scholarly journals Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites

2021 ◽  
Vol 22 (2) ◽  
pp. 697
Author(s):  
Kenneth K. Wu
Keyword(s):  
Cellular Senescence ◽  
Morphological Changes ◽  
Aerobic Glycolysis ◽  
Mapk Signaling ◽  
Ros Generation ◽  
New Class ◽  
Age Related ◽  
Tryptophan Metabolites ◽  
Mesenchymal Stromal Stem Cell ◽  
And Function

Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases.

scholarly journals Targeting Senescent Cells to Counter Aging and Aging-Related Conditions

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 818-818
Author(s):  
Nathan LeBrasseur
Keyword(s):  
Human Populations ◽  
Geriatric Syndromes ◽  
Preclinical Models ◽  
Pharmacological Agents ◽  
New Class ◽  
Age Related ◽  
Selective Elimination ◽  
Early Phase Clinical Trials ◽  
And Function ◽  
State Of The Science

Abstract In response to various forms of age-associated damage, cells can enter a state of senescence. Senescent cells can compromise the health and function of a tissue, and their accumulation with advancing age is believed to contribute to age-related diseases and geriatric syndromes. In preclinical models (i.e., mice), selective elimination of senescent cells through either genetic approaches or a new class of pharmacological agents, termed “senolytics”, has been show to effectively delay, prevent, or reverse the onset and/or progression of pulmonary disease, osteoporosis, atherosclerosis, diabetes, cognitive decline, and several other conditions. Thus, considerable efforts are underway to optimize pharmacological strategies and test their effectiveness in human populations. This seminar will highlight the state-of-the-science of senolytic drugs, and the opportunities and challenges for early phase clinical trials in humans.

scholarly journals Role of Age-Related Mitochondrial Dysfunction in Sarcopenia

2020 ◽  
Vol 21 (15) ◽  
pp. 5236 ◽  
Author(s):  
Evelyn Ferri ◽  
Emanuele Marzetti ◽  
Riccardo Calvani ◽  
Anna Picca ◽  
Matteo Cesari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Significant Loss ◽  
Muscle Aging ◽  
Age Related ◽  
Mitochondrial Functions ◽  
Health Quality ◽  
Skeletal Muscle Aging ◽  
And Function

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

scholarly journals Lipid Players of Cellular Senescence

Metabolites ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 339
Author(s):  
Alec Millner ◽  
G. Ekin Atilla-Gokcumen
Keyword(s):  
Cellular Senescence ◽  
Morphological Changes ◽  
Surrounding Tissue ◽  
Membrane Remodeling ◽  
Protein Targets ◽  
Current State ◽  
New Findings ◽  
Secretory Phenotype ◽  
And Function ◽  
Inflammatory Phenotypes

Lipids are emerging as key players of senescence. Here, we review the exciting new findings on the diverse roles of lipids in cellular senescence, most of which are enabled by the advancements in omics approaches. Senescence is a cellular process in which the cell undergoes growth arrest while retaining metabolic activity. At the organismal level, senescence contributes to organismal aging and has been linked to numerous diseases. Current research has documented that senescent cells exhibit global alterations in lipid composition, leading to extensive morphological changes through membrane remodeling. Moreover, senescent cells adopt a secretory phenotype, releasing various components to their environment that can affect the surrounding tissue and induce an inflammatory response. All of these changes are membrane and, thus, lipid related. Our work, and that of others, has revealed that fatty acids, sphingolipids, and glycerolipids are involved in the initiation and maintenance of senescence and its associated inflammatory components. These studies opened up an exciting frontier to investigate the deeper mechanistic understanding of the regulation and function of these lipids in senescence. In this review, we will provide a comprehensive snapshot of the current state of the field and share our enthusiasm for the prospect of potential lipid-related protein targets for small-molecule therapy in pathologies involving senescence and its related inflammatory phenotypes.

scholarly journals Skin Aging, Cellular Senescence and Natural Polyphenols

2021 ◽  
Vol 22 (23) ◽  
pp. 12641
Author(s):  
Erika Csekes ◽  
Lucia Račková
Keyword(s):  
Cellular Senescence ◽  
Skin Aging ◽  
The Body ◽  
Skin Changes ◽  
Natural Polyphenols ◽  
Current State ◽  
Age Related ◽  
Aged Skin ◽  
And Function

The skin, being the barrier organ of the body, is constitutively exposed to various stimuli impacting its morphology and function. Senescent cells have been found to accumulate with age and may contribute to age-related skin changes and pathologies. Natural polyphenols exert many health benefits, including ameliorative effects on skin aging. By affecting molecular pathways of senescence, polyphenols are able to prevent or delay the senescence formation and, consequently, avoid or ameliorate aging and age-associated pathologies of the skin. This review aims to provide an overview of the current state of knowledge in skin aging and cellular senescence, and to summarize the recent in vitro studies related to the anti-senescent mechanisms of natural polyphenols carried out on keratinocytes, melanocytes and fibroblasts. Aged skin in the context of the COVID-19 pandemic will be also discussed.

scholarly journals Selective knockdown of hexokinase 2 in rods leads to age-related photoreceptor degeneration and retinal metabolic remodeling

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Rui Zhang ◽  
Weiyong Shen ◽  
Jianhai Du ◽  
Mark C. Gillies
Keyword(s):  
Mass Spectrometry ◽  
Aerobic Glycolysis ◽  
Tca Cycle ◽  
Structure And Function ◽  
Photoreceptor Degeneration ◽  
Age Related ◽  
The Tca Cycle ◽  
Metabolic Remodeling ◽  
Specific Proteins ◽  
And Function

Abstract Photoreceptors, the primary site of phototransduction in the retina, require energy and metabolites to constantly renew their outer segments. They preferentially consume most glucose through aerobic glycolysis despite possessing abundant mitochondria and enzymes for oxidative phosphorylation (OXPHOS). Exactly how photoreceptors balance aerobic glycolysis and mitochondrial OXPHOS to regulate their survival is still unclear. We crossed rhodopsin-Cre mice with hexokinase 2 (HK2)-floxed mice to study the effect of knocking down HK2, the first rate-limiting enzyme in glycolysis, on retinal health and metabolic remodeling. Immunohistochemistry and Western blots were performed to study changes in photoreceptor-specific proteins and key enzymes in glycolysis and the tricarboxylic acid (TCA) cycle. Changes in retinal structure and function were studied by optical coherence tomography and electroretinography. Mass spectrometry was performed to profile changes in 13C-glucose-derived metabolites in glycolysis and the TCA cycle. We found that knocking down HK2 in rods led to age-related photoreceptor degeneration, evidenced by reduced expression of photoreceptor-specific proteins, age-related reductions of the outer nuclear layer, photoreceptor inner and outer segments and impaired electroretinographic responses. Loss of HK2 in rods led to upregulation of HK1, phosphorylation of pyruvate kinase muscle isozyme 2, mitochondrial stress proteins and enzymes in the TCA cycle. Mass spectrometry found that the deletion of HK2 in rods resulted in accumulation of 13C-glucose along with decreased pyruvate and increased metabolites in the TCA cycle. Our data suggest that HK2-mediated aerobic glycolysis is indispensable for the maintenance of photoreceptor structure and function and that long-term inhibition of glycolysis leads to photoreceptor degeneration.

The effects of aging, injury and disease on microglial function: a case for cellular senescence

2007 ◽  
Vol 3 (3) ◽  
pp. 245-253 ◽  
Author(s):  
Kelly R. Miller ◽  
Wolfgang J. Streit
Keyword(s):  
Neurodegenerative Diseases ◽  
Cellular Senescence ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Aging Brain ◽  
Normal Brain ◽  
Age Related ◽  
Anti Inflammatory ◽  
Effects Of Aging ◽  
And Function

AbstractNeuroinflammation resulting from chronic reactive microgliosis is thought to contribute to age-related neurodegeneration, as well as age-related neurodegenerative diseases, specifically Alzheimer's disease (AD). Support of this theory comes from studies reporting a progressive, age-associated increase in microglia with an activated phenotype. Although the underlying cause(s) of this microglial reactivity is idiopathic, an accepted therapeutic strategy for the treatment of AD is inhibition of microglial activation using anti-inflammatory agents. Although the effectiveness of anti-inflammatory treatment for AD remains equivocal, microglial inhibition is being tested as a potential treatment for additional neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Given the important and necessary functions of microglia in normal brain, careful evaluation of microglial function in the aged brain is a necessary first step in targeting more precise treatment strategies for aging-related neurodegenerative diseases. Studies from our laboratory have shown multiple age-related changes in microglial morphology and function that are suggestive of cellular senescence. In this manuscript, we review current knowledge of microglia in the aging brain and present new, unpublished work that further supports the theory that microglia experience an age-related decline in proliferative function as a result of cellular senescence.

scholarly journals Are Canadian protein and physical activity guidelines optimal for sarcopenia prevention in older adults?

2018 ◽  
Vol 43 (12) ◽  
pp. 1215-1223 ◽  
Author(s):  
Camila L.P. Oliveira ◽  
Isabelle J. Dionne ◽  
Carla M. Prado
Keyword(s):  
Physical Activity ◽  
Older Adults ◽  
Resistance Exercise ◽  
Protein Intake ◽  
Protein Quality ◽  
Morphological Changes ◽  
Activity Levels ◽  
Physical Activity Guidelines ◽  
Age Related ◽  
And Function

Aging is characterized by physiological and morphological changes that affect body composition, strength, and function, ultimately leading to sarcopenia. This condition results in physical disability, falls, fractures, poor quality of life, and increased health care costs. Evidence suggests that increased consumption of dietary protein and physical activity levels, especially resistance exercise, can counteract the trajectory of sarcopenia. Canadian guidelines for protein intake and physical activity were last updated in 2005 and 2011, respectively, and new evidence on sarcopenia diagnosis, prevention, and treatment is rapidly evolving. Protein recommendations are set as “one-size-fits-all” for both young and older adults. Recent evidence demonstrates that current recommendations are insufficient to meet the minimum protein requirement to counteract muscle loss and to stimulate hypertrophy in healthy older adults. Beyond quantity, protein quality is also essential to benefit muscle anabolism in older adults. In terms of physical activity, resistance exercise training is a potential strategy to counteract age-related effects, as it can elicit muscle hypertrophic response in addition to increases in muscle strength and function in older adults. Canadian physical activity guidelines lack details on how this modality of training should be performed. Current guidelines for protein intake and physical activity do not reflect recent knowledge on sarcopenia prevention. The gap between guidelines and the latest evidence on the maintenance and promotion of older adult’s health highlight the need for updated protein and physical activity recommendations.

scholarly journals Reproductive competency and mitochondrial variation in aged Syrian hamster oocytes

2017 ◽  
Vol 29 (7) ◽  
pp. 1384 ◽  
Author(s):  
Fang Li ◽  
Frank J. Castora ◽  
Wentia Ford ◽  
Khalid Alarid ◽  
Howard W. Jones ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Ovarian Tissue ◽  
Polar Body ◽  
Oxygen Species ◽  
Contributing Factors ◽  
Age Related ◽  
Human Reproductive ◽  
Study Support ◽  
Mitochondrial Number ◽  
And Function

The hamster is a useful model of human reproductive biology because its oocytes are similar to those in humans in terms of size and structural stability. In the present study we evaluated fecundity rate, ovarian follicular numbers, ova production, mitochondrial number, structure and function, and cytoplasmic lamellae (CL) in young (2–4 months) and old (12–18 months) Syrian hamsters (Mesocricetus auratus). Young hamsters had higher fertilisation rates and larger litters than old hamsters (100 vs 50% and 9.3 ± 0.6 vs 5.5 ± 0.6, respectively). Ovarian tissue from superovulated animals showed a 46% decrease in preantral follicles in old versus young hamsters. There was a 39% reduction in MII oocyte number in old versus young hamsters. Young ova had no collapsed CL, whereas old ova were replete with areas of collapsed, non-luminal CL. Eighty-nine per cent of young ova were expanded against the zona pellucida with a clear indentation at the polar body, compared with 58.64% for old ova; the remaining old ova had increased perivitelline space with no polar body indentation. Higher reactive oxygen species levels and lower mitochondrial membrane potentials were seen in ova from old versus young hamsters. A significant decrease in mitochondrial number (36%) and lower frequency of clear mitochondria (31%) were observed in MII oocytes from old versus young hamster. In conclusion, the results of the present study support the theory of oocyte depletion during mammalian aging, and suggest that morphological changes of mitochondria and CL in oocytes may be contributing factors in the age-related decline in fertility rates.

scholarly journals Redox Signaling and Sarcopenia: Searching for the Primary Suspect

2021 ◽  
Vol 22 (16) ◽  
pp. 9045
Author(s):  
Nicholas A. Foreman ◽  
Anton S. Hesse ◽  
Li Li Ji
Keyword(s):  
Health Hazard ◽  
Critical Role ◽  
The Elderly ◽  
Redox Signaling ◽  
Ros Generation ◽  
Mitochondrial Homeostasis ◽  
Metabolic Functions ◽  
Age Related ◽  
And Function ◽  
Fundamental Mechanism

Sarcopenia, the age-related decline in muscle mass and function, derives from multiple etiological mechanisms. Accumulative research suggests that reactive oxygen species (ROS) generation plays a critical role in the development of this pathophysiological disorder. In this communication, we review the various signaling pathways that control muscle metabolic and functional integrity such as protein turnover, cell death and regeneration, inflammation, organismic damage, and metabolic functions. Although no single pathway can be identified as the most crucial factor that causes sarcopenia, age-associated dysregulation of redox signaling appears to underlie many deteriorations at physiological, subcellular, and molecular levels. Furthermore, discord of mitochondrial homeostasis with aging affects most observed problems and requires our attention. The search for the primary suspect of the fundamental mechanism for sarcopenia will likely take more intense research for the secret of this health hazard to the elderly to be unlocked.

scholarly journals Aging, Osteo-Sarcopenia, and Musculoskeletal Mechano-Transduction

2021 ◽  
Vol 2 ◽  
Author(s):  
Jenna M. Leser ◽  
Anicca Harriot ◽  
Heather V. Buck ◽  
Christopher W. Ward ◽  
Joseph P. Stains
Keyword(s):  
Oxidative Stress ◽  
Chronic Disease ◽  
Cellular Senescence ◽  
Healthy Aging ◽  
Mechanical Load ◽  
Low Energy ◽  
Load Sensing ◽  
Age Related ◽  
Increased Risk ◽  
And Function

The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, falls, low-energy fractures, and increased risk of co-morbid disease that leads to musculoskeletal frailty. The biology of osteo-sarcopenia is most understood in the context of systemic neuro-endocrine and immune/inflammatory alterations that drive inflammation, oxidative stress, reduced autophagy, and cellular senescence in the bone and muscle. Here we integrate these concepts to our growing understanding of how bone and muscle senses, responds and adapts to mechanical load. We propose that age-related alterations in cytoskeletal mechanics alter load-sensing and mechano-transduction in bone osteocytes and muscle fibers which underscores osteo-sarcopenia. Lastly, we examine the evidence for exercise as an effective countermeasure to osteo-sarcopenia.

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