Senescence-accelerated Mouse Prone 1 Research Articles

Comparison between the timing of the occurrence of taste sensitivity changes and short-term memory decline due to aging in SAMP1 mice.

Several studies have suggested that cognitive impairment affects taste sensitivity. However, the mechanism behind this is still unclear. In this study, we focused on short-term memory. Using senescence-accelerated mouse prone 1 (SAMP1) mice, we compared whether the effects of aging are observed earlier in taste sensitivity or short-term memory. We used 8-week-old mice as the young group, and 70- and 80-week-old mice as aged groups. Taste sensitivity was evaluated using a 48-hour two-bottle preference test, and short-term memory was evaluated using the Y-maze test. SAMP1 mice showed apparently changes in taste sensitivity at 70-weeks-old. However, the influence of aging on spontaneous alternation behavior, which is indicative of short-term memory alterations, was not observed in 70-week-old mice. At 80-weeks-old, the influence of aging was observed, and spontaneous alternation behavior was significantly decreased. This suggests that age-dependent changes in taste sensitivity occur prior to short-term memory function decline. In addition, there was no significant influence of aging on the mRNA expression of long-term potentiation-related genes in the hippocampus of 80-week-old mice. Therefore, the age-related decline of short-term memory may not affect taste sensitivity.

Effects of combined exercise training and Chlorella intake on vasorelaxation mediated by nitric oxide in aged mice.

Chronic Chlorella intake and aerobic exercise training reduce arterial stiffness and increase circulating nitric oxide (NO) levels, which has beneficial effects. This study aimed to clarify the combined aortic NO-mediated effects of chronic Chlorella intake and aerobic exercise training on endothelial vasorelaxation in aged mice. In this study, 38-week-old male senescence-accelerated mouse prone 1 (SAMP1) mice were divided into aged sedentary control (Con), aerobic exercise training (AT; voluntary wheel running for 12 weeks), Chlorella intake (CH; 0.5% Chlorella powder in normal diet), and AT and CH combined (AT+CH) groups. Endothelium-dependent vasorelaxation by addition of acetylcholine to the isolated mouse aortic rings was significantly higher in the AT, CH, and AT+CH groups than in the Con group; a significantly greater effect was seen in the AT+CH group than in the AT and CH groups. Similarly, plasma and arterial nitrite/nitrate levels and arterial endothelial NO synthase phosphorylation were significantly higher in the AT, CH, and AT+CH groups than in the Con group; the AT+CH group had higher values than the AT and CH groups. Thus, chronic Chlorella intake combined with aerobic exercise training had pronounced effects on endothelial vasorelaxation in aged mice via an additive increase in arterial NO production. Novelty: Endothelium-dependent vasorelaxation was improved by Chlorella intake and exercise. Chlorella intake and exercise increased arterial Akt/eNOS/NO signaling. This combination approach further improved vasorelaxation via arterial NO production.

β-Cryptoxanthin Improves p62 Accumulation and Muscle Atrophy in the Soleus Muscle of Senescence-Accelerated Mouse-Prone 1 Mice.

We investigated the effects of β-cryptoxanthin on skeletal muscle atrophy in senescence-accelerated mouse-prone 1 (SAMP1) mice. For 15 weeks, SAMP1 mice were intragastrically administered vehicle or β-cryptoxanthin. At 35 weeks of age, the skeletal muscle mass in SAMP1 mice was reduced compared with that in control senescence-accelerated mouse-resistant 1 (SAMR1) mice. β-cryptoxanthin increased muscle mass with an increase in the size of muscle fibers in the soleus muscle of SAMP1 mice. The expressions of autophagy-related factors such as beclin-1, p62, LC3-I, and LC3-II were increased in the soleus muscle of SAMP1 mice; however, β-cryptoxanthin administration inhibited this increase. Unlike in SAMR1 mice, p62 was punctately distributed throughout the cytosol in the soleus muscle fibers of SAMP1 mice; however, β-cryptoxanthin inhibited this punctate distribution. The cross-sectional area of p62-positive fiber was smaller than that of p62-negative fiber, and the ratio of p62-positive fibers to p62-negative fibers was increased in SAMP1 mice. β-cryptoxanthin decreased this ratio in SAMP1 mice. Furthermore, β-cryptoxanthin decreased the autophagy-related factor expression in murine C2C12 myotube. The autophagy inhibitor bafilomycin A1, but not the proteasome inhibitor MG132, inhibited the β-cryptoxanthin-induced decrease in p62 and LC3-II expressions. These results indicate that β-cryptoxanthin inhibits the p62 accumulation in fibers and improves muscle atrophy in the soleus muscle of SAMP1 mice.

Long-Term Intake of Glucoraphanin-Enriched Kale Suppresses Skin Aging via Activating Nrf2 and the TβRII/Smad Pathway in SAMP1 Mice.

Sulforaphane, a potent antioxidant compound, is unstable at ambient temperature, whereas its precursor glucoraphanin is stable and metabolized to sulforaphane. Thus, we hypothesized that glucoraphanin-rich diet could effectively induce antioxidant enzyme activities and investigated the protective effects of long-term intake of a glucoraphanin-enriched kale (GEK) diet on skin aging in senescence-accelerated mouse prone 1 (SAMP1) mice. The senescence grading score was significantly lower after treatment with GEK for 39 weeks than that of the control mice. GEK also suppressed the thinning of the dorsal skin layer. Moreover, the GEK treatment enhanced the collagen production and increased the nuclear translocation of Nrf2 and HO-1 expression level in the skin tissue. TβRII and Smad3 expressions were clearly higher in the GEK-treated group than in the control group. Thus, GEK suppressed senescence in SAMP1 mice by enhancing the antioxidant activity and collagen production via the TβRII/Smad3 pathway, suggesting its practical applications for protection against skin aging.

Wild-type and SAMP8 mice show age-dependent changes in distinct stem cell compartments of the interfollicular epidermis.

Delayed wound healing and reduced barrier function with an increased risk of cancer are characteristics of aged skin and one possible mechanism is misregulation or dysfunction of epidermal stem cells during aging. Recent studies have identified heterogeneous stem cell populations within the mouse interfollicular epidermis that are defined by territorial distribution and cell division frequency; however, it is unknown whether the individual stem cell populations undergo distinct aging processes. Here we provide comprehensive characterization of age-related changes in the mouse epidermis within the specific territories of slow-cycling and fast-dividing stem cells using old wild-type, senescence-accelerated mouse prone 1 (SAMP1) and SAMP8 mice. During aging, the epidermis exhibits structural changes such as irregular micro-undulations and overall thinning of the tissue. We also find that, in the old epidermis, proliferation is preferentially decreased in the region where fast-dividing stem cells reside whereas the lineage differentiation marker appears to be more affected in the slow-cycling stem cell region. Furthermore, SAMP8, but not SAMP1, exhibits precocious aging similar to that of aged wild-type mice, suggesting a potential use of this model for aging study of the epidermis and its stem cells. Taken together, our study reveals distinct aging processes governing the two epidermal stem cell populations and suggests a potential mechanism in differential responses of compartmentalized stem cells and their niches to aging.

Effects of lifelong intake of lemon polyphenols on aging and intestinal microbiome in the senescence-accelerated mouse prone 1 (SAMP1)

Polyphenols have been examined for their beneficial effects on health, particularly in rodents, but their lifelong effects are unclear. Lemons (Citrus limon), containing lemon polyphenols (LPP), are widely consumed but the effects of LPP on aging are unknown. Therefore, we examined the effects of LPP on aging such as aging-related scores, locomotor activity, cognitive functions, and intestinal microbiome using senescence-accelerated mouse prone 1 (SAMP1) and senescence-accelerated resistant mouse 1 (SAMR1). All mice had ad libitum access to water (P1_water group, SAMR1) or 0.1% LPP (P1_LPP group). In the P1_LPP group, LPP intake prolonged the lifespan by approximately 3 weeks and delayed increases in aging-related scores (e.g., periophthalmic lesions) and locomotor atrophy. The P1_water group showed large changes in the intestinal microbiome structure, while the R1 and P1_LPP groups did not. The phylum Bacteroidetes/Firmicutes, which is associated with obesity, in the P1_water group was significantly lower and higher than that in the P1_LPP and R1 groups, respectively. Although the relative abundance of Lactobacillus significantly increased in both P1 groups with aging, the P1_LPP group showed a significantly lower increase than the P1_water group. Thus, lifelong intake of LPP may have anti-aging effects on both phenotypes and the intestinal environment.

5-Hydroxy-7-methoxyflavone derivatives from Kaempferia parviflora induce skeletal muscle hypertrophy.

Skeletal muscle plays a critical role in locomotion and energy metabolism. Maintenance or enhancement of skeletal muscle mass contributes to the improvement of mobility and prevents the development of metabolic diseases. The extracts from Kaempferia parviflora rhizomes contain at least ten methoxyflavone derivatives that exhibit enhancing effects on ATP production and glucose uptake in skeletal muscle cells. In the present study, we investigated the effects of ten K. parviflora‐derived methoxyflavone derivatives (six 5,7‐dimethoxyflavone (DMF) derivatives and four 5‐hydroxy‐7‐methoxyflavone (HMF) derivatives) on skeletal muscle hypertrophy. Murine C2C12 myotubes and senescence‐accelerated mouse‐prone 1 (SAMP1) mice treated with methoxyflavones were used as experimental models to determine the effects of HMF derivatives on myotube diameter and size and muscle mass. The four HMF derivatives, but not the six DMF derivatives, increased myotube diameter. The 5‐hydroxyflavone, 7‐methoxyflavone, and 5,7‐dihydroxyflavone had no influence on myotube size, a result that differed from HMF. Dietary administration of the mixture composed of the four HMF derivatives resulted in increase in the soleus muscle size and mass in SAMP1 mice. HMF derivatives also promoted protein synthesis in myotubes, and treatment with the intracellular Ca2+ chelator BAPTA‐AM, which depletes intracellular Ca2+ levels, inhibited this promotion. Furthermore, BAPTA‐AM inhibited HMF‐promoted protein synthesis even when myotubes were incubated in Ca2+‐free medium. These results indicate that HMF derivatives induce myotube hypertrophy and that both the 5‐hydroxyl group and the 7‐methoxy group in the flavones are necessary for myotube hypertrophy. Furthermore, these results suggest that HMF‐induced protein synthesis requires intracellular Ca2+, but not extracellular Ca2+.

Exercise enhances cognitive function and neurotrophin expression in the hippocampus accompanied by changes in epigenetic programming in senescence-accelerated mice.

Aerobic exercise is known to increase expression of neurotrophins, particularly brain-derived neurotrophic factor (BDNF), in the hippocampus and to improve cognitive function. Exercise exerts neuroprotective effects in the hippocampus by inducing epigenetic changes, which play crucial roles in aging and neurodegenerative diseases. Specifically, the activity levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate histone acetylation and modulate gene transcription. The objective of the present study was to assess the interactive effects of exercise and aging on cognitive function, expression of neurotrophins (BDNF and neurotrophin-4) and their receptors (tyrosine receptor kinase B and p75), and epigenetic regulations, including the activity of HATs and HADCs in the hippocampus. We used the senescence-accelerated mouse (SAM) model, specifically 13-month-old SAM resistant 1(SAMR1) and SAM prone 1 (SAMP1) lines. Mice were distributed into four groups based on accelerated senescence and exercise status. Mice in the exercise groups exercised on a treadmill for approximately 60min a day, 5days a week. Aerobic exercise for 4 weeks improved cognitive function, accompanied by an increase in BDNF expression and a decrease in p75 transcription in both SAMR1 and SAMP1. In addition, the exercise regimen activated both HAT and HDAC in the hippocampus. Therefore, the present study reveals that despite accelerated senescence, long-term exercise improved cognitive function, upregulated the expression of BDNF, and downregulated p75, a receptor involved in apoptotic signaling. Furthermore, long-term exercise enhanced activity of both HAT and HDAC, which may contribute to the transcriptional regulation underlying the improvement of cognitive function.

Establishment and Application of an Automated Chiral Two-dimensional High Performance Liquid Chromatography Method for Bio-analysis of D-Acidic Amino Acids

The physiological and bio-marker function of D-acidic amino acids is now becoming the focus in metabolomics study and new drug discovery. A fully automated two-dimensional high performance liquid chromatography (2D-HPLC) was established by using silica-based monolithic ODS column as the first dimension column with acetonitrile-trifluoro acetic acid-water (9:0.05:91, V/V) as the mobile phase, micro Chiralpak QD-1-AX column as the enantiomer separation column with 10 mM citric acid in methanol- acetonitrile (50:50, V/V) as the mobile phase for the second dimension separation, and 4-fluoro-7-nitro-2,1,3- benzoxadiazole (NBD-F) as the fluorometrical derivative reagent. The method has a higher separation efficiency (Rs > 2.5) and a higher detection sensitivity (LOD = 1 fmol) than that of existing methods in the determination of acidic amino acids enantiomers, meanwhile, an online confirmation of the enantiomers amounts were achieved by this method. The recoveries were around 97%–104%, and the RSDs of intra-day and inter-day were less than 5%. Furthermore, by analyzing the aging model senescence accelerated mouse prone 1 (SAMP1) mice which have low immunocompetence, the amounts of D-aspartic acid in thymus and spleen were determined as (206 ± 18) nmol g−1 and (264 ± 21) nmol g−1, respectively. In the experiment, it was found for the first time that there was an obvious increasing trend of D-aspartic acid (p < 0.01) in thymus and spleen of SAMP1 mice compared to senescence accelerated mouse resistant 1 (SAMR1) mice.

Differences in the Histopathology and Cytokine Expression Pattern between Chronological Aging and Photoaging of Hairless Mice Skin

Skin photoaging is a complex, multifactorial process resulting in functional and structural changes of the skin, and different phenotypes from chronological skin aging are well-recognized. Ultraviolet (UV)-irradiated hairless mice have been used as a skin photoaging animal model. However, differences in morphology and gene expression patterns between UV-induced and chronological skin changes in this mouse model have not been fully elucidated. Here we investigated differences in histopathology and cytokine expression between UV-irradiated and non-irradiated aged hairless mice to clarify the factor(s) that differentiate photoaging from chronological skin aging phenotypes. Eight-week-old HR-1 hairless mice were divided into UV-irradiated (UV-irradiated mice) and non-irradiated (control mice) groups. Irradiation was performed three times per week for 10 weeks. In addition, 30-week-old HR-1 hairless mice were reared until 70 weeks of age without UV irradiation (aged mice). Histopathologies revealed that the flattening of dermal-epidermal junctions and epidermal thickening were observed only in UV-irradiated mice. Decreases in fine elastic fibers just beneath the epidermis, the thickening of elastic fibers in the reticular dermis, and the accumulation of glycosaminoglycans were more prominent in UV-irradiated mice as compared to non-irradiated aged mice. Quantitative PCR analyses revealed that UV-irradiated mice showed an increase in the expression of IFN-γ. In contrast, aged mice exhibited proportional up-regulation of both pro-inflammatory and anti-inflammatory cytokines. The IFN-γ/IL-4 ratio, an indicator for the balance of pro-inflammatory and anti-inflammatory cytokines, was significantly higher in UV-irradiated mice as compared to control and non-irradiated aged mice. An elevated IFN-γ/IL-4 ratio was also observed in aged senescence-accelerated mouse-prone 1 (SAMP1) mice, a spontaneous skin photoaging model we recently reported. Thus, an imbalance between pro-inflammatory and anti-inflammatory cytokines might be a key factor to differentiate photoaged skin from chronologically-aged skin.

Ubiquinol-10 Supplementation Activates Mitochondria Functions to Decelerate Senescence in Senescence-Accelerated Mice

The present study was conducted to define the relationship between the anti-aging effect of ubiquinol-10 supplementation and mitochondrial activation in senescence-accelerated mouse prone 1 (SAMP1) mice. Here, we report that dietary supplementation with ubiquinol-10 prevents age-related decreases in the expression of sirtuin gene family members, which results in the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a major factor that controls mitochondrial biogenesis and respiration, as well as superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2), which are major mitochondrial antioxidant enzymes. Ubiquinol-10 supplementation can also increase mitochondrial complex I activity and decrease levels of oxidative stress markers, including protein carbonyls, apurinic/apyrimidinic sites, malondialdehydes, and increase the reduced glutathione/oxidized glutathione ratio. Furthermore, ubiquinol-10 may activate Sirt1 and PGC-1α by increasing cyclic adenosine monophosphate (cAMP) levels that, in turn, activate cAMP response element-binding protein (CREB) and AMP-activated protein kinase (AMPK). These results show that ubiquinol-10 may enhance mitochondrial activity by increasing levels of SIRT1, PGC-1α, and SIRT3 that slow the rate of age-related hearing loss and protect against the progression of aging and symptoms of age-related diseases.

SMAP1/Sku as a Murine Model for Tubulointerstitial Nephritis: a Study Using Unilateral Ureteral Obstruction

The SAMP1/Sku mouse is a substrain of the SAMP1 (senescence-accelerated-mouse prone 1) which exhibits renal mononuclear cell infiltration from a younger age. We hypothesized that this renal characteristic is related to the incidence of tubulointerstitial nephritis (TIN). The purpose of the present study was to evaluate the applicability of the SAMP1/Sku mouse as a murine model for TIN. TIN was experimentally induced by unilateral ureteral obstruction (UUO). The SAMP1/Sku and control ICR of both sexes received either a sham or UUO operation and were sacrificed 7 days after the operation. The kidneys of the mice were observed histopathologically, immunohistochemically and semiquantitatively. UUO kidneys showed mononuclear cell infiltration, tubular atrophy and interstitial fibrosis. In males, semiquantitative scores of mononuclear cell infiltration, tubular atrophy, and F4/80, alpha-smooth muscle actin (alpha-SMA) and transforming growth factor (TGF)-beta1 reactions were significantly higher in SAMP1/Sku than in ICR. Likewise, in females, tubular atrophy and F4/80 reaction scores were significantly higher in SAMP1/Sku than in ICR. In conclusion, induction of TIN damage by UUO was more serious in SAMP1/Sku mice than in ICR. Therefore, we propose that SAMP1/Sku mice, especially male SAMP1/Sku, have congenital risk factors for the development of TIN.

The Effects of Aging and Treadmill Running on Soleus and Gastrocnemius Muscle Morphology in the Senescence-Accelerated Mouse (SAMP1)

We investigated the effects of aging on the soleus and gastrocnemius muscles in male SAMP1 (senescence-accelerated mouse prone 1). Body mass, muscle wet weight, fiber size, and the percent of type II fibers declined from 50 weeks of age. Voluntary motor behavior also significantly declined with age. Furthermore, we examined the effects of high (twice daily) and low (once daily) frequency treadmill running, for 6 weeks at 5 days per week, beginning when the mice were 50 weeks old. Muscle fiber size for the high frequency running significantly increased. Pathological fiber alterations in these mice were increased by running, especially by high frequency running. This suggests that age-related muscle morphological changes in SAMP1 occurs from 50 weeks of age, and that the decline in voluntary motor behavior is an important factor in aging muscle atrophy. In addition, high frequency running is more beneficial for aged muscle hypertrophy. This model is useful for studying the acceleration of the aging process in skeletal muscle of the SAM.

Life span and renal morphological characterization of the SAMP1//Ka mouse.

The senescence-accelerated-mouse prone 1 (SAMP1) is considered to be a model of accelerated senility and it also develops severe kidney damage. The SAMP1//Ka mouse is a specific pathogen free (SPF) subline of SAMP1. The present study examined the life span of the SAMP1//Ka mouse and morphologically investigated the kidneys of this animal at 3, 4, 5, 9, 12, 15, 18 and 24 months of age. Males survived for an average of 25 months and females for 28 months. The median lifespan was 18 months for males and 20 for females. Focal cell infiltration and thickening of the basement membrane in the glomerular capsules or tubules appeared from 4 months of age. At 12 months old, glomerular lesions with expansion of the mesangial matrix and thickening of the basement membrane as well as scar lesions in the outer cortex appeared, and amyloid was deposited in the interstitium or glomeruli from 18 months of age. Morphometrically, although the area of the kidney sections was increased at 24 months of age, the diameter of the renal corpuscles, the number of nuclei of the proximal convoluted tubules and the percentage of renal corpuscles with a cuboidal glomerular capsule did not change with age. The results of the present study indicate that the life span of the SAMP1//Ka is increased and that their age-related renal changes differ from those of the original SAMP1.