Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

Vitiello, Davide; Dakhovnik, Alexander; Statzer, Cyril; Ewald, Collin Y.

doi:10.3389/fgene.2021.694033

Cited by 7 publications

(5 citation statements)

References 63 publications

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“…Heterozygous ILK/ pat-4 mutants were shorter-lived and blocked daf-2 -longevity (Supplementary Figure 10D, Supplementary Table 7), consistent with severe pat-4 knockdown leads to detachment of the cytoskeleton and shortening of lifespan, whereas mild pat-4 knockdown has a mild effect on cytoskeleton detachment and increases lifespan (Nishimura et al, 2014). Consistent with our screening hits and proteomics data are cytoskeleton remodelers implicated in longevity by our and other groups (Figure 5F) (Baird et al, 2014; Ewald et al, 2017; Mansfeld et al, 2015; Vitiello et al, 2021). This points towards a hemidesmosome-to-integrin-to-cytoskeleton remodeling axis to mediate downstream mechanotransduction and organismal longevity.…”

Section: Resultssupporting

confidence: 92%

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: Resultssupporting

confidence: 92%

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Teuscher

Statzer

Goyala

et al. 2022

Preprint

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“…In mice, sex-related differences can be seen in physical performance, which was shown to be lower in aging males ( Tran et al, 2021 ), while anxiety-like behaviors were increased in aging males ( Kobayashi et al, 2021 ). Even on the tissue and molecular level, there are vast sex-specific differences in mice’s gene expression signatures associated with longevity ( Vitiello et al, 2021 ). Further, sexual dimorphisms can be observed in geroprotective interventions aiming to increase lifespan or healthspan ( Sampathkumar et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Sex differences in pharmacological interventions and their effects on lifespan and healthspan outcomes: a systematic review

et al. 2023

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With an increasing aging population, the burden of age-related diseases magnifies. To alleviate this burden, geroprotection has been an area of intense research focus with the development of pharmacological interventions that target lifespan and/or healthspan. However, there are often sex differences, with compounds mostly tested in male animals. Given the importance of considering both sexes in preclinical research, this neglects potential benefits for the female population, as interventions tested in both sexes often show clear sexual dimorphisms in their biological responses. To further understand the prevalence of sex differences in pharmacological geroprotective intervention studies, we performed a systematic review of the literature according to the PRISMA guidelines. Seventy-two studies met our inclusion criteria and were classified into one of five subclasses: FDA-repurposed drugs, novel small molecules, probiotics, traditional Chinese medicine, and antioxidants, vitamins, or other dietary supplements. Interventions were analyzed for their effects on median and maximal lifespan and healthspan markers, including frailty, muscle function and coordination, cognitive function and learning, metabolism, and cancer. With our systematic review, we found that twenty-two out of sixty-four compounds tested were able to prolong both lifespan and healthspan measures. Focusing on the use of female and male mice, and on comparing their outcomes, we found that 40% of studies only used male mice or did not clarify the sex. Notably, of the 36% of pharmacologic interventions that did use both male and female mice, 73% of these studies showed sex-specific outcomes on healthspan and/or lifespan. These data highlight the importance of studying both sexes in the search for geroprotectors, as the biology of aging is not the same in male and female mice.Systematic Review Registration: [website], identifier [registration number].

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“…Furthermore, the binding partner of the ILK-a heterozygous mutation in β1-integrin-delayed aging and mortality in Drosophila [ 247 ]. In mice, cytoskeletal remodeler Coronin-7 ( Coro7 ) is associated with a longer lifespan [ 249 ]. In human fibroblasts-via matricellular cell adhesive protein CCN1-β1 integrin caused senescence in wound healing [ 250 ].…”

Section: Extracellular Matrix Dynamics During Aging and Longevitymentioning

confidence: 99%

Extracellular Matrix Dynamics as an Emerging yet Understudied Hallmark of Aging and Longevity

2023

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The biomechanical properties of extracellular matrices (ECM) and their consequences for cellular homeostasis have recently emerged as a driver of aging. Here we review the age-dependent deterioration of ECM in the context of our current understanding of the aging processes. We discuss the reciprocal interactions of longevity interventions with ECM remodeling. And the relevance of ECM dynamics captured by the matrisome and the matreotypes associated with health, disease, and longevity. Furthermore, we highlight that many established longevity compounds promote ECM homeostasis. A large body of evidence for the ECM to qualify as a hallmark of aging is emerging, and the data in invertebrates is promising. However, direct experimental proof that activating ECM homeostasis is sufficient to slow aging in mammals is lacking. We conclude that further research is required and anticipate that a conceptual framework for ECM biomechanics and homeostasis will provide new strategies to promote health during aging.

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Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

Cited by 7 publications

References 63 publications

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Sex differences in pharmacological interventions and their effects on lifespan and healthspan outcomes: a systematic review

Extracellular Matrix Dynamics as an Emerging yet Understudied Hallmark of Aging and Longevity

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