Longevity interventions temporally scale healthspan in Caenorhabditis elegans

Statzer, Cyril; Reichert, Peter; Dual, Jürg; Ewald, Collin Y.

doi:10.1016/j.isci.2022.103983

Cited by 18 publications

(19 citation statements)

References 57 publications

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“…Our observed time course of the collagen mass changes coincides with the growth rates in body size during adulthood, whereby after the final molt from L4 to adult, C. elegans continuously grows until day 6-8 of adulthood and then starts to shrink (Hulme et al, 2010;Shi et al, 2017;Statzer et al, 2022). C. elegans growth during early adulthood means an extension of the cuticular exoskeleton.…”

Section: A Feedback Loop Is Sufficient and Required For Ecm Homeostas...supporting

confidence: 67%

“…C. elegans growth during early adulthood means an extension of the cuticular exoskeleton. We have previously shown that longevity interventions prolong this adult growth phase compared to wild type (Statzer et al, 2022). The longer this adulthood growth phase is, the longer-lived is an individual C. elegans (Hulme et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Section: A Feedback Loop Is Sufficient and Required For Ecm Homeostas...mentioning

confidence: 95%

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Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Teuscher

Statzer

Goyala

et al. 2022

Preprint

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Although it is postulated that dysfunctional extracellular matrices (ECM) drive aging and disease, how ECM integrity assures longevity is unknown. Here, using proteomics and in-vivo monitoring of fluorescently tagged ECM proteins, we systematically examined the ECM composition during Caenorhabditis elegans aging revealing three distinct collagen dynamics. We show that age-dependent stiffening of inert collagen was slowed by longevity interventions through prolonged replenishing of collagens. In genetic and automated lifespan screens for the regulators that drive this remodeling, we identify hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression across tissues. The hemidesmosome tension-induced adaptation is mediated via transcriptional co-activator YAP. Our data reveal a novel mechanism of mechano-coupling and synchronizing of two functionally distinct and spatially distant ECMs that is indispensable for longevity. Thus, besides signaling molecules, mechanotransduction-coordinated ECM remodeling systemically promotes healthy aging.

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Section: A Feedback Loop Is Sufficient and Required For Ecm Homeostas...supporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

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Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Teuscher

Statzer

Goyala

et al. 2022

Preprint

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“…The aging process is one of the highest and most critical risk factors for cancer, type 2 diabetes, cardiovascular diseases, neurodegenerative, and other age-related pathologies. Although the aging process seems to be a stochastic decay of physiological processes and complicated ( Freund, 2019 ; Vertti-Quintero et al, 2021 ; Statzer et al, 2022b ), recently, the field has defined nine hallmarks of aging: genomic instability, epigenetic changes, loss of proteostasis, dysregulated nutrient sensing, mitochondria dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and telomere attrition ( Lopez-Otin et al, 2013 ). One aspect not included in the hallmarks of aging is the recent emerging, yet not understood role of the extracellular matrix during aging and longevity.…”

Section: Introductionmentioning

confidence: 99%

Longevity-Promoting Pathways and Transcription Factors Respond to and Control Extracellular Matrix Dynamics During Aging and Disease

Vidović¹,

Ewald²

2022

Front. Aging

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Aging is one of the largest risk factors for cancer, type 2 diabetes, osteoarthritis, cardiovascular diseases, and other age-related pathologies. Here, we give a detailed description of the interplay of chronic age-related pathologies with the remodeling of the extracellular matrix during disease development and progression. Longevity-promoting signaling pathways slow or prevent age-related diseases. In particular, we focus on the mTOR signaling pathway, sirtuins, and canonical longevity-promoting transcription factors, such as FOXO, NF-κB, and Nrf2. We extend our analysis using chromatin immunoprecipitation (ChIP) sequencing and transcriptomic data and report that many established and emerging longevity-promoting transcription factors, such as CREB1, FOXO1,3, GATA1,2,3,4, HIF1A, JUN, KLF4, MYC, NFE2L2/Nrf2, RELA/NF-κB, REST, STAT3,5A, and TP53/p53, directly regulate many extracellular matrix genes and remodelers. We propose that modulation of these pathways increases lifespan and protects from age-related diseases in part due to their effects on extracellular matrix remodeling. Therefore, to successfully treat age-related diseases, it is necessary to better understand the connection between extracellular matrix components and longevity pathways.

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“…Several studies have highlighted the relationship between proteome remodeling, protein aggregation, and normal aging in the nematode (David et al, 2010;Ciryam et al, 2013;Walther et al, 2015;Huang et al, 2019). One recent study showed long-lived nematode mutants had a delayed onset of declining health, motivating a better understanding of how the aging process induces ageassociated declines (Statzer et al, 2022). Animal models of tau aggregation have consistently reported a decrease in lifespan attributable to the overexpression of human tau (Wittmann et al, 2001;Sealey et al, 2017;Higham et al, 2019;Macdonald et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Age-dependent accumulation of tau aggregation in Caenorhabditis elegans

et al. 2022

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Aging is the primary risk factor for Alzheimer’s disease (AD) and related disorders (ADRDs). Tau aggregation is a hallmark of AD and other tauopathies. Even in normal aging, tau aggregation is found in brains, but in disease states, significantly more aggregated tau is present in brain regions demonstrating synaptic degeneration and neuronal loss. It is unclear how tau aggregation and aging interact to give rise to the phenotypes observed in disease states. Most AD/ADRD animal models have focused on late stages, after significant tau aggregation has occurred. There are fewer where we can observe the early aggregation events and progression during aging. In an attempt to address this gap, we created C. elegans models expressing a GFP-tagged version of the human tau protein. Here we examined how tau-gfp behaved during aging, comparing wild-type tau (hTau40), a disease-associated mutation (P301S), and an aggregation-prone variant (3PO). We measured age-dependent changes in GFP intensity and correlated those changes to normal aging in the nematode. We found differences in tau stability and accumulation depending on the tau variant expressed. hTau40GFP and P301SGFP were localized to axons and cell bodies, while 3POGFP was more concentrated within cell bodies. Expression of 3POGFP resulted in decreased lifespan and variations in locomotor rate, consistent with a pathological effect. Finally, we found that the human tau interacted genetically with the C. elegans ortholog of human tau, ptl-1, where the loss of ptl-1 significantly accelerated the time to death in animals expressing 3PO.

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Longevity interventions temporally scale healthspan in Caenorhabditis elegans

Cited by 18 publications

References 57 publications

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Longevity-Promoting Pathways and Transcription Factors Respond to and Control Extracellular Matrix Dynamics During Aging and Disease

Age-dependent accumulation of tau aggregation in Caenorhabditis elegans

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