Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells

Féart, Catherine; Pallet, Véronique; Boucheron, Catherine; Higueret, D.; Alfos, Serge; Letenneur, Luc; Dartigues, J F; Higueret, Paul

doi:10.1530/eje.1.01858

Cited by 45 publications

(32 citation statements)

References 66 publications

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“…In humans, the demonstration that brain retinoid signaling is affected by aging remains to be done. Nevertheless, the potential relevance of our findings for understanding the molecular bases of human senescence is strengthened by a recent report on peripheral retinoid hyposignaling in aged humans (Feart et al, 2005). Furthermore, at the cognitive level, the predictive validity of our LTDM model was demonstrated recently by a translational approach.…”

Section: Hippocampal Retinoid Signaling and Organizational Capabilitiessupporting

confidence: 59%

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

Mingaud¹,

Mormède²,

Etchamendy³

et al. 2008

J. Neurosci.

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An increasing body of evidence indicates that the vitamin A metabolite retinoic acid (RA) plays a role in adult brain plasticity by activating gene transcription through nuclear receptors. Our previous studies in mice have shown that a moderate downregulation of retinoidmediated transcription contributed to aging-related deficits in hippocampal long-term potentiation and long-term declarative memory (LTDM). Here, knock-out, pharmacological, and nutritional approaches were used in a series of radial-arm maze experiments with mice to further assess the hypothesis that retinoid-mediated nuclear events are causally involved in preferential degradation of hippocampal function in aging. Molecular and behavioral findings confirmed our hypothesis. First, a lifelong vitamin A supplementation, like shortterm RA administration, was shown to counteract the aging-related hippocampal (but not striatal) hypoexpression of a plasticity-related retinoid target-gene, GAP43 (reverse transcription-PCR analyses, experiment 1), as well as short-term/working memory (STWM) deterioration seen particularly in organization demanding trials (STWM task, experiment 2). Second, using a two-stage paradigm of LTDM, we demonstrated that the vitamin A supplementation normalized memory encoding-induced recruitment of (hippocampo-prefrontal) declarative memory circuits, without affecting (striatal) procedural memory system activity in aged mice (Fos neuroimaging, experiment 3A) and alleviated their LTDM impairment (experiment 3B). Finally, we showed that (knock-out, experiment 4) RA receptor ␤ and retinoid X receptor ␥, known to be involved in STWM (Wietrzych et al., 2005), are also required for LTDM. Hence, aging-related retinoid signaling hypoexpression disrupts hippocampal cellular properties critically required for STWM organization and LTDM formation, and nutritional vitamin A supplementation represents a preventive strategy. These findings are discussed within current neurobiological perspectives questioning the historical consensus on STWM and LTDM system partition.

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Section: Hippocampal Retinoid Signaling and Organizational Capabilitiessupporting

confidence: 59%

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

Mingaud¹,

Mormède²,

Etchamendy³

et al. 2008

J. Neurosci.

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“…Significant difference was only observed in retinol and RBP levels of the WS group. These results associated with decreased T3 and increased TSH plasma levels allowed us to compare the status of these patients to a subclinical hypothyroidism as observed in previous studies [7]. Interestingly, TRβ expression was lower, both in PBMC and adipose tissue of the WG group, without modification of the level of TRβ mRNA in PBMC of the two other obese groups.…”

Section: Discussionsupporting

confidence: 65%

“…Preparation of PBMC Isolation of human blood mononuclear cells was performed by density gradient centrifugation using Ficoll-Plaque Plus solution (Amersham Biosciences, F-91898 Orsay France) as previously described [7,8]. The PBMC were then suspended in TRIZOL® Reagent (Invitrogen, Cergy Pontoise, France) and stored at -80°C before RNA extraction.…”

Section: Methodsmentioning

confidence: 99%

“…Various studies showed disease-characteristic gene expression patterns in PBMC, in particular, some studies previously performed in our laboratory, which have shown that hypothyroid and aged subjects present hypoactivation of the retinoid nuclear pathway in PBMC [7,8], suggesting that alterations in the messenger RNA (mRNA) levels of these nuclear receptors are manifested at this peripheral level.…”

mentioning

confidence: 95%

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RARγ and TRβ expressions are decreased in PBMC and SWAT of obese subjects in weight gain

Bairras¹,

Redonnet²,

Dabadie

et al. 2010

J Physiol Biochem

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In order to evaluate the expression of nuclear receptors at the peripheral level in obese subjects, messenger RNA (mRNA) levels of different isoforms of retinoic acid receptor (RAR), triiodothyronine (TR), and peroxisome proliferator-activated receptor (PPAR) were determined and compared in peripheral mononuclear blood cells (PBMC) and subcutaneous white adipose tissue (SWAT). Twelve lean subjects and 68 obese subjects divided into weight gain (WG), weight-stable (WS), and weight loss (WL) groups were studied. Nuclear receptor mRNA levels were assessed in PBMC and SWAT using a quantitative real-time reverse transcription polymerase chain reaction method. mRNA levels of RARgamma were significantly lower in PBMC of obese subjects (WG -19%, WS -30%, and WL -24.7%) as in SWAT of WG (-50%). Lower mRNA levels of TRbeta were observed in PBMC and SWAT of WG (-50.7% and -28%, respectively) just as for TRalpha in PBMC of WG (-19%). In contrast, retinoid X receptors alpha (RXRalpha) and RARalpha mRNA levels were higher in PBMC of obese subjects (+53% and +54.5% in WG, +56% and +67% in WS, and +68% and +49.7% in WL, respectively), while expression of RXRalpha was lower in SWAT of WG (-24.5%). As for PPARgamma, its mRNA level was significantly higher in PBMC of WG subjects (+34%) while its expression was not modified in SWAT, contrary to the PPARgamma2 isoform which was significantly higher. These data show that in both adipose tissue and blood compartment of obese subjects, expressions of RARgamma and TRbeta were downregulated. Thus, we suggest that the expression in PBMC of obese subjects may constitute new cellular indicators of nuclear receptor retinoid and thyroid status.

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“…10,36 The lack of a demonstrable effect of retinoid therapy on retinoid and IFN-regulated gene expression here may be related to the age-dependent nature of gene expression and regulation in PBMCs, 37 or the fact that PBMCs are not good surrogates for assessing response in RCC.…”

Section: Discussionmentioning

confidence: 99%

Phase 1/2 Clinical Trial of Interferon α2b and Weekly Liposome-encapsulated All-trans Retinoic Acid in Patients With Advanced Renal Cell Carcinoma

Boorjian¹,

Milowsky²,

Kaplan³

et al. 2007

Journal of Immunotherapy

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To evaluate the feasibility, efficacy, and biologic effects of weekly liposome-encapsulated all-trans retinoic acid (ATRA-IV) plus interferon alpha2b (IFN) in patients with advanced renal cell carcinoma (RCC). Twenty-six patients with metastatic RCC were treated on a phase 1/2 trial with weekly ATRA-IV and IFN SQ daily 5 d/wk. Twelve patients received ATRA-IV at three dose levels (60, 75, and 90 mg/m2) according to phase 1 methodology, and 14 additional patients received 90 mg/m2. Response was assessed according to an intention-to-treat analysis. Serum retinoic acid (RA) concentrations were assayed and peripheral blood mononuclear cell mRNA expression of RA and IFN-inducible genes (RARalpha, RARbeta2, IRF1, CRABP2, and TRAIL) were examined. No dose limiting toxicities occurred at 60 mg/m2; grade 3 leukopenia affected 1/6 patients at 75 mg/m2, whereas 3 patients received 90 mg/m2 without a dose limiting toxicities. Fourteen additional patients received 90 mg/m2 ATRA-IV without grade 3/4 toxicity. Five of 26 (19%) patients achieved a major response, with a median duration of 14 months (range 9 to 23); 9 additional patients (41%) demonstrated stable disease or minor response lasting > or =4 months. No significant differences in serum (RA) after ATRA infusion were detected between weeks 1 and 8 of treatment. Peripheral blood mononuclear cell mRNA expression did not correlate with clinical response. The addition of weekly ATRA-IV to IFN therapy is feasible and well tolerated, resulting in sustainable increased serum (RA). This regimen demonstrates antitumor activity in metastatic RCC, and suggests ATRA-IV augments IFN therapy.

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Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells

Cited by 45 publications

References 66 publications

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

RARγ and TRβ expressions are decreased in PBMC and SWAT of obese subjects in weight gain

Phase 1/2 Clinical Trial of Interferon α2b and Weekly Liposome-encapsulated All-trans Retinoic Acid in Patients With Advanced Renal Cell Carcinoma

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