Long-term administration of pDC-Stimulative Lactococcus lactis strain decelerates senescence and prolongs the lifespan of mice

https://doi.org/10.1016/j.intimp.2018.03.024Get rights and content

Highlights

  • SAMP6 mice given Lc. Plasma showed a significant improvement in survival rate.

  • The senescence score was significantly improved in Lc. Plasma mice.

  • Long-term administration of Lc. Plasma activates pDCs and mDCs in aged mice.

  • The transcription level of IL-1β and pathogenesis were suppressed in Lc. Plasma mice.

  • Senescence of skin and muscle was significantly suppressed in Lc. Plasma mice.

Abstract

The decline in immune function caused by aging increases the risk of infectious diseases, tumorigeneses and chronic inflammation, resulting in accelerating senescence. We previously reported a lactic acid bacteria, Lactococcus lactis strain Plasma (synonym of Lactococcus lactis subsp. lactis JCM 5805, Lc-Plasma), that stimulates plasmacytoid dendritic cells (pDCs), which play a crucial role in phylaxis from viral infection. In this study, we investigated the anti-aging effects of long-term oral administration of Lc-Plasma in a senescence-accelerated mouse strain, SAMP6. Mice given Lc-Plasma showed a significant improvement in survival rate at 82 weeks and a decreased senescence score as compared with control mice throughout this study. Anatomic analysis at 82 weeks revealed that the frequency of altered hepatocellular foci was significantly lower, and the incidence of other pathological findings in the liver and lungs tended to be lower in Lc-Plasma mice than in control mice. Transcription level of the IL-1β gene in lungs also tended to be lower in Lc-Plasma mice. Furthermore, the thinning of skin and age-related decrease in muscle mass were also significantly suppressed in the Lc-Plasma group as compared with the control group. Consistent with these phenotypic features, pDCs activity was significantly higher in Lc-Plasma mice than in control mice. In conclusion, long-term administration of Lc-Plasma can decelerate senescence and prolong lifespan via maintenance of the immune system due to activation of pDCs.

Introduction

Immune function decreases during aging, resulting in increased susceptibility to infectious diseases and risk of cancer [1,2]. The decline in immune function induces chronic inflammation, resulting in accelerating senescence [3]. A number of studies reporting age-related dysfunctions in adaptive immunity have been published. Decreased thymic T cell generation and disruption of homeostatic T cell proliferation have been reported [4,5]. The number of B cells decreases due to the loss of early precursors [6], and immunoglobulin class switching is depressed [7,8]. Age-related dysfunction of innate immune cells — namely, macrophages, NK cells and dendritic cells (DCs) — has also been reported [9,10]. In addition, DC tumor antigen presentation has been shown to be defective in mDCs from aged mice, and a selective decrease in DC-SIGN has been observed [11].

Plasmacytoid dendritic cells (pDCs) are a crucial subset of cells in anti-viral immunity that act as proficient producers of type I IFN [12,13]. Furthermore, pDCs and pDC-derived type I IFNs act as regulators in both adaptive and innate immunity by controlling various immune factors, such as T cells [[14], [15], [16], [17]], B cells [18,19], and NK cells [20]. Any deterioration in the function of pDCs seriously affects the whole immune system, because they are responsible for not only innate immune functions such as phagocytosis and cytokine secretion in response to antigens, but also acquired immunity by means of antigen presentation and priming T cells and B cells [21,22].

We previously discovered a unique type of lactic acid bacteria (LAB), Lactococcus lactis strain Plasma (Lc-Plasma), which stimulates murine pDCs in vitro and in vivo [23]. Lc-Plasma is a synonym of Lactococcus lactis subsp. lactis JCM 5805. The active component responsible for pDC activation is demonstrated to be DNA. We revealed that IFN-α production by pDC was induced by Lc-Plasma derived DNA, in addition, it was depending on the TLR9-MyD88 pathway [23]. Animal experiments using a parainfluenza-infection model revealed that oral administration of Lc-Plasma markedly increased the survival rate against infection and enhanced lung anti-viral immune responses through the activation of intestinal pDCs [24]. Lc-Plasma could also activate human pDCs in vitro and in vivo [25]. In a human clinical study, oral administration of Lc-Plasma for 10 weeks decreased the pathogenesis of an influenza-like illness via enhancement of an IFN-α response to influenza virus [26].

LAB are widely accepted as safe and can be easily incorporated in the daily diet; therefore, our research has focused on the effects of lifelong daily administration of Lc-Plasma on phenotypes caused by aging. Senescence-accelerated mouse (SAM) is an animal model of accelerated senescence and senescence-associated disorders that presents age-related phenotypes closely mimicking human aging dysfunctions [27,28]. SAMP6 strain is known to have some aging features, such as senile osteoporosis, secondary amyloidosis, and colitis; on the other hand, dysfunction of the immune system, as in SAMP1, SAMP2 and SAMP8 strains, has not been reported [29]. Therefore, SAMP6 might be useful for evaluating the natural aging dysfunction of the immune system.

Some LAB and their products have been reported to be effective in suppressing various phenotypes and dysfunctions of the immune system in SAM. For example, oral administration of Lactococcus lactis subsp. cremoris H61 to aged SAMP6 for 5 months was associated with a reduction of bone density loss [30]. Administration of Lactobacillus gasseri TMC0356 to SAMP1 for 4 and 8 weeks indicated the potential to upregulate cell-mediated immunity [31]. Administration of LAB-fermented milk for 4 months had a preventive effect against inflammatory bowel disease in SAMP1/Yit mice [32]. However, the effect of long-term administration of LAB and the relationship between immune function and aging remain unknown.

Here, we investigated the anti-aging effects of lifelong administration of Lc-Plasma in female SAMP6 mice. Age-related phenotypes were improved by the suppression of inflammation; furthermore, lifespan was prolonged markedly.

Section snippets

Preparation of LAB

Lactococcus lactis subsp. lactis JCM 5805 (Lc-Plasma) were purchased from the Japan Collection of Microorganisms. LAB strains were grown at 30 °C for 48 h in M17 broth (Oxoid Ltd.) in accordance with the manufacturer's instructions, washed twice with sterile distilled water, and heat-killed at 100 °C for 30 min.

Mice

Five-weeks-old SAMP6 female mice were purchased from Japan SLC, Inc. We have confirmed the effect to activate pDCs by administration of Lc-Plasma on female mice [22], therefore we chose

Long-term administration of Lc-Plasma decelerates senescence and prolongs lifespan

At 82 weeks of age, the survival rate was 62.5% (10/16) in the control group, and 93.75% (15/16) in Lc-Plasma group (Fig. 1A). The cumulative survival rate was significantly higher in the Lc-Plasma group than in the control group (P < 0.05).

Senescence scores were evaluated once every 8 weeks from 27 weeks until 82 weeks of age, as described in Materials and Methods. The total scores were lower in the Lc-Plasma group than in the control group throughout the study; in particular, there were

Discussion

We previously reported that administration of Lc-Plasma activates pDCs, resulting in protection from viral infection in both mice and humans [[23], [24], [25], [26]]. In this study, we found that administration of Lc-Plasma is also effective in decelerating senescence. Furthermore, our data indicated the significant effect of prolonging lifespan. At 82 weeks of age, the survival rate of SAMP6 mice fed Lc-Plasma was higher than that of the control mice. Six out of 16 mice died in the control

Acknowledgments

We thank Dr. Hideyuki Tamakawa, Mr. Ryohei Tsuji and Ms. Kumiko Ikado for their technical assistance and valuable discussion.

Author contributions

D.F., T.S. conceived and designed the experiments, T.S., K.J., K.O. and others performed the experiments, T.S., K.J., K.O. and others analyzed the data, T.S., K.J., D.F. wrote the manuscript.

Financial support

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Competing interests

The authors declare no competing interests.

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