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14 pages, 2086 KiB

Open AccessArticle

Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer’s Disease

by Morteza Abyadeh, Nahid Tofigh, Saeedeh Hosseinian, Mafruha Hasan, Ardeshir Amirkhani, Matthew J. Fitzhenry, Veer Gupta, Nitin Chitranshi, Ghasem H. Salekdeh, Paul A. Haynes, Vivek Gupta, Koorosh Shahpasand and Mehdi Mirzaei

Cells 2022, 11(6), 987; https://doi.org/10.3390/cells11060987 - 14 Mar 2022

Cited by 18 | Viewed by 3832

Abstract

Alzheimer’s disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly [...] Read more.

Alzheimer’s disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly increased the pressure on healthcare systems worldwide. The pathogenesis of AD is being extensively investigated, yet several unknown key components remain. Therefore, we aimed to extract new knowledge from existing data. Ten gene expression datasets from different brain regions including the hippocampus, cerebellum, entorhinal, frontal and temporal cortices of 820 AD cases and 626 healthy controls were analyzed using the robust rank aggregation (RRA) method. Our results returned 1713 robust differentially expressed genes (DEGs) between five brain regions of AD cases and healthy controls. Subsequent analysis revealed pathways that were altered in each brain region, of which the GABAergic synapse pathway and the retrograde endocannabinoid signaling pathway were shared between all AD affected brain regions except the cerebellum, which is relatively less sensitive to the effects of AD. Furthermore, we obtained common robust DEGs between these two pathways and predicted three miRNAs as potential candidates targeting these genes; hsa-mir-17-5p, hsa-mir-106a-5p and hsa-mir-373-3p. Three transcription factors (TFs) were also identified as the potential upstream regulators of the robust DEGs; ELK-1, GATA1 and GATA2. Our results provide the foundation for further research investigating the role of these pathways in AD pathogenesis, and potential application of these miRNAs and TFs as therapeutic and diagnostic targets. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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15 pages, 2025 KiB

Open AccessArticle

Statins as a Therapeutic Approach for the Treatment of Pseudoxanthoma Elasticum Patients: Evaluation of the Spectrum Efficacy of Atorvastatin In Vitro

by Janina Tiemann, Christopher Lindenkamp, Ricarda Plümers, Isabel Faust, Cornelius Knabbe and Doris Hendig

Cells 2021, 10(2), 442; https://doi.org/10.3390/cells10020442 - 19 Feb 2021

Cited by 6 | Viewed by 2408

Abstract

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by mutations in the ATP-binding cassette sub-family C member 6 gene. Our previous studies revealed that PXE might be associated with premature aging. Treatment with statins showed positive effects not only for PXE but [...] Read more.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by mutations in the ATP-binding cassette sub-family C member 6 gene. Our previous studies revealed that PXE might be associated with premature aging. Treatment with statins showed positive effects not only for PXE but also for other diseases associated with premature aging like Hutchinson–Gilford progeria syndrome. Nevertheless, the molecular mechanisms in the case of PXE remain unclear. Thus, this study was performed to evaluate the efficiency of atorvastatin by analyzing key characteristics of the PXE phenotype in primary human dermal fibroblasts of PXE patients. Our data indicate that an atorvastatin treatment has a positive effect, especially on factors associated with cholesterol biosynthesis and prenylation processes, whereas the effect on age- and calcification-related factors was less pronounced. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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Review

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29 pages, 1447 KiB

Open AccessReview

Role of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease

by Seodhna M. Lynch, Guangran Guo, David S. Gibson, Anthony J. Bjourson and Taranjit Singh Rai

Cells 2021, 10(12), 3367; https://doi.org/10.3390/cells10123367 - 30 Nov 2021

Cited by 44 | Viewed by 7609

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by [...] Read more.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by a pathological hyperinflammatory response which results in a dysregulated immune response. Current advancements in aging research indicates that aging pathways have fundamental roles in dictating healthspan in addition to lifespan. Our review discusses the aging immune system and highlights that senescence and aging together, play a central role in COVID-19 pathogenesis. In our review, we primarily focus on the immune system response to SARS-CoV-2 infection, the interconnection between severe COVID-19, immunosenescence, aging, vaccination, and the emerging problem of Long-COVID. We hope to highlight the importance of identifying specific senescent endotypes (or “sendotypes”), which can used as determinants of COVID-19 severity and mortality. Indeed, identified sendotypes could be therapeutically exploited for therapeutic intervention. We highlight that senolytics, which eliminate senescent cells, can target aging-associated pathways and therefore are proving attractive as potential therapeutic options to alleviate symptoms, prevent severe infection, and reduce mortality burden in COVID-19 and thus ultimately enhance healthspan. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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32 pages, 1465 KiB

Open AccessFeature PaperReview

Exosomes in Ageing and Motor Neurone Disease: Biogenesis, Uptake Mechanisms, Modifications in Disease and Uses in the Development of Biomarkers and Therapeutics

by Ekene Anakor, Laura Le Gall, Julie Dumonceaux, William John Duddy and Stephanie Duguez

Cells 2021, 10(11), 2930; https://doi.org/10.3390/cells10112930 - 28 Oct 2021

Cited by 27 | Viewed by 6525

Abstract

Intercellular communication between neurons and their surrounding cells occurs through the secretion of soluble molecules or release of vesicles such as exosomes into the extracellular space, participating in brain homeostasis. Under neuro-degenerative conditions associated with ageing, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s [...] Read more.

Intercellular communication between neurons and their surrounding cells occurs through the secretion of soluble molecules or release of vesicles such as exosomes into the extracellular space, participating in brain homeostasis. Under neuro-degenerative conditions associated with ageing, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s or Parkinson’s disease, exosomes are suspected to propagate toxic proteins. The topic of this review is the role of exosomes in ageing conditions and more specifically in ALS. Our current understanding of exosomes and exosome-related mechanisms is first summarized in a general sense, including their biogenesis and secretion, heterogeneity, cellular interaction and intracellular fate. Their role in the Central Nervous System (CNS) and ageing of the neuromotor system is then considered in the context of exosome-induced signaling. The review then focuses on exosomes in age-associated neurodegenerative disease. The role of exosomes in ALS is highlighted, and their use as potential biomarkers to diagnose and prognose ALS is presented. The therapeutic implications of exosomes for ALS are considered, whether as delivery vehicles, neurotoxic targets or as corrective drugs in and of themselves. A diverse set of mechanisms underpin the functional roles, both confirmed and potential, of exosomes, generally in ageing and specifically in motor neurone disease. Aspects of their contents, biogenesis, uptake and modifications offer many plausible routes towards the development of novel biomarkers and therapeutics. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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34 pages, 24068 KiB

Open AccessReview

Role of Deep Learning in Predicting Aging-Related Diseases: A Scoping Review

by Jyotsna Talreja Wassan, Huiru Zheng and Haiying Wang

Cells 2021, 10(11), 2924; https://doi.org/10.3390/cells10112924 - 28 Oct 2021

Cited by 4 | Viewed by 9345

Abstract

Aging refers to progressive physiological changes in a cell, an organ, or the whole body of an individual, over time. Aging-related diseases are highly prevalent and could impact an individual’s physical health. Recently, artificial intelligence (AI) methods have been used to predict aging-related [...] Read more.

Aging refers to progressive physiological changes in a cell, an organ, or the whole body of an individual, over time. Aging-related diseases are highly prevalent and could impact an individual’s physical health. Recently, artificial intelligence (AI) methods have been used to predict aging-related diseases and issues, aiding clinical providers in decision-making based on patient’s medical records. Deep learning (DL), as one of the most recent generations of AI technologies, has embraced rapid progress in the early prediction and classification of aging-related issues. In this paper, a scoping review of publications using DL approaches to predict common aging-related diseases (such as age-related macular degeneration, cardiovascular and respiratory diseases, arthritis, Alzheimer’s and lifestyle patterns related to disease progression), was performed. Google Scholar, IEEE and PubMed are used to search DL papers on common aging-related issues published between January 2017 and August 2021. These papers were reviewed, evaluated, and the findings were summarized. Overall, 34 studies met the inclusion criteria. These studies indicate that DL could help clinicians in diagnosing disease at its early stages by mapping diagnostic predictions into observable clinical presentations; and achieving high predictive performance (e.g., more than 90% accurate predictions of diseases in aging). Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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16 pages, 2624 KiB

Open AccessReview

Potential Therapeutic Candidates for Age-Related Macular Degeneration (AMD)

by Sonali Nashine

Cells 2021, 10(9), 2483; https://doi.org/10.3390/cells10092483 - 19 Sep 2021

Cited by 43 | Viewed by 8689

Abstract

Aging contributes to the risk of development of ocular diseases including, but not limited to, Age-related Macular Degeneration (AMD) that is a leading cause of blindness in the United States as well as worldwide. Retinal aging, that contributes to AMD pathogenesis, is characterized [...] Read more.

Aging contributes to the risk of development of ocular diseases including, but not limited to, Age-related Macular Degeneration (AMD) that is a leading cause of blindness in the United States as well as worldwide. Retinal aging, that contributes to AMD pathogenesis, is characterized by accumulation of drusen deposits, alteration in the composition of Bruch’s membrane and extracellular matrix, vascular inflammation and dysregulation, mitochondrial dysfunction, and accumulation of reactive oxygen species (ROS), and subsequent retinal pigment epithelium (RPE) cell senescence. Since there are limited options available for the prophylaxis and treatment of AMD, new therapeutic interventions are constantly being looked into to identify new therapeutic targets for AMD. This review article discusses the potential candidates for AMD therapy and their known mechanisms of cytoprotection in AMD. These target therapeutic candidates include APE/REF-1, MRZ-99030, Ciliary NeuroTrophic Factor (CNTF), RAP1 GTPase, Celecoxib, and SS-31/Elamipretide. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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18 pages, 4195 KiB

Open AccessReview

The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism

by Tara Warren, Roisin McAllister, Amy Morgan, Taranjit Singh Rai, Victoria McGilligan, Matthew Ennis, Christopher Page, Catriona Kelly, Aaron Peace, Bernard M. Corfe, Mark Mc Auley and Steven Watterson

Cells 2021, 10(8), 2007; https://doi.org/10.3390/cells10082007 - 6 Aug 2021

Cited by 31 | Viewed by 7927

Abstract

Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is [...] Read more.

Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is the leading cause of cardiovascular disease. It is therefore important to understand vitamin D metabolism as a contributory factor. From the literature, we compile evidence of how these systems interact, relating the understanding of the molecular mechanisms involved to the results from observational studies. We also present the first systems biology pathway map of the joint cholesterol and vitamin D metabolisms made available using the Systems Biology Graphical Notation (SBGN) Markup Language (SBGNML). It is shown that the relationship between vitamin D supplementation, total cholesterol, and LDL-C status, and between latitude, vitamin D, and cholesterol status are consistent with our knowledge of molecular mechanisms. We also highlight the results that cannot be explained with our current knowledge of molecular mechanisms: (i) vitamin D supplementation mitigates the side-effects of statin therapy; (ii) statin therapy does not impact upon vitamin D status; and critically (iii) vitamin D supplementation does not improve cardiovascular outcomes, despite improving cardiovascular risk factors. For (iii), we present a hypothesis, based on observations in the literature, that describes how vitamin D regulates the balance between cellular and plasma cholesterol. Answering these questions will create significant opportunities for advancement in our understanding of cardiovascular health. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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26 pages, 1941 KiB

Open AccessReview

The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy

by Gemma Aragonès, Sheldon Rowan, Sarah G. Francisco, Elizabeth A. Whitcomb, Wenxin Yang, Giuliana Perini-Villanueva, Casper G. Schalkwijk, Allen Taylor and Eloy Bejarano

Cells 2021, 10(8), 1852; https://doi.org/10.3390/cells10081852 - 22 Jul 2021

Cited by 24 | Viewed by 4684

Abstract

The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a [...] Read more.

The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age-related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue-dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, we summarize the current state of knowledge related to the protective mechanisms against glycative stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying the reactive intermediates of glycation. This review focuses on glyoxalase 1 (GLO1), the first enzyme of the glyoxalase system, and the rate-limiting enzyme of this catalytic process. Although GLO1 is ubiquitously expressed, protein levels and activities are regulated in a tissue-dependent manner. We provide a comparative analysis of GLO1 protein in different tissues. Our findings indicate a role for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to delay the development of age-related diseases and summarize the literature that describes the current knowledge about nutritional compounds with properties to modulate the glyoxalase system. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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21 pages, 1226 KiB

Open AccessReview

Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging

by Gabriela Rapozo Guimarães, Palloma Porto Almeida, Leandro de Oliveira Santos, Leane Perim Rodrigues, Juliana Lott de Carvalho and Mariana Boroni

Cells 2021, 10(6), 1323; https://doi.org/10.3390/cells10061323 - 26 May 2021

Cited by 40 | Viewed by 11215

Abstract

The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced [...] Read more.

The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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21 pages, 1125 KiB

Open AccessReview

Sirtuin 1 and Skin: Implications in Intrinsic and Extrinsic Aging—A Systematic Review

by Angelika Bielach-Bazyluk, Edyta Zbroch, Hanna Mysliwiec, Alicja Rydzewska-Rosolowska, Katarzyna Kakareko, Iwona Flisiak and Tomasz Hryszko

Cells 2021, 10(4), 813; https://doi.org/10.3390/cells10040813 - 6 Apr 2021

Cited by 33 | Viewed by 5971

Abstract

Skin, as the outermost organ of the body, is constantly exposed to both intrinsic and extrinsic causative factors of aging. Intrinsic aging is related to compromised cellular proliferative capacity, and may be accelerated by harmful environmental influences with the greatest significance of ultraviolet [...] Read more.

Skin, as the outermost organ of the body, is constantly exposed to both intrinsic and extrinsic causative factors of aging. Intrinsic aging is related to compromised cellular proliferative capacity, and may be accelerated by harmful environmental influences with the greatest significance of ultraviolet radiation exposure, contributing not only to premature aging, but also to skin carcinogenesis. The overall skin cancer burden and steadily increasing global antiaging market provide an incentive for searching novel targets to improve skin resistance against external injury. Sirtuin 1, initially linked to extension of yeast and rodent lifespan, plays a key role in epigenetic modification of proteins, histones, and chromatin by which regulates the expression of genes implicated in the oxidative stress response and apoptosis. The spectrum of cellular pathways regulated by sirtuin 1 suggests its beneficial impact on skin aging. However, the data on its role in carcinogenesis remains controversial. The aim of this review was to discuss the relevance of sirtuin 1 in skin aging, in the context of intrinsic factors, related to genetic premature aging syndromes, as well as extrinsic modifiable ones, with the assessment of its future application. PubMed were searched from inception to 4 January 2021 for relevant papers with further search carried out on ClinicalTrials.gov. The systematic review included 46 eligible original articles. The evidence from numerous studies proves sirtuin 1 significance in both chronological and premature aging as well as its dual role in cancer development. Several botanical compounds hold the potential to improve skin aging symptoms. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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18 pages, 1333 KiB

Open AccessReview

Role of Telomeres Shortening in Atherogenesis: An Overview

by Yegor E. Yegorov, Anastasia V. Poznyak, Nikita G. Nikiforov, Antonina V. Starodubova and Alexander N. Orekhov

Cells 2021, 10(2), 395; https://doi.org/10.3390/cells10020395 - 15 Feb 2021

Cited by 17 | Viewed by 3369

Abstract

It is known that the shortening of the telomeres leads to cell senescence, accompanied by acquiring of pro-inflammatory phenotype. The expression of telomerase can elongate telomeres and resist the onset of senescence. The initiation of atherosclerosis is believed to be associated with local [...] Read more.

It is known that the shortening of the telomeres leads to cell senescence, accompanied by acquiring of pro-inflammatory phenotype. The expression of telomerase can elongate telomeres and resist the onset of senescence. The initiation of atherosclerosis is believed to be associated with local senescence of the endothelial cells of the arteries in places with either low or multidirectional oscillatory wall shear stress. The process of regeneration of the artery surface that has begun does not lead to success for several reasons. Atherosclerotic plaques are formed, which, when developed, lead to fatal consequences, which are the leading causes of death in the modern world. The pronounced age dependence of the manifestations of atherosclerosis pushes scientists to try to link the development of atherosclerosis with telomere length. The study of the role of telomere shortening in atherosclerosis is mainly limited to measuring the telomeres of blood cells, and only in rare cases (surgery or post-mortem examination) are the telomeres of local cells available for measurement. The review discusses the basic issues of cellular aging and the interpretation of telomere measurement data in atherosclerosis, as well as the prospects for the prevention and possible treatment of atherosclerosis. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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24 pages, 9719 KiB

Open AccessReview

The Jekyll and Hyde of Cellular Senescence in Cancer

by Dilara Demirci, Bengisu Dayanc, Fatma Aybuke Mazi and Serif Senturk

Cells 2021, 10(2), 208; https://doi.org/10.3390/cells10020208 - 21 Jan 2021

Cited by 30 | Viewed by 10349

Abstract

Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of [...] Read more.

Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of normal physiology with tumor suppressive functions. In the last few decades, novel cancer treatment strategies exploiting pro-senescence therapies have attracted considerable interest. Recent insight, however, suggests that therapy-induced senescence (TIS) elicits cell-autonomous and non-cell-autonomous implications that potentially entail detrimental consequences, reflecting the Jekyll and Hyde nature of cancer cell senescence. In essence, the undesirable manifestations that generally culminate in inflammation, cancer stemness, senescence reversal, therapy resistance, and disease recurrence are dictated by the persistent accumulation of senescent cells and the SASP. Thus, mitigating these pro-tumorigenic effects by eliminating these cells or inhibiting their SASP production holds great promise for developing innovative therapeutic strategies. In this review, we describe the fundamental aspects and dynamics of cancer cell senescence and summarize the comprehensive research on the adverse outcomes of TIS. Furthermore, we underline the rationale and motivation of emerging senotherapeutic modalities surrounding the removal of senescent cells and the SASP to help maximize the overall efficacy of cancer therapies. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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21 pages, 1675 KiB

Open AccessReview

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging

by Madison Schank, Juan Zhao, Jonathan P. Moorman and Zhi Q. Yao

Cells 2021, 10(1), 174; https://doi.org/10.3390/cells10010174 - 16 Jan 2021

Cited by 80 | Viewed by 9818

Abstract

According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with [...] Read more.

According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV. Full article

(This article belongs to the Special Issue Mechanisms of Aging and Therapeutic Approaches to Target Age-Associated Chronic Diseases)

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