Press Release | The mechanism of programmed aging: The way to creation a real remedy for senescence

 

 

The article by Dr. Alexander G. Trubitsyn is published in Current Aging Science, 2019

BENTHAM SCIENCE PUBLISHERS

Nature has sentenced humans to an inevitable death from the time of birth; the natural instrument of execution is the aging process. According to modern scientific notions, only two root causes of aging can be: stochastic physiological damage or the implementation of a special genetic program in the body. The first supposition is dominated from the onset of gerontology to the present day. Indeed, experiments provide conclusive evidence that infections produce toxins, that mitochondria generate ROS which cause mutations in nuclear and mitochondrial DNA, that errors occur in the processes of DNA reduplication, transcription and translation, that lipid peroxidation occurs in membranes, that non-enzymatic glycolysis and crosslinking between molecules occurs, and more; all of this accumulates over time. These facts leave no doubt about the cause of aging and suggest the clear measures to combat it. Almost all experiments aimed at increasing the maximum longevity of animals are reduced ultimately to methods that involve the prevention or restoration of this damage. A lot of different approaches have been tried, but the maximum animal longevity has remained unshakable. These results testify unequivocally that the concept of stochastic physiological damages accumulation is incorrect and therefore the alternative concept of genetically programmed aging is true.

In support of this conclusion, in the last decade, convincing experimental evidence has been found that the aging process is under direct genetic control: dysfunction of a single gene can increase the maximum lifespan of animals (several times for some invertebrates). About 80 such genes have been identified to date. However, this way of prolonging life has proved unsuitable for human due to dangerous side effects. Currently, only unfounded assumptions have been made about the existence of a genetic aging program, but there is no explanation for many empirically discovered phenomena, including this life-extending effect.

A fundamentally new mechanism of programmed aging is presented in this article by Alexander G. Trubitsyn (Institute of Biology, Russian Academy of Sciences). The mechanism of programmed aging has turned out to be much more complicated than that of accumulation of stochastic physiological damages. The destructive stochastic processes that are observed by researchers serve as the mechanism of execution of aging program rather than its root cause which should be fought.

A special bioenergetics aging clock follows from this mechanism of programmed aging and some other empirical data as a logical consequence. This clock gives us an opportunity to clarify nature of the above mentioned empirically found methods of life extending. It is this clock that sets the maximum species-specific longevity. This clock enables us to interpret all discovered phenomena concerning aging and longevity: the nature of the life-lengthening effect under calorie restriction (CR) and numerous CR-mimetic factors. It gives us an opportunity to understand why a bat and a bird lives 10 times longer than a terrestrial animal of a similar size, and a naked mole-rat (Heterocephalus glaber) has an impressively longer longevity in comparison with a home mouse, the nature of negligible senescence of some species and why cancer cells are immortal, and so on.

Most importantly, this special aging clock opens up a fundamentally new way of searching the means to control the aging process. Fundamental research in the field of molecular biology and related areas has already discovered the basic details of this clock, although even the authors of these studies are mostly not aware of the role of their discoveries in the mechanism of programed aging. These data, gathered together, provide insights into the molecular structure and functioning of the bioenergetics aging clock. This makes it possible to outline practical research on the management of the course of this clock, and hence the longevity. Three possible approaches to modify the course of this clock are visible. A creation of actual remedy for senescence in the near future looks like a real possibility. For more information, please visit: https://www.eurekaselect.com/node/175622/article/the-mechanism-of-programmed-aging-the-way-to-creation-a-real-remedy-for-senescence

 

 

Read full press release to find out more at:  https://www.eurekalert.org/pub_releases/2019-11/bsp-tmo112519.php

MOST ACCESSED ARTICLE – Estimating Alzheimer’s Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia

 

Journal Name: Current Alzheimer Research

Author(s): Matthew Davis, Thomas O`Connell,Scott Johnson,Stephanie Cline*, Elizabeth Merikle, Ferenc Martenyi, Kit Simpson.

 

 

Abstract:

Background: Alzheimer’s Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum.

Objective: To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes.

Methods: Patient-level longitudinal data from the National Alzheimer’s Coordinating Center for n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional probabilities between normal cognition, MCI due to AD, and AD severity states (defined by Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization for each health state, conditional on age and time from the previous evaluation. These probabilities were used to populate a transition matrix describing the likelihood of progressing to a particular disease state or death for any given current state and age. Finally, a health state model was developed to estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon.

Results: Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10% annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively. This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased life expectancy.

Conclusion: Transition probabilities from normal cognition through AD severity states are important for understanding patient progression across the AD spectrum. These estimates can be used to evaluate the clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health outcomes.

 

Read more here: http://www.eurekaselect.com/159189

 

MOST ACCESSED ARTICLE – Protein Tyrosine Nitration – Current Aging Science

Journal: Current Aging Science

Author(s): Bulbul Chakravarti, Deb N. Chakravarti*

Graphical Abstract:

Abstract:

Background: Aging is the inevitable fate of all living organisms, but the molecular basis of physiological aging is poorly understood. Oxidative stress is believed to play a key role in the aging process. In addition to Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS) are generated during aerobic metabolism in living organisms. Although protein damage and functional modification by ROS have been demonstrated in details, fewer studies have been reported on protein damage by RNS and its implication in the aging process. Proteins undergoing tyrosine nitration are associated with pathophysiology of several diseases, as well as physiological aging. The purpose of the current review article is to provide a brief summary of the biochemical mechanisms of tyrosine nitration, methodologies used for the detection of these modified proteins, effect of RNS induced post translational modification on biological functions and the putative role of tyrosine nitrated proteins in the aging process.

Methods: Published studies on the role of RNS in age related functional alteration of various organs/ tissues were critically reviewed and evaluated.

Results: Covalent modification of various proteins by tyrosine nitration is associated with modification of biological functions of various organs/tissues such as skeletal muscle, heart, brain and liver due to aging.

Conclusion: This information will be helpful to further investigate the interplay of different biochemical pathways and networks involved in the tyrosine nitration of various proteins due to aging with the ultimate goal to prevent the detrimental effects of RNS on the functional activities of these proteins.

Read more here: http://www.eurekaselect.com/150883/article

 

EDITOR’S CHOICE – Coping with Stress During Aging – Current Neuropharmacology

Journal: Current Neuropharmacology

Author(s): P. Sampedro-Piquero*, P. Alvarez-Suarez, A. Begega

Graphical Abstract:

 

Abstract:

Background: Resilience is the ability to achieve a positive outcome when we are in the face of adversity. It supposes an active resistance to adversity by coping mechanisms in which genetic, molecular, neural and environmental factors are involved. Resilience has been usually studied in early ages and few is known about it during aging.

Methods: In this review, we will address the age-related changes in the brain mechanisms involved in regulating the stress response. Furthermore, using the EE paradigm, we analyse the resilient potential of this intervention and its neurobiological basis. In this case, we will focus on identifying the characteristics of a resilient brain (modifications in HPA structure and function, neurogenesis, specific neuron types, glia, neurotrophic factors, nitric oxide synthase or microRNAs, among others).

Results: The evidence suggests that a healthy lifestyle has a crucial role to promote a resilient brain during aging. Along with the behavioral changes described, a better regulation of HPA axis, enhanced levels of postmitotic type-3 cells or changes in GABAergic neurotransmission are some of the brain mechanisms involved in resilience.

Conclusion: Future research should identify different biomarkers that increase the resistance to develop mood disorders and based on this knowledge, develop new potential therapeutic targets.

Read more here: http://www.eurekaselect.com/155614/article

 

OPEN ACCESS ARTICLE – Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s):  Kenneth Maiese

Abstract:

Background: The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease.

Methods: In light of the significant role circadian rhythm can hold over the body’s normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis.

Results: In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer’s disease and Parkinson’s disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth.

Conclusion: Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.

Read more here: http://www.eurekaselect.com/154252

Highlighted Article – Sleep-Wake Patterns And Cognition of Older Adults with Amnestic Mild Cognitive Impairment (aMCI) – Current Alzheimer Research

http://www.eurekaselect.com/152638

Most Accessed Article – Warming Up to New Possibilities with the Capsaicin Receptor TRPV1: mTOR, AMPK, and Erythropoietin – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s): Kenneth Maiese.

Abstract:

Background: Transient receptor potential (TRP) channels are a superfamily of ion channels termed after the trp gene in Drosophila that are diverse in structure and control a wide range of biological functions including cell development and growth, thermal regulation, and vascular physiology. Of significant interest is the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, also known as the capsaicin receptor and the vanilloid receptor 1, that is a non-selective cation channel sensitive to a host of external stimuli including capsaicin and camphor, venoms, acid/basic pH changes, and temperature.

Methods: Given the multiple modalities that TRPV1 receptors impact in the body, we examined and discussed the role of these receptors in vasomotor control, metabolic disorders, cellular injury, oxidative stress, apoptosis, autophagy, and neurodegenerative disorders and their overlap with other signal transduction pathways that impact trophic factors.

Results: Surprisingly, TRPV1 receptors do not rely entirely upon calcium signaling to affect cellular biology, but also have a close relationship with the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and protein kinase B (Akt) that have roles in pain sensitivity, stem cell development, cellular survival, and cellular metabolism. These pathways with TRPV1 converge in the signaling of growth factors with recent work highlighting a relationship with erythropoietin (EPO). Angiogenesis and endothelial tube formation controlled by EPO requires, in part, the activation of TRPV1 receptors in conjunction with Akt and AMPK pathways.

Conclusion: TRPV1 receptors could prove to become vital to target disorders of vascular origin and neurodegeneration. Broader and currently unrealized implementations for both EPO and TRPV1 receptors can be envisioned for for the development of novel therapeutic strategies in multiple systems of the body.

 

To access the article, please visit: http://www.eurekaselect.com/150838

Article by Disease – “Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism”

Article by Disease on “Metabolic Disorders”

Abstract:

Introduction: The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission.

Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia.

Highlights: This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.

Read more: http://www.eurekaselect.com/node/138027/article 

Editor’s Choice – “Potential for Stem Cells Therapy in Alzheimer’s Disease: Do Neurotrophic Factors Play Critical Role?”

Journal: Current Alzheimer Research

Author(s): Parul Bali, Debomoy K. Lahiri, Avijit Banik, Bimla Nehru and Akshay Anand

Abstract:

Alzheimer’s disease (AD) is one of the most common causes of dementia. Despite several decades of research in AD, there is no standard disease- modifying therapy available and currentlyapproved drugs provide only symptomatic relief. Stem cells hold immense potential to regenerate damaged tissues and are currently tested in some brain-related disorders, such as AD, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). We review stem cell transplantation studies using preclinical and clinical tools. We describe different sources of stem cells used in various animal models and explaining the putative molecular mechanisms that can rescue neurodegenerative disorders. The clinical studies suggest safety, efficacy and translational potential of stem cell therapy. The therapeutic outcome of stem cell transplantation has been promising in many studies, but no unifying hypothesis can convincingly explain the underlying mechanism. Some studies have reported paracrine effects exerted by these stem cells via the release of neurotrophic factors, while other studies describe the immunomodulatory effects exerted by the transplanted cells. There are also reports which indicate that stem cell transplantation might result in endogenous cell proliferation or replacement of diseased cells. In animal models of AD, stem cell transplantation is also believed to increase expression of synaptic proteins.

Read more here: http://benthamscience.com/journals/current-alzheimer-research/volume/14/issue/2/page/208/

Most Accessed Article – “Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging”

Abstract: Calcium (Ca²⁺) release from intracellular stores controls numerous cellular processes, including cardiac and skeletal muscle contraction, synaptic transmission and metabolism. The ryanodine receptors (RyRs: RyR1, RyR2, RyR3) and inositol 1,4,5-trisphosphate receptors (IP3Rs: IP3R1, IP3R2, IP3R3) are the major Ca²⁺ release channels (CRCs) on the endo/sarcoplasmic reticulum (ER/SR). RyRs and IP3Rs comprise macromolecular signaling complexes that include modulatory proteins which regulate channel activity in response to extracellular signals resulting in intracellular Ca²⁺ release. Here we focus on the roles of CRCs in heart, skeletal muscle, brain, metabolism, and aging.

Find out more: http://benthamscience.com/journals/current-molecular-pharmacology/volume/8/issue/2/page/206/