scholarly journals Toward a unified theory of aging and regeneration

2019 ◽  
Vol 14 (9) ◽  
pp. 867-886 ◽  
Author(s):  
Michael D West ◽  
Hal Sternberg ◽  
Ivan Labat ◽  
Jeffrey Janus ◽  
Karen B Chapman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Regeneration ◽  
Antagonistic Pleiotropy ◽  
Unified Theory ◽  
Degenerative Diseases ◽  
Therapeutic Approaches ◽  
Regenerative Capacity ◽  
New Therapeutic Approaches ◽  
Age Related ◽  
Theory Of Aging

Growing evidence supports the antagonistic pleiotropy theory of mammalian aging. Accordingly, changes in gene expression following the pluripotency transition, and subsequent transitions such as the embryonic–fetal transition, while providing tumor suppressive and antiviral survival benefits also result in a loss of regenerative potential leading to age-related fibrosis and degenerative diseases. However, reprogramming somatic cells to pluripotency demonstrates the possibility of restoring telomerase and embryonic regeneration pathways and thus reversing the age-related decline in regenerative capacity. A unified model of aging and loss of regenerative potential is emerging that may ultimately be translated into new therapeutic approaches for establishing induced tissue regeneration and modulation of the embryo-onco phenotype of cancer.

scholarly journals Regenerative Capacity of Endogenous Factor: Growth Differentiation Factor 11; a New Approach of the Management of Age-Related Cardiovascular Events

2018 ◽  
Vol 19 (12) ◽  
pp. 3998 ◽  
Author(s):  
Luc Rochette ◽  
Alexandre Meloux ◽  
Eve Rigal ◽  
Marianne Zeller ◽  
Yves Cottin ◽  
...  
Keyword(s):  
Tissue Regeneration ◽  
Negative Regulator ◽  
Regenerative Capacity ◽  
Peripheral Tissues ◽  
New Approach ◽  
Pathophysiological Process ◽  
Differentiation Factor ◽  
Age Related ◽  
Endogenous Compound ◽  
Endogenous Regulators

Aging is a complicated pathophysiological process accompanied by a wide array of biological adaptations. The physiological deterioration correlates with the reduced regenerative capacity of tissues. The rejuvenation of tissue regeneration in aging organisms has also been observed after heterochronic parabiosis. With this model, it has been shown that exposure to young blood can rejuvenate the regenerative capacity of peripheral tissues and brain in aged animals. An endogenous compound called growth differentiation factor 11 (GDF11) is a circulating negative regulator of cardiac hypertrophy, suggesting that raising GDF11 levels could potentially treat or prevent cardiac diseases. The protein GDF11 is found in humans as well as animals. The existence of endogenous regulators of regenerative capacity, such as GDF11, in peripheral tissues and brain has now been demonstrated. It will be important to investigate the mechanisms with therapeutic promise that induce the regenerative effects of GDF11 for a variety of age-related diseases.

scholarly journals Shaping proteostasis at the cellular, tissue, and organismal level

2017 ◽  
Vol 216 (5) ◽  
pp. 1231-1241 ◽  
Author(s):  
Ambre J. Sala ◽  
Laura C. Bott ◽  
Richard I. Morimoto
Keyword(s):  
Cellular Tissue ◽  
Degenerative Diseases ◽  
Cell Type ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Precise Understanding ◽  
Systemic Level ◽  
Cell Type Specific ◽  
Multicellular Organisms ◽  
Pn Regulation

The proteostasis network (PN) regulates protein synthesis, folding, transport, and degradation to maintain proteome integrity and limit the accumulation of protein aggregates, a hallmark of aging and degenerative diseases. In multicellular organisms, the PN is regulated at the cellular, tissue, and systemic level to ensure organismal health and longevity. Here we review these three layers of PN regulation and examine how they collectively maintain cellular homeostasis, achieve cell type-specific proteomes, and coordinate proteostasis across tissues. A precise understanding of these layers of control has important implications for organismal health and could offer new therapeutic approaches for neurodegenerative diseases and other chronic disorders related to PN dysfunction.

scholarly journals Unified Theory of Bacterial Sialometabolism: How and Why Bacteria Metabolize Host Sialic Acids

2013 ◽  
Vol 2013 ◽  
pp. 1-26 ◽  
Author(s):  
Eric R. Vimr
Keyword(s):  
Bacterial Colonization ◽  
Sialic Acids ◽  
Unified Theory ◽  
Therapeutic Approaches ◽  
Metabolic Potential ◽  
New Therapeutic Approaches ◽  
Microbial Genomic ◽  
Molecule Interactions ◽  
Research Stage ◽  
Potential Carbon

Sialic acids are structurally diverse nine-carbon ketosugars found mostly in humans and other animals as the terminal units on carbohydrate chains linked to proteins or lipids. The sialic acids function in cell-cell and cell-molecule interactions necessary for organismic development and homeostasis. They not only pose a barrier to microorganisms inhabiting or invading an animal mucosal surface, but also present a source of potential carbon, nitrogen, and cell wall metabolites necessary for bacterial colonization, persistence, growth, and, occasionally, disease. The explosion of microbial genomic sequencing projects reveals remarkable diversity in bacterial sialic acid metabolic potential. How bacteria exploit host sialic acids includes a surprisingly complex array of metabolic and regulatory capabilities that is just now entering a mature research stage. This paper attempts to describe the variety of bacterial sialometabolic systems by focusing on recent advances at the molecular and host-microbe-interaction levels. The hope is that this focus will provide a framework for further research that holds promise for better understanding of the metabolic interplay between bacterial growth and the host environment. An ability to modify or block this interplay has already yielded important new insights into potentially new therapeutic approaches for modifying or blocking bacterial colonization or infection.

scholarly journals The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

2021 ◽  
Vol 14 (2) ◽  
pp. 96
Author(s):  
Susie L. Brown ◽  
Samantha Kendrick
Keyword(s):  
Gene Expression ◽  
Secondary Structure ◽  
Biological Function ◽  
Molecular Target ◽  
Therapeutic Approaches ◽  
Promoter Regions ◽  
New Therapeutic Approaches ◽  
G Quadruplex ◽  
Dna Elements ◽  
Insight Into

Stretches of cytosine-rich DNA are capable of adopting a dynamic secondary structure, the i-motif. When within promoter regions, the i-motif has the potential to act as a molecular switch for controlling gene expression. However, i-motif structures in genomic areas of repetitive nucleotide sequences may play a role in facilitating or hindering expansion of these DNA elements. Despite research on the i-motif trailing behind the complementary G-quadruplex structure, recent discoveries including the identification of a specific i-motif antibody are pushing this field forward. This perspective reviews initial and current work characterizing the i-motif and providing insight into the biological function of this DNA structure, with a focus on how the i-motif can serve as a molecular target for developing new therapeutic approaches to modulate gene expression and extension of repetitive DNA.

Abstract 13652: An Innate YAP/TAZ Mechanosensing Deficit in Hutchinson-Gilford Progeria Syndrome

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Brandon K Walther ◽  
Anahita Mojiri ◽  
Navaneeth Krishna Rajeeva Pandian ◽  
Jacques Ohayon ◽  
Huie Wang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Accelerated Aging ◽  
Scaffolding Protein ◽  
Therapeutic Approaches ◽  
Gene Encoding ◽  
New Therapeutic Approaches ◽  
Age Related ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Mechanical Aging

Hutchinson-Gilford Progeria Syndrome (HGPS) is a disease of accelerated aging causing death in the mid-teens from myocardial infarction or stroke. The disease is caused by a point mutation in the gene encoding lamin-A. The mutated scaffolding protein is aberrantly farnesylated inducing a constellation of defects included nuclear abnormalities, genomic damage, and rapid senescence. Therapy targeting the abnormal farnesylation provides a modest extension of life, thus new insights and therapeutic approaches are urgently needed for these children. Consistent with previous morphological observations and new studies implicating YAP/TAZ mechanobiology as an important mechanical pathway for endothelial cell (EC) health under shear stress, we hypothesized that HGPS ECs have an innate mechanical disturbance rendering them unable to respond to external, atheroprotective cues. We used a microfluidic vessel-on-a-chip with channel geometries and fluid flow to precisely model the hemodynamic stimuli present in vasculature as we have previously described. We cultured iPSC-derived HGPS ECs in this system to study mechanoresponse to shear stress and YAP/TAZ signaling. HGPS ECs manifest a rounded, flattened appearance characteristic of senescent ECs, are unable to align in response to flow, and have aberrant YAP/TAZ activity despite unidirectional laminar flow. To explore the physical underpinnings of such biochemical disturbances, we used atomic force microscopy (AFM) to precisely characterize the shape of individual HGPS cells, and their deformation to a controlled force applied by the AFM cantilever. Preliminary measurements confirmed that HGPS cells have a reduced profile and are compositely stiffer (nuclear modulus + cytoskeletal modulus) than cells derived from the unaffected parent of the child. These data provide evidence of altered biophysical properties of senescent cells which we term “mechanical aging,” which is associated with aberrant signaling in response to hemodynamic stimuli. Further characterization of mechanical aging may lead to new therapeutic approaches for HGPS and other age-related diseases.

scholarly journals Aging and Mitochondrial DNA

2010 ◽  
Vol 3 (1) ◽  
pp. 177 ◽  
Author(s):  
P. Das ◽  
G. Guha
Keyword(s):  
Mitochondrial Dna ◽  
Functional Decline ◽  
Oxygen Species ◽  
Degenerative Diseases ◽  
Mtdna Mutations ◽  
Wide Acceptance ◽  
Age Related ◽  
Transport Chain ◽  
Theory Of Aging ◽  
Cellular Pathology

According to the mitochondrial theory of aging, accrual of mutations in mitochondrial DNA (mtDNA) plays the paramount function in the cellular pathology of aging and in development of age-related degenerative ailments. Reactive oxygen species (ROS), which are byproducts of oxidative phosphorylation (OX-PHOS) in aerobic (mitochondrial) respiration, cause oxidative stress-induced damage to mtDNA. This damaged DNA, whose normal role is to encode proteins many of which are players in the electron transport chain (ETC), now codes for defective proteins. Such faulty proteins lead to a considerable impairment in the efficacy of ETC, thereby generating more ROS, which cause further damage to mtDNA in turn, leading to further defects in proteins, aggravated ETC dysfunction, and even more ROS. Hence, a ‘vicious cycle’ propagates that ultimately directs tissue cells towards structural and functional decline, or in other words, degeneration and aging. However, in spite of a wide acceptance of this theory, there have simultaneously been a considerable number of criticisms against it. This review is aimed at discussing the paradigm of aging and degenerative diseases in light of the mitochondrial paraphernalia, with reference to the evidences in support as well as in antagonism to the mitochondrial theory of aging.Keywords: Aging; Degenerative diseases; mtDNA mutations; ROS; Cell death.© 2011 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi:10.3329/jsr.v3i1.5078                J. Sci. Res. 3 (1), 176-186 (2011)

scholarly journals Long-lived rodents reveal signatures of positive selection in genes associated with lifespan and eusociality

2017 ◽  
Author(s):  
Arne Sahm ◽  
Martin Bens ◽  
Karol Szafranski ◽  
Susanne Holtze ◽  
Marco Groth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Mitochondrial Biogenesis ◽  
Antioxidant Defense ◽  
Antagonistic Pleiotropy ◽  
Transcriptomic Data ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Genetic Mechanisms ◽  
Theory Of Aging

AbstractThe genetic mechanisms that determine lifespan are poorly understood. Most research has been done on short lived animals and it is unclear if these insights can be transferred to long-lived mammals like humans. Some African mole-rats (Bathyergidae) have life expectancies that are multiple times higher than similar sized and phylogenetically closely related rodents. We obtained genomic and transcriptomic data from 17 rodent species and systematically scanned eleven lineages associated with the evolution of longevity and eusociality for positively selected genes (PSGs). The set of 319 PSGs contains regulators of mTOR and is enriched in functional terms associated with (i) processes that are regulated by the mTOR pathway, e.g. translation, autophagy and mitochondrial biogenesis, (ii) the immune system and (iii) antioxidant defense. Analyzing gene expression of PSGs during aging in the long-lived naked mole-rat and up-regulation in the short-lived rat, we found a pattern fitting the antagonistic pleiotropy theory of aging.

scholarly journals Chemoprevention in Gastrointestinal Physiology and Disease. Natural products and microbiome

2014 ◽  
Vol 307 (1) ◽  
pp. G1-G15 ◽  
Author(s):  
Allen K. Greiner ◽  
Rao V. L. Papineni ◽  
Shahid Umar
Keyword(s):  
Functional Gastrointestinal Disorders ◽  
Modern Society ◽  
Well Being ◽  
Ancestral State ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Age Related ◽  
Or Groups ◽  
Complex Ecosystem ◽  
Human Intestinal Tract

The human intestinal tract harbors a complex ecosystem of commensal bacteria that play a fundamental role in the well-being of their host. There is a general consensus that diet rich in plant-based foods has many advantages in relation to the health and well-being of an individual. In adults, diets that have a high proportion of fruit and vegetables and a low consumption of meat are associated with a highly diverse microbiota and are defined by a greater abundance of Prevotella compared with Bacteroides, whereas the reverse is associated with a diet that contains a low proportion of plant-based foods. In a philosophical term, our consumption of processed foods, widespread use of antibiotics and disinfectants, and our modern lifestyle may have forever altered our ancient gut microbiome. We may never be able to identify or restore our microbiomes to their ancestral state, but dietary modulation to manipulate specific gut microbial species or groups of species may offer new therapeutic approaches to conditions that are prevalent in modern society, such as functional gastrointestinal disorders, obesity, and age-related nutritional deficiency. We believe that this will become an increasingly important area of health research.

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