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Adult-onset, short-term dietary restriction reduces cell senescence in mice.

Wang C, Maddick M, Miwa S, Jurk D, Czapiewski R, Saretzki G, Langie SA, Godschalk RW, Cameron K, von Zglinicki T - Aging (Albany NY) (2010)

Bottom Line: This reduction was associated with improved telomere maintenance without increased telomerase activity.We also found a decrease in cumulative oxidative stress markers in the same compartments despite absence of significant changes in steady-state oxidative stress markers at the whole tissue level.The data suggest the possibility that reduction of cell senescence may be a primary consequence of DR which in turn may explain known effects of DR such as improved mitochondrial function and reduced production of reactive oxygen species.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK.

ABSTRACT
Dietary restriction (DR) extends the lifespan of a wide variety of species and reduces the incidence of major age-related diseases. Cell senescence has been proposed as one causal mechanism for tissue and organism ageing. We show for the first time that adult-onset, short-term DR reduced frequencies of senescent cells in the small intestinal epithelium and liver of mice, which are tissues known to accumulate increased numbers of senescent cells with advancing age. This reduction was associated with improved telomere maintenance without increased telomerase activity. We also found a decrease in cumulative oxidative stress markers in the same compartments despite absence of significant changes in steady-state oxidative stress markers at the whole tissue level. The data suggest the possibility that reduction of cell senescence may be a primary consequence of DR which in turn may explain known effects of DR such as improved mitochondrial function and reduced production of reactive oxygen species.

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DR decreased lipid peroxidation in liver.(A) Representative 4-HNE immunohistochemistry in small intestine from AL (left) and DR(right) mice. Brown: 4-HNE staining; blue: nuclei. (B) Representative 4-HNE images from centrilobular areas in liver. Brown: 4-HNE, Blue: nuclei. Arrows indicate examples of positive cells. (C) Frequencies of 4-HNE-positive hepatocytes in periportal and centrilobular areas of liver. Data are mean±S.E.M. * p<0.05, n=5 animals/group. (D) Co-localisation of γ-H2A.X (green) and 4-HNE (red) in AL liver. Representative image, double immunofluorescence, cryosection. Cells with nuclei (DAPI, blue) positive for γ-H2A.X are marked by arrows. Cells were scored as either single positive (H2AX+ HNE - or H2A.X- HNE +), double positive (H2A.X+ HNE+) or double negative (H2A.X- HNE -). Data are from four animals from the AL group.
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Figure 3: DR decreased lipid peroxidation in liver.(A) Representative 4-HNE immunohistochemistry in small intestine from AL (left) and DR(right) mice. Brown: 4-HNE staining; blue: nuclei. (B) Representative 4-HNE images from centrilobular areas in liver. Brown: 4-HNE, Blue: nuclei. Arrows indicate examples of positive cells. (C) Frequencies of 4-HNE-positive hepatocytes in periportal and centrilobular areas of liver. Data are mean±S.E.M. * p<0.05, n=5 animals/group. (D) Co-localisation of γ-H2A.X (green) and 4-HNE (red) in AL liver. Representative image, double immunofluorescence, cryosection. Cells with nuclei (DAPI, blue) positive for γ-H2A.X are marked by arrows. Cells were scored as either single positive (H2AX+ HNE - or H2A.X- HNE +), double positive (H2A.X+ HNE+) or double negative (H2A.X- HNE -). Data are from four animals from the AL group.

Mentions: 4-HNE is a major end product of lipid peroxidation and has been shown to accumulate in tissues with age [59]. We found few 4-HNE positive cells in intestinal crypts, and almost all were located in the lamina propria (Figure 3A). Confirming earlier results [28], HNE-positive hepatocytes were more frequent in centrilobular than in periportal areas. Importantly, frequencies of HNE-positive hepatocytes decreased under DR in both areas (Figure 3B, C p<0.05). To directly see whether there was an association between cell senescence and oxidative stress in liver hepatocytes, we performed a double staining for γ-H2A.X and 4-HNE (Figure 3D). Quantitative evaluation showed that the majority of senescent hepatocytes (as measured by γ-H2A.X) were also positive for 4-HNE and, vice versa, about three quarters of 4-HNE-positive hepatocytes were probably senescent (Figure 3D), thus confirming a cell-specific association between senescence and a marker of oxidative damage.


Adult-onset, short-term dietary restriction reduces cell senescence in mice.

Wang C, Maddick M, Miwa S, Jurk D, Czapiewski R, Saretzki G, Langie SA, Godschalk RW, Cameron K, von Zglinicki T - Aging (Albany NY) (2010)

DR decreased lipid peroxidation in liver.(A) Representative 4-HNE immunohistochemistry in small intestine from AL (left) and DR(right) mice. Brown: 4-HNE staining; blue: nuclei. (B) Representative 4-HNE images from centrilobular areas in liver. Brown: 4-HNE, Blue: nuclei. Arrows indicate examples of positive cells. (C) Frequencies of 4-HNE-positive hepatocytes in periportal and centrilobular areas of liver. Data are mean±S.E.M. * p<0.05, n=5 animals/group. (D) Co-localisation of γ-H2A.X (green) and 4-HNE (red) in AL liver. Representative image, double immunofluorescence, cryosection. Cells with nuclei (DAPI, blue) positive for γ-H2A.X are marked by arrows. Cells were scored as either single positive (H2AX+ HNE - or H2A.X- HNE +), double positive (H2A.X+ HNE+) or double negative (H2A.X- HNE -). Data are from four animals from the AL group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984605&req=5

Figure 3: DR decreased lipid peroxidation in liver.(A) Representative 4-HNE immunohistochemistry in small intestine from AL (left) and DR(right) mice. Brown: 4-HNE staining; blue: nuclei. (B) Representative 4-HNE images from centrilobular areas in liver. Brown: 4-HNE, Blue: nuclei. Arrows indicate examples of positive cells. (C) Frequencies of 4-HNE-positive hepatocytes in periportal and centrilobular areas of liver. Data are mean±S.E.M. * p<0.05, n=5 animals/group. (D) Co-localisation of γ-H2A.X (green) and 4-HNE (red) in AL liver. Representative image, double immunofluorescence, cryosection. Cells with nuclei (DAPI, blue) positive for γ-H2A.X are marked by arrows. Cells were scored as either single positive (H2AX+ HNE - or H2A.X- HNE +), double positive (H2A.X+ HNE+) or double negative (H2A.X- HNE -). Data are from four animals from the AL group.
Mentions: 4-HNE is a major end product of lipid peroxidation and has been shown to accumulate in tissues with age [59]. We found few 4-HNE positive cells in intestinal crypts, and almost all were located in the lamina propria (Figure 3A). Confirming earlier results [28], HNE-positive hepatocytes were more frequent in centrilobular than in periportal areas. Importantly, frequencies of HNE-positive hepatocytes decreased under DR in both areas (Figure 3B, C p<0.05). To directly see whether there was an association between cell senescence and oxidative stress in liver hepatocytes, we performed a double staining for γ-H2A.X and 4-HNE (Figure 3D). Quantitative evaluation showed that the majority of senescent hepatocytes (as measured by γ-H2A.X) were also positive for 4-HNE and, vice versa, about three quarters of 4-HNE-positive hepatocytes were probably senescent (Figure 3D), thus confirming a cell-specific association between senescence and a marker of oxidative damage.

Bottom Line: This reduction was associated with improved telomere maintenance without increased telomerase activity.We also found a decrease in cumulative oxidative stress markers in the same compartments despite absence of significant changes in steady-state oxidative stress markers at the whole tissue level.The data suggest the possibility that reduction of cell senescence may be a primary consequence of DR which in turn may explain known effects of DR such as improved mitochondrial function and reduced production of reactive oxygen species.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK.

ABSTRACT
Dietary restriction (DR) extends the lifespan of a wide variety of species and reduces the incidence of major age-related diseases. Cell senescence has been proposed as one causal mechanism for tissue and organism ageing. We show for the first time that adult-onset, short-term DR reduced frequencies of senescent cells in the small intestinal epithelium and liver of mice, which are tissues known to accumulate increased numbers of senescent cells with advancing age. This reduction was associated with improved telomere maintenance without increased telomerase activity. We also found a decrease in cumulative oxidative stress markers in the same compartments despite absence of significant changes in steady-state oxidative stress markers at the whole tissue level. The data suggest the possibility that reduction of cell senescence may be a primary consequence of DR which in turn may explain known effects of DR such as improved mitochondrial function and reduced production of reactive oxygen species.

Show MeSH
Related in: MedlinePlus