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Mechanisms of promising repurposed anti-ageing drugs. Metformin and rapamycin are thought to act synergistically to improve protein and energy homeostasis. Inhibitors of IL-6 and NF-κB could act to reverse systemic inflammation and TFGβ inhibitors have been shown to reverse aberrant signalling caused by an aged stem cell niche (of which extracellular matrix is a major component). Green arrows indicate stimulation of the indicated process. Red, flat arrows indicate inhibition. Indirect interactions are indicated by dashed arrows. Processes that have effects at the tissue or organ level are surrounded by blue circles. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)  

Mechanisms of promising repurposed anti-ageing drugs. Metformin and rapamycin are thought to act synergistically to improve protein and energy homeostasis. Inhibitors of IL-6 and NF-κB could act to reverse systemic inflammation and TFGβ inhibitors have been shown to reverse aberrant signalling caused by an aged stem cell niche (of which extracellular matrix is a major component). Green arrows indicate stimulation of the indicated process. Red, flat arrows indicate inhibition. Indirect interactions are indicated by dashed arrows. Processes that have effects at the tissue or organ level are surrounded by blue circles. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)  

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Article
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Ageing is a leading risk factor for many debilitating diseases. While age-related diseases have been the subject of over a century of intense investigation, until recently, physiological ageing was considered unavoidable. Pharmacological and genetic studies have since shown that ageing is a malleable process and that its abrogation can prevent its...

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... of mTORC1 leads to pleiotropic effects that are thought to improve protein and organelle ho- meostasis by relieving inhibition of autophagy and proteasome function while simultaneously suppressing protein translation ( Hill et al., 2010;Yu et al., 2010). mTOR also regulates mitochondrial biogenesis and lipid homeostasis through PPARγ and PGC1α ( Fig. 2; reviewed by Laplante & Sabatini, 2009). Rapamycin treatment has been shown to re- verse amyloid-β aggregation and improve brain vascularisation in Alzheimer's disease mouse models, as well as cognitive function in these disease models and wild-type mice (reviewed by . Rapamycin also prevented neuronal cell death in toxin- induced ...
Context 2
... is an anti-diabetic drug that is thought to activate adeno- sine monophosphate-activated kinase (AMPK) to modulate glucose ho- meostasis ( Shaw et al., 2005). However, other reports suggest that metformin possesses pleiotropic activity ( Foretz et al., 2010) and can modulate a variety of downstream processes related to ageing (Fig. 2). Ageing affects several systems acting at several hierarchical levels from molecular events such as mitochondrial dysfunction and genomic lesions, through to cellular events such as senescence or over-proliferation. Dysfunctional cells lead to tissue dysfunction, culminating in organ failure and death. Interactions between levels serve ...

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... To understand the actual reasons for our mortality, studies have been focused on ageing to sustain the quality of life in the ageing population globally. However, ageing studies are complex because ageing is influenced by genetic and environmental factors throughout life, which also shows great discrepancy among the subjects [3]. of subdominant species [17], an increase in the number of certain proteobacteria, and a reduction of Bifidobacteria and Firmicutes to Bacteroides ratio [18,19]. For instance, in the vaginally delivered breast-fed infants, the numbers of Bifidobacteria decreases throughout the course of life from 90% of the total colon microbiota following birth to less than 5% in the colon of adults, and these numbers were even less in the elderly [20]. ...
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With the implementation of modern scientific protocols, the average human lifespan has significantly improved, but age-related problems remain a challenge. With the advent of ageing, there are alterations in gut microbiota and gut barrier functions, weak immune responses, increased oxidative stress, and other age-related disorders. This review has highlighted and discussed the current understanding on the significance of gut microbiota dysbiosis and ageing and its inherent effects against age-related oxidative stress as well as on the gut health and gut-brain axis. Further, we have discussed the key mechanism of action of Lactobacillus strains in the longevity of life, alleviating gut dysbiosis, and improving oxidative stress and inflammation to provide an outline of the role of Lactobacillus strains in restoration of gut microbiota dysbiosis and alleviating certain conditions during ageing. Microbiota-targeted interventions of some characterized strains of probiotic Lactobacillus for the restoration of gut microbial community are considered as a potential approach to improve several neurological conditions. However, very limited human studies are available on this alarmed issue and recommend further studies to identify the unique Lactobacillus strains with potential anti-ageing properties and to discover its novel core microbiome-association, which will help to increase the therapeutic potential of probiotic Lactobacillus strains to ageing.
... Moreover, irreversible side effects, such as diabetes [4], are also main concerns that have prevented the use of rapamycin at a larger scale. In recent years, a variety of similar studies have proposed geroprotector candidates that could potentially promote life spans [5][6][7]. ...
... Such severe imbalanced datasets challenged the ML approaches and could be difficult in measuring model performance for future predictions. To avoid models from being heavily influenced only by the majority class, we randomly selected the same number of negative and positive samples in model 1 and model 2. We used samples across all the cell lines in LINCS for models (1)(2), and compared them with the remaining models (3)(4)(5)(6)(7)(8) Pharmaceuticals 2021, 14, 948 13 of 18 that used the imbalanced dataset extracted from two cell lines "U266" and "NOMO1", which contained less data points and, thus, were easier for traditional machine learning benchmarks to train (details are provided in Table 7). Table 7. Detailed model layouts on predictive labels, sample cell lines, used feature set, and whether the negative class is being downsampled. ...
Article
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Aging is considered an inevitable process that causes deleterious effects in the functioning and appearance of cells, tissues, and organs. Recent emergence of large-scale gene expression datasets and significant advances in machine learning techniques have enabled drug repurposing efforts in promoting longevity. In this work, we further developed our previous approach—DeepCOP, a quantitative chemogenomic model that predicts gene regulating effects, and extended its application across multiple cell lines presented in LINCS to predict aging gene regulating effects induced by small molecules. As a result, a quantitative chemogenomic Deep Model was trained using gene ontology labels, molecular fingerprints, and cell line descriptors to predict gene expression responses to chemical perturbations. Other state-of-the-art machine learning approaches were also evaluated as benchmarks. Among those, the deep neural network (DNN) classifier has top-ranked known drugs with beneficial effects on aging genes, and some of these drugs were previously shown to promote longevity, illustrating the potential utility of this methodology. These results further demonstrate the capability of “hybrid” chemogenomic models, incorporating quantitative descriptors from biomarkers to capture cell specific drug–gene interactions. Such models can therefore be used for discovering drugs with desired gene regulatory effects associated with longevity.
... Drug repurposing is a strategy that involves searching for new applications of prevailing therapeutics that will allow drugs to reach a greater number of patients for a wider indication. This procedure can bypass several steps of drug development including determination of mechanism of action, formulation and pharmacokinetics which would take on average 10-17 years in contrast to development time of 3-12 years for repurposed drugs [20,21]. Interestingly, there are 103 compounds listed by geroprotectors.org ...
Article
Aging is a risk factor for major central nervous system (CNS) disorders. More specifically, aging can be inked to neurodegenerative diseases (NDs) because of its deteriorating impact on neurovascular unit (NVU). Metformin, a first line FDA-approved anti-diabetic drug, has gained increasing interest among researchers for its role in improving aging-related neurodegenerative disorders. Additionally, numerous studies have illustrated metformin's role in ischemic stroke, a cerebrovascular disorder in which the NVU becomes dysfunctional which can lead to permanent life-threatening disabilities. Considering metformin's beneficial preclinical actions on various disorders, and the drug's role in alleviating severity of these conditions through involvement in commonly characterized cellular pathways, we discuss the potential of metformin as a suitable drug candidate for repurposing in CNS disorders.
... This is potentially valuable in the case of AD in which the underlying disease mechanisms remain poorly understood and the potential for multiple distinct disease drivers exists. Repurposing drugs for AD has received increasing attention 6,7 , but approaches to date have been largely hypothesis-driven, based on overlap between an existing pharmacological mechanism of action (MOA) and a putative diseasecausing mechanism 8 or results of a clinical trial 9,10 . While some of these leads are promising, no successes have been reported to date. ...
Article
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Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.
... Several hundreds of potential geroprotectors have been reported to modulate ageing in one or more species (see recent reviews [24][25][26][27][28][29][30][31][32][33] for more complete lists). Here, we review a select list of agents, grouped as Tier 1 or Tier 2, that, in our view, are the most developed experimentally and nearest to clinical testing or are intriguing based on information linked to the mechanisms of ageing 20 . ...
Article
Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD⁺ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.
... 3 in the case of AD in which the underlying disease mechanisms remain poorly understood and the potential for multiple distinct disease etiologies exists. Repurposing drugs for AD has received increasing attention 5,6 , but approaches to date have been largely hypothesis-driven, based on overlap between an existing pharmacological mechanism of action (MOA) and a putative disease-causing mechanism 7 or results of a clinical trial 8,9 . While some of these leads are promising, no successes have been reported to date. ...
... Memory and Aging Project (ROSMAP), The Mayo Clinic Brain Bank (MAYO) and The Mount Sinai/JJ Peters VA Medical Center Brain Bank (MSBB), each encompassing measurements from one or more regions of the brain (Fig. 1b). Braak staging scores 18 , assigned through neuropathological assessment, were used to group samples into three categories of disease progression: early (A; stages 1-2), intermediate (B; stages 3-4) and late (C; stages [5][6]. This grouping recapitulates the spatio-temporal progression of neurofibrillary tangles from the entorhinal region to the hippocampus area and, subsequently, to neocortical association areas 21 . ...
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Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. Repurposing can yield a useful therapeutic and also accelerate proof of concept studies that ultimately lead to a new molecular entity. We present a novel machine learning framework, DRIAD (Drug Repurposing In AD), that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD was validated on gene lists known to be associated with AD from other studies and subsequently applied to evaluate lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs were inspected for common trends among their nominal molecular targets and their "off-targets", revealing a high prevalence of kinases from the Janus (JAK), Unc-51-like (ULK) and NIMA-related (NEK) families. These kinase families are known to modulate pathways related to innate immune signaling, autophagy, and microtubule formation and function, suggesting possible disease-modifying mechanisms of action. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be evaluated in a clinical trial.
... Though clinical application with some compounds has been shown to benefit healthy life in older individuals, barriers couldn't be ignored. The quantification of human aging and the period for human test make clinical trials on humans unrealistic [81]. The safety and bioavailability of long-term interventions should be comprehensively assessed before running trials on humans [82]. ...
Article
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The remarkable breakthroughs in aging research pave the way allowing us to explore potential interventions to slow down aging process, and more importantly, to improve healthiness. Multiple approaches, including pharmacological and non-pharmacological interventions (e.g. caloric restriction, physical exercise), to a great extent, successfully tackle challenges of age-related phenotypic deficits across species. To date, molecular compounds are largely emerging, such as caloric restriction mimetics, NAD+ boosters, and senolytics. The use of mouse models is essential, as one of the best tools, to evaluate the potentials of molecules against aging and to provide a translational basis for treating human frailty. Here, we briefly overview present advances on therapeutic interventions against aging in laboratory mouse models and discuss the benefits and pitfalls on their clinical application for anti-aging and aging-related pathologies in humans. Keywords: Pharmacological intervention of aging, Mouse model
... The skin also contains all the enzymes required to synthesise steroid hormones from cholesterol and this provides a major source of estrone in postmenopausal skin [74]. Indeed, a more detailed understanding of estrogen's dramatic effects on the elastic fibre system is essential to develop new pharmacological interventions to extracellular matrix maintenance and age-associated pathologies [75]. Such treatments may be based on the manipulation of ER signalling, as have previously been achieved of ERb selective agonist effects on wound repair [52,58,76]. ...
Preprint
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Remodelling of the dermal extracellular matrix makes a major contribution to skin fragility in the elderly. The peri-menopausal period in females is also associated with an age-like phenotype which can be reversed by hormone replacement therapy. This suggests a direct link between circulating hormone levels and tissue ageing. Despite work investigating the role of estrogen as a regulator of collagen fibril abundance and structure, the influence of estrogen on the elastic fibre system remains poorly defined. Here we used an ovariectomised (Ovx) mouse surgical menopause model to show that just 7 weeks of acute hormone deficiency significantly decreased skin tensile strength and elasticity. Systemic replacement of 17β-estradiol to physiological levels protected against these changes to the skin mechanical properties. Moreover, acute hormone deficiency differentially influenced dermal structural networks, significantly decreasing dermal elastic fibre abundance without discernible effect on collagen fibril organisation or abundance. We suggest that this specific elastic fibre proteolysis may be driven by extracellular protease activity, or be a consequence of significant adipocyte hypertrophy. 17β-estradiol supplementation in Ovx mice in vivo protected the elastic fibre system. Treatment of human dermal fibroblasts with 17β-estradiol in vitro induced the selective upregulation of tropoelastin, fibrillin-1 and associated elastic fibre-associated proteins (including EMILINs and fibulins). In summary, these data show that the elastic fibre system is significantly perturbed by estrogen deprivation. Thus, pharmacological intervention may slow the acute effects of menopause and potentially the chronic effects of ageing in skin.
... Black lightning symbolizes organ damage or failure; SASP refers to the senescence-associated secretory phenotype. Figure reprinted with permission from Mallikarjun V, Swift J (2016) EBioMedicine, 14, 24-31 [50] differentially at senescence and are conferred with atherosclerosis development and vascular calcification. Mainly the genes IL8, IL1β, ICAM1, ESM1, TNFAP3, and CCL2 having the roles in inflammation; ADM, VEGFβ, VEGF, and MMP14 in tissue remodeling; and BMP2, MGP, DCN, OPG, and SPP1 in vascular calcification have been examined [7]. ...
Chapter
Ageing is a gradual impairment of physiological processes, leading to compromised cellular functions enhancing susceptibility to death. Ageing also becomes the primary cause of major human pathological disorders, comprising neurodegenerative diseases, cardiovascular disorders, cancer, and many more. In the developed as well as the developing world, ageing represents the biggest cause of illness and mortality. Ageing can be controlled to some extent by targeting genetic corridors and biochemical pathways implicated with human health. The idea of targeting ageing by reversing the pathogenesis of diseases seems to be promising but poses its own challenges. This chapter elucidates the genetic disorders affecting the aged people highlighting the challenges related to their healthcare system.
... Pharmacological Targeting of Aging As with most diseases, traditional pharmacological approaches are the most straightforward and widely explored way to target aging. This topic has been reviewed [1,4,11,12] and therefore is only briefly discussed [ 3 9 6 _ T D $ D I F F ] here (Box 1). 202 deaths per annum from an average yearly population size of 315 109 368 were recorded (0.818%). ...
... Other companies are using big-data techniques to find new uses for already approved drugs [12]. This is an attractive approach as pharmaceutical companies incur US$1.8 billion in capitalized costs to develop and obtain approval for drugs from scratch, while the safety of approved drugs is already known [33]. ...
... Even if this is successful, there are many practical challenges in performing clinical trials for aging, including how long it will take and how much it will cost [1,58,59]. As mentioned above, we also still lack suitable biomarkers of aging, which is a major impediment [12]. Recent advances in the development of epigenetic biomarkers of agingan 'epigenetic clock'offer promise [60] but it remains unclear whether these are suitable for clinical trials. ...
Article
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Age-related conditions are the leading causes of death and health-care costs. Reducing the rate of aging would have enormous medical and financial benefits. Myriad genes and pathways are known to regulate aging in model organisms, fostering a new crop of anti-aging companies. Approaches range from drug discovery efforts to big-data methods and direct-to-consumer (DTC) strategies. Challenges and pitfalls of commercialization include reliance on findings from short-lived model organisms, poor biological understanding of aging, and hurdles in performing clinical trials for aging. A large number of potential aging-associated interventions and targets exist, but given the long validation times only a small fraction can be explored for clinical applications. If even one company succeeds, however, the impact will be huge.