Inadequate mito-biogenesis in primary dermal fibroblasts from old humans is associated with impairment of PGC1A-independent stimulation

Kalfalah, Faiza; Sobek, Stefan; Bornholz, Beatrice; Götz-Rösch, Christine; Tigges, Julia; Fritsche, Ellen; Krutmann, Jean; Köhrer, Karl; Deenen, René; Ohse, Sebastian; Boerries, Melanie; Busch, Hauke; Boege, Fritz

doi:10.1016/j.exger.2014.03.017

Cited by 33 publications

(42 citation statements)

References 56 publications

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“…Next, we considered gene expression data from the same in situ aged fibroblasts already published by Kalfalah and colleagues [ 10 ]. It was reported that about 17,000 transcripts were successfully quantified, whereof a total of 137 genes exhibited a significant age-associated differential expression ( Tab.…”

Section: Resultsmentioning

confidence: 99%

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Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts

Waldera-Lupa

Kalfalah

Florea

et al. 2014

Aging

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We analyzed an ex vivo model of in situ aged human dermal fibroblasts, obtained from 15 adult healthy donors from three different age groups using an unbiased quantitative proteome-wide approach applying label-free mass spectrometry. Thereby, we identified 2409 proteins, including 43 proteins with an age-associated abundance change. Most of the differentially abundant proteins have not been described in the context of fibroblasts’ aging before, but the deduced biological processes confirmed known hallmarks of aging and led to a consistent picture of eight biological categories involved in fibroblast aging, namely proteostasis, cell cycle and proliferation, development and differentiation, cell death, cell organization and cytoskeleton, response to stress, cell communication and signal transduction, as well as RNA metabolism and translation. The exhaustive analysis of protein and mRNA data revealed that 77% of the age-associated proteins were not linked to expression changes of the corresponding transcripts. This is in line with an associated miRNA study and led us to the conclusion that most of the age-associated alterations detected at the proteome level are likely caused post-transcriptionally rather than by differential gene expression. In summary, our findings led to the characterization of novel proteins potentially associated with fibroblast aging and revealed that primary cultures of in situ aged fibroblasts are characterized by moderate age-related proteomic changes comprising the multifactorial process of aging.

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Section: Resultsmentioning

confidence: 99%

“…2 ) [ 11 ]. To determine if these miRNAs play a role in mRNA abundance, we compared their targets with the mRNAs from Kalfalah and colleagues [ 10 ]. This comparison revealed 164 mRNAs as candidate targets of the 12 candidate miRNAs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts

Waldera-Lupa

Kalfalah

Florea

et al. 2014

Aging

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“…; Kalfalah et al . ). Thus, the present findings of increased PGC‐1α with quercetin enrichment might manifest more potently in aged mice and underscore the aforementioned considerations of animal age.…”

Section: Discussionmentioning

confidence: 97%

Long‐term dietary quercetin enrichment as a cardioprotective countermeasure in mdx mice

Ballmann

Denney

Beyers

et al. 2017

Experimental Physiology

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New Findings r What is the central question of this study?The central question of this study is to understand whether dietary quercetin enrichment attenuates physiologic, histological, and biochemical indices of cardiac pathology. r What is the main finding and its importance?Novel findings from this investigation, in comparison to prior published studies, suggest that mouse strain-dependent cardiac outcomes in performance and remodelling exist. Unlike Mdx/Utrn −/+ mice, mdx mice receiving lifelong quercetin treatment did not exhibit improvements cardiac function. Similar to prior work in Mdx/Utrn −/+ mice, histological evidence of remodelling suggests that quercetin consumption may have benefited hearts of mdx mice. Positive outcomes may be related to indirect markers that suggest improved mitochondrial wellbeing and to selected indices of inflammation that were lower in hearts from quercetin-fed mice.Duchenne muscular dystrophy causes a decline in cardiac health, resulting in premature mortality. As a potential countermeasure, quercetin is a polyphenol possessing inherent anti-inflammatory and antioxidant effects that activate proliferator-activated γ coactivator 1α (PGC-1α), increasing the abundance of mitochondrial biogenesis proteins. We investigated the extent to which lifelong 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in mdx mice. Dystrophic animals were fed a quercetin-enriched or control diet for 12 months, while control C57 mice were fed a control diet. Cardiac function was assessed via 7 T magnetic resonance imaging at 2, 10 and 14 months. At 14 months, hearts were harvested for histology and Western blotting. The results indicated an mdx strain-dependent decline in cardiac performance at 14 months and that dietary quercetin enrichment did not attenuate functional losses. In contrast, histological analyses provided evidence that quercetin feeding was associated with decreased fibronectin and indirect damage indices (Haematoxylin and Eosin) compared with untreated mdx mice. Dietary quercetin enrichment increased cardiac protein abundance of PGC-1α, cytochrome c, electron transport chain complexes I-V, citrate synthase, superoxide dismutase 2 and glutathione peroxidase (GPX) versus untreated mdx mice. The protein abundance of the inflammatory markers nuclear factor-κB, phosphorylated nuclear factor kappa beta (P-NFκB) and phosphorylated nuclear factor of kappa light polypeptide

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“…Fibroblasts were isolated and cultivated as described elsewhere (Tigges et al, 2012;Kalfalah et al, 2014) and not expanded beyond PN 6 to exclude replicative senescence (for more information see supplementary material and Supplementary Table S8 online).…”

Section: Cell Isolation and Culturementioning

confidence: 99%

Characterization of Skin Aging–Associated Secreted Proteins (SAASP) Produced by Dermal Fibroblasts Isolated from Intrinsically Aged Human Skin

Lupa

Kalfalah

Safferling

et al. 2015

Journal of Investigative Dermatology

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156

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Most molecular hallmarks of cellular senescence have been identified in studies of cells aged in vitro by driving them into replicative or stress-induced senescence. Comparatively, less is known about the characteristic features of cells that have aged in vivo. Here we provide a systematic molecular analysis of normal human dermal fibroblasts (NHDFs) that were isolated from intrinsically aged human skin of young versus middle aged versus old donors. Intrinsically aged NHDFs in culture exhibited more frequently nuclear foci positive for p53 binding protein 1 and promyelocytic leukemia protein reminiscent of 'DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS)'. Formation of such foci was neither accompanied by increased DNA double strand breaks, nor decreased cell viability, nor telomere shortening. However, it was associated with the development of a secretory phenotype, indicating incipient cell senescence. By quantitative analysis of the entire secretome present in conditioned cell culture supernatant, combined with a multiplex cytokine determination, we identified 998 proteins secreted by intrinsically aged NHDFs in culture. Seventy of these proteins exhibited an age-dependent secretion pattern and were accordingly denoted 'skin aging-associated secreted proteins (SAASP)'. Systematic comparison of SAASP with the classical senescence-associated secretory phenotype (SASP) revealed that matrix degradation as well as proinflammatory processes are common aspects of both conditions. However, secretion of 27 proteins involved in the biological processes of 'metabolism' and 'adherens junction interactions' was unique for NHDFs isolated from intrinsically aged skin. In conclusion, fibroblasts isolated from intrinsically aged skin exhibit some, but not all, molecular hallmarks of cellular senescence. Most importantly, they secrete a unique pattern of proteins that is distinct from the canonical SASP and might reflect specific processes of skin aging.

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Inadequate mito-biogenesis in primary dermal fibroblasts from old humans is associated with impairment of PGC1A-independent stimulation

Cited by 33 publications

References 56 publications

Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts

Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts

Long‐term dietary quercetin enrichment as a cardioprotective countermeasure in mdx mice

Characterization of Skin Aging–Associated Secreted Proteins (SAASP) Produced by Dermal Fibroblasts Isolated from Intrinsically Aged Human Skin

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