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Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

Imai R, Asai K, Hanai J, Takenaka M - Aging (Albany NY) (2015)

Bottom Line: The GMF-TG mice exhibited appearance phenotypes associated with premature aging.The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies.The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks.

View Article: PubMed Central - PubMed

Affiliation: Clinical Nutrition and Internal Medicine, Kobe Women's University, Kobe 654-8585, Japan.

ABSTRACT
Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

No MeSH data available.


Related in: MedlinePlus

Photograph of WT and GMF-TG mice(A-B) These photographs show the representative appearance of WT (A) and GMF-TG (B) mice at 80 weeks, respectively. The GMF-TG mice showed alopecia and skin atrophy. These phenotypes were not detected in the aged-matched wild-type mice. (C-D) Indicators of aging phenotypes, such as spinal curvature, were detected in the GMF-TG (D) mice, but not in the WT (C) mice at 110 weeks.
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Figure 2: Photograph of WT and GMF-TG mice(A-B) These photographs show the representative appearance of WT (A) and GMF-TG (B) mice at 80 weeks, respectively. The GMF-TG mice showed alopecia and skin atrophy. These phenotypes were not detected in the aged-matched wild-type mice. (C-D) Indicators of aging phenotypes, such as spinal curvature, were detected in the GMF-TG (D) mice, but not in the WT (C) mice at 110 weeks.

Mentions: We bred GMF-TG mice with wild-type mice. During the breeding period, only the GMF-TG mice began to show signs of aging in appearance [21], including hair graying and lack of hair glossiness, at about the age of 30 weeks (hereafter, 30 weeks, etc.). It is generally recognized that oxidative stress is one of the major factors that promote the aging process in organisms [22, 23]. We hypothesized that GMF overexpression in non-brain tissue resulted in accelerated aging, probably through cellular vulnerability to oxidative stress [14]. Prematurely aged mice exhibit early aging-like appearance phenotypes, including increased hair loss, lordokyphosis of the spine, a shortened lifespan and growth retardation, compared to wild-type mice [24–28]. We monitored the aging-related phenotypes of the GMF-TG and wild-type mice during an experimental period of 155 weeks. The GMF-TG mice developed alopecia early, by about 75 weeks, while the wild-type mice started to show alopecia after about 100 weeks (Figure 2A-B and Supplemental Table 1). Some GMF-TG mice also exhibited skin atrophy and spinal curvature. These phenotypes were not detected in the wild-type mice (Figure 2 and Supplemental Table 1). We also found that some of the GMF-TG mice died within 60 weeks. The average lifespan of the GMF-TG mice was about 119 weeks, and that of the wild-type mice was about 126 weeks. Kaplan-Meier representations of the survival curves demonstrated that the GMF-TG mice died significantly earlier than the wild-type mice (Figure 3). There was no statistically significant difference in the body weight and size in mature-adult mice (at about 20 weeks) (data not shown).


Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

Imai R, Asai K, Hanai J, Takenaka M - Aging (Albany NY) (2015)

Photograph of WT and GMF-TG mice(A-B) These photographs show the representative appearance of WT (A) and GMF-TG (B) mice at 80 weeks, respectively. The GMF-TG mice showed alopecia and skin atrophy. These phenotypes were not detected in the aged-matched wild-type mice. (C-D) Indicators of aging phenotypes, such as spinal curvature, were detected in the GMF-TG (D) mice, but not in the WT (C) mice at 110 weeks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543038&req=5

Figure 2: Photograph of WT and GMF-TG mice(A-B) These photographs show the representative appearance of WT (A) and GMF-TG (B) mice at 80 weeks, respectively. The GMF-TG mice showed alopecia and skin atrophy. These phenotypes were not detected in the aged-matched wild-type mice. (C-D) Indicators of aging phenotypes, such as spinal curvature, were detected in the GMF-TG (D) mice, but not in the WT (C) mice at 110 weeks.
Mentions: We bred GMF-TG mice with wild-type mice. During the breeding period, only the GMF-TG mice began to show signs of aging in appearance [21], including hair graying and lack of hair glossiness, at about the age of 30 weeks (hereafter, 30 weeks, etc.). It is generally recognized that oxidative stress is one of the major factors that promote the aging process in organisms [22, 23]. We hypothesized that GMF overexpression in non-brain tissue resulted in accelerated aging, probably through cellular vulnerability to oxidative stress [14]. Prematurely aged mice exhibit early aging-like appearance phenotypes, including increased hair loss, lordokyphosis of the spine, a shortened lifespan and growth retardation, compared to wild-type mice [24–28]. We monitored the aging-related phenotypes of the GMF-TG and wild-type mice during an experimental period of 155 weeks. The GMF-TG mice developed alopecia early, by about 75 weeks, while the wild-type mice started to show alopecia after about 100 weeks (Figure 2A-B and Supplemental Table 1). Some GMF-TG mice also exhibited skin atrophy and spinal curvature. These phenotypes were not detected in the wild-type mice (Figure 2 and Supplemental Table 1). We also found that some of the GMF-TG mice died within 60 weeks. The average lifespan of the GMF-TG mice was about 119 weeks, and that of the wild-type mice was about 126 weeks. Kaplan-Meier representations of the survival curves demonstrated that the GMF-TG mice died significantly earlier than the wild-type mice (Figure 3). There was no statistically significant difference in the body weight and size in mature-adult mice (at about 20 weeks) (data not shown).

Bottom Line: The GMF-TG mice exhibited appearance phenotypes associated with premature aging.The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies.The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks.

View Article: PubMed Central - PubMed

Affiliation: Clinical Nutrition and Internal Medicine, Kobe Women's University, Kobe 654-8585, Japan.

ABSTRACT
Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

No MeSH data available.


Related in: MedlinePlus