PUFA, astaxanthin, a powerful antioxidant, and choline which is an essential neurotransmitter precursor exhibiting neuroprotective properties. Hence, we hypothesized that KO supplementation would improve deficiencies in spatial learning, hippocampal neurogenesis and unwarranted microglia migration induced by high fat diet and normal aging in rats.
Methods:
Thirty-two male, Sprague Dawley rats, aged 15 months were divided into four dietary groups consisting of varying amounts of saturated fats, with and without krill oil supplementation: Control (CON), Control with krill oil (CONKO), High fat (HF), High fat with krill oil (HFKO). High fat and control diets consisted of 60% and 23% calories from fats, respectively, while 8% krill oil was added to both experiment KO diets. Food intake and body weight were assessed weekly. After 12-weeks of dietary interventions, spatial learning was assessed utilizing Morris Water Maze testing, followed by cortex and hippocampus tissue analysis. Microglia migration and neurogenesis was quantified by immunostaining and stereology techniques utilizing doublecortin (DCX) and ionized calcium-binding adaptor protein (Iba-1).
Results:
Despite evidence of learning by each group over the course of MWM testing, no significant difference in time-to-platform or probe trial times between dietary groups was identified. Total food consumption was significantly less in the HF group when compared to CON (p=0.047) and CONKO (p=0.030), whereas body weight was significantly higher in the HFKO group when compared to CON (p=0.024) and CONKO (p=0.030). Otherwise, no other differences in food consumption or body weight were identified. Furthermore, no significant difference was found in cortex (p=0.623) or hippocampus (p=0.863) microglia counts between dietary groups. Similarly, DCX totals were not significantly different (p=0.454).
Conclusions:
KO supplementation did not significantly alter the effects of aging and high fat diet consumption on spatial memory, microglia migration or hippocampal neurogenesis. Some evidence suggests that the unique properties of KO have the potential to positively influence brain health. Therefore, considering the negative effects of aging and fatty foods and the associated risks of neurodegenerative diseases, exploration of neuroprotective dietary interventions such as krill oil is paramount and warrants further investigation.
This work was supported by the Central Michigan University Office of Research and Graduate Studies and College of Health Professions
This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
DALLAS -- Uric acid was shown to be the most successful neuroprotectant among rodents in a study from the Stroke Preclinical Assessment Network (SPAN), a nationwide trial platform that applies clinical research practices to preclinical studies in hopes of better informing human studies.
Of the six interventions studied in the randomized rodent trial, uric acid 16 mg/kg administered intravenously at the time of reperfusion exceeded the efficacy boundaries, reported Lauren H. Sansing, MD, of Yale University in New Haven, Connecticut, and colleagues during the American Stroke Association's International Stroke Conferenceopens in a new tab or window.
The other interventions included the Rho-associated kinase inhibitor fasudil, the PARP inhibitor veliparib, the immunosuppressive drug tocilizumab (Actemra), the S1P analogue fingolimod (Gilenya), and remote ischemic conditioning, which were analyzed via corner test at 28 days.
Three interventions fell below SPAN's inferiority barriers after just the first stage. Only uric acid remained within the study's efficacy boundaries after four stages, ultimately surpassing their original acceptable outcomes.
The study showed that SPAN is an effective preclinical research tool, noted James C. Grotta, MD, a vascular neurologist at Memorial Hermann-Texas Medical Center in Houston, who was not involved in the study.
"The SPAN project entailed a tremendous amount of careful planning and meticulous work by a large team, and kudos to the network for a successful result. The 'winner,' e.g., uric acid, has withstood rigorous testing and the stroke community is now looking forward to the clinical trial of this approach that may complement existing reperfusion strategies," he told MedPage Today.
During a press conference, Sansing explained that "experimental rigor is something we can control. SPAN embraced all of the rigor of a clinical trial."
The study also aimed to "embrace heterogeneity," allowing for some variation in its subjects in an effort to mimic clinical trials, she and her colleagues noted.
Sansing cited growing public distrust in scientific research, recently exacerbated by the COVID-19 pandemic, as part of the reason behind the development of SPAN. Stroke research is no exception. Several neuroprotectant agents have performed well during the course of preclinical trials, but failed to prove effective when introduced in human trials -- a trend that has been documented for decades.
Sansing also pointed to an opinion piece published in Trends in Neurosciencesopens in a new tab or window in 2007 that cited research that showed that as the quality or rigor of a preclinical study on treatments for stroke increased, their efficacy decreased, with the authors noting that animal models for stroke research were "profoundly biased by aspects of study design."
More recent researchopens in a new tab or window compiled evidence listing albumin, the potassium channel activator BMS-204352, and the sodium channel blocker lubeluzole as just a few of many therapies that showed promise as neuroprotectors in animal studies, which then fell short in clinical research on humans.
For this National Institute of Neurological Disorders and Stroke (NINDS)-funded study, six independent labs were used to conduct the research, including Yale University, Massachusetts General Hospital, Johns Hopkins University, the University of Texas Health Science Center at Houston, the Medical College of Georgia at Augusta University, and the University of Iowa.
A total of 2,651 rodents were included in the study, including young mice, aging mice, mice experiencing diet-induced obesity or hyperglycemia, young rats, and spontaneously hypertensive rats, with an equal number of male and female rodents.
After receiving more funding from NINDS, SPAN 2.0 will continue to test neuroprotectants, utilizing six more experimental sites.
The positive results for uric acid, the experimental rigor present in the trials, and the renewal of the SPAN program may bring change to years of issues regarding neuroprotectants, commented Gregory Albers, MD, director of the Stanford Stroke Center in Palo Alto, California, during a Q&A session on SPAN's results.
"I think it's really exciting that the winning drug had a lot of clinical data prior to going into SPAN," he said. "We have seen a number of these agents that have gotten into the human trials where the trial was close but didn't quite make it, some subgroups looked great, and then you repeat, focusing on those subgroups, and then again they didn't make it. What I think we now have is a much higher level of enthusiasm for this drug than what we just had from the prior clinical work that was done for that."
![author['full_name']](https://clf1.medpagetoday.com/media/images/author/EShort_188.jpg)
Disclosures
The study was funded by the National Institute of Neurological Disorders and Stroke.
Sansing reported no disclosures. Co-authors reported several relationships with industry.
Primary Source
International Stroke Conference
Source Reference: opens in a new tab or windowSansing LH, et al "Primary results of the Stroke Preclinical Assessment Network" ISC 2023.
Infarct size is associated with stroke severity in clinical studies, so reducing it has become an important target and research hotspot in the treatment of ischemic stroke. Some preclinical studies have shown transcranial direct current stimulation (tDCS) reduced infarct size and improved neurological deficit, but others have not found beneficial effects. Besides, the optimal pattern of tDCS for ischemic stroke remains largely unknown. To shed light on the current circumstance and future research directions, the systematic review evaluated the effect of different tDCS paradigms in reducing infarct size and improving neurological deficit in rodent models of ischemic stroke and assessed the methodological quality of current literature. We searched the MEDLINE (via PubMed), EMBASE, Web of Science, and Scopus from their inception to August 18, 2021, to identify studies evaluating the effects of tDCS in rodent models of ischemic stroke. Eight studies were included, of which seven studies were included in the meta-analysis. The results showed cathodal tDCS, rather than anodal tDCS, reduced infarct size mainly measured by tetrazolium chloride and magnetic resonance imaging (standardized mean difference: −1.13; 95% CI: −1.72, −0.53; p = 0.0002) and improved neurological deficit assessed by a modified neurological severity score (standardized mean difference: −2.10; 95% CI: −3.78, −0.42; p = 0.01) in an early stage of focal ischemic stroke in rodent models. Subgroup analyses showed effects of cathodal tDCS on infarct size were not varied by ischemia duration (ischemia for 1, 1.5, and 2 h or permanent ischemia) and anesthesia (involving isoflurane and ketamine). The overall quality of studies included was low, thus the results must be interpreted cautiously. Published studies suggest that cathodal tDCS may be a promising avenue to explore for augmenting rehabilitation from focal ischemic stroke. Considering the methodological limitations, it is unreliable to blindly extrapolate the animal data to the clinical practice. Future research is needed to investigate the mechanism of tDCS in a randomized and blinded fashion in clinically relevant stroke models, such as elderly animals, female animals, and animals with comorbidities, to find an optimal treatment protocol.
More at link.
Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture.
Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (KitW-sh/W-sh mice).
Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus KitW-sh/W-sh mice).
These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.
Rupture of intracranial aneurysms causes aneurysmal subarachnoid hemorrhage. The 30-day mortality rate after aneurysmal subarachnoid hemorrhage can be as high as 45%.1 Therefore, surgical clipping or endovascular coiling are offered to patients with unruptured aneurysms for the prevention of aneurysmal rupture. Significant technical advancements and refinements have been made in these invasive treatments. However, the adverse outcome rates resulting from the clipping and coiling of unruptured aneurysms are still not negligible.2 Therefore, pharmacological prevention of aneurysmal rupture may be an attractive alternative approach in patients with unruptured aneurysms.3
Inflammation is increasingly recognized as a critical component in the pathophysiology of intracranial aneurysms.4–9 Observational studies have shown the presence of inflammatory cells and inflammatory markers in human intracranial aneurysm tissues and serum samples.5,10 Mast cells have been detected in human intracranial aneurysm tissues,7,11 and the presence of mast cells was associated with intramural microhemorrhage and wall degeneration of human intracranial aneurysms.11
Mast cells, classically known as key regulators of allergic reactions, have emerged as integral players in cardiovascular diseases.12–17 By releasing cytokines, including tryptase, chymases, cathepsins, and interleukins, mast cells can affect vascular inflammation and remodeling.12,18–20 Blocking the cytokine release from mast cells reduces the development and progression of atherosclerosis and abdominal aortic aneurysm in animals.14,16 Although previous studies suggested an association between mast cell activation and pathological remodeling of aneurysm walls,21,22 the direct link between mast cell activation and the development of aneurysmal rupture has not been established. Therefore, we tested whether mast cells contribute to the development of aneurysmal rupture using the genetic and pharmacological tools in a mouse model of intracranial aneurysm.
Jiapeng Huang
Kehong Zhao1,2,3, 
