Pill That Slows Aging? Meds May Boost Health Span

 All this earlier research which your INCOMPETENT? DOCTOR DID NOTHING! And you and the hospital president haven't fired them yet? Why are you tolerating incompetence when it impacts your recovery?

• Metformin (21 posts to July 2012)
• rapamycin (8 posts to May 2017)
• caloric restriction (16 posts to February 2012)
• senescent cells (12 posts to January 2016)
• biological aging (8 posts to August 2023)

The latest here:

Pill That Slows Aging? Meds May Boost Health Span

Aging is the strongest risk factor for most chronic diseases; however, medicine has historically treated each condition individually. Geroscience is a new discipline that aims to define and modify aging-related biological pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival.

A review in JAMA outlines the aims, methods, recent advances, and ongoing challenges of geroscience.

The review was authored by Stephen B. Kritchevsky, PhD, Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina, and Steven R. Cummings, MD, California Pacific Medical Center Research Institute, San Francisco, and Department of Epidemiology and Biostatistics, University of California, San Francisco.

In Italy, the prevention of aging is particularly relevant. Data from the Italian National Institute of Statistics (2023) show that 24.1% of the Italian population — 14.2 million people — is older than 65 years, making Italy the world’s second-oldest country after Japan.

By 2050, 35% of Italians are expected to be 65 years or older. 

The 2023 Osservasalute Report found that 87% of Italian senior citizens live with at least one chronic condition, and 67% have two or more, at an annual cost to the National Health Service exceeding €66 billion.

Traditional Limits

Disease-specific prevention has shown notable results. For example, statins lower the risk for composite cardiovascular events by 28% in primary prevention.

But the authors emphasized significant limitations: “Disease-focused approaches to prevent and treat conditions do not address age-related health issues such as fatigue, mobility limitations, and frailty that are common even in the absence of overt disease.”

Frailty illustrates this gap. In the Cardiovascular Health Study, which followed more than 5200 adults for over 30 years, 16% were frailer than expected based on their comorbidities. “After adjusting for comorbidity count, the frailest group experienced 2-3 fewer years of disability-free life compared with those who were not frail,” the authors wrote. 

Age is a disproportionate risk factor. During the COVID-19 pandemic, the mortality rate was seven times higher in those aged 85 years or older (1.6%) than in those aged 65-74 years (0.2%). 

Multimorbidity also rises sharply with age, and “the incidence of developing a third disease among those with two chronic medical conditions is 5.2% among those aged 50-59 years and 16% in those aged 70-79 years,” the authors wrote.

The authors emphasized that single-disease paradigms fail to account for age as the strongest determinant of risk for many diseases, including coronary heart disease, cancer, chronic obstructive pulmonary disease, stroke, dementia, and chronic kidney disease.

Biologic Age

The geroscience hypothesis holds that biologic aging is a process distinct from chronologic aging.

Biologic age quantifies how much a person’s physiology deviates from what would be expected of their chronologic age. For example, “a 50-year-old woman with a maximal oxygen consumption of 32 mL/kg/min, typical of women 10 years younger, would have a biologic age of 40 years,” the authors noted.

Age advancement, defined as the difference between biologic and chronologic age, predicts mortality and other age-related outcomes independently of chronologic age. For example, “an individual with a biologic age 8.3 years older than their chronologic age, based on DNA methylation, had a 2.2-fold higher hazard of death than a person with a similar chronologic age.”

Survivors of childhood cancer also show accelerated biologic aging: “At an average age of 35 years, survivors were biologically 2.2-6.5 years older than age- and sex-matched controls using seven different approaches based on physiologic measures or DNA methylation.”

Cellular Pathways

Biologists specializing in aging have identified cellular pathways that influence lifespan, defined as the total length of life, and health span, defined as the length of life spent free from disease. These pathways involve multiple aspects of cellular physiology, including the accumulation of somatic DNA variations and the regulation and accuracy of DNA transcription.

Regulation includes the maintenance of telomeres and regions of repetitive DNA sequences at the ends of chromosomes that shorten with replication. When telomeres are too short, DNA replication cannot occur. Methylation of DNA bases and other epigenetic changes can alter gene transcription with age.

Maintaining protein structure and function, or protein homeostasis, is strongly associated with aging. In particular, autophagy removes damaged intracellular proteins. Other pathways are related to nutrient sensing, such as signaling induced by amino acids, insulin, or insulin-like growth factor 1, sustaining stem cell populations, and preserving mitochondrial function.

Variations in mitochondrial DNA accumulate with age. One genetic variant, m.3243A>G, is linked to inherited mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode syndrome.

In a cohort of 789 adults aged 70-80 years, approximately 33% carried this variant in 6%-19% of their leukocyte mitochondrial DNA. These individuals showed slower performance, greater arterial stiffness, and reduced grip strength.

Participants with a higher abundance of this variant had increased 17-year mortality rates from dementia and stroke compared with those with the lowest abundance.

Caloric Restriction

Caloric restriction is the most extensively studied intervention in geroscience. 

The authors reported important results: “In one strain of mice, a 20% caloric restriction increased median survival from 785 to 1096 days in females (40%) and from 807 to 999 days (24%) in males.”

The CALERIE trial provided the first evidence of this in humans. The CALERIE trial randomized 218 adults without obesity, aged 21-51 years, to a 2-year intervention comparing caloric restriction with no caloric restriction. The results showed significant cellular changes: Caloric restriction upregulated autophagy and DNA repair and downregulated the inflammatory response, as measured by rank-based pathway enrichment analysis. Participants in the restriction group aged 0.6 years less over the 24 months of the study than participants with no caloric restriction.

Incretin therapies such as semaglutide and tirzepatide offer durable caloric restriction surpassing behavioral interventions and significantly reducing clinical risks in adults with or without type 2 diabetes. Semaglutide (2.4 mg/wk) achieved 14.9% weight loss over 68 weeks. These therapies also lower cardiovascular events by 20% and all-cause mortality by 19%.

Metformin

The review also focuses on metformin, a biguanide and first-line treatment for type 2 diabetes, which may slow age-related biologic processes through its effects on multiple aging pathways.

“Metformin inhibits mitochondrial complex I, which increases AMPK [adenosine monophosphate-activated protein kinase] activity, thereby inhibiting mTOR complex 1 and activating peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These actions enhance autophagy and mitochondrial biogenesis.”

Observational data suggest broad benefits. Among 5528 Veterans Affairs patients with type 2 diabetes, metformin users had a lower incidence of neurodegenerative diseases, including dementia, Parkinson’s disease, Huntington’s disease, and mild cognitive impairment compared with nonusers (11.48 vs 25.45 per 1000 person-years).

Among patients with type 2 diabetes hospitalized with COVID-19 infection, metformin use was associated with a lower 28-day mortality rate (16.0% vs 23.6%). But the authors noted that “Studies of the effects of metformin on patients with diabetes and prediabetes have had inconsistent results,” highlighting the need for studies designed to measure aging-related outcomes.

Rapamycin

Rapamycin, developed to prevent transplant rejection, has shown antiaging effects by acting on mTOR, a regulatory component of the cellular nutrient-sensing pathway. “Reducing mTOR activity increases cellular autophagy,” the authors noted.

“Inhibition of mTORC1 [mTOR complex 1] by rapamycin increased lifespan in multiple model organisms, including mice, even when treatment began at 20 months of age.”

Human evidence is promising but limited. “In a clinical trial of 218 adults aged 65 years or older, 6 weeks of everolimus at 0.5 mg daily or 5 mg weekly was safe and significantly improved the response to influenza vaccination compared with placebo.”

The authors noted that “Lower intermittent doses may improve aging-related biologic pathways while producing fewer adverse effects.”

Senescent Cells

Senolytic drugs are among the most novel geroscience strategies.

“Senescent cells no longer divide, resist apoptosis, and secrete inflammatory cytokines, chemokines, proteases, and other substances collectively known as the senescence-associated secretory phenotype,” the authors explained.

The accumulation of these cells has been documented. Senescent cells accumulate with age.

In a survey of senescent cell markers with age in human tissues, the concentration of kidney cells expressing the senescence marker p21 was 1% in five older donors aged 71-79 years, compared with less than 0.2% in five younger donors aged 19-30 years.

In preclinical studies, eliminating p16-positive cells with AP20187, which induced apoptosis in genetically modified mice expressing p16, increased the median lifespan by up to 27% (from 624 to 793 days) and reduced cancer mortality, delayed cataract formation, and enhanced spontaneous physical activity.

Early clinical trials have shown that this strategy is safe and that senolytic treatment reduces the number of cells expressing p16 and p21, two senescence markers.

Regulatory Hurdles

According to the authors, a significant obstacle to the development of effective prevention strategies is the current regulations. “The FDA does not recognize slowing aging or reducing aging-related conditions, such as sarcopenia or mobility limitation, as approved indications.” 

The authors emphasized that “evaluating approved drugs for age-modifying effects will require broad inclusion criteria, alternative dosing regimens, and longer study durations than those used to establish therapeutic efficacy for their original indications. If multiple clinical trials, including those testing potential indications such as peripheral artery disease, heart failure, or osteoporosis, collect these outcomes, response patterns may be identified to guide future studies with measures more directly linked to specific aging-related biologic targets.” The authors also cautioned about the limitations: “This review had several limitations. First, it was not a systematic review, and the quality of the included evidence was not formally assessed. Second, geroscience is a rapidly evolving field, and relevant references may have been missed.”

Conclusion

Despite these limitations, the authors concluded that “therapies that target aging biology, including caloric restriction, metformin, senolytics, and rapalogs, may slow disease development and progression as well as functional decline in humans.”

This represents a fundamental paradigm shift. Instead of waiting for specific diseases to develop and then treating them individually using disease-specific approaches, geroscience proposes modifying the fundamental biological processes that increase susceptibility to age-related comorbidities.

Therapies that target the biology of aging could not only extend lifespan but, more importantly, improve the “health span” of the years lived in good health without disability or chronic disease. In today’s era of rapid population aging, these strategies could help turn aging from a problem to an opportunity, moving beyond the limits of traditional approaches.

This story was translated from Univadis Italy.

Scientists confirm breakthrough in search for ways to extend human life

 But is it a healthy life?

Scientists confirm breakthrough in search for ways to extend human life

For centuries, humans have searched for ways to extend life. Alchemists never found the philosopher’s stone, but scientists have consistently shown that a longer life can be attained by eating less, at least in certain lab animals. But can we find a way to live longer while still enjoying our food?

dieting could be the answer, and the two most popular diet-mimicking drugs are rapamycin and metformin. In a new study, my colleagues and I found that rapamycin prolongs life almost as consistently as eating less, whereas metformin does not.

Eating less, or dietary restriction, has been the gold standard for achieving a longer life ever since a study nearly a century ago in which laboratory rats that ate less surprised scientists by outliving their well-fed lab mates.

But for many people, sticking to a permanent diet is hard and far from enjoyable. Also, if taken to extremes, it can even be bad for health. That is why we wanted to know whether drugs that are dieting mimics could bring the same benefit of eating less without the unwanted side-effects.

Rapamycin was first discovered in bacteria living in Easter Island soil in the 1970s, and medical professionals now use it to prevent organ-transplant rejection, as it is a powerful immunosuppressant. It works by blocking a molecular switch that tells cells when nutrients are abundant.

A combination of rapamycin and trametinib was recently found to extend mouse lifespan (K. Link/Max Planck Institute for Biology of Aging)

Metformin, meanwhile, is a synthetic descendant of a compound found in French lilac (also known as goat’s rue) and is widely prescribed to control blood sugar in type 2 diabetes. Both drugs are involved in the body’s ability to sense nutrients and energy, so biologists like us hoped they might copy the mechanisms activated by eating less.

To find out, we pooled the results of many studies to see if there were any overall patterns. We carefully examined thousands of scientific papers to finally home in on 167 studies on eight vertebrate species, from fish to monkeys, that provided sufficient details on survival and how the study was done. Then we compared three longevity strategies: eating less, taking rapamycin and taking metformin.

We found that eating less still came out on top as the most consistent way to prolong life in all animals but rapamycin was close behind. Metformin, in contrast, showed no clear benefit. The life-extension effect of eating less was the same in both sexes, and it didn’t matter whether the diet plan involved eating smaller portions or intermittent fasting.

That makes rapamycin one of the most exciting leads for new anti-ageing therapies. Ageing might not be considered a disease, but it is a risk factor behind many diseases, from cancer to dementia. If we slow that underlying process, the benefit will be extra years of quality life and lower healthcare bills as the world’s population grows older.

Encouraging early signs, but we’re not quite there yet

However, there are some important points to consider. First, we discovered considerable variation from experiment to experiment with some studies even showing that eating less or taking rapamycin reduced lifespan.

Also, most of the evidence originates from mice and rats that have many of our genes but are clearly not exactly like us.

Finally, rapamycin may have side effects such as repressing immunity and reproduction. Researchers are now investigating milder doses of rapamycin to see if they provide the advantages without the side effects.

The preliminary signs are encouraging. In an ongoing human rapamycin trial, volunteers given low, intermittent doses of rapamycin have experienced positive effects on indicators of healthspan. For metformin, the human trial is still in progress and the findings are expected to be out in a few years' time.

For now, nobody should run to their doctor asking for prescriptions of rapamycin to live longer. But this drug, extracted from obscure soil bacteria, shows us that interfering with a single molecular pathway can be enough to mimic the benefits of eating less. The challenge is to use this discovery to produce therapies that make us healthier for longer without compromising our quality of life – or our taste for the occasional slice of chocolate cake.

Zahida Sultanova is a Post Doctoral Research Fellow in the School of Biological Sciences at the University of East Anglia.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Transferrin and Borneol-Enhanced Liposomes for Targeted Rapamycin Delivery in TBI

 With all this earlier research on rapamycin  for stroke I bet our incompetent stroke medical 'professionals' have done ABSOLUTELY NOTHING! Aren't you glad they are so fucking incompetent that your children and grandchildren won't recover from a stroke? It took me all of two minutes to Google Scholar for 'rapamycin for stroke' and find all this; and I'm obviously stroke-addled and know nothing!

Rapamycin in ischemic stroke: Old drug, new tricks? 2019

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats 2018

The effect of rapamycin treatment on cerebral ischemia: a systematic review and meta-analysis of animal model studies 2019

Rapamycin Treatment Improves Neuron Viability in an In Vitro Model of Stroke 2013 

The rationale of targeting mammalian target of rapamycin for ischemic stroke 2013

Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke 2014

Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke 2014

The latest here:

Transferrin and Borneol-Enhanced Liposomes for Targeted Rapamycin Delivery in TBI

Authors Cai S, Yuan Z, Chen Y, Gong M, Lai J, Yan P, Mei Z

Received 29 July 2024

Accepted for publication 28 February 2025

Published 11 April 2025 Volume 2025:20 Pages 4503—4518

DOI https://doi.org/10.2147/IJN.S489165

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Kamakhya Misra

Download Article [PDF] 

Shihong Cai,^1,2,* Zhongwen Yuan,^1,* Yanfang Chen,³ Mingjie Gong,¹ Jianqi Lai,¹ Pengke Yan,¹ Zhengrong Mei<sup>1

1</sup>Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; ²Zhanjiang Healthcare Security Service Management Center, Zhanjiang, People’s Republic of China; ³Department of Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Pengke Yan, Email gysyypk@126.com Zhengrong Mei, Email meizhengrong@126.com

Background: The therapeutic potential of rapamycin (RAPA) for traumatic brain injury (TBI) is limited by its low bioavailability and poor penetration across the blood-brain barrier (BBB). We developed transferrin-modified rapamycin and borneol co-delivery liposomes (TF-RAPA/BO-LIP) to overcome these barriers, aiming to enhance both drug delivery to the brain and the treatment efficacy.
Methods: We employed the emulsion-solvent evaporation method to prepare TF-RAPA/BO-LIP and characterized their particle size, zeta potential, morphology, stability, and encapsulation efficiency. Pharmacokinetic studies were conducted in SD rats, and drug concentration was analyzed using LC-MS/MS. The brain-targeting capability and therapeutic efficacy were evaluated through in vitro cellular uptake studies, and in vivo in a TBI mouse model using both neurological and cognitive assessments.
Results: TF-RAPA/BO-LIP displayed optimal characteristics (95 nm particle size, > 90% encapsulation efficiency) and demonstrated enhanced stability. Pharmacokinetic analyses revealed reduced drug clearance and increased drug concentration-time curve area, indicating improved systemic and brain-specific drug bioavailability. Notably, TF-RAPA/BO-LIP achieved significantly higher RAPA accumulation in the brain tissue. Importantly, treatment with TF-RAPA/BO-LIP significantly ameliorated neurological deficits and improved spatial memory in TBI mice, as evidenced by behavioral tests.
Conclusion: Our study highlights TF-RAPA/BO-LIP as a promising strategy for delivering RAPA across the BBB, substantially enhancing its therapeutic efficacy for TBI. This novel liposomal system not only improves RAPA bioavailability but also offers significant neuroprotection, potentially transforming the clinical management of TBI.

Drug-Activated Protein Boosts Memory

 Did your competent? doctor and hospital do anything with this earlier research on rapamycin?

rapamycin (5 posts to May 2017)

Or anything with these 26 posts on memory loss?

• memory loss (26 posts to December 2015)

Or are you dealing with total incompetence in your stroke medical 'professionals'?

Drug-Activated Protein Boosts Memory

Summary: Researchers made a breakthrough in memory research by genetically modifying the LIMK1 protein, crucial for memory, to be controlled by the drug rapamycin.

This study demonstrates the ability to enhance memory functions by manipulating synaptic plasticity in the brain.

The engineered protein showed significant memory improvement in animal models with age-related cognitive decline, offering potential for innovative treatments for neuropsychiatric diseases like dementia. This ‘chemogenetic’ approach, blending genetics and chemistry, opens new avenues in neurological research and therapy.

Key Facts:

1. The LIMK1 protein, essential for memory formation, was genetically modified to be activated by rapamycin.
2. The modification improved memory in animal models, suggesting potential for treating memory-related neurodegenerative diseases.
3. The study represents a pioneering ‘chemogenetic’ strategy, offering a new method to control synaptic plasticity and memory functions.

Source: Universita Cattolica del Sacro Cuore

Neuroscientists at the Faculty of Medicine and Surgery of the Catholic University, Rome, and the Fondazione Policlinico Universitario Agostino Gemelli IRCCS have genetically modified a molecule, the protein LIMK1, which is normally active in the brain, with a key role in memory.

They added a “molecular switch” that is activated by administering a drug, rapamycin, known for its several anti-aging effects on the brain.

Credit: Neuroscience News

This is the result of a study published in the journal Science Advances, which involves the Catholic University, Rome, and the Fondazione Policlinico Universitario Agostino Gemelli IRCCS. The study was coordinated by Claudio Grassi, Full Professor of Physiology and Director of the Department of Neuroscience.

The research, supported by the Italian Ministry of Education, University and Research, the American Alzheimer’s Association Foundation, and the Italian Ministry of Health, has great potential applications, by improving our understanding of memory function and facilitating the identification of innovative solutions for neuropsychiatric diseases like dementia.

The LIMK1 protein plays a crucial role in determining structural changes in neurons, namely the formation of dendritic spines, which enhance information transmission in neural networks and are crucial in learning and memory processes.

Prof. Claudio Grassi, senior author of the study, explains: “Memory is a complex process that involves modifications in synapses, which are the connections between neurons, in specific brain areas such as the hippocampus, which is a neural structure playing a critical role in memory formation.

“This phenomenon, known as synaptic plasticity, involves changes in the structure and function of synapses that occur when a neural circuit is activated, for example, by sensory experiences. These experiences promote the activation of complex signaling pathways involving numerous proteins” Prof. Grassi adds.

“Some of these proteins are particularly important for memory, in fact reduced expression or modifications of these proteins are associated with alterations in cognitive functions.

“One of these proteins is LIMK1. The goal of our study was to regulate the activity of this protein, as it plays a key role in the maturation of dendritic spines between neurons. Controlling LIMK1 with a drug means being able to promote synaptic plasticity and, therefore, the physiological processes that depend on it,” Prof. Grassi emphasizes.

Cristian Ripoli, Associate Professor of Physiology at the Catholic University, and first author of the study, adds: “the key to this innovative ‘chemogenetic’ strategy, which combines genetics and chemistry, is precisely linked to the use of rapamycin”, an immunosuppressive drug known to increase life expectancy and for its beneficial effects on the brain, in preclinical models.

“We have therefore modified the sequence of the LIMK1 protein by inserting a molecular switch that allowed us to activate it, on command, through the administration of rapamycin” Prof. Ripoli emphasizes.

“In animals with age-related cognitive decline, using this gene therapy to modify the LIMK1 protein and activate it with the drug resulted in a significant memory improvement. This approach allows us to manipulate synaptic plasticity processes and memory in physiological and pathological conditions.

“Furthermore, it paves the way for the development of further ‘engineered’ proteins that could revolutionize research and therapy in the field of neurology,” the expert emphasizes.

“The next step will be to verify the effectiveness of this treatment in experimental models of neurodegenerative diseases exhibiting memory deficits, such as Alzheimer’s disease. Further studies will also be necessary to validate the use of this technology in humans” Prof. Grassi concludes.

About this memory research news

Author: Nicola Cerbino
Source: Universita Cattolica del Sacro Cuore
Contact: Nicola Cerbino – Universita Cattolica del Sacro Cuore
Image: The image is credited to Neuroscience News

Original Research: The findings will appear in Science Advances

mTOR pathway – a potential therapeutic target in stroke

Somebody should take responsibility for creating protocols using rapamycin and hamartin.

. But nothing will occur, there is NO leadership in stroke and NO strategy to solve stroke. You're screwed along with your children and grandchildren when they have strokes. 

• rapamycin (4 posts to May 2017)

  • hamartin (1 post to February 2013)

   

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mTOR pathway – a potential therapeutic target in stroke

Konstantinos Melanis https://orcid.org/0000-0002-3224-3053 melaniskos@gmail.com, Maria-Ioanna Stefanou https://orcid.org/0000-0002-2305-6627, […], and Themistoklis Papasilekas+1View all authors and affiliations

All Articles

https://doi.org/10.1177/17562864231187770

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• • Abstract
  • Introduction
  • Stroke pathophysiology and the role of autophagy and inflammation
  • The mTOR pathway
  • mTOR and stroke
  • Targeting the mTOR pathway in stroke
  • TSC complex and stroke
  • Conclusion
  • Acknowledgments
  • ORCID iDs
  • Footnotes
  • References
• PDF / ePub
• • Cite article
  • Share options
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Abstract

Stroke is ranked as the second leading cause of death worldwide and a major cause of long-term disability. A potential therapeutic target that could offer favorable outcomes in stroke is the mammalian target of rapamycin (mTOR) pathway. mTOR is a serine/threonine kinase that composes two protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and is regulated by other proteins such as the tuberous sclerosis complex. Through a significant number of signaling pathways, the mTOR pathway can modulate the processes of post-ischemic inflammation and autophagy, both of which play an integral part in the pathophysiological cascade of stroke. Promoting or inhibiting such processes under ischemic conditions can lead to apoptosis or instead sustained viability of neurons. The purpose of this review is to examine the pathophysiological role of mTOR in acute ischemic stroke, while highlighting promising neuroprotective agents such as hamartin for therapeutic modulation of this pathway. The therapeutic potential of mTOR is also discussed, with emphasis on implicated molecules and pathway steps that warrant further elucidation in order for their neuroprotective properties to be efficiently tested in future clinical trials.

Introduction

Ischemic stroke is a severely debilitating and life-threatening neurological disorder characterized by disturbed cerebral blood supply that results into cerebral hypoperfusion and – ultimately – neuronal cell death. Worldwide it is ranked as the second leading cause of death and a major cause of long-term disability.^1,2 Stroke is categorized in two main types, ischemic and hemorrhagic.³ Because of the wide variety of acute ischemic stroke (AIS) causes, several classification schemes have been proposed based on the underlying etiology, including the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification system, that distinguishes between five different AIS types: cardioembolic, thromboembolic, lacunar, cryptogenic, and AIS due to other causes.⁴

The mainstay treatment for ischemic stroke consists today of intravenous thrombolysis and endovascular thrombectomy, both aiming at recanalization of the occluded vessel and reperfusion of the ischemic cerebral tissue.^5,6 The secondary purpose of acute stroke treatments is to mobilize any agents which can alleviate the damage which has already been inflicted upon the nervous tissue. Despite tremendous advances in the field of stroke therapies, time to reperfusion remains the main limiting factor. With this in mind, neuroprotective agents that will attenuate neuronal damage until vessel recanalization may be achieved while also preventing a potential reperfusion injury have recently come into the focus of stroke research. An attractive target for such agents seems to be the mammalian target of rapamycin (mTOR) pathway, which is involved in both autophagy-related apoptosis and inflammation, processes of equally great importance in stroke pathophysiology.

Stroke pathophysiology and the role of autophagy and inflammation

To gain insight into the pathophysiological importance of the mTOR pathway in stroke, the complex pathophysiological processes implicated in cerebral ischemia must first be elucidated.

The chain of events leading to neuronal cell death in ischemic stroke starts with a decrease in cerebral blood flow within a certain area of the brain. This propagates a cascade of cellular and molecular events, known as the ischemic cascade.⁷ During the initial stages of ischemia, glucose- and oxygen-deprived neurons are forced into anaerobic metabolism. This, being an inherently less efficient energy production mode, results into a significant decrease in adenosine triphosphate (ATP) production, while at the same time, triggers release of lactic acid as a byproduct.⁶ Subsequently, ATP-dependent ion transport pumps fail, causing the cell membranes to become depolarized and leading to a large influx of Ca⁺². Intracellular Ca⁺² levels are further increased through the release of glutamate, an excitatory neurotransmitter that binds to and opens Ca⁺²-permeable N-methyl-D-aspartate receptors.⁸ The result of these cascades is activation of lytic enzymes and formation of free radicals.⁹ In this context, of great importance is the role of calpain, a calcium-activated cytosolic protease which cleaves a number of different cytoplasmic and nuclear substrates.¹⁰ Cells affected by ischemia eventually lose their structural integrity with their membranes becoming permeable to all sorts of ions and toxic chemicals and their organelles rendered inoperative. The end result of ischemia is activation of apoptosis and cellular death. Of note, autophagy and inflammation are mechanisms with a prominent role throughout this process. Triggered initially as processes for clearance of necrotic cells and toxic debris, they soon become somewhat of a ‘liability’ propagating brain injury.

Autophagy is a lysosome-mediated process that aims to remove, when activated, misfolded or aggregated cytosolic contents such as those encountered in stroke-affected cells.^11,12 Three types of autophagy are described in the literature, microautophagy, chaperone-mediated autophagy and macroautophagy.¹³ Macroautophagy utilizes double membrane vacuoles called phagophores to transport degraded cytoplasmic material to lysosomes in a five-step process.¹³ First, phagophores engulf their target molecules in a process known as enucleation. Subsequently, this turns them into autophagosomes, organelles that will ultimately merge with lysosomes creating autolysosomes.¹⁴ Autophagosomes have been identified in the hippocampus and also in the penumbra of stroke test animals and their importance in stroke pathophysiology has been well-documented.¹⁵ In particular, the formation of autophagosomes is induced by upregulation of microtubule-associated protein 1 light chain (LC3)-II (Figure 1). Two different forms of LC3 exist (Figure 1). The cytosolic type of LC3 (LC3-I) is conjugated to phosphatidylethanolamine and forms LC3-phosphatidylethanolamine conjugate (LC3-II), which is responsible for the development of autophagosomal membrane¹⁶ (Figure 1). In turn, within autolysosomes, enucleated macromolecules are eliminated through enzymatic cleavage. In the next phases which follow, elongation and expansion of the phagophore take place. Finally, through the transport of proteins to the lysosome the maturation of phagosome is achieved.^17,18 This whole process is regulated through sophisticated signaling pathways, namely those of mTOR and adenosine-monophosphate activated protein kinase (AMPK)^19,20 (Figure 1). mTOR inhibits autophagy by phosphorylating Unc-51-like kinase (ULK)²¹ (Figure 1). AMPK on the other hand promotes autophagy by suppressing mTOR while also directly activating ULK to induce it.²² It should be noted that ischemia propagates autophagy through AMPK activation^23,24 (Figure 1).

Figure 1. Regulation of the autophagic process.

In the autophagic process, mammalian target of rapamycin complex 1 (mTORC1) and adenosine-monophosphate activated protein kinase (AMPK) have an opposing effect. By phosphorylating the Unc-51-like kinase (ULK) complex, AMPK promotes autophagy whereas mTORC1 blocks it. ULK complex is the first step for the initiation of autophagy and an integral part for the development of preautophagosome. The next step for membrane nucleation is the mobilization the transmembrane complex, beclin-1. Autophagy-related genes 4,7,3 (Atg4, Atg7, Atg3) are responsible for the conversion of light chain 3 (LC3) into LC3-II which is important for the development of autophagosome. The double blue structure represents the cell membrane. Black arrows correspond to blocking of activity and red ones correspond to induction. ‘P’ corresponds to phosphorylation.

More at link.

Editorial: Inflammation in ischemic stroke and novel therapeutic strategies for stroke treatment

Somebody should take responsibility for creating protocols using metformin, rapamycin, and NMN. But nothing will occur, there is NO leadership in stroke and NO strategy to solve stroke. You're screwed along with your children and grandchildren when they have strokes. 

• Metformin (13 posts to July 2012)

• rapamycin (3 posts to May 2017)

• Distribution of Nicotinamide Mononucleotide(NMN) after Intravenous Injection in Normal and Ischemic Stroke Mice

   

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Editorial: Inflammation in ischemic stroke and novel therapeutic strategies for stroke treatment

Hany E. Marei^1*, Changjun Yang², Carlo Cenciarelli^3* and Assia Jaillard⁴

• ¹Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
• ²Department of Neuroscience, University of Florida, Gainesville, FL, United States
• ³Institute of Translational Pharmacology (IFT)-CNR, Rome, Italy
• ⁴Université Grenoble Alpes Saint Martin d'Hères, Grenoble, France

Editorial on the Research Topic
Inflammation in ischemic stroke and novel therapeutic strategies for stroke treatment

Stroke is one of the leading causes of death and long-term disability worldwide (1). An ischemic stroke occurs when a major cerebral blood vessel becomes blocked, depriving downstream tissue of oxygen and nutrients and resulting in cell death within minutes at the core of the infarct. Dying cells release pro-inflammatory signals, which activate resident astrocytes/microglia and initiate immune cell infiltration from the periphery into the damaged tissue, contributing to blood–brain barrier disruption and exacerbating cell death in a process known as secondary inflammation(NO, that doesn't sound critical enough, the Rockefeller University called it the cascade of death in 2009. NOW THAT SOUNDS IMPORTANT ENOUGH TO STOP IMMEDIATELY!) which can last for days to weeks after the initial insult (2). The premise of tissue repair in acute ischemic stroke is the proper termination of cell-death-induced neural inflammation (AIS). Macrophages scavenge cell corpses and produce inflammatory mediators that coordinate immune responses (3).

Stem cell therapy is a hot research area and a promising clinical therapeutic modality for ischemic stroke. Cell-engineering approaches are expected to usher in a new generation of stem cell-based therapies, greatly expanding their therapeutic utility for a variety of traumatic and neurodegenerative diseases, including ischemic stroke (4).

This Research Topic includes five manuscripts that highlight current knowledge and future directions in the role of neuroinflammation and the potential use of cell-based therapies in ischemic stroke. Zhou et al. look into whether L-4F displays neurorestorative benefits in the ischemic brain and the underlying molecular mechanisms after stroke in type 2 diabetes mellitus (T2DM). They concluded that administering L-4F post-stroke may provide a restorative strategy for type 2 diabetes mellites (T2DM)-stroke by promoting neurovascular and white matter (WM) remodeling. Reducing neuroinflammation in the injured brain may aid the restorative effects of L-4F that are not mediated by the ABCA1 signaling pathway (Zhou et al.). Yu et al. have looked at the effects of metformin, rapamycin, and nicotinamide mono nucleotide (NMN) on cognitive function, white matter integrity, microglial response, and phagocytosis in a rat model of vascular cognitive impairment (VCI) caused by bilateral common carotid artery occlusion (BCCAO). According to the findings, metformin, rapamycin, or NMN may protect or mitigate cognitive impairment and WMLs by modifying microglial polarization and inhibiting phagocytosis. The findings could pave the way for a new approach to VCI treatment (Yu et al.). Zhao et al. compared the remote ischemic postconditioning (RIPostC) group to a control group in a meta-analysis of eligible randomized controlled trials in patients with ischemic stroke. They concluded that RIPostC is safe and effective, with a positive cerebral protective effect in patients with ischemic stroke, and that large-sample, multicenter trials are needed to validate RIPostC's cerebral protective effect in the future (5). Custodia et al. review the most recent advances in preclinical and clinical research on the use of endothelial progenitor cells (EPCs) after stroke, not only as a single treatment but also in combination with novel therapeutic approaches. Following cerebrovascular damage, EPCs can repair damaged vessels as well as generate new ones. EPCs are circulating cells that have endothelial cell and adult stem cell characteristics, including the ability to differentiate into mature endothelial cells and self-renew. Furthermore, EPCs have the advantage of already being present in healthy conditions as circulating cells that participate in endothelial maintenance in a direct and paracrine manner. Based on clinical data demonstrating a better neurological and functional outcome in ischemic stroke patients with higher levels of circulating EPCs, novel and promising therapeutic approaches would be EPCs-promoting pharmacological treatments as well as EPCs-based therapies (5). In rodent stroke models, Satani et al. have proposed that systemic administration of marrow stromal cells (MSCs) causes the release of a wide range of factors that mediate recovery. In this study they have investigated the immunomodulatory interactions between MSCs and peripheral blood-derived monocytes (Mo) obtained from acute stroke patients. This study found MSCs had a differential effect on Mo derived from acute stroke patients vs. those derived from healthy controls, suggesting that immunomodulation of immune cells may represent a therapeutic target for MSCs in patients with acute stroke (Satani et al.).

Rapamycin restores brain vasculature, metabolism, and blood-brain barrier in an inflammaging model

 

Your doctors and stroke hospital should contact researchers and get appropriate human research going. Not doing so is an indictment of the complete stroke hospital starting at the top with the board of directors.

Rapamycin restores brain vasculature, metabolism, and blood-brain barrier in an inflammaging model

• Rheal A. Towner,
• Rafal Gulej,
• Michelle Zalles,
• Debra Saunders,
• Nataliya Smith,
• Megan Lerner,
• Kathryn A. Morton &
• Arlan Richardson 

GeroScience (2021)Cite this article

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Abstract

Rapamycin (RAPA) is found to have neuro-protective properties in various neuroinflammatory pathologies, including brain aging. With magnetic resonance imaging (MRI) techniques, we investigated the effect of RAPA in a lipopolysaccharide (LPS)-induced inflammaging model in rat brains. Rats were exposed to saline (control), or LPS alone or LPS combined with RAPA treatment (via food over 6 weeks). Arterial spin labeling (ASL) perfusion imaging was used to measure relative cerebral blood flow (rCBF). MR spectroscopy (MRS) was used to measure brain metabolite levels. Contrast-enhanced MRI (CE-MRI) was used to assess blood-brain barrier (BBB) permeability. Immunohistochemistry (IHC) was used to confirm neuroinflammation. RAPA restored NF-κB and HIF-1α to normal levels. RAPA was able to significantly restore rCBF in the cerebral cortex post-LPS exposure (p < 0.05), but not in the hippocampus. In the hippocampus, RAPA was able to restore total creatine (Cr) acutely, and N-acetyl aspartate (NAA) at 6 weeks, post-LPS. Myo-inositol (Myo-Ins) levels were found to decrease with RAPA treatment acutely post-LPS. RAPA was also able to significantly restore the BBB acutely post-LPS in both the cortex and hippocampus (p < 0.05 for both). RAPA was found to increase the percent change in BOLD signal in the cortex at 3 weeks, and in the hippocampus at 6 weeks post-LPS, compared to LPS alone. RAPA treatment also restored the neuronal and macro-vascular marker, EphB2, back to normal levels. These results indicate that RAPA may play an important therapeutic role in inhibiting neuroinflammation by normalizing brain vascularity, BBB, and some brain metabolites, and has a high translational capability.

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