mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review

Weichhart, Thomas

doi:10.1159/000484629

Cited by 412 publications

(311 citation statements)

References 66 publications

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“…Changes in nutritional and epigenetic state are integral to aging. This can be judged by the central role of the mTOR pathway [ 9,10 ] and histone/DNA methylation [ 58,59 ] in organismal aging. αKG has emerged as master regulatory metabolite in aging biology as it is a key TCA intermediate, a cofactor for numerous transamination reactions, [ 60,61 ] a cofactor for the prolyl hydroxylase dependent hydroxylation of the transcription factor hypoxia inducible factor‐1 (HIF‐1) [ 62–64 ] and a cofactor for epigenetic enzymes, histone, and DNA demethylases.…”

Section: Application Of Metabolomics For Biomarker Discovery In Agingmentioning

confidence: 99%

The Aging Metabolome—Biomarkers to Hub Metabolites

Sharma

Ramanathan

2020

Proteomics

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Aging biology is intimately associated with dysregulated metabolism, which is one of the hallmarks of aging. Aging‐related pathways such as mTOR and AMPK, which are major targets of anti‐aging interventions including rapamcyin, metformin, and exercise, either directly regulate or intersect with metabolic pathways. In this review, numerous candidate bio‐markers of aging that have emerged using metabolomics are outlined. Metabolomics studies also reveal that not all metabolites are created equally. A set of core “hub” metabolites are emerging as central mediators of aging. The hub metabolites reviewed here are nicotinamide adenine dinucleotide, reduced nicotinamide dinucleotide phosphate, α‐ketoglutarate, and β‐hydroxybutyrate. These “hub” metabolites have signaling and epigenetic roles along with their canonical roles as co‐factors or intermediates of carbon metabolism. Together these hub metabolites suggest a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging.

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Section: Application Of Metabolomics For Biomarker Discovery In Agingmentioning

confidence: 99%

The Aging Metabolome—Biomarkers to Hub Metabolites

Sharma

Ramanathan

2020

Proteomics

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“…In that regard, the establishment of the senescent phenotype is accompanied by an increase in the activity of mTOR, which is considered as a hallmark of organismal aging . mTOR inhibition extends life span and improves age‐related pathologies in a variety of species . Interestingly, a recent report established that mTOR is activated through a PI3K/Akt/mTOR pathway during replicative senescence in vascular smooth muscle cells .…”

Section: Oxidants and Cellular Senescence Beyond Cell Cycle Arrestmentioning

confidence: 70%

“…[104][105][106] mTOR inhibition extends life span and improves age-related pathologies in a variety of species. [80,[106][107][108] Interestingly, a recent report established that mTOR is activated through a PI3K/Akt/mTOR pathway during replicative senescence in vascular smooth muscle cells. [100] Linking geroconversion to oxidants, we have shown that activation of Akt by a O 2…”

Section: Oxidants and Geroconversionmentioning

confidence: 99%

Organismal Aging and Oxidants beyond Macromolecules Damage

Clément

Luo

2020

Proteomics

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The relationship between oxidants and organismal aging was first articulated through the free radical theory of aging. One of the major predictions of the free radical theory of aging is that oxidative stress shortens organisms’ lifespan because of an increased level of oxidants, which are damaging to macromolecules. However, challenging the role of oxidants in age‐related diseases, there is now sufficient evidence that antioxidant supplements do not provide significant health benefits. Interestingly, in addition to an increase in oxidant‐mediated macromolecules damage, there is convincing experimental data to support the role of senescent cells in the process of aging. Here, the current knowledge regarding the role of oxidants and cellular senescence in organismal aging is reviewed and it is proposed that, in addition to the role of oxidants as inducers of macromolecular damage, oxidants may also function as regulators of signaling pathways involved in the establishment of cellular senescence. If this role for oxidants is established, it may be necessary to modify the free radical theory of aging from “Organisms age because cells accumulate reactive oxygen species‐dependent damage over time” to: “Organisms age because cells accumulate oxidants’‐dependent damage and oxidants’‐dependent senescent characteristics over time.”

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“…Spleen cell culture. To examine T-cell growth, single-cell suspensions were prepared by mincing mice a macrolide antibiotic, is known to inhibit the target of the rapamycin (TOR) signaling pathway and extend the lifespan of genetically heterogeneous mice (20,47,52,54). Rapamycin was highly effective in inhibiting T-cell activation (IC 50 = 0.16 nM) ( Figs.…”

Section: Methodsmentioning

confidence: 99%

T-cell activation-inhibitory assay: a proposed novel method for screening caloric restriction mimetics

et al. 2019

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Caloric restriction (CR) is a major contributor to good health and longevity. CR mimetics (CRMs) are a group of plant-derived compounds capable of inducing the benefits of CR. Since a longevity gene, SIRT1, inhibits T-cell activation and SIRT1 loss results in increased T-cell activation, we hypothesized that compounds capable of activating SIRT1 signaling can inhibit T-cell activation and function as CRMs. Thus we propose, in the present study, the application of a T-cell activation-inhibitory assay to screen candidate CRMs. Well-known CRMs, such as resveratrol, butein, and fisetin, suppressed the anti-CD3/CD28 antibody-induced activation of mouse spleen T-cells. We next randomly assessed 68 plant-derived compounds for screening novel candidate CRMs using this bioassay and found that all four compounds showing IC 50 values <5 μM, such as curcumin, α-mangostin, nobiletin, and heptamethoxyflavone, have beneficial functions for health such as anti-inflammatory effect. These results suggest that the T-cell activation-inhibitory assay can be used to screen candidate CRMs.

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mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review

Cited by 412 publications

References 66 publications

The Aging Metabolome—Biomarkers to Hub Metabolites

The Aging Metabolome—Biomarkers to Hub Metabolites

Organismal Aging and Oxidants beyond Macromolecules Damage

T-cell activation-inhibitory assay: a proposed novel method for screening caloric restriction mimetics

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