New drugs for pharmacological extension of replicative life span in normal and progeroid cells

Vatolin, Sergei; Radivoyevitch, Tomas; Maciejewski, Jaroslaw P.

doi:10.1038/s41514-018-0032-4

Cited by 9 publications

(5 citation statements)

References 44 publications

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“…Screens in mammalian cell culture have also been performed in a recent approach identifying compounds that reduce senescent markers 369 . Interestingly, the two most potent compounds identified also robustly extended C. elegans lifespan, pointing once again to the conserved nature of longevity pathways across species [Au: Edit OK?…”

Section: Box 2 In Vivo Screening To Identify Geroprotectorsmentioning

confidence: 99%

The quest to slow ageing through drug discovery

Partridge

Fuentealba

Kennedy

2020

Nat Rev Drug Discov

338

249

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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 chemical interventions to slow ageing, and group them into two tiers based on the robustness of the preclinical, and some clinical, results. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these chemicals, with the overall aim of maintaining health for longer before the end of life.

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Section: Box 2 In Vivo Screening To Identify Geroprotectorsmentioning

confidence: 99%

The quest to slow ageing through drug discovery

Partridge

Fuentealba

Kennedy

2020

Nat Rev Drug Discov

338

249

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“…The use of NAD + precurors to increase cellular NAD + levels has resulted in improvement of cardiovascular and other age-related functional deficits [ [260] , [261] , [262] ], although many aspects of targeting NAD metabolism as a therapeutic approach in aging remain to be defined [ 263 ]. Interestingly, a recent high throughput anti-aging drug screen identified 2 compounds from more than 2600 screened, both of which affected pyridine nucleotide redox ratios and one of these compounds functioned via NQO1 catalysis [ 264 ]. Given the proposed roles of NQO1 to ameliorate oxidative stress via multiple mechanisms, its function as a redox switch and capacity to generate NAD + and influence proteostasis, the role of NQO1 in the aging phenotype is worthy of further examination.…”

Section: Nqo1 and Agingmentioning

confidence: 99%

The diverse functionality of NQO1 and its roles in redox control

2021

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In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD + generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.

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“…A screen of 2684 compounds identified the redox-active compounds violuric acid (VA) and 1-naphthoquinone-2-monoxime (N2N1) as the top hits that delayed cellular senescence [306]. These compounds were then shown to increase the lifespan of C. elegans and mice.…”

Section: Pharmacological Modulation Of Cellular Redox Status To Pmentioning

confidence: 99%

Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

Bradshaw

2019

Nutrients

132

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The reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) protects against redox stress by providing reducing equivalents to antioxidants such as glutathione and thioredoxin. NADPH levels decline with aging in several tissues, but whether this is a major driving force for the aging process has not been well established. Global or neural overexpression of several cytoplasmic enzymes that synthesize NADPH have been shown to extend lifespan in model organisms such as Drosophila suggesting a positive relationship between cytoplasmic NADPH levels and longevity. Mitochondrial NADPH plays an important role in the protection against redox stress and cell death and mitochondrial NADPH-utilizing thioredoxin reductase 2 levels correlate with species longevity in cells from rodents and primates. Mitochondrial NADPH shuttles allow for some NADPH flux between the cytoplasm and mitochondria. Since a decline of nicotinamide adenine dinucleotide (NAD+) is linked with aging and because NADP+ is exclusively synthesized from NAD+ by cytoplasmic and mitochondrial NAD+ kinases, a decline in the cytoplasmic or mitochondrial NADPH pool may also contribute to the aging process. Therefore pro-longevity therapies should aim to maintain the levels of both NAD+ and NADPH in aging tissues.

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New drugs for pharmacological extension of replicative life span in normal and progeroid cells

Cited by 9 publications

References 44 publications

The quest to slow ageing through drug discovery

The quest to slow ageing through drug discovery

The diverse functionality of NQO1 and its roles in redox control

Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

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