Volume 9, Issue 10

Miyano M, Sayaman RW, Stoiber MH, Lin C, Stampfer MR, Brown JB, LaBarge MA, . Age-related gene expression in luminal epithelial cells is driven by a microenvironment made from myoepithelial cells. . 9:2026-2051. https://doi.org/10.18632/aging.101298

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                TY  - JOUR
                AU  - Miyano, Masaru 
                AU  - Sayaman, Rosalyn W. 
                AU  - Stoiber, Marcus H. 
                AU  - Lin, Chun-Han 
                AU  - Stampfer, Martha R. 
                AU  - Brown, James B. 
                AU  - LaBarge, Mark A. 
                TI  - Age-related gene expression in luminal epithelial cells is driven by a microenvironment made from myoepithelial cells
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101298
                DO  - 10.18632/aging.101298
                SP  - 2026
                EP  - 2051
                PY  - 
                AB  - Luminal epithelial cells in the breast gradually alter gene and protein expression with age, appearing to lose lineage-specificity by acquiring myoepithelial-like characteristics. We hypothesize that the luminal lineage is particularly sensitive to microenvironment changes, and age-related microenvironment changes cause altered luminal cell phenotypes. To evaluate the effects of different microenvironments on the fidelity of epigenetically regulated luminal and myoepithelial gene expression, we generated a set of lineage-specific probes for genes that are controlled through DNA methylation. Culturing primary luminal cells under conditions that favor myoepithelial propogation led to their reprogramming at the level of gene methylation, and to a more myoepithelial-like expression profile. Primary luminal cells’ lineage-specific gene expression could be maintained when they were cultured as bilayers with primary myoepithelial cells. Isogenic stromal fibroblast co-cultures were unable to maintain the luminal phenotype. Mixed-age luminal-myoepithelial bilayers revealed that luminal cells adopt transcription and methylation patterns consistent with the chronological age of the myoepithelial cells. We provide evidence that the luminal epithelial phenotype is exquisitely sensitive to microenvironment conditions, and that states of aging are cell non-autonomously communicated through microenvironment cues over at least one cell diameter.
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PKCζ-dependent upregulation of p27kip1 contributes to oxidative stress induced retinal pigment epithelial cell multinucleation

Dinusha Rajapakse, Mei Chen, Tim M. Curtis, Heping Xu,

https://doi.org/10.18632/aging.101299 pp 2052—2068

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Rajapakse D, Chen M, Curtis TM, Xu H, . PKCζ-dependent upregulation of p27kip1 contributes to oxidative stress induced retinal pigment epithelial cell multinucleation. . 9:2052-2068. https://doi.org/10.18632/aging.101299

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                TY  - JOUR
                AU  - Rajapakse, Dinusha 
                AU  - Chen, Mei 
                AU  - Curtis, Tim M. 
                AU  - Xu, Heping 
                TI  - PKCζ-dependent upregulation of p27kip1 contributes to oxidative stress induced retinal pigment epithelial cell multinucleation
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101299
                DO  - 10.18632/aging.101299
                SP  - 2052
                EP  - 2068
                PY  - 
                AB  - Retinal pigment epithelial (RPE) cells increase in size and multinucleate during aging. We have shown using human and mouse cell lines that oxidised photoreceptor outer segments (oxPOS)-induced cytokinesis failure is related to RPE cell multinucleation, although the underlying mechanism remains unknown. This study investigated the role of the PKC pathway in oxPOS-induced RPE multinucleation using ARPE19 cells. oxPOS treatment promoted PKC activity and upregulated the mRNA expression of PKC α, δ, ζ, ι and μ. Inhibition of PKCα with Gӧ6976 resulted in a 33% reduction of multinucleate ARPE19 cells, whereas inhibition of PKCζ with Gӧ6983 led to a 50% reduction in multinucleate ARPE19 cells. Furthermore, oxPOS treatment induced a PKCζ-dependent upregulation of the Cdk inhibitor p27kip1, its inhibition using A2CE reduced oxPOS-induced ARPE19 multinucleation. Our results suggest that oxPOS-induced ARPE19 cytokinesis failure is, at least in part, due to the upregulation of p27kip1 through activating the PKC, particularly PKCζ pathway. Targeting the PKCζ-p27kip1 signalling axis may be a novel approach to restore RPE repair capacity during aging.
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Natural product celastrol suppressed macrophage M1 polarization against inflammation in diet-induced obese mice via regulating Nrf2/HO-1, MAP kinase and NF-κB pathways

Dan Luo, Yumeng Guo, Yuanyuan Cheng, Jia Zhao, Yu Wang, Jianhui Rong,

https://doi.org/10.18632/aging.101302 pp 2069—2082

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Luo D, Guo Y, Cheng Y, Zhao J, Wang Y, Rong J, . Natural product celastrol suppressed macrophage M1 polarization against inflammation in diet-induced obese mice via regulating Nrf2/HO-1, MAP kinase and NF-κB pathways. . 9:2069-2082. https://doi.org/10.18632/aging.101302

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                TY  - JOUR
                AU  - Luo, Dan 
                AU  - Guo, Yumeng 
                AU  - Cheng, Yuanyuan 
                AU  - Zhao, Jia 
                AU  - Wang, Yu 
                AU  - Rong, Jianhui 
                TI  - Natural product celastrol suppressed macrophage M1 polarization against inflammation in diet-induced obese mice via regulating Nrf2/HO-1, MAP kinase and NF-κB pathways
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101302
                DO  - 10.18632/aging.101302
                SP  - 2069
                EP  - 2082
                PY  - 
                AB  - Macrophage polarization is implicated in the inflammation in obesity. The aim of the present study was to examine the anti-inflammatory activities of botanical triterpene celastrol against diet-induced obesity. We treated diet-induced obese C57BL/6N male mice with celastrol (5, 7.5 mg/kg/d) for 3 weeks, and investigated macrophage M1/M2 polarization in adipose and hepatic tissues. Celastrol reduced fat accumulation and ameliorated glucose tolerance and insulin sensitivity. Celastrol down-regulated the mRNA levels of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) in cell culture and in mice. The underlying mechanisms were investigated in murine macrophage RAW264.7 cells. Our results demonstrated that celastrol might control macrophage polarization through modulating the cross-talk between the following three mechanisms: 1) suppressing LPS-induced activation of MAP kinases (e.g., ERK1/2, p38, JNK) in a concentration dependent manner; 2) attenuating LPS-induced nuclear translocation of NF-κB p65 subunit in a time dependent manner; 3) activating Nrf2 and subsequently inducing HO-1 expression. HO-1 inhibitor SnPP diminished the inhibitory effects of celastrol on the activation of NF-κB pathway and the pro-inflammatory M1 macrophage polarization. Taken together, celastrol exhibited anti-obesity effects via suppressing pro-inflammatory M1 macrophage polarization. Thus, our results provide new evidence for the potential of celastrol in the treatment of obesity.
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Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A_2A receptor

Cynthia Laflamme, Geneviève Bertheau Mailhot, Marc Pouliot,

https://doi.org/10.18632/aging.101303 pp 2083—2097

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Laflamme C, Mailhot GB, Pouliot M, . Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A_2A receptor. . 9:2083-2097. https://doi.org/10.18632/aging.101303

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                TY  - JOUR
                AU  - Laflamme, Cynthia 
                AU  - Mailhot, Geneviève Bertheau 
                AU  - Pouliot, Marc 
                TI  - Age-related decline of the acute local inflammation response: a mitigating role for the adenosine A<sub>2A</sub> receptor
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101303
                DO  - 10.18632/aging.101303
                SP  - 2083
                EP  - 2097
                PY  - 
                AB  - Aging is accompanied by an increase in markers of innate immunity. How aging affects neutrophil functions remains of debate.The adenosine A2A receptor (A2AR), essential to the resolution of inflammation, modulates neutrophil functions. We sought to determine whether or not A2AR protects against the effects of aging. We monitored neutrophil influx, viability, and activation as well as cytokine accumulation in wild-type (WT) and A2AR-knockout mice (KO) at three different ages.Several readouts decreased with aging: neutrophil counts in dorsal air pouches (by up to 55%), neutrophil viability (by up to 56%), elastase and total protein in exudates (by up to 80%), and local levels of cytokines (by up to 90%). Each of these parameters was significantly more affected in A2AR-KO mice. CXCL1-3 levels were largely unaffected. The effects of aging were not observed systemically. Preventing neutrophil influx into the air pouch caused a comparable cytokine pattern in young WT mice. Gene expression (mRNA) in leukocytes was affected, with CXCL1 and CCL4 increasing and with TNF and IL-1α decreasing.ConclusionAging has deleterious effects on the acute inflammatory response and neutrophil-related activities, and defective migration appears as an important factor. A functional A2AR signaling pathway delays some of these.
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A new mutation-independent approach to cancer therapy: Inhibiting oncogenic RAS and MYC, by targeting mitochondrial biogenesis

Bela Ozsvari, Federica Sotgia, Michael P. Lisanti,

https://doi.org/10.18632/aging.101304 pp 2098—2116

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Ozsvari B, Sotgia F, Lisanti MP, . A new mutation-independent approach to cancer therapy: Inhibiting oncogenic RAS and MYC, by targeting mitochondrial biogenesis. . 9:2098-2116. https://doi.org/10.18632/aging.101304

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                TY  - JOUR
                AU  - Ozsvari, Bela 
                AU  - Sotgia, Federica 
                AU  - Lisanti, Michael P. 
                TI  - A new mutation-independent approach to cancer therapy: Inhibiting oncogenic RAS and MYC, by targeting mitochondrial biogenesis
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101304
                DO  - 10.18632/aging.101304
                SP  - 2098
                EP  - 2116
                PY  - 
                AB  - Here, we used MCF7 cells as a model system to interrogate how MYC/RAS co-operativity contributes to metabolic flux and stemness in breast cancer cells. We compared the behavior of isogenic MCF7 cell lines transduced with c-Myc or H-Ras (G12V), either individually or in combination. Cancer stem cell (CSC) activity was measured using the mammosphere assay. c-Myc augmented both mammosphere formation and mitochondrial respiration, without any effects on glycolytic flux. In contrast, H-Ras (G12V) synergistically augmented both mammosphere formation and glycolysis, but only in combination with c-Myc, directly demonstrating MYC/RAS co-operativity. As c-Myc is known to exert its effects, in part, by stimulating mitochondrial biogenesis, we next examined the effects of another stimulus known to affect mitochondrial biogenesis, i.e. ROS production. To pharmacologically induce oxidative stress, we used Rotenone (a mitochondrial inhibitor) to target mitochondrial complex I. Treatment with Rotenone showed bi-phasic effects; low-dose Rotenone (1 to 2.5 nM) elevated mammosphere formation, while higher doses (10 to 100 nM) were inhibitory. Importantly, the stimulatory effects of Rotenone on CSC propagation were blocked using a mitochondrial-specific anti-oxidant, namely Mito-tempo. Thus, “mild” mitochondrial oxidative stress, originating at Complex I, was sufficient to pheno-copy the effects of c-Myc, effectively promoting CSC propagation. To validate the idea that mitochondrial biogenesis is required to stimulate CSC propagation, we employed Doxycycline, a well-established inhibitor of mitochondrial protein translation. Treatment with Doxycycline was indeed sufficient to block the stimulatory effects of H-Ras (G12V), c-Myc, and Rotenone on CSC propagation. As such, Doxycycline provides a strong rationale for designing new therapeutics to target mitochondrial biogenesis, suggesting a new “mutation-independent” approach to cancer therapy. In support of this notion, most currently successful anti-cancer agents therapeutically target “cell phenotypes”, such as increased cell proliferation, rather than specific genetic mutations. Remarkably, we demonstrated that Doxycycline inhibits the effects of diverse oncogenic stimuli, of both i) genetic (MYC/RAS) and ii) environmental (Rotenone) origins. Finally, we discuss the advantages of our “Proteomics-to-Genomics (PTG)” approach for in silico validation of new biomarkers and novel drug targets. In this context, we developed a new Myc-based Mito-Signature consisting of 3 mitochondrial genes (HSPD1; COX5B; TIMM44) for effectively predicting tumor recurrence (HR=4.69; p=2.4e-08) and distant metastasis (HR=4.94; p=2.8e-07), in ER(+) in breast cancer patients. This gene signature could serve as a new companion diagnostic for the early prediction of treatment failure in patients receiving hormonal therapy.
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Identification of polymorphisms in cancer patients that differentially affect survival with age

Aoife Doherty, Yelena Kernogitski, Alexander M. Kulminski, João Pedro de Magalhães,

https://doi.org/10.18632/aging.101305 pp 2117—2136

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Doherty A, Kernogitski Y, Kulminski AM, Pedro de Magalhães J, . Identification of polymorphisms in cancer patients that differentially affect survival with age. . 9:2117-2136. https://doi.org/10.18632/aging.101305

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                TY  - JOUR
                AU  - Doherty, Aoife 
                AU  - Kernogitski, Yelena 
                AU  - Kulminski, Alexander M. 
                AU  - Pedro de Magalhães, João 
                TI  - Identification of polymorphisms in cancer patients that differentially affect survival with age
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101305
                DO  - 10.18632/aging.101305
                SP  - 2117
                EP  - 2136
                PY  - 
                AB  - The World Health Organization predicts that the proportion of the world’s population over 60 will almost double from 12% to 22% between 2015 and 2050. Ageing is the biggest risk factor for cancer, which is a leading cause of deaths worldwide. Unfortunately, research describing how genetic variants affect cancer progression commonly neglects to account for the ageing process. Herein is the first systematic analysis that combines a large longitudinal data set with a targeted candidate gene approach to examine the effect of genetic variation on survival as a function of age in cancer patients. Survival was significantly decreased in individuals with heterozygote or rare homozygote (i.e. variant) genotypes compared to those with a common homozygote genotype (i.e. wild type) for two single nucleotide polymorphisms (rs11574358 and rs4147918), one gene (SIRT3) and one pathway (FoxO signalling) in an age-dependent manner. All identified genes and pathways have previously been associated with ageing and cancer. These observations demonstrate that there are ageing-related genetic elements that differentially affect mortality in cancer patients in an age-dependent manner. Understanding the genetic determinants affecting prognosis differently with age will be invaluable to develop age-specific prognostic biomarkers and personalized therapies that may improve clinical outcomes for older individuals.
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SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes

Emmanuelle Saint-Germain, Lian Mignacca, Mathieu Vernier, Diwakar Bobbala, Subburaj Ilangumaran, Gerardo Ferbeyre,

https://doi.org/10.18632/aging.101306 pp 2137—2162

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Saint-Germain E, Mignacca L, Vernier M, Bobbala D, Ilangumaran S, Ferbeyre G, . SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes. . 9:2137-2162. https://doi.org/10.18632/aging.101306

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                TY  - JOUR
                AU  - Saint-Germain, Emmanuelle 
                AU  - Mignacca, Lian 
                AU  - Vernier, Mathieu 
                AU  - Bobbala, Diwakar 
                AU  - Ilangumaran, Subburaj 
                AU  - Ferbeyre, Gerardo 
                TI  - SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101306
                DO  - 10.18632/aging.101306
                SP  - 2137
                EP  - 2162
                PY  - 
                AB  - The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis. Exogenous SOCS1 was sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis. This effect correlated with the ability of SOCS1 to reduce the expression of the cystine transporter SLC7A11 and the levels of glutathione. SOCS1 and SOCS1-dependent p53 target genes were induced during the senescence response to oncogenic STAT5A, RasV12 or the tumor suppressor PML. However, while SOCS1 sensitized cells to ferroptosis neither RasV12 nor STAT5A mimicked the effect. Intriguingly, PML turned cells highly resistant to ferroptosis. The results indicate different susceptibilities to ferroptosis in senescent cells depending on the trigger and suggest the possibility of killing senescent cells by inhibiting pathways that mediate ferroptosis resistance.
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SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy

Alexander Lang, Ruchika Anand, Simone Altinoluk-Hambüchen, Hakima Ezzahoini, Anja Stefanski, Afshin Iram, Laura Bergmann, Jennifer Urbach, Philip Böhler, Jan Hänsel, Manuel Franke, Kai Stühler, Jean Krutmann, Jürgen Scheller, Björn Stork, Andreas S. Reichert, Roland P. Piekorz,

https://doi.org/10.18632/aging.101307 pp 2163—2189

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Lang A, Anand R, Altinoluk-Hambüchen S, Ezzahoini H, Stefanski A, Iram A, Bergmann L, Urbach J, Böhler P, Hänsel J, Franke M, Stühler K, Krutmann J, et al, . SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy. . 9:2163-2189. https://doi.org/10.18632/aging.101307

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                TY  - JOUR
                AU  - Lang, Alexander 
                AU  - Anand, Ruchika 
                AU  - Altinoluk-Hambüchen, Simone 
                AU  - Ezzahoini, Hakima 
                AU  - Stefanski, Anja 
                AU  - Iram, Afshin 
                AU  - Bergmann, Laura 
                AU  - Urbach, Jennifer 
                AU  - Böhler, Philip 
                AU  - Hänsel, Jan 
                AU  - Franke, Manuel 
                AU  - Stühler, Kai 
                AU  - Krutmann, Jean 
                AU  - Scheller, Jürgen 
                AU  - Stork, Björn 
                AU  - Reichert, Andreas S. 
                AU  - Piekorz, Roland P. 
                TI  - SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101307
                DO  - 10.18632/aging.101307
                SP  - 2163
                EP  - 2189
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Lang, Alexander 
                AU  - Anand, Ruchika 
                AU  - Altinoluk-Hambüchen, Simone 
                AU  - Ezzahoini, Hakima 
                AU  - Stefanski, Anja 
                AU  - Iram, Afshin 
                AU  - Bergmann, Laura 
                AU  - Urbach, Jennifer 
                AU  - Böhler, Philip 
                AU  - Hänsel, Jan 
                AU  - Franke, Manuel 
                AU  - Stühler, Kai 
                AU  - Krutmann, Jean 
                AU  - Scheller, Jürgen 
                AU  - Stork, Björn 
                AU  - Reichert, Andreas S. 
                AU  - Piekorz, Roland P. 
                TI  - SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101307
                DO  - 10.18632/aging.101307
                SP  - 2163
                EP  - 2189
                PY  - 
                AB  - The stress-responsive mitochondrial sirtuin SIRT4 controls cellular energy metabolism in a NAD+-dependent manner and is implicated in cellular senescence and aging. Here we reveal a novel function of SIRT4 in mitochondrial morphology/quality control and regulation of mitophagy. We report that moderate overexpression of SIRT4, but not its enzymatically inactive mutant H161Y, sensitized cells to mitochondrial stress. CCCP-triggered dissipation of the mitochondrial membrane potential resulted in increased mitochondrial ROS levels and autophagic flux, but surprisingly led to increased mitochondrial mass and decreased Parkin-regulated mitophagy. The anti-respiratory effect of elevated SIRT4 was accompanied by increased levels of the inner-membrane bound long form of the GTPase OPA1 (L-OPA1) that promotes mitochondrial fusion and thereby counteracts fission and mitophagy. Consistent with this, upregulation of endogenous SIRT4 expression in fibroblast models of senescence either by transfection with miR-15b inhibitors or by ionizing radiation increased L-OPA1 levels and mitochondrial fusion in a SIRT4-dependent manner. We further demonstrate that SIRT4 interacts physically with OPA1 in co-immunoprecipitation experiments. Overall, we propose that the SIRT4-OPA1 axis is causally linked to mitochondrial dysfunction and altered mitochondrial dynamics that translates into aging-associated decreased mitophagy based on an unbalanced mitochondrial fusion/fission cycle.
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Degeneration of the osteocyte network in the C57BL/6 mouse model of aging

LeAnn M. Tiede-Lewis, Yixia Xie, Molly A. Hulbert, Richard Campos, Mark R. Dallas, Vladimir Dusevich, Lynda F. Bonewald, Sarah L. Dallas,

https://doi.org/10.18632/aging.101308 pp 2190—2208

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Tiede-Lewis LM, Xie Y, Hulbert MA, Campos R, Dallas MR, Dusevich V, Bonewald LF, Dallas SL, . Degeneration of the osteocyte network in the C57BL/6 mouse model of aging. . 9:2190-2208. https://doi.org/10.18632/aging.101308

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                TY  - JOUR
                AU  - Tiede-Lewis, LeAnn M. 
                AU  - Xie, Yixia 
                AU  - Hulbert, Molly A. 
                AU  - Campos, Richard 
                AU  - Dallas, Mark R. 
                AU  - Dusevich, Vladimir 
                AU  - Bonewald, Lynda F. 
                AU  - Dallas, Sarah L. 
                TI  - Degeneration of the osteocyte network in the C57BL/6 mouse model of aging
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101308
                DO  - 10.18632/aging.101308
                SP  - 2190
                EP  - 2208
                PY  - 
                AB  - Age-related bone loss and associated fracture risk are major problems in musculoskeletal health. Osteocytes have emerged as key regulators of bone mass and as a therapeutic target for preventing bone loss. As aging is associated with changes in the osteocyte lacunocanalicular system, we focused on the responsible cellular mechanisms in osteocytes. Bone phenotypic analysis was performed in young-(5mo) and aged-(22mo) C57BL/6 mice and changes in bone structure/geometry correlated with alterations in osteocyte parameters determined using novel multiplexed-3D-confocal imaging techniques. Age-related bone changes analogous to those in humans were observed, including increased cortical diameter, decreased cortical thickness, reduced trabecular BV/TV and cortical porosities. This was associated with a dramatic reduction in osteocyte dendrite number and cell density, particularly in females, where osteocyte dendricity decreased linearly from 5, 12, 18 to 22mo and correlated significantly with cortical bone parameters. Reduced dendricity preceded decreased osteocyte number, suggesting dendrite loss may trigger loss of viability. Age-related degeneration of osteocyte networks may impair bone anabolic responses to loading and gender differences in osteocyte cell body and lacunar fluid volumes we observed in aged mice may lead to gender-related differences in mechanosensitivity. Therapies to preserve osteocyte dendricity and viability may be beneficial for bone health in aging.
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Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)

Fiorella Colasuonno, Rossella Borghi, Alessia Niceforo, Maurizio Muzzi, Enrico Bertini, Andrea Di Giulio, Sandra Moreno, Claudia Compagnucci,

https://doi.org/10.18632/aging.101309 pp 2209—2222

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Colasuonno F, Borghi R, Niceforo A, Muzzi M, Bertini E, Di Giulio A, Moreno S, Compagnucci C, . Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs). . 9:2209-2222. https://doi.org/10.18632/aging.101309

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                TY  - JOUR
                AU  - Colasuonno, Fiorella 
                AU  - Borghi, Rossella 
                AU  - Niceforo, Alessia 
                AU  - Muzzi, Maurizio 
                AU  - Bertini, Enrico 
                AU  - Di Giulio, Andrea 
                AU  - Moreno, Sandra 
                AU  - Compagnucci, Claudia 
                TI  - Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101309
                DO  - 10.18632/aging.101309
                SP  - 2209
                EP  - 2222
                PY  - 
                AB  - Induced pluripotent stem cells (iPSCs) hold great promise for developing personalized regenerative medicine, however characterization of their biological features is still incomplete. Moreover, changes occurring in long-term cultured iPSCs have been reported, suggesting these as a model of cellular aging. For this reason, we addressed the ultrastructural characterization of iPSCs, with a focus on possible time-dependent changes, involving specific cell compartments. To this aim, we comparatively analysed cultures at different timepoints, by an innovative electron microscopic technology (FIB/SEM). We observed progressive loss of cell-to-cell contacts, associated with increased occurrence of exosomes. Mitochondria gradually increased, while acquiring an elongated shape, with well-developed cristae. Such mitochondrial maturation was accompanied by their turnover, as assessed by the presence of autophagomes (undetectable in young iPSCs), some containing recognizable mitochondria. This finding was especially frequent in middle-aged iPSCs, while being occasional in aged cells, suggesting early autophagic activation followed by a decreased efficiency of the process with culturing time. Accordingly, confocal microscopy showed age-dependent alterations to the expression and distribution of autophagic markers. Interestingly, responsivity to rapamycin, highest in young iPSCs, was almost lost in aged cells. Overall, our results strongly support long-term cultured iPSCs as a model for studying relevant aspects of cellular senescence, involving intercellular communication, energy metabolism, and autophagy.
                ER  -

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Thyroid status and mortality in nonagenarians from long-lived families and the general population

Nicolien A. van Vliet, Evie van der Spoel, Marian Beekman, P. Eline Slagboom, Gerard Jan Blauw, Jacobijn Gussekloo, Rudi G.J. Westendorp, Diana van Heemst,

https://doi.org/10.18632/aging.101310 pp 2223—2234

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van Vliet NA, van der Spoel E, Beekman M, Slagboom PE, Blauw GJ, Gussekloo J, Westendorp RG, van Heemst D, . Thyroid status and mortality in nonagenarians from long-lived families and the general population. . 9:2223-2234. https://doi.org/10.18632/aging.101310

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                TY  - JOUR
                AU  - van Vliet, Nicolien A. 
                AU  - van der Spoel, Evie 
                AU  - Beekman, Marian 
                AU  - Slagboom, P. Eline 
                AU  - Blauw, Gerard Jan 
                AU  - Gussekloo, Jacobijn 
                AU  - Westendorp, Rudi G.J. 
                AU  - van Heemst, Diana 
                TI  - Thyroid status and mortality in nonagenarians from long-lived families and the general population
                JO  - 
                JA  - 
                VL  - 9
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101310
                DO  - 10.18632/aging.101310
                SP  - 2223
                EP  - 2234
                PY  - 
                AB  - The relationship between thyroid status and longevity has been investigated extensively. However, data on thyroid status and survival in old age is scarce. In this study we investigated associations of different parameters of thyroid status with mortality in nonagenarians, and whether these associations were different in nonagenarians from long-lived families than in nonagenarians from the general population. In total, 805 nonagenarians from the Leiden Longevity Study and 259 nonagenarians from the Leiden 85-plus Study were followed up to collect mortality data. At baseline, levels of thyrotropin (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured. In nonagenarians from long-lived families and from the general population, associations between thyroid parameters and mortality were similar. We found no interaction between study population and parameters of thyroid status on mortality (P-values&gt;0.70). The results from both studies were combined to derive generalizable associations. Hazard ratios (HRs) for the highest compared to lowest tertiles were determined, resulting in TSH HR 0.91 (P=0.25), fT4 HR 1.22 (P=0.02), fT3 HR 0.74 (P=1.31e-4), and fT3/fT4 HR 0.66 (P=5.64e-7). In conclusion, higher fT3/fT4 ratios, higher levels of fT3, and lower levels of fT4 were associated with lower mortality rate in nonagenarians and independent of familial longevity status.
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Volume 9, Issue 10

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J. Bradford Kline, Nicholas C. Nicolaides,

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Masaki Kobayashi, Yoshikazu Higami,

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Nicolien A. van Vliet, Evie van der Spoel, Marian Beekman, P. Eline Slagboom, Gerard Jan Blauw, Jacobijn Gussekloo, Rudi G.J. Westendorp, Diana van Heemst,

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