bims-longev 2023-01-22 papers

bims-longev

Biomed News

on Longevity

Issue of 2023–01–22
twenty-one papers selected by
Andreea Nitescu

Mitochondrial stress and mitokines in aging.
A Proteome-Centric View of Ageing, including that of the Skin and Age-Related Diseases: Considerations of a Common Cause and Common Preventative and Curative Interventions.
Blood-to-brain communication in aging and rejuvenation.
Programmed Death of Microglia in Alzheimer's Disease: Autophagy, Ferroptosis, and Pyroptosis.
Early Stage Alzheimer's Disease: Are Skeletal Muscle and Exercise the Key?
Compound combinations targeting longevity: challenges and perspectives.
Is aging "normal"?
Role of Gut Microbiome in Cardiovascular Events: A Systematic Review.
Epigenetic age acceleration correlates with BMI in young adults.
The influence of hypertension, diabetes, lipid disorders and the presence of the APOE4 allele on the cognitive functions of patients over 65 years of age.
Can Immersive Sound Therapy Counteract Neurodegeneration by Enhancing Glymphatic Clearance? Comment on Sachdeva et al. Effects of Sound Interventions on the Permeability of the Blood-Brain Barrier and Meningeal Lymphatic Clearance. Brain Sci. 2022, 12, 742.
Nutraceuticals in the Prevention and Therapeutic Treatment of Cardiovascular and Cerebrovascular Disease.
Gut Enterobacteriaceae and uraemic toxins - Perpetrators for ageing.
Reduction in Lens Epithelial Cell Senescence Burden through Dasatinib Plus Quercetin or Rapamycin Alleviates D-Galactose-Induced Cataract Progression.
Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimer's disease hallmarks.
Fisetin alleviates cellular senescence through PTEN mediated inhibition of PKCδ-NOX1 pathway in vascular smooth muscle cells.
Effects of Low-Dose Colchicine on Serum High-Sensitivity C-Reactive Protein Level in Coronary Artery Disease Patients with Type 2 Diabetes Mellitus and Enhanced Inflammatory Response Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase 2, Dose-Finding Study.
The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans.
A New Target in Inflammatory Diseases: Lycopene.
Type D personality as a risk factor for adverse outcome in patients with cardiovascular disease: an individual patient data meta-analysis.
Progress in the study of ferroptosis in cancer treatment: State-of-the-Art.

Aging Cell. 2023 Jan 15. e13770

Mitochondrial stress and mitokines in aging.

Johannes Burtscher, Afsaneh Soltany, Nishant P Visavadiya, Martin Burtscher, Grégoire P Millet, Kayvan Khoramipour, Andy V Khamoui.

  Mitokines are signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues. Among those molecules are FGF21, GDF15 (both expressed in the nucleus) and several mitochondrial-derived peptides, including humanin. Their responsiveness to mitochondrial stress induces mitokine-signaling in response for example to exercise, following mitochondrial challenges in skeletal muscle. Such signaling is emerging as an important mediator of exercise-derived and dietary strategy-related molecular and systemic health benefits, including healthy aging. A compensatory increase in mitokine synthesis and secretion could preserve mitochondrial function and overall cellular vitality. Conversely, resistance against mitokine actions may also develop. Alterations of mitokine-levels, and therefore of mitokine-related inter-tissue cross talk, are associated with general aging processes and could influence the development of age-related chronic metabolic, cardiovascular and neurological diseases; whether these changes contribute to aging or represent "rescue factors" remains to be conclusively shown. The aim of the present review is to summarize the expanding knowledge on mitokines, the potential to modulate them by lifestyle and their involvement in aging and age-related diseases. We highlight the importance of well-balanced mitokine-levels, the preventive and therapeutic properties of maintaining mitokine homeostasis and sensitivity of mitokine signaling but also the risks arising from the dysregulation of mitokines. While reduced mitokine levels may impair inter-organ crosstalk, also excessive mitokine concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure. Preservation of healthy mitokine signaling levels can be achieved by regular exercise and is associated with an increased lifespan.

Keywords:  FGF21; GDF15; humanin; mitochondria-derived peptides; mitochondrial stress response; mitohormesis; mitokines

DOI:  https://doi.org/10.1111/acel.13770
Clin Cosmet Investig Dermatol. 2023 ;16 79-85

A Proteome-Centric View of Ageing, including that of the Skin and Age-Related Diseases: Considerations of a Common Cause and Common Preventative and Curative Interventions.

Isabelle Benoit, Elodie Burty-Valin, Miroslav Radman.

  The proteome comprises all proteins of a cell or organism. To carry their catalytic and structure-related functions, proteins must be correctly folded into their unique native three-dimensional structures. Common oxidative protein damage affects their functionality by impairing their catalytic and interactive specificities. Oxidative damage occurs preferentially to misfolded proteins and fixes the misfolded state. This review provides an overview of the mechanism and consequences of oxidative proteome damage - specifically irreversible protein carbonylation - in relation to ageing, including that of the skin as well as to age-related degeneration and diseases (ARDD) and their mitigation. A literature review of published manuscripts, available from PubMed, focusing on proteome, proteostasis, proteotoxicity, protein carbonylation, related inflammatory diseases, ARDD and the impact of the damaged proteome on ageing. During ageing, proteome damage, especially protein carbonylation, correlates with biological age. Carbonylated proteins form aggregates which can be considered as markers and accelerators of ageing and are common markers of most ARDD. Protein carbonylation leads to general ageing of the organism and organs including the skin and potentially to diseases including Alzheimer and Parkinson disease, diabetes, psoriasis, and skin cancer. Current research is promising and may open new therapeutic approaches and perspectives by targeting proteome protection as an age and ARDD management strategy.

Keywords:  antioxidant chemical chaperones; oxidative stress; protein carbonylation; protein folding; proteome; skin ageing

DOI:  https://doi.org/10.2147/CCID.S397751
Nat Neurosci. 2023 Jan 16.

Blood-to-brain communication in aging and rejuvenation.

Gregor Bieri, Adam B Schroer, Saul A Villeda.

Aging induces molecular, cellular and functional changes in the adult brain that drive cognitive decline and increase vulnerability to dementia-related neurodegenerative diseases. Leveraging systemic and lifestyle interventions, such as heterochronic parabiosis, administration of 'young blood', exercise and caloric restriction, has challenged prevalent views of brain aging as a rigid process and has demonstrated that aging-associated cognitive and cellular impairments can be restored to more youthful levels. Technological advances in proteomic and transcriptomic analyses have further facilitated investigations into the functional impact of intertissue communication on brain aging and have led to the identification of a growing number of pro-aging and pro-youthful factors in blood. In this review, we discuss blood-to-brain communication from a systems physiology perspective with an emphasis on blood-derived signals as potent drivers of both age-related brain dysfunction and brain rejuvenation.

DOI: https://doi.org/10.1038/s41593-022-01238-8
J Prev Alzheimers Dis. 2023 ;10(1): 95-103

Programmed Death of Microglia in Alzheimer's Disease: Autophagy, Ferroptosis, and Pyroptosis.

Z Qiu, H Zhang, M Xia, J Gu, K Guo, H Wang, C Miao.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Increasing evidence has demonstrated that the damage of cell plays an important role in AD. Cell death is a critical phenomenon for physiological functions, which promotes AD pathogenesis. Programmed cell death, including necroptosis, pyroptosis, autophagy, and ferroptosis, have been discovered that have unique biological functions and pathophysiological characteristics. Here, we review the available evidence detailing the mechanisms of programmed microglial death, including pyroptosis, autophagy, and ferroptosis. We also highlight the role of programmed death of microglia during the process of AD and focus on the connection between the disease and cell death.

Keywords:  Alzheimer’s disease; autophagy; cell death; ferroptosis; microglia; pyroptosis

DOI:  https://doi.org/10.14283/jpad.2023.3
J Appl Physiol (1985). 2023 Jan 19.

Early Stage Alzheimer's Disease: Are Skeletal Muscle and Exercise the Key?

Matthew H Brisendine, Joshua C Drake.

  Alzheimer's disease (AD) is the most common form of dementia affecting approximately 6.5 million people in the United States alone. The development of AD progresses over a span of years to possible decades before resulting in cognitive impairment and clinically diagnosed AD. The time leading up to a clinical diagnosis is known as the preclinical phase, a time in which recent literature has noted a more severe loss of body mass and more specifically lean muscle mass and strength prior to diagnosis. Mitochondria dysfunction in neurons is also closely associated with AD, and mitochondrial dysfunction has been seen to occur in skeletal muscle with mild cognitive impairment prior to AD manifestation. Evidence from animal models of AD suggest a close link between skeletal muscle mass, mitochondria function, and cognition. Exercise is a powerful stimulus for improving mitochondria function, muscle health, and offers benefits to cognition has been suggested as a possible therapeutic strategy for AD. However, evidence for beneficial effects of exercise in AD afflicted populations and animal models have produced conflicting results. In this mini-review, we discuss these findings and highlight potential avenues for further investigation that may lead to the implementation of exercise as a therapeutic intervention to delay or prevent the development of AD.

Keywords:  alzheimer's disease; exercise; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00659.2022
Ageing Res Rev. 2023 Jan 12. pii: S1568-1637(23)00010-7. [Epub ahead of print] 101851

Compound combinations targeting longevity: challenges and perspectives.

Olga Y Rybina, Alexander V Symonenko, Elena G Pasyukova.

  Aging is one of the world's greatest concerns, requiring urgent, effective, large-scale interventions to decrease the number of late-life chronic diseases and improve human healthspan. Anti-aging drug therapy is one of the most promising strategies to combat the effects of aging. However, most geroprotective compounds are known to successfully affect only a few aging-related targets. Given this, there is a great biological rationale for the use of combinations of anti-aging interventions. In this review, we characterize the various types of compound combinations used to modulate lifespan, discuss the existing evidence on their role in life extension, and present some key points about current challenges and future prospects for the development of combination drug anti-aging therapy.

Keywords:  aging; antioxidants; compound combinations; epigenetic drugs; lifespan; senolytics

DOI:  https://doi.org/10.1016/j.arr.2023.101851
Aging Pathobiol Ther. 2022 ;4(4): 98-99

Is aging "normal"?

Chloe Johnson, Warren Ladiges.

The descriptive term "normal" aging is often used in scientific literature to indicate commonly occurring changes with increasing age in the absence of overt disease. However, significant molecular and geropathological changes are increasingly present to indicate there is nothing normal about aging. Thus, the term "normal" aging is scientifically incorrect. There are changes in multiple genetic and epigenetic processes and pathways that drive aging, and some individuals are more resilient to these changes than others. Thus, "resilient" aging would be a more correct term to represent a major emphasis on investigating mechanisms and therapeutic targets for resilience, rather than a label of "normal" aging that is misleading and currently receives relatively little attention.

Keywords: Aging; age-related changes; geropathology; resilient aging; “Normal” aging
Cureus. 2022 Dec;14(12): e32465

Role of Gut Microbiome in Cardiovascular Events: A Systematic Review.

Naushad M Mansuri, Neelam K Mann, Shariqa Rizwan, Afrah E Mohamed, Ahmed E Elshafey, Akanchha Khadka, Emmanuel Mudika Mosuka, Kalanchige N Thilakarathne, Lubna Mohammed.

  The gut microbiome helps maintain homeostasis in the body, but what if the gut experiences imbalance? It would lead to dysbiosis - which is involved in multiple diseases, including but not limited to cardiovascular diseases, the most common cause of mortality around the globe. This research paper aims to explain all the possible mechanisms known linking the gut microbiome to the contribution of worsening cardiovascular events. PubMed and Google Scholar were thoroughly explored to learn the role of the gut microbiome in cardiovascular events. A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to analyze the possible pathways and the metabolites included in the study. Thirteen review articles were selected based on the assessment of multiple systematic reviews (AMSTAR) and the scale for the assessment of non-systematic review articles (SANRA) checklist scores. In this article, we have discussed the role of the gut microbiome in atherosclerosis, hypertension, metabolic disorders such as diabetes and obesity, coronary artery disease, etc. Various pathways to modify the gut microbiome are also discussed, along with the use of probiotics. Finally, we discussed the role of trimethylamine N-oxide (TMAO), a gut microbiome metabolite, as a biomarker for the prognosis of various diseases. This study concluded that the gut microbiome does play a crucial role in the worsening of cardiovascular diseases and the metabolites of which can be used as biomarkers in the prognosis of cardiovascular events.

Keywords:  atherosclerosis; bacteria in the intestines; bacteroidetes; cardiovascular disease; cardiovascular events; firmicutes; gastrointestinal flora; gut microbiome; gut microbiota; myocardial infarction

DOI:  https://doi.org/10.7759/cureus.32465
Aging (Albany NY). 2023 Jan 18. 15

Epigenetic age acceleration correlates with BMI in young adults.

Christy Anne Foster, Malcolm Barker-Kamps, Marlon Goering, Amit Patki, Hemant K Tiwari, Sylvie Mrug.

   INTRODUCTION: Obesity increases the risk of Type 2 diabetes, cardiovascular disease, several types of cancer, and other age-related disorders. Among older adults, obesity is also related to epigenetic age, typically measured with DNA methylation (DNAm). Because less is known about obesity and epigenetic aging earlier in the lifespan, this study examined the relationship between obesity and DNAm in young adulthood and whether these relationships vary by sex.
METHODS: A cross-sectional community sample of 290 healthy young adults (mean age 27.39 years, 60% female; 80% African American, 18% White) had their BMI and waist circumference measured. Four epigenetic age estimators were derived from salivary DNA: Hannum DNAm, Horvath DNAm, Phenoage DNAm, and GrimAge DNAm. Sociodemographic covariates included age, sex, race, parental education, and income-to-needs ratio.
RESULTS: After adjusting for covariates, higher BMI and waist were associated with higher DNAm PhenoAge in both sexes, with a stronger effect on BMI in males (β = 0.35, p < .001) compared to females (β = 0.13, p = .002). Higher waist, but not BMI, was associated with higher Horvath DNA methylation age. Both BMI and waist circumference were associated with higher Hannum DNAm age in men but not in women. Neither BMI nor waist circumference were related to GrimAge.
DISCUSSION: This study extends prior research by linking obesity with accelerated epigenetic aging in young adulthood, replicating the associations across two measures of obesity and four indices of salivary epigenetic aging. The results add to evidence that higher BMI accelerates aging early in the lifespan.

Keywords:  DNA methylation; epigenetic acceleration; epigenetic aging; obesity; young adult

DOI:  https://doi.org/10.18632/aging.204492
Pol Merkur Lekarski. 2022 Dec 22. 50(300): 391-394

The influence of hypertension, diabetes, lipid disorders and the presence of the APOE4 allele on the cognitive functions of patients over 65 years of age.

Radosław Zachara, Adam Właszczuk, Agnieszka Gorzkowska, Halina Jędrzejowska-Szypułka.

Diabetes mellitus (DM) and hypertension (HA) are common diseases in the population of people over 65 years of age. Many studies show the impact of the long-lasting decompensation of these chronic diseases, often diagnosed in middle age, on the cognitive functioning of elderly patients.
RESULTS: There is almost 30% prevalence of cognitive impairment among patients diagnosed with arterial hypertension. Possible explanation includes intensification of inflammatory processes in the central nervous system, influence on cerebral blood flow and acceleration of atherosclerosis. Another analyzed factor is the presence of diabetes. DM impacts the development of Alzheimer's disease. The inflammatory processes are intensified by advanced glycation products promoting atherosclerotic changes in blood vessels. In addition to that, the presence of hypoglycemic episodes significantly increases the risk of dementia. Moreover, approximately 78% of adult diabetic patients are also diagnosed with arterial hypertension, resulting in the coexistence of these CNS damaging mechanisms. The effect of elevated total cholesterol concentration on cognitive performance is still under debate and more research is needed. The role of the presence of ApoE4 in the development of cognitive dysfunctions, including Alzheimer's disease is emphasized.
CONCLUSIONS: In daily medical practice, extraordinary attention should be paid to control of chronic diseases of the patient, especially in the middle age. It improves cognitive functioning, possibly extending the quality-adjusted life year expectancy.

Keywords: APOE4; cognition; diabetes mellitus; hyperlipidemia; hypertension
Brain Sci. 2023 Jan 04. pii: 98. [Epub ahead of print]13(1):

Can Immersive Sound Therapy Counteract Neurodegeneration by Enhancing Glymphatic Clearance? Comment on Sachdeva et al. Effects of Sound Interventions on the Permeability of the Blood-Brain Barrier and Meningeal Lymphatic Clearance. Brain Sci. 2022, 12, 742.

Peter Wostyn, Piet Goddaer.

  We would like to congratulate Sachdeva and colleagues for establishing an informative review regarding the effects of music/sound exposure on blood-brain barrier permeability and meningeal lymphatic/glymphatic clearance, and would appreciate the opportunity to make a comment. The review by Sachdeva and colleagues documents the beneficial effects of sound interventions on blood-brain barrier permeability and the activity of the meningeal lymphatic/glymphatic system. The authors further note that sound interventions may have the potential to reduce the accumulation of amyloid-β within the brain in Alzheimer's disease through improved meningeal lymphatic/glymphatic clearance. The authors also nicely discuss evidence that music influences sleep quality, which may facilitate glymphatic solute clearance as a result of an increase in the interstitial space, which results in reduced resistance to fluid transport. We fully agree with this notion, since we recently hypothesized that immersive sound therapy may be an innovative approach to reduce the individual risk of developing neurodegenerative diseases, such as Alzheimer's disease, by inducing EEG slow-wave delta oscillations (which characterize deep sleep), thereby promoting glymphatic clearance.

Keywords:  Alzheimer’s disease; glymphatic system; immersive sound; meditation; neurodegenerative disorders; slow-wave activity

DOI:  https://doi.org/10.3390/brainsci13010098
J Cardiopulm Rehabil Prev. 2023 Jan 19.

Nutraceuticals in the Prevention and Therapeutic Treatment of Cardiovascular and Cerebrovascular Disease.

Bradley S Fleenor, Nicholas A Carlini, Christopher R Martens.

PURPOSE: This review overviews and highlights arterial stiffening as a key physiological process and target for the prevention and/or lowering of cardio- and cerebrovascular disease (collectively CVD) risk.
METHODS: We identified nutraceutical approaches from randomized controlled trials and discussed the associated mechanisms by which these compounds lower age-related arterial stiffness. Age-related CVD are the leading cause of mortality in modernized societies. Arterial dysfunction, specifically stiffening of the large elastic arteries during midlife, is a key physiological process resulting in increased CVD risk. Current pharmaceutical approaches for lowering age-related arterial stiffness have limited efficacy, thus highlighting the need to identify novel approaches for lowering arterial stiffness and thereby CVD risk. Lifestyle interventions are a historical first-line approach to prevent and/or lower the adverse arterial stiffening effects observed with aging. Nutraceutical interventions, defined as a food or part of a food providing health benefits, are a nonpharmacological, novel lifestyle approach to lower age-associated arterial stiffness. Therefore, identifying nutraceutical approaches to lower CVD risk is clinically significant.
SUMMARY: This review provides a basic, yet essential, understanding for emerging nutraceutical strategies for the prevention and therapeutic treatment of CVD.

DOI: https://doi.org/10.1097/HCR.0000000000000773
Exp Gerontol. 2023 Jan 13. pii: S0531-5565(23)00009-8. [Epub ahead of print]173 112088

Gut Enterobacteriaceae and uraemic toxins - Perpetrators for ageing.

Seenivasan Boopathi, R M Saravana Kumar, P Snega Priya, B Haridevamuthu, S P Ramya Ranjan Nayak, Laura Chulenbayeva, Kushugulova Almagul, Jesu Arockiaraj.

  Ageing is a complex process that is associated with changes in the composition and functions of gut microbiota. Reduction of gut commensals is the hallmarks of ageing, which favours the expansion of pathogens even in healthy centenarians. Interestingly, gut Enterobacteriaceae have been found to be increased with age and also consistently observed in the patients with metabolic diseases. Thus, they are associated with all-cause mortality, regardless of genetic origin, lifestyle, and fatality rate. Moreover, Enterobacteriaceae are also implicated in accelerating the ageing process through telomere attrition, cellular senescence, inflammasome activation and impairing the functions of mitochondria. However, acceleration of ageing is likely to be determined by intrinsic interactions between Enterobacteriaceae and other associated gut bacteria. Several studies suggested that Enterobacteriaceae possess genes for the synthesis of uraemic toxins. In addition to intestine, Enterobacteriaceae and their toxic metabolites have also been found in other organs, such as adipose tissue and liver and that are implicated in multiorgan dysfunction and age-related diseases. Therefore, targeting Enterobacteriaceae is a nuance approach for reducing inflammaging and enhancing the longevity of older people. This review is intended to highlight the current knowledge of Enterobacteriaceae-mediated acceleration of ageing process.

Keywords:  Enterobacteriaceae; Gut dysbiosis; Inflammaging; Metabolic diseases; Uraemic toxins

DOI:  https://doi.org/10.1016/j.exger.2023.112088
J Funct Biomater. 2022 Dec 21. pii: 6. [Epub ahead of print]14(1):

Reduction in Lens Epithelial Cell Senescence Burden through Dasatinib Plus Quercetin or Rapamycin Alleviates D-Galactose-Induced Cataract Progression.

Yinhao Wang, Yulin Tseng, Keyu Chen, Xinglin Wang, Zebin Mao, Xuemin Li.

  Senescent cells accumulate in aged organisms and promote the progression of age-related diseases including cataracts. Therefore, we aimed to study the therapeutic effects of senescence-targeting drugs on cataracts. In this study, a 28-day D-galactose-induced cataract rat model was used. The opacity index, a grading based on slit-lamp observations, was used to assess lens cloudiness. Furthermore, the average lens density (ALD), lens density standard deviation (LDSD), and maximum lens density (MLD) obtained from Scheimpflug images were used to assess lens transparency. Immunohistochemical stainings for p16 and γH2AX were used as hallmarks of senescence. We treated rat cataract models with the senolytic drug combination dasatinib plus quercetin (D+Q) and senescence-associated secretory phenotype (SASP) inhibitors. In comparison to control lenses, D-galactose-induced cataract lenses showed a higher opacity index, ALD, LDSD, and MLD values, as well as accumulation of senescent lens epithelial cells (LECs). After D+Q treatment, ALD, LDSD, and MLD values on day 21 were significantly lower than those of vehicle-treated model rats. The expression levels of p16 and γH2AX were also reduced after D+Q administration. In addition, the SASP inhibitor rapamycin decreased the opacity index, ALD, LDSD, and MLD values on day 21. In conclusion, D+Q alleviated D-galactose-induced cataract progression by reducing the senescent LEC burden in the early stage of cataract.

Keywords:  cataract; senescence; senescence-associated secretory phenotype; senolytic

DOI:  https://doi.org/10.3390/jfb14010006
Aging Cell. 2023 Jan 15. e13775

Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimer's disease hallmarks.

Nikhil Dave, Jessica M Judd, Annika Decker, Wendy Winslow, Patrick Sarette, Oscar Villarreal Espinosa, Savannah Tallino, Samantha K Bartholomew, Alina Bilal, Jessica Sandler, Ian McDonough, Joanna K Winstone, Erik A Blackwood, Christopher Glembotski, Timothy Karr, Ramon Velazquez.

  There is an urgent need to identify modifiable environmental risk factors that reduce the incidence of Alzheimer's disease (AD). The B-like vitamin choline plays key roles in body- and brain-related functions. Choline produced endogenously by the phosphatidylethanolamine N-methyltransferase protein in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. ~90% of Americans do not reach the recommended daily intake of dietary choline. Thus, it's imperative to determine whether dietary choline deficiency increases disease outcomes. Here, we placed 3xTg-AD, a model of AD, and non-transgenic (NonTg) control mice on either a standard laboratory diet with sufficient choline (ChN; 2.0 g/kg choline bitartrate) or a choline-deficient diet (Ch-; 0.0 g/kg choline bitartrate) from 3 to 12 (early to late adulthood) months of age. A Ch- diet reduced blood plasma choline levels, increased weight, and impaired both motor function and glucose metabolism in NonTg mice, with 3xTg-AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, elevated soluble and insoluble Amyloid-β and Thioflavin S structures, and tau hyperphosphorylation at various pathological epitopes in the hippocampus and cortex of 3xTg-AD Ch- mice. To gain mechanistic insight, we performed unbiased proteomics of hippocampal and blood plasma samples. Dietary choline deficiency altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, dietary choline deficiency altered protein networks associated with insulin metabolism, mitochondrial function, inflammation, and fructose metabolic processing. Our data highlight that dietary choline intake is necessary to prevent systems-wide organ pathology and reduce hallmark AD pathologies.

Keywords:  aging; aldob; amyloid-beta; cardiac hypertrophy; choline; liver; motor function; tau pathogenesis

DOI:  https://doi.org/10.1111/acel.13775
Arch Gerontol Geriatr. 2023 Jan 11. pii: S0167-4943(23)00007-9. [Epub ahead of print]108 104927

Fisetin alleviates cellular senescence through PTEN mediated inhibition of PKCδ-NOX1 pathway in vascular smooth muscle cells.

Seul Gi Kim, Jin Young Sung, Young Jin Kang, Hyoung Chul Choi.

  Reactive oxygen species (ROS) are a key risk factor of cellular senescence and age-related diseases, and protein kinase C (PKC) has been shown to activate NADPH oxidases (NOXs), which generate ROS. Although PKC activation induces oxidative stress, leading to the cellular dysfunction in various cell types, the correlation between PKC and senescence has not been reported in vascular smooth muscle cell (VSMC). Several studies have indicated cellular senescence is accompanied by phosphatase and tensin homolog (PTEN) loss and that an interaction exists between PTEN and PKC. Therefore, we aimed to determine whether PTEN and PKC are associated with VSMC senescence and to investigate the mechanism involved. We found hydrogen peroxide (H2O2) decreased PTEN expression and increased PKCδ phosphorylation. Moreover, H2O2 upregulated the NOX1 subunits, p22phox and p47phox, and induced VSMC senescence via p53-p21 signaling pathway. We identified PKCδ activation contributed to VSMC senescence through activation of NOX1 and ROS production. However, fisetin inhibited cellular senescence induced by the PTEN-PKCδ-NOX1-ROS signaling pathway, and this anti-aging effect was attributed to reduced ROS production caused by suppressing NOX1 activation. These results suggest that the PTEN-PCKδ signaling pathway is directly related to senescence via NOX1 activation and that the downregulation of PKCδ by flavonoids provides a potential means of treating age-associated diseases.

Keywords:  Fisetin; NADPH oxidase 1; PKCδ; Senescence; Vascular smooth muscle cell

DOI:  https://doi.org/10.1016/j.archger.2023.104927
Biomed Hub. 2022 Sep-Dec;7(3):7(3): 156-164

Effects of Low-Dose Colchicine on Serum High-Sensitivity C-Reactive Protein Level in Coronary Artery Disease Patients with Type 2 Diabetes Mellitus and Enhanced Inflammatory Response Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase 2, Dose-Finding Study.

Yoshikazu Miwa, Akiko Mutoh, Takeshi Morimoto, Yumi Ikehara, Takanori Yasu, Shinji Koba, Junya Ako, Yukihito Higashi, Masato Kajikawa, Hiroki Uehara, Kazuo Ishikawa, Ichiro Sakuma, Hirofumi Tomiyama, Koichi Node, Yuji Kumagai, Shinichiro Ueda.

  Although cardiovascular mortality in Japan is lower than in other industrialized countries, clinical outcomes in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM) remain poor despite multiple evidence-based drug therapies and interventions. We assumed that part of residual risk in these patients may be attributable to enhanced inflammation, which can be inhibited presumably by colchicine. However, dose-responsiveness of anti-inflammatory effect of colchicine has not been elucidated. Therefore, we designed a multicenter, randomized, double-blinded, parallel-group study to explore the dose-dependent effects of low-dose colchicine on serum high-sensitivity C-reactive protein (hs-CRP) concentration and safety in CAD patients with T2DM and enhanced inflammatory response as a phase 2 study. Enhanced inflammatory response was defined as peripheral white-blood cell count ≥7,000/μL. Patients (N = 63) will be randomly assigned to two doses of colchicine 0.25 mg/day, 0.5 mg/day, or placebo in a 1:1:1 ratio once daily for 12 weeks. Changes in serum hs-CRP levels will be evaluated as the primary endpoint, and changes in flow-mediated vasodilation and plasma myeloperoxidase levels will be evaluated as secondary endpoints. The results of this study will contribute to the development of a protocol for a planned future phase 3 trial to estimate the reduction in CAD. The present study describes the rationale, design, and methods of the trial.

Keywords:  Colchicine; Coronary artery disease; High-sensitivity C-reactive protein; Inflammation; Type 2 diabetes

DOI:  https://doi.org/10.1159/000527411
Nat Commun. 2023 Jan 16. 14(1): 240

The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans.

Nan Wu, Yi-Cheng Ma, Xin-Qian Gong, Pei-Ji Zhao, Yong-Jian Jia, Qiu Zhao, Jia-Hong Duan, Cheng-Gang Zou.

Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional program involved in peroxisome function and biogenesis in long-lived glp-1(e2141ts) mutant Caenorhabditis elegans worms. Subsequently, we show that supplementation with α-ketobutyrate, an intermediate of the transsulfuration pathway, extends lifespan in wild-type worms. Alpha-ketobutyrate augments the production of NAD+ via the lactate dehydrogenase LDH-1, leading to SIR-2.1/SIRT1-mediated enhanced peroxisome function and biogenesis, along with a concomitant increase in the expression of acox-1.2/ACOX1 in the peroxisomal fatty acid β-oxidation pathway. ACOX-1.2/ACOX1 promotes H2O2 formation, thereby resulting in activation of SKN-1/NRF2. This transcription factor in turn extends the lifespan of worms by driving expression of autophagic and lysosomal genes. Finally, we show that α-ketobutyrate also delays the cellular senescence in fibroblast cells through the SIRT1-ACOX1-H2O2-NRF2 pathway. This finding uncovers a previously unknown role for α-ketobutyrate in organismal lifespan and healthspan by coordinating the NAD+-SIRT1 signaling and peroxisomal function.

DOI: https://doi.org/10.1038/s41467-023-35899-1
Eurasian J Med. 2022 Dec;54(Suppl1): 23-28

A New Target in Inflammatory Diseases: Lycopene.

Zeynep Karaköy, Elif Cadirci, Busra Dincer.

Inflammation is a response to various injuries, illnesses, and severe trauma. The primary function of inflammation is to combat pathogens, eliminate them from the body, and initiate wound healing. However, inflammation also contributes to numerous diseases, such as cancer, cardiovascular disease, diabetes, obesity, osteoporosis, rheumatoid arthritis, inflammatory bowel disease, and asthma. As the importance of nutrition in maintaining human health has become increasingly recognized, the consumption of natural antioxidants has gained popularity, especially in developed countries. A growing body of research has shown that consuming foods rich in lycopene can protect individuals from a range of conditions, including cancer, heart disease, and other diseases. As a result, lycopene is gaining recognition as a potential protective antioxidant in the fields of medicine and pharmacology. This review aims to highlight the effects of lycopene on inflammatory diseases and provide a foundational understanding for researchers interested in further research on lycopene.

DOI: https://doi.org/10.5152/eurasianjmed.2022.22303
Psychosom Med. 2023 Jan 16.

Type D personality as a risk factor for adverse outcome in patients with cardiovascular disease: an individual patient data meta-analysis.

Paul Lodder, Jelte M Wicherts, Marijn Antens, Christian Albus, Ivan S Bessonov, Emelie Condén, Karolijn Dulfer, Sara Gostoli, Gesine Grande, Pär Hedberg, Christoph Herrmann-Lingen, Tiny Jaarsma, Malcolm Koo, Ping Lin, Tin-Kwang Lin, Thomas Meyer, Georgiy Pushkarev, Chiara Rafanelli, Olga I Raykh, Alexandre Schaan de Quadros, Marcia Schmidt, Alexei N Sumin, Elisabeth M W J Utens, Dirk J van Veldhuisen, Yini Wang, Nina Kupper.

OBJECTIVE: Type D personality, a joint tendency toward negative affectivity (NA) and social inhibition (SI), has been linked to adverse events in patients with heart disease, though with inconsistent findings. Here, we apply an individual patient-data meta-analysis to data from 19 prospective cohort studies (N = 11151), to investigate the prediction of adverse outcomes by Type D personality in acquired cardiovascular disease (CVD) patients.
METHOD: For each outcome (all-cause mortality, cardiac mortality, myocardial infarction (MI), coronary artery bypass grafting, percutaneous coronary intervention, major adverse cardiac event (MACE), any adverse event), we estimated Type D's prognostic influence and the moderation by age, sex, and disease type.
RESULTS: In CVD patients, evidence for a Type D effect in terms of the Bayes factor (BF) was strong for MACE (BF = 42.5; OR = 1.14) and any adverse event (BF = 129.4; OR = 1.15). Evidence for the null hypothesis was found for all-cause mortality (BF = 45.9; OR = 1.03), cardiac mortality (BF = 23.7; OR = 0.99) and MI (BF = 16.9; OR = 1.12), suggesting Type D had no effect on these outcomes. This evidence was similar in the subset of coronary artery disease (CAD) patients, but inconclusive for heart failure (HF) patients. Positive effects were found for NA on cardiac- and all-cause mortality, the latter being more pronounced in males than females.
CONCLUSION: Across 19 prospective cohort studies, Type D predicts adverse events in CAD patients, while evidence in HF patients was inconclusive. In both CAD and HF patients, we found evidence for a null effect of Type D on cardiac- and all-cause mortality.

DOI: https://doi.org/10.1097/PSY.0000000000001164
Chem Biol Interact. 2023 Jan 13. pii: S0009-2797(23)00015-7. [Epub ahead of print]371 110348

Progress in the study of ferroptosis in cancer treatment: State-of-the-Art.

Dong Wang.

  As a regulatory cell death mode defined in recent years, Ferroptosis is mainly characterized by increased intracellular free iron and the accumulation of lipid peroxides. Ferroptosis is closely related to iron ion metabolism, lipid metabolism, and amino acid metabolism. Cancer is the second leading cause of death worldwide, and effective removal of tumour cells while protecting normal cells is the key to tumour treatment. The continuous development and refinement of molecular mechanisms related to ferroptosis have shown promising applications in tumour therapy. There is increasing evidence that triggering ferroptosis in tumour cells is expected to be a new therapeutic strategy for tumour treatment.

Keywords:  Cancer stem cells; Ferroptosis; Metabolic modulation; Nanoparticles; Tumor microenvironment; Tumor therapy

DOI:  https://doi.org/10.1016/j.cbi.2023.110348