Pharmacological lifespan extension of invertebrates

Lucanic, Mark; Lithgow, Gordon J.; Alavez, Silvestre

doi:10.1016/j.arr.2012.06.006

Cited by 69 publications

(61 citation statements)

References 155 publications

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“…As aging is the major risk factor for multiple pathologies, including cardiovascular diseases, neurodegenerative disorders and cancer (Niccoli & Partridge, 2012), finding interventions that can increase health during aging is of importance. Lifespan of laboratory model organisms can be greatly extended by genetic and environmental interventions, which also improve health and function during aging (Clancy et al, 2001; Lucanic, Lithgow, & Alavez, 2013; Xiao et al, 2013). Many of these interventions target components of the nutrient‐sensing network and decrease the activity of IGF/insulin and/or TOR signalling (Fontana, Partridge, & Longo, 2010).…”

Section: Introductionmentioning

confidence: 99%

Gene expression‐based drug repurposing to target aging

et al. 2018

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Aging is the largest risk factor for a variety of noncommunicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both lifespan and healthspan. Aging is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target‐centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat aging in human brain. Using multiple gene expression data sets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterize aging. Then, we compared these changes in gene expression with drug‐perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as antiaging drugs by reversing the detrimental changes that occur during aging, others by mimicking the cellular defence mechanisms. The drugs that we identified included significant number of already identified prolongevity drugs, indicating that the method can discover de novo drugs that meliorate aging. The approach has the advantages that using data from human brain aging data, it focuses on processes relevant in human aging and that it is unbiased, making it possible to discover new targets for aging studies.

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Section: Introductionmentioning

confidence: 99%

Gene expression‐based drug repurposing to target aging

et al. 2018

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“…Caenorhabditis elegans has proved to be a good model organism for the discovery of chemical compounds and plant extracts that modulate aging (Collins et al ., 2006; Lucanic et al ., 2013a; Carretero et al ., 2015). In an effort to identify novel modulators of DR, we have undertaken small‐molecule screens in C. elegans to identify new chemical structures that can delay aging.…”

Section: Introductionmentioning

confidence: 99%

Chemical activation of a food deprivation signal extends lifespan

Lucanic

Garrett

et al. 2016

Aging Cell

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SummaryModel organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug‐like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.

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“…A positive impact on lifespan rarely exceeds 40% in invertebrates and is often less in mammals (Spindler, 2012; Lucanic et al ., 2013). In contrast, much larger effects have been observed with genetic interventions, for instance a 10‐fold enhancement induced by mutations in a PI3K subunit gene (Ayyadevara et al ., 2008).…”

Section: Discussionmentioning

confidence: 99%

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

et al. 2016

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SummaryIn the coming decades, a massive shift in the aging segment of the population will have major social and economic consequences around the world. One way to offset this increase is to expedite the development of geroprotectors, substances that slow aging, repair age‐associated damage and extend healthy lifespan, or healthspan. While over 200 geroprotectors are now reported in model organisms and some are in human use for specific disease indications, the path toward determining whether they affect aging in humans remains obscure. Translation to the clinic is hampered by multiple issues including absence of a common set of criteria to define, select, and classify these substances, given the complexity of the aging process and their enormous diversity in mechanism of action. Translational research efforts would benefit from the formation of a scientific consensus on the following: the definition of ‘geroprotector’, the selection criteria for geroprotectors, a comprehensive classification system, and an analytical model. Here, we review current approaches to selection and put forth our own suggested selection criteria. Standardizing selection of geroprotectors will streamline discovery and analysis of new candidates, saving time and cost involved in translation to clinic.

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Pharmacological lifespan extension of invertebrates

Cited by 69 publications

References 155 publications

Gene expression‐based drug repurposing to target aging

Gene expression‐based drug repurposing to target aging

Chemical activation of a food deprivation signal extends lifespan

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

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