Ten New articles on ageing published on Ageing Research Reviews
In this issue, we would like to share ten latest articles on ageing published on the journal Ageing Research Reviews.
Title: Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology
Authors: Moisés Selman, Annie Pardo
Type: Review from Ageing Research Reviews
Highlights:
• Tissue fibrosis is frequently associated with ageing.
• Extracellular matrix gets stiffer with aging.
• Stiff extracellular matrix turns-on several profibrotic feedback loops.
• Stiff extracellular matrix contributes to ageing hallmarks.
Abstract:
Ageing is a multifactorial biological process leading to a progressive decline of physiological functions. The process of ageing includes numerous changes in the cells and the interactions between cell-cell and cell-microenvironment remaining as a critical risk factor for the development of chronic degenerative diseases. Systemic inflammation, known as inflammageing, increases as a consequence of ageing contributing to age-related morbidities. But also, persistent and uncontrolled activation of fibrotic pathways, with excessive accumulation of extracellular matrix (ECM) and organ dysfunction is markedly more frequent in the elderly. In this context, we introduce here the concept of Fibroageing, that is, the propensity to develop tissue fibrosis associated with ageing, and propose that ECM is a key player underlying this process. During ageing, molecules of the ECM become damaged through many modifications including glycation, crosslinking, and accumulation, leading to matrix stiffness which intensifies ageing-associated alterations. We provide a framework with some mechanistic hypotheses proposing that stiff ECM, in addition to the well-known activation of fibrotic positive feedback loops, affect several of the hallmarks of ageing, such as cell senescence and mitochondrial dysfunction, and in this context, is a key mechanism and a driver thread of Fibroageing.
Access this article: https://doi.org/10.1016/j.arr.2021.101393
Title: Gene targeting techniques for Huntington's disease
Authors: Eric Fields, Erik Vaughan, Deepika Tripu, Isabelle Lim, Katherine Shrout, Jessica Conway, Nicole Salib, Yubin Lee, Akash Dhamsania, Michael Jacobsen, Ashley Woo, Huijing Xue, Kan Cao
Type: Review from Ageing Research Reviews
Highlights:
• The exact function of human huntingtin protein is still uncertain, but evidence for its roles in key functions is increasing.
• Targeted efforts to downregulate the mutant huntingtin protein in both allele-specific and non-allele specific ways have been explored.
• Prime editing technology provides a potential new avenue for regulating mutant huntingtin expression.
Abstract:
Huntington’s disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT’s normal cellular functions and cause additional detrimental effects. In this review, we discuss multiple approaches targeting DNA and RNA to reduce mHTT expression. These approaches are categorized into non-allele-specific silencing and allele-specific-silencing using Single Nucleotide Polymorphisms (SNPs) and haplogroup analysis. Additionally, this review discusses a potential application of recent CRISPR prime editing technology in targeting HD.
Access this article: https://doi.org/10.1016/j.arr.2021.101385
Title: Interspecific interactions that affect ageing: Age-distorters manipulate host ageing to their own evolutionary benefits
Authors: Jérôme Teulière, Charles Bernard, Eric Bapteste
Type: Review from Ageing Research Reviews
Highlights:
• Genetic causes of cell/organismal ageing external to a focal species may be neglected.
• Many age-distorters may interfere with ageing in other species for their own interest.
• Co-evolution/arms races with age-distorters would affect genetics of ageing evolution.
• Genes in viruses, parasites or symbionts may often turn hosts into disposable soma.
• Modelling age-distorters can expand the scope of major non-adaptive theories of ageing.
Abstract:
Genetic causes for ageing are traditionally investigated within a species. Yet, the lifecycles of many organisms intersect. Additional evolutionary and genetic causes of ageing, external to a focal species/organism, may thus be overlooked. Here, we introduce the phrase and concept of age-distorters and its evidence. Age-distorters carry ageing interfering genes, used to manipulate the biological age of other entities upon which the reproduction of age-distorters relies, e.g. age-distorters bias the reproduction/maintenance trade-offs of cells/organisms for their own evolutionary interests. Candidate age-distorters include viruses, parasites and symbionts, operating through specific, genetically encoded interferences resulting from co-evolution and arms race between manipulative non-kins and manipulable species. This interference results in organismal ageing when age-distorters prompt manipulated organisms to favor their reproduction at the expense of their maintenance, turning these hosts into expanded disposable soma. By relying on reproduction/maintenance trade-offs affecting disposable entities, which are left ageing to the reproductive benefit of other physically connected lineages with conflicting evolutionary interests, the concept of age-distorters expands the logic of the Disposable Soma theory beyond species with fixed germen/soma distinctions. Moreover, acknowledging age-distorters as external sources of mutation accumulation and antagonistic pleiotropic genes expands the scope of the mutation accumulation and of the antagonistic pleiotropy theories.
Access this article: https://doi.org/10.1016/j.arr.2021.101375
Title: Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology
Authors: Fernando Maestú, Willemde Haan, Marc Aurel Busche, Javier DeFelipe
Type: Review from Ageing Research Reviews
Highlights:
• The E/I balance is a fundamental mechanism for maintaining effective neuronal communication and support cognitive performance.
• AD research has been approached by different levels of analysis with no integration between them. Results need harmonization in a common framework.
• E/I imbalance is the endpoint of all AD-related micro-level synaptic pathology, and the starting point of the network disruption and cognitive impairment.
• Computational neurophysiological models can integrate data from different levels, creating a framework to test hypotheses and propose new strategies of intervention.
Abstract:
Our incomplete understanding of the link between Alzheimer’s Disease pathology and symptomatology is a crucial obstacle for therapeutic success. Recently, translational studies have begun to connect the dots between protein alterations and deposition, brain network dysfunction and cognitive deficits. Disturbance of neuronal activity, and in particular an imbalance in underlying excitation/inhibition (E/I), appears early in AD, and can be regarded as forming a central link between structural brain pathology and cognitive dysfunction. While there are emerging (non-)pharmacological options to influence this imbalance, the complexity of human brain dynamics has hindered identification of an optimal approach. We suggest that focusing on the integration of neurophysiological aspects of AD at the micro-, meso- and macroscale, with the support of computational network modeling, can unite fundamental and clinical knowledge, provide a general framework, and suggest rational therapeutic targets.
Access this article: https://doi.org/10.1016/j.arr.2021.101372
Title: The role of senescence in the pathogenesis of atrial fibrillation: A target process for health improvement and drug development
Authors: Guangran Guo, Steven Watterson, Shu-Dong Zhang, Anthony Bjourson, Victoria McGilligan, Aaron Peace, Taranjit Singh Rai
Type: Review from Ageing Research Reviews
Highlights:
• Atrial fibrillation (AF) is an ageing-related chronic disease.
• Atrial electrical and structural remodeling act as substrate for AF maintenance.
• Atrial fibrosis is regarded as basis for atrial fibrillation development and maintenance.
• Senescence contributes to AF by causing atrial fibrosis through extracellular matrix, Angiotensin II, TGF-ß/Smad and thrombin signalling.
• Eliminating senescent cardiac cells by means of senolytic compounds, immune cells, CAR T cells and sEVs may attenuate atrial fibrillation.
Abstract:
Cellular senescence is a state of growth arrest that occurs after cells encounter various stresses. Senescence contributes to tumour suppression, embryonic development, and wound healing. It impacts on the pathology of various diseases by secreting inflammatory chemokines, immune modulators and other bioactive factors. These secretory biosignatures ultimately cause inflammation, tissue fibrosis, immunosenescence and many ageing-related diseases such as atrial fibrillation (AF). Because the molecular mechanisms underpinning AF development remain unclear, current treatments are suboptimal and have serious side effects. In this review, we summarize recent results describing the role of senescence in AF. We propose that senescence factors induce AF and have a causative role. Hence, targeting senescence and its secretory phenotype may attenuate AF.
Access this article: https://doi.org/10.1016/j.arr.2021.101363
Title: A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration
Authors: Lara Oblak, Jeroenvan der Zaag, Albert T. Higgins-Chen, Morgan E. Levine, Marco P.Boks
Type: Review from Ageing Research Reviews
Highlights:
• 156 publications have reported on factors related to accelerated epigenetic aging.
• GrimAge, Hannum, Horvath and Levine clocks tend to agree in direction of effects, but vary in size.
• BMI, HIV infection, and male sex are associated with epigenetic clock acceleration.
• Epigenetic age acceleration is related to mortality, CVD, cancer and diabetes.
• Chronological and mortality clocks show more divergence in psychiatric compared to physical outcomes.
Abstract:
Aging involves a diverse set of biological changes accumulating over time that leads to increased risk of morbidity and mortality. Epigenetic clocks are now widely used to quantify biological aging, in order to investigate determinants that modify the rate of aging and to predict age-related outcomes. Numerous biological, social and environmental factors have been investigated for their relationship to epigenetic clock acceleration and deceleration. The aim of this review was to synthesize general trends concerning the associations between human epigenetic clocks and these investigated factors. We conducted a systematic review of all available literature and included 156 publications across 4 resource databases. We compiled a list of all presently existing blood-based epigenetic clocks. Subsequently, we created an extensive dataset of over 1300 study findings in which epigenetic clocks were utilized in blood tissue of human subjects to assess the relationship between these clocks and numeral environmental exposures and human traits. Statistical analysis was possible on 57 such relationships, measured across 4 different epigenetic clocks (Hannum, Horvath, Levine and GrimAge). We found that the Horvath, Hannum, Levine and GrimAge epigenetic clocks tend to agree in direction of effects, but vary in size. Body mass index, HIV infection, and male sex were significantly associated with acceleration of one or more epigenetic clocks. Acceleration of epigenetic clocks was also significantly related to mortality, cardiovascular disease, cancer and diabetes. Our findings provide a graphical and numerical synopsis of the past decade of epigenetic age estimation research and indicate areas where further attention could be focused in the coming years.
Graphical abstract:
Access this article: https://doi.org/10.1016/j.arr.2021.101348
Title: Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease
Authors: Brittani R. Price, Lance A. Johnson, Christopher M. Norris
Type: Review from Ageing Research Reviews
Highlights:
• Many Alzheimer’s disease pathophysiological processes are linked through astrocyte reactivity and/or dysfunction.
• Astrocyte signaling mechanisms are extensively intertwined and likely impact one another in deleterious ways.
• Modifying or resolving reactive astrocyte phenotypes could lead to effective anti-AD treatments.
Abstract:
Astrocyte reactivity is a hallmark of neuroinflammation that arises with Alzheimer’s disease (AD) and nearly every other neurodegenerative condition. While astrocytes certainly contribute to classic inflammatory processes (e.g. cytokine release, waste clearance, and tissue repair), newly emerging technologies for measuring and targeting cell specific activities in the brain have uncovered essential roles for astrocytes in synapse function, brain metabolism, neurovascular coupling, and sleep/wake patterns. In this review, we use a holistic approach to incorporate, and expand upon, classic neuroinflammatory concepts to consider how astrocyte dysfunction/reactivity modulates multiple pathological and clinical hallmarks of AD. Our ever-evolving understanding of astrocyte signaling in neurodegeneration is not only revealing new drug targets and treatments for dementia but is suggesting we reimagine AD pathophysiological mechanisms.
Graphical abstract:
Access this article: https://doi.org/10.1016/j.arr.2021.101335
Title: Senescence in tissue samples of humans with age-related diseases: A systematic review
Authors: Camilla S. L. Tuttle, Suzanne W. M. Luesken, Mariette E. C. Waaijer, Andrea B. Maier
Type: Review from Ageing Research Reviews
Highlights:
• Higher numbers of senescent cells have been implicated in age-related diseases.
• In humans, senescence is most studied in the heart and the respiratory system.
• The cell cycle regulator p16ink4a is most often investigated.
• Higher numbers of senescent cells are observed in human diseased tissues.
• The higher expression is independent of the marker used to detect senescence.
Abstract:
Background:
Higher numbers of senescent cells have been implicated in age-related disease pathologies. However, whether different diseases have different senescent phenotypes is unknown. Here we provide a systematic overview of the current available evidence of senescent cells in age-related diseases pathologies in humans and the markers currently used to detect senescence levels in humans.
Methods:
PubMed, Web of Science and EMBASE were systematically searched from inception to the 29th of September 2019, using keywords related to ‘senescence’, ‘age-related diseases’ and ‘biopsies’.
Results:
In total 12,590 articles were retrieved of which 103 articles were included in this review. The role of senescence in age-related disease has been assessed in 9 different human organ system and 27 different age-related diseases of which heart (27/103) and the respiratory systems (18/103) are the most investigated. Overall, 27 different markers of senescence have been used to determine cellular senescence and the cell cycle regulator p16ink4a is most often used (23/27 age-related pathologies).
Conclusion:
This review demonstrates that a higher expression of senescence markers are observed within disease pathologies. However, not all markers to detect senescence have been assessed in all tissue types.
Access this article: https://doi.org/10.1016/j.arr.2021.101334
Title: Emerging pathogenic role of peripheral blood factors following BBB disruption in neurodegenerative disease
Authors: Min-Tae Jeon, Kyu-Sung Kim, Eun Seon Kim, Suji Lee, Jieun Kim, Hyang-Sook Hoe, Do-Geun Kim
Type: Review from Ageing Research Reviews
Highlights:
• Regulating inflammation in the brain and peripheral organs is an important strategy to develop the therapeutics for neurodegenerative diseases.
• The blood-brain barrier (BBB) is disrupted in patients with NDs and mouse models of NDs.
• Strengthening BBB integrity and preventing BBB disruption may attenuate ND progression and associated functional loss.
Abstract:
The responses of central nervous system (CNS) cells such as neurons and glia in neurodegenerative diseases (NDs) suggest that regulation of neuronal and glial functions could be a strategy for ND prevention and/or treatment. However, attempts to develop such therapeutics for NDs have been hindered by the challenge of blood-brain barrier (BBB) permeability and continued constitutive neuronal loss. These limitations indicate the need for additional perspectives for the prevention/treatment of NDs. In particular, the disruption of the blood-brain barrier (BBB) that accompanies NDs allows brain infiltration by peripheral factors, which may stimulate innate immune responses involved in the progression of neurodegeneration. The accumulation of blood factors like thrombin, fibrinogen, c-reactive protein (CRP) and complement components in the brain has been observed in NDs and may activate the innate immune system in the CNS. Thus, strengthening the integrity of the BBB may enhance its protective role to attenuate ND progression and functional loss. In this review, we describe the innate immune system in the CNS and the contribution of blood factors to the role of the CNS immune system in neurodegeneration and neuroprotection.
Access this article: https://doi.org/10.1016/j.arr.2021.101333
Title: Altered endocytosis in cellular senescence
Authors: Eun-Young Shin, Nak-Kyun Soung, Martin Alexander Schwartz, Eung-Gook Kim
Type: Review from Ageing Research Reviews
Highlights:
• Dysfunctional endocytic components contribute to cellular senescence.
• Downregulation of amphiphysin-1 and βPIX induces senescence through altered CME.
• Overexpression of ING1a induces cellular senescence through altered CME.
• Elevated caveolin-1 regulates CavME and induces senescence.
Abstract:
Cellular senescence occurs in response to diverse stresses (e.g., telomere shortening, DNA damage, oxidative stress, oncogene activation). A growing body of evidence indicates that alterations in multiple components of endocytic pathways contribute to cellular senescence. Clathrin-mediated endocytosis (CME) and caveolae-mediated endocytosis (CavME) represent major types of endocytosis that are implicated in senescence. More recent research has also identified a chromatin modifier and tumor suppressor that contributes to the induction of senescence via altered endocytosis. Here, molecular regulators of aberrant endocytosis-induced senescence are reviewed and discussed in the context of their capacity to serve as senescence-inducing stressors or modifiers.
Access this article: https://doi.org/10.1016/j.arr.2021.101332
