Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend <i>Caenorhabditis elegans</i>’ Lifespan

Zhang, Peichuan; Zhai, Yuying; Cregg, James M.; Ang, Kenny Kean‐Hooi; Arkin, Michelle R.; Kenyon, Cynthia

doi:10.1534/g3.119.400618

Cited by 10 publications

(11 citation statements)

References 95 publications

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“…HSF1 phosphorylation at serine residues Ser307 (inhibitory) and Ser326 (stimulatory) shows that with normalization to either GAPDH or HSF1 protein levels that "inhibitory" phosphoserine 307 levels decline with age by 40% (*p = 0.0097), whereas the "activating" phosphoserine 326 levels do not change. critical role of the heat shock axis in regulating exceptional longevity [52,53]. Having probed both positive and negative regulatory checkpoints of the heat shock axis in dwarf mice, the bulk of evidence suggests that exceptional longevity is linked to maintenance of the heat shock response with enhancement or agedependent compensation of several HSF1 regulatory checkpoints in favor of a robust heat shock axis [45,54,55].…”

Section: Discussionmentioning

confidence: 99%

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

et al. 2021

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How the heat shock axis, repair pathways, and proteostasis impact the rate of aging is not fully understood. Recent reports indicate that normal aging leads to a 50% change in several regulatory elements of the heat shock axis. Most notably is the age-dependent enhancement of inhibitory signals associated with accumulated heat shock proteins and hyper-acetylation associated with marked attenuation of heat shock factor 1 (HSF1)–DNA binding activity. Because exceptional longevity is associated with increased resistance to stress, this study evaluated regulatory check points of the heat shock axis in liver extracts from 12 months and 24 months long-lived Ames dwarf mice and compared these findings with aging wild-type mice. This analysis showed that 12M dwarf and wild-type mice have comparable stress responses, whereas old dwarf mice, unlike old wild-type mice, preserve and enhance activating elements of the heat shock axis. Old dwarf mice thwart negative regulation of the heat shock axis typically observed in usual aging such as noted in HSF1 phosphorylation at Ser307 residue, acetylation within its DNA binding domain, and reduction in proteins that attenuate HSF1–DNA binding. Unlike usual aging, dwarf HSF1 protein and mRNA levels increase with age and further enhance by stress. Together these observations suggest that exceptional longevity is associated with compensatory and enhanced HSF1 regulation as an adaptation to age-dependent forces that otherwise downregulate the heat shock axis.

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Section: Discussionmentioning

confidence: 99%

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

et al. 2021

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“…While this study was under revision and subsequent to its deposition at bioRxiv ( https://biorxiv.org/content/10.1101/778548v1 ), Zhang et al . ( 51 ) described the results of a screen in which they identified small molecules that promoted resistance to hydrogen peroxide in human fibroblasts. As in our study, several of their hits appeared to activate Nrf2 signaling, consistent with the known role of this pathway in oxidative stress response.…”

Section: Discussionmentioning

confidence: 99%

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

et al. 2020

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Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

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“…NRF2 can similarly be modified by other α, β-unsaturated ketone-containing natural products such as chalcones, from which flavonoids are structurally derived [86]. Notably these compounds exhibit activity while not containing any hydroxyl groups.…”

Section: Nrf2-mediated Upregulation Of Proteasome Activity By Polyphementioning

confidence: 99%

Structural basis of the anti-ageing effects of polyphenolics: mitigation of oxidative stress

Rolt

Cox

2020

BMC Chemistry

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Ageing, and particularly the onset of age-related diseases, is associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Polyphenolic natural products such as stilbenoids, flavonoids and chalcones have been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis and cellular senescence, both in vitro and in vivo. Here we aim to identify the structural basis underlying the pharmacology of polyphenols towards ROS and related biochemical pathways involved in age-related disease. We compile and describe SAR trends across different polyphenol chemotypes including stilbenoids, flavonoids and chalcones, review their different molecular targets and indications, and identify common structural ground between chemotypes and mechanisms of action. In particular, we focus on the structural requirements for the direct scavenging of reactive oxygen/nitrogen species such as radicals as well as coordination of a broader antioxidant response. We further suggest that it is important to consider multiple (rather than single) biological activities when identifying and developing new medicinal chemistry entities with utility in modulating complex biological properties such as cell ageing.

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Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan

Cited by 10 publications

References 95 publications

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

Structural basis of the anti-ageing effects of polyphenolics: mitigation of oxidative stress

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