scholarly journals Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging

2021 ◽  
Vol 22 (15) ◽  
pp. 7958
Author(s):  
Janina Tokarz ◽  
Gabriele Möller ◽  
Anna Artati ◽  
Simone Huber ◽  
Anja Zeigerer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Nutrient Sensing ◽  
Biological Aging ◽  
Aging Research ◽  
Muscle Health ◽  
Old Mice ◽  
Health Function ◽  
Metabolic Signatures

Biological aging research is expected to reveal modifiable molecular mechanisms that can be harnessed to slow or possibly reverse unhealthy trajectories. However, there is first an urgent need to define consensus molecular markers of healthy and unhealthy aging. Established aging hallmarks are all linked to metabolism, and a ‘rewired’ metabolic circuitry has been shown to accelerate or delay biological aging. To identify metabolic signatures distinguishing healthy from unhealthy aging trajectories, we performed nontargeted metabolomics on skeletal muscles from 2-month-old and 21-month-old mice, and after dietary and lifestyle interventions known to impact biological aging. We hypothesized that common metabolic signatures would highlight specific pathways and processes promoting healthy aging, while revealing the molecular underpinnings of unhealthy aging. Here, we report 50 metabolites that commonly distinguished aging trajectories in all cohorts, including 18 commonly reduced under unhealthy aging and 32 increased. We stratified these metabolites according to known relationships with various aging hallmarks and found the greatest associations with oxidative stress and nutrient sensing. Collectively, our data suggest interventions aimed at maintaining skeletal muscle arginine and lysine may be useful therapeutic strategies to minimize biological aging and maintain skeletal muscle health, function, and regenerative capacity in old age.

scholarly journals Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy

2020 ◽  
Vol 11 ◽  
Author(s):  
Alex P. Seabright ◽  
Yu-Chiang Lai
Keyword(s):  
Skeletal Muscle ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Mitochondrial Fission ◽  
Muscle Cells ◽  
Critical Question ◽  
Ampk Signaling ◽  
Age Related ◽  
Muscle Health ◽  
Amp Activated Protein Kinase

The selective removal of damaged mitochondria, also known as mitophagy, is an important mechanism that regulates mitochondrial quality control. Evidence suggests that mitophagy is adversely affected in aged skeletal muscle, and this is thought to contribute toward the age-related decline of muscle health. While our knowledge of the molecular mechanisms that regulate mitophagy are derived mostly from work in non-muscle cells, whether these mechanisms are conferred in muscle under physiological conditions has not been thoroughly investigated. Recent findings from our laboratory and those of others have made several novel contributions to this field. Herein, we consolidate current literature, including our recent work, while evaluating how ubiquitin-dependent mitophagy is regulated both in muscle and non-muscle cells through the steps of mitochondrial fission, ubiquitylation, and autophagosomal engulfment. During ubiquitin-dependent mitophagy in non-muscle cells, mitochondrial depolarization activates PINK1-Parkin signaling to elicit mitochondrial ubiquitylation. TANK-binding kinase 1 (TBK1) then activates autophagy receptors, which in turn, tether ubiquitylated mitochondria to autophagosomes prior to lysosomal degradation. In skeletal muscle, evidence supporting the involvement of PINK1-Parkin signaling in mitophagy is lacking. Instead, 5′-AMP-activated protein kinase (AMPK) is emerging as a critical regulator. Mechanistically, AMPK activation promotes mitochondrial fission before enhancing autophagosomal engulfment of damaged mitochondria possibly via TBK1. While TBK1 may be a point of convergence between PINK1-Parkin and AMPK signaling in muscle, the critical question that remains is: whether mitochondrial ubiquitylation is required for mitophagy. In future, improving understanding of molecular processes that regulate mitophagy in muscle will help to develop novel strategies to promote healthy aging.

scholarly journals FTIR Spectroscopy as a Tool to Study Age-Related Changes in Cardiac and Skeletal Muscle of Female C57BL/6J Mice

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6410
Author(s):  
Sandra Magalhães ◽  
Idália Almeida ◽  
Filipa Martins ◽  
Fátima Camões ◽  
Ana R. Soares ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ftir Spectroscopy ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Protein Secondary Structure ◽  
Multivariate Statistical ◽  
Age Related ◽  
Muscle Tissues ◽  
Aging Studies ◽  
Old Mice

Studying aging is important to further understand the molecular mechanisms underlying this physiological process and, ideally, to identify a panel of aging biomarkers. Animals, in particular mice, are often used in aging studies, since they mimic important features of human aging, age quickly, and are easy to manipulate. The present work describes the use of Fourier Transform Infrared (FTIR) spectroscopy to identify an age-related spectroscopic profile of the cardiac and skeletal muscle tissues of C57BL/6J female mice. We acquired ATR-FTIR spectra of cardiac and skeletal muscle at four different ages: 6; 12; 17 and 24 months (10 samples at each age) and analyzed the data using multivariate statistical tools (PCA and PLS) and peak intensity analyses. The results suggest deep changes in protein secondary structure in 24-month-old mice compared to both tissues in 6-month-old mice. Oligomeric structures decreased with age in both tissues, while intermolecular β-sheet structures increased with aging in cardiac muscle but not in skeletal muscle. Despite FTIR spectroscopy being unable to identify the proteins responsible for these conformational changes, this study gives insights into the potential of FTIR to monitor the aging process and identify an age-specific spectroscopic signature.

scholarly journals Relationship between insulin sensitivity and gene expression in human skeletal muscle

2020 ◽  
Author(s):  
Hemang Parikh ◽  
Targ Elgzyri ◽  
Amra Alibegovic ◽  
Natalie Hiscock ◽  
Ola Ekström ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Human Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Independent Study ◽  
Nutrient Sensing ◽  
Muscle Gene Expression

Abstract BackgroundInsulin resistance in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases, and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood. MethodsTo explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to physiological measures of insulin sensitivity. Results We identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including CPT1B and SIRT2 , involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expression of CPT1B , SIRT2 and FBXW5 was also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g. PPARGC1A . ConclusionsThese data suggest that activation of genes involved in lipid metabolism, e.g. CPT1B and SIRT2 , and genes regulating autophagy and mTOR signaling, e.g. FBXW5 , are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.

scholarly journals The INSPIRE Bio-resource Research Platform for Healthy Aging and Geroscience: Focus on the Human Translational Research Cohort (The INSPIRE-T Cohort)

2020 ◽  
pp. 1-11 ◽  
Author(s):  
S. Guyonnet ◽  
Y. Rolland ◽  
C. Takeda ◽  
P.-J. Ousset ◽  
I. Ader ◽  
...  
Keyword(s):  
Health Care ◽  
Translational Research ◽  
Healthy Aging ◽  
Care Pathway ◽  
Integrative Approach ◽  
Biological Aging ◽  
Imaging Data ◽  
Aging Research ◽  
Age Related

Background: The Geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (IC) (body functions) leading to dependency. A better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. Objectives: The main objective of the INStitute for Prevention healthy agIng and medicine Rejuvenative (INSPIRE) Platform initiative is to build a program for Geroscience and healthy aging research going from animal models to humans and the health care system. The specific aim of the INSPIRE human translational cohort (INSPIRE-T cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans. Methods: The INSPIRE-T cohort consists in a population study comprising 1000 individuals in Toulouse and surrounding areas (France) of different ages (20 years or over - no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. Diversified data are collected annually in research facilities or at home according to standardized procedures. Between two annual visits, IC domains are monitored every 4-month by using the ICOPE Monitor app developed in collaboration with WHO. Once IC decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time IC declines are detected. Biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. Nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. Feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up. Expected Results: Recruitment started on October 2019 and is expected to last for two years. Bio-resources collected and explored in the INSPIRE-T cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and IC evolution that could be pharmacologically or non-pharmacologically targetable. The INSPIRE-T will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging.

scholarly journals Relationship between insulin sensitivity and gene expression in human skeletal muscle

2020 ◽  
Author(s):  
Hemang Parikh ◽  
Targ Elgzyri ◽  
Amra Alibegovic ◽  
Natalie Hiscock ◽  
Ola Ekström ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Human Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Independent Study ◽  
Nutrient Sensing ◽  
Model Assessment

Abstract Background: Insulin resistance in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood. Methods: To explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR). Results: We identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g. PPARGC1A. Conclusions: These data suggest that activation of genes involved in lipid metabolism, e.g. SIRT2, and genes regulating autophagy and mTOR signaling, e.g. FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.

scholarly journals Nutrients and Pathways that Regulate Health Span and Life Span

Geriatrics ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. 95
Author(s):  
Carla Pignatti ◽  
Stefania D’Adamo ◽  
Claudio Stefanelli ◽  
Flavio Flamigni ◽  
Silvia Cetrullo
Keyword(s):  
Health Status ◽  
Life Span ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Dietary Habits ◽  
Human Life ◽  
Nutrient Sensing ◽  
Model Organisms ◽  
Health Span ◽  
Nutritional Conditions

Both life span and health span are influenced by genetic, environmental and lifestyle factors. With the genetic influence on human life span estimated to be about 20–25%, epigenetic changes play an important role in modulating individual health status and aging. Thus, a main part of life expectance and healthy aging is determined by dietary habits and nutritional factors. Excessive or restricted food consumption have direct effects on health status. Moreover, some dietary interventions including a reduced intake of dietary calories without malnutrition, or a restriction of specific dietary component may promote health benefits and decrease the incidence of aging-related comorbidities, thus representing intriguing potential approaches to improve healthy aging. However, the relationship between nutrition, health and aging is still not fully understood as well as the mechanisms by which nutrients and nutritional status may affect health span and longevity in model organisms. The broad effect of different nutritional conditions on health span and longevity occurs through multiple mechanisms that involve evolutionary conserved nutrient-sensing pathways in tissues and organs. These pathways interacting each other include the evolutionary conserved key regulators mammalian target of rapamycin, AMP-activated protein kinase, insulin/insulin-like growth factor 1 pathway and sirtuins. In this review we provide a summary of the main molecular mechanisms by which different nutritional conditions, i.e., specific nutrient abundance or restriction, may affect health span and life span.

scholarly journals Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 660
Author(s):  
Mengdi Yu ◽  
Hongxia Zhang ◽  
Brian Wang ◽  
Yinuo Zhang ◽  
Xiaoying Zheng ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Sirtuin 1 ◽  
Public Health Issue ◽  
Biological Aging ◽  
Related Disease ◽  
Age Related ◽  
General Decline

Aging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.

scholarly journals The INSPIRE research initiative: a program for GeroScience and healthy aging research going from animal models to humans and the healthcare system

2020 ◽  
pp. 1-8
Author(s):  
P. de Souto Barreto ◽  
S. GUYONNET ◽  
I. Ader ◽  
S. Andrieu ◽  
L. Casteilla ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Care Pathway ◽  
Functional Decline ◽  
World Health ◽  
Biological Aging ◽  
Aging Research ◽  
Research Initiative ◽  
Centered Care ◽  
Clinical Gerontology ◽  
Health Organization

Aging is the most important risk factor for the onset of several chronic diseases and functional decline. Understanding the interplays between biological aging and the biology of diseases and functional loss as well as integrating a function-centered approach to the care pathway of older adults are crucial steps towards the elaboration of preventive strategies (both pharmacological and non-pharmacological) against the onset and severity of burdensome chronic conditions during aging. In order to tackle these two crucial challenges, ie, how both the manipulation of biological aging and the implementation of a function-centered care pathway (the Integrated Care for Older People (ICOPE) model of the World Health Organization) may contribute to the trajectories of healthy aging, a new initiative on Gerosciences was built: the INSPIRE research program. The present article describes the scientific background on which the foundations of the INSPIRE program have been constructed and provides the general lines of this initiative that involves researchers from basic and translational science, clinical gerontology, geriatrics and primary care, and public health.

scholarly journals Relationship between insulin sensitivity and gene expression in human skeletal muscle

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hemang M. Parikh ◽  
Targ Elgzyri ◽  
Amra Alibegovic ◽  
Natalie Hiscock ◽  
Ola Ekström ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Human Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Independent Study ◽  
Nutrient Sensing ◽  
Model Assessment

Abstract Background Insulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood. Methods To explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR). Results We identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g.PPARGC1A. Conclusions The muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism, e.g.SIRT2, and genes regulating autophagy and mTOR signaling, e.g.FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.

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