bims-longev 2023-03-05 papers

bims-longev

Biomed News

on Longevity

Issue of 2023‒03‒05
eleven papers selected by
Andreea Nitescu

Intestinal stem cell aging at single-cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics.
Rapamycin suppresses inflammation and increases the interaction between p65 and IκBα in rapamycin-induced fatty livers.
Fighting age-related orthopedic diseases: focusing on ferroptosis.
The interplay between selective types of (macro)autophagy: Mitophagy and xenophagy.
Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal.
Techniques in Facial Fat Grafting: Optimal Results Based on the Science of Facial Aging.
Both prolonged high-fat diet consumption and calorie restriction boost hepatic NAD+ metabolism in mice.
Genetic evidence for causal effects of socioeconomic, lifestyle, and cardiometabolic factors on epigenetic age acceleration.
Relationship of Muscle Apolipoprotein E Expression with Markers of Cellular Stress, Metabolism, and Blood Biomarkers in Cognitively Healthy and Impaired Older Adults.
Sex differences in markers of oxidation and inflammation. Implications for ageing.
Naringin Prevents Cognitive Dysfunction in Aging Rats by Inhibiting Toll-Like Receptor 4 (TLR4)/NF-κB Pathway and Endoplasmic Reticulum Stress.

Aging Cell. 2023 Mar 02. e13802

Intestinal stem cell aging at single-cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics.

Jiahn Choi, Michele Houston, Ruixuan Wang, Kenny Ye, Wenge Li, Xusheng Zhang, Derek M Huffman, Leonard H Augenlicht.

  The intestinal epithelium consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an ordered fashion as the cells progress along the crypt-luminal axis. Perturbed function of Lgr5hi ISCs with aging is documented, but the consequent impact on overall mucosal homeostasis has not been defined. Using single-cell RNA sequencing, the progressive maturation of progeny was dissected in the mouse intestine, which revealed that transcriptional reprogramming with aging in Lgr5hi ISCs retarded the maturation of cells in their progression along the crypt-luminal axis. Importantly, treatment with metformin or rapamycin at a late stage of mouse lifespan reversed the effects of aging on the function of Lgr5hi ISCs and subsequent maturation of progenitors. The effects of metformin and rapamycin overlapped in reversing changes of transcriptional profiles but were also complementary, with metformin more efficient than rapamycin in correcting the developmental trajectory. Therefore, our data identify novel effects of aging on stem cells and the maturation of their daughter cells contributing to the decline of epithelial regeneration and the correction by geroprotectors.

Keywords:  gerotherapeutics; intestinal stem cell aging; intestinal stem cells; metformin; rapamycin; single-cell RNA sequencing

DOI:  https://doi.org/10.1111/acel.13802
PLoS One. 2023 ;18(3): e0281888

Rapamycin suppresses inflammation and increases the interaction between p65 and IκBα in rapamycin-induced fatty livers.

Chenliang Ge, Changguo Ma, Jiesheng Cui, Xingbo Dong, Luyang Sun, Yanjiao Li, An Yu.

Rapamycin treatment significantly increases lifespan and ameliorates several aging-related diseases in mice, making it a potential anti-aging drug. However, there are several obvious side effects of rapamycin, which may limit the broad applications of this drug. Lipid metabolism disorders such as fatty liver and hyperlipidemia are some of those unwanted side effects. Fatty liver is characterized as ectopic lipid accumulation in livers, which is usually accompanied by increased inflammation levels. Rapamycin is also a well-known anti-inflammation chemical. How rapamycin affects the inflammation level in rapamycin-induced fatty liver remains poorly understood. Here, we show that eight-day rapamycin treatment induced fatty liver and increased liver free fatty acid levels in mice, while the expression levels of inflammatory markers are even lower than those in the control mice. Mechanistically, the upstream of the pro-inflammatory pathway was activated in rapamycin-induced fatty livers, however, there is no increased NFκB nuclear translocation probably because the interaction between p65 and IκBα was enhanced by rapamycin treatment. The lipolysis pathway in the liver is also suppressed by rapamycin. Liver cirrhosis is an adverse consequence of fatty liver, while prolonged rapamycin treatment did not increase liver cirrhosis markers. Our results indicate that although fatty livers are induced by rapamycin, the fatty livers are not accompanied by increased inflammation levels, implying that rapamycin-induced fatty livers might not be as harmful as other types of fatty livers, such as high-fat diet and alcohol-induced fatty livers.

DOI: https://doi.org/10.1371/journal.pone.0281888
Bone Res. 2023 Mar 01. 11(1): 12

Fighting age-related orthopedic diseases: focusing on ferroptosis.

Qin Ru, Yusheng Li, Wenqing Xie, Yilan Ding, Lin Chen, Guodong Xu, Yuxiang Wu, Fudi Wang.

Ferroptosis, a unique type of cell death, is characterized by iron-dependent accumulation and lipid peroxidation. It is closely related to multiple biological processes, including iron metabolism, polyunsaturated fatty acid metabolism, and the biosynthesis of compounds with antioxidant activities, including glutathione. In the past 10 years, increasing evidence has indicated a potentially strong relationship between ferroptosis and the onset and progression of age-related orthopedic diseases, such as osteoporosis and osteoarthritis. Therefore, in-depth knowledge of the regulatory mechanisms of ferroptosis in age-related orthopedic diseases may help improve disease treatment and prevention. This review provides an overview of recent research on ferroptosis and its influences on bone and cartilage homeostasis. It begins with a brief overview of systemic iron metabolism and ferroptosis, particularly the potential mechanisms of ferroptosis. It presents a discussion on the role of ferroptosis in age-related orthopedic diseases, including promotion of bone loss and cartilage degradation and the inhibition of osteogenesis. Finally, it focuses on the future of targeting ferroptosis to treat age-related orthopedic diseases with the intention of inspiring further clinical research and the development of therapeutic strategies.

DOI: https://doi.org/10.1038/s41413-023-00247-y
Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(22)00137-X. [Epub ahead of print]374 129-157

The interplay between selective types of (macro)autophagy: Mitophagy and xenophagy.

Teresa Rubio-Tomás, Aggeliki Sotiriou, Nektarios Tavernarakis.

  Autophagy is a physiological response, activated by a myriad of endogenous and exogenous cues, including DNA damage, perturbation of proteostasis, depletion of nutrients or oxygen and pathogen infection. Upon sensing those stimuli, cells employ multiple non-selective and selective autophagy pathways to promote fitness and survival. Importantly, there are a variety of selective types of autophagy. In this review we will focus on autophagy of bacteria (xenophagy) and autophagy of mitochondria (mitophagy). We provide a brief introduction to bulk autophagy, as well as xenophagy and mitophagy, highlighting their common molecular factors. We also describe the role of xenophagy and mitophagy in the detection and elimination of pathogens by the immune system and the adaptive mechanisms that some pathogens have developed through evolution to escape the host autophagic response. Finally, we summarize the recent articles (from the last five years) linking bulk autophagy with xenophagy and/or mitophagy in the context on developmental biology, cancer and metabolism.

Keywords:  (Macro)autophagy; Cancer; Development; Metabolism; Mitophagy; Pathogens; Xenophagy

DOI:  https://doi.org/10.1016/bs.ircmb.2022.10.003
Front Neurol. 2023 ;14 1123290

Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal.

Jeffrey L B Bohnen, Roger L Albin, Nicolaas I Bohnen.

  Background: There is increasing interest in therapeutic ketosis as a potential therapy for neurodegenerative disorders-in particular, mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD)-following a proof-of-concept study in Parkinson's disease published in 2005.Methods: To provide an objective assessment of emerging clinical evidence and targeted recommendations for future research, we reviewed clinical trials involving ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease reported since 2005. Levels of clinical evidence were systematically reviewed using the American Academy of Neurology criteria for rating therapeutic trials.
Results: 10 AD, 3 MCI, and 5 PD therapeutic ketogenic trials were identified. Respective grades of clinical evidence were objectively assessed using the American Academy of Neurology criteria for rating therapeutic trials. We found class "B" evidence (probably effective) for cognitive improvement in subjects with mild cognitive impairment and subjects with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele (APOε4-). We found class "U" evidence (unproven) for cognitive stabilization in individuals with mild-to-moderate Alzheimer's disease positive for the apolipoprotein ε4 allele (APOε4+). We found class "C" evidence (possibly effective) for improvement of non-motor features and class "U" evidence (unproven) for motor features in individuals with Parkinson's disease. The number of trials in Parkinson's disease is very small with best evidence that acute supplementation holds promise for improving exercise endurance.
Conclusions: Limitations of the literature to date include the range of ketogenic interventions currently assessed in the literature (i.e., primarily diet or medium-chain triglyceride interventions), with fewer studies using more potent formulations (e.g., exogenous ketone esters). Collectively, the strongest evidence to date exists for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele. Larger-scale, pivotal trials are justified in these populations. Further research is required to optimize the utilization of ketogenic interventions in differing clinical contexts and to better characterize the response to therapeutic ketosis in patients who are positive for the apolipoprotein ε4 allele, as modified interventions may be necessary.

Keywords:  Alzheimer's disease; Parkinson's disease; effectiveness; ketogenic; mild cognitive impairment

DOI:  https://doi.org/10.3389/fneur.2023.1123290
Plast Reconstr Surg. 2023 Feb 28. pii: e010314. [Epub ahead of print]

Techniques in Facial Fat Grafting: Optimal Results Based on the Science of Facial Aging.

Nelson A Rodriguez-Unda, Matthew D Novak, Rod J Rohrich.

SUMMARY: A thorough understanding of the science of facial aging is imperative to the precise and natural restoration of a youthful appearance and a hallmark of the aging process is fat atrophy. For this reason, fat grafting has become a keystone of the modern facelift. As a result, fat grafting techniques have been refined to achieve optimal results. This is done through the differential use of fractionated and unfractionated fat throughout the face. The following article reviews a single surgeon's technique for achieving optimal results in facial fat grafting.

DOI: https://doi.org/10.1097/PRS.0000000000010314
J Nutr Biochem. 2023 Feb 25. pii: S0955-2863(23)00030-X. [Epub ahead of print] 109296

Both prolonged high-fat diet consumption and calorie restriction boost hepatic NAD+ metabolism in mice.

Xiaojing Wei, Chuanfei Wei, Yutian Tan, Ximing Dong, Zhao Yang, Jianqun Yan, Xiao Luo.

  Hepatic NAD+ homeostasis is essential to metabolic flexibility upon energy balance challenges. The molecular mechanism is unclear. This study aimed to determine how the enzymes involved in NAD+ salvage (Nampt, Nmnat1, Nrk1), clearance (Nnmt, Aox1, Cyp2e1) and consumption pathways (Sirt1, Sirt3, Sirt6, Parp1, Cd38) were regulated in liver upon energy overload or shortage, as well as their relationships with glucose and lipid metabolism. Male C57BL/6N mice were fed ad libitum with the CHOW diet, high-fat diet (HFD), or subjected to 40% calorie restriction (CR) CHOW diet for 16 weeks respectively. HFD feeding increased hepatic lipids content and inflammatory markers, while lipids accumulation was not changed by CR. Both HFD feeding and CR elevated the hepatic NAD+ levels, as well as gene and protein levels of Nampt and Nmnat1. Furthermore, both HFD feeding and CR lowered acetylation of PGC-1α in parallel with the reduced hepatic lipogenesis and enhanced fatty acid oxidation, while CR enhanced hepatic AMPK activity and gluconeogenesis. Hepatic Nampt and Nnmt gene expression negatively correlated with fasting plasma glucose levels concomitant with positive correlations with Pck1 gene expression. Nrk1 and Cyp2e1 gene expression positively correlated with fat mass and plasma cholesterol levels, as well as Srebf1 gene expression. These data highlight that hepatic NAD+ metabolism will be induced for either the down-regulation of lipogenesis upon over nutrition or up-regulation of gluconeogenesis in response to CR, thus contributing to the hepatic metabolic flexibility upon energy balance challenges.

Keywords:  Calorie restriction; Hepatic NAD(+) metabolism; High-fat diet; Sirtuin

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109296
J Gerontol A Biol Sci Med Sci. 2023 Mar 04. pii: glad078. [Epub ahead of print]

Genetic evidence for causal effects of socioeconomic, lifestyle, and cardiometabolic factors on epigenetic age acceleration.

Lijie Kong, Chaojie Ye, Yiying Wang, Tianzhichao Hou, Jie Zheng, Zhiyun Zhao, Mian Li, Yu Xu, Jieli Lu, Yuhong Chen, Min Xu, Weiqing Wang, Guang Ning, Yufang Bi, Tiange Wang.

  GrimAge acceleration (GrimAgeAccel) and PhenoAge acceleration (PhenoAgeAccel) are DNA methylation-based markers of accelerated biological aging, standing out in predicting mortality and age-related cardiometabolic morbidities. Causal risk factors for GrimAgeAccel and PhenoAgeAccel are unclear. In this study, we performed two-sample univariable and multivariable Mendelian randomization (MR) to investigate causal associations of 19 modifiable socioeconomic, lifestyle, and cardiometabolic factors with GrimAgeAccel and PhenoAgeAccel. Instrument variants representing 19 modifiable factors were extracted from genome-wide association studies (GWASs) with up to 1 million Europeans. Summary statistics for GrimAgeAccel and PhenoAgeAccel were derived from a GWAS of 34,710 Europeans. We identified 12 and eight factors causally associated with GrimAgeAccel and PhenoAgeAccel, respectively. Smoking was the strongest risk factor (β [SE]: 1.299 [0.107] year) for GrimAgeAccel, followed by higher alcohol intake, higher waist circumference, daytime napping, higher body fat percentage, higher body mass index, higher C-reactive protein, higher triglycerides, childhood obesity, and type 2 diabetes; whereas education was the strongest protective factor (β [SE]: -1.143 [0.121] year), followed by household income. Furthermore, higher waist circumference (β [SE]: 0.850 [0.269] year) and education (β [SE]: -0.718 [0.151] year) were the leading causal risk and protective factors for PhenoAgeAccel, respectively. Sensitivity analyses strengthened the robustness of these causal associations. Multivariable MR analyses further demonstrated independent effects of the strongest risk and protective factors on GrimAgeAccel and PhenoAgeAccel, respectively. In conclusion, our findings provide novel quantitative evidence on modifiable causal risk factors for accelerated epigenetic aging, suggesting promising intervention targets against age-related morbidity and improving healthy longevity.

Keywords:  Causal risk factors; DNA methylation; Epigenetic aging; Mendelian randomization

DOI:  https://doi.org/10.1093/gerona/glad078
J Alzheimers Dis. 2023 Feb 21.

Relationship of Muscle Apolipoprotein E Expression with Markers of Cellular Stress, Metabolism, and Blood Biomarkers in Cognitively Healthy and Impaired Older Adults.

Chelsea N Johnson, Colin S McCoin, Paul J Kueck, Amelia G Hawley, Casey S John, John P Thyfault, Russell H Swerdlow, Paige C Geiger, Jill K Morris.

  BACKGROUND: Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer's disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain.OBJECTIVE: Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers.
METHODS: We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n = 9) or MCI (n = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max.
RESULTS: Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age.
CONCLUSION: This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.

Keywords:  APOE4; Alzheimer’s disease; Hsp72; mitochondria; skeletal muscle; stress

DOI:  https://doi.org/10.3233/JAD-221192
Mech Ageing Dev. 2023 Mar 01. pii: S0047-6374(23)00023-4. [Epub ahead of print] 111797

Sex differences in markers of oxidation and inflammation. Implications for ageing.

Irene Martínez de Toda, Gonzalez-SanchezMónica González-Sánchez, Estefanía Díaz-Del Cerro, Gemma Valero, Julia Carracedo, Guerra-PerezNatalia Guerra-Pérez.

  Sexual dimorphism is a key factor to consider in the ageing process given the impact that it has on life expectancy. The oxidative-inflammatory theory of ageing states that the ageing process is the result of the establishment of oxidative stress which, due to the interplay of the immune system, translates into inflammatory stress, and that both processes are responsible for the damage and loss of function of an organism. We show that there are relevant gender differences in a number of oxidative and inflammatory markers and propose that they may account for the differential lifespan between sexes, given that males display, in general, higher oxidation and basal inflammation. In addition, we explain the significant role of circulating cell-free DNA as a marker of oxidative damage and an inductor of inflammation, connecting both processes and having the potential to become a useful ageing marker. Finally, we discuss how oxidative and inflammatory changes take place differentially with ageing in each sex, which could also have an impact on the sex-differential lifespan. Further research including sex as an essential variable is needed to understand the grounds of sex differences in ageing and to better comprehend ageing itself.

Keywords:  cytokines; gender; immunity; lifespan; longevity; redox

DOI:  https://doi.org/10.1016/j.mad.2023.111797
Evid Based Complement Alternat Med. 2023 ;2023 2919811

Naringin Prevents Cognitive Dysfunction in Aging Rats by Inhibiting Toll-Like Receptor 4 (TLR4)/NF-κB Pathway and Endoplasmic Reticulum Stress.

Xiao-Jie Dai, Yi Jia, Rui Cao, Mei-Ning Zhou.

Objective: Naringin is a flavonoid derived from Chinese herbs. According to earlier studies, naringin may have the potential to alleviate aging-induced cognitive dysfunction. Therefore, this study attempted to explore the protective effect and underlying mechanism of naringin on aging rats with cognitive dysfunction.Methods: After the construction of a model of aging rats with cognitive dysfunction through subcutaneous injection of D-galactose (D-gal; 150 mg/kg), intragastric administration of naringin (100 mg/kg) was performed for treatment. Behavioral tests, including Morris water maze test (MWM), novel object recognition test (NORT), and fear conditioning test, were used to measure the cognitive function; ELISA and biochemical tests were used to determine the levels of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the hippocampus of rats in each group, respectively; H&E staining was used to observe the pathological changes in the hippocampus; Western blot was used to examine the expression of toll-like receptor 4 (TLR4)/NF-κB pathway-related proteins and endoplasmic reticulum (ER) stress-related proteins in the hippocampus.
Results: The model was successfully constructed by subcutaneous injection of D-gal (150 mg/kg). The behavioral test results showed that naringin could ameliorate the cognitive dysfunction and alleviate the histopathological damage of hippocampus. Moreover, naringin significantly improve the inflammatory response (the levels of IL-1β, IL-6, and MCP-1 were decreased), oxidative stress response (MDA level was increased while GSH-Px activity was decreased), and ER stress (the expression of glucose-regulated protein 78 (GRP78), C/-EBP homologous protein (CHOP), and transcription factor 6 (ATF6) expression was downregulated), and increased the levels of neurotrophic factors BDNF and NGF in D-gal rats. Besides, further mechanistic studies revealed the downregulation of naringin on TLR4/NF-κB pathway activity.
Conclusion: Naringin may inhibit inflammatory response, oxidative stress, and ER stress by downregulating TLR4/NF-κB pathway activity, thereby improving cognitive dysfunction and alleviating histopathological damage of hippocampus in aging rats. Briefly, naringin is an effective drug for the treatment of cognitive dysfunction.

DOI: https://doi.org/10.1155/2023/2919811