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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 improves telomere maintenance.(A) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of enterocyte telomere fluorescence intensity per nucleus (right panels, n≥2230 nuclei, 5 animals) in intestinal crypts. Mean nuclear telomere fluorescence intensity is indicated by blue vertical lines. p<0.001, Mann-Whitney rank sum test. (B) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of hepatocyte telomere fluorescence intensity in centrilobular (CV, top, n≥560 nuclei) and periportal (PV, bottom, n≥650 nuclei) in liver areas. Mean fluorescence intensities are indicated for AL (blue) and DR (pink). P-values for AL vs DR were calculated by Mann-Whitney rank sum test. (C) Telomerase catalytic activity (% of TRAP activity in 3T3 cells) in whole liver (left, n=4) and intestinal mucosa (right, n=5) homogenates. Data are mean±S.E.M. n.s.: not significant (T-test).
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Figure 2: DR improves telomere maintenance.(A) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of enterocyte telomere fluorescence intensity per nucleus (right panels, n≥2230 nuclei, 5 animals) in intestinal crypts. Mean nuclear telomere fluorescence intensity is indicated by blue vertical lines. p<0.001, Mann-Whitney rank sum test. (B) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of hepatocyte telomere fluorescence intensity in centrilobular (CV, top, n≥560 nuclei) and periportal (PV, bottom, n≥650 nuclei) in liver areas. Mean fluorescence intensities are indicated for AL (blue) and DR (pink). P-values for AL vs DR were calculated by Mann-Whitney rank sum test. (C) Telomerase catalytic activity (% of TRAP activity in 3T3 cells) in whole liver (left, n=4) and intestinal mucosa (right, n=5) homogenates. Data are mean±S.E.M. n.s.: not significant (T-test).

Mentions: Despite the presence of active telomerase, telomeres shorten with age in various tissues of laboratory mice [28,53]. However, even in very old mice, telomeres are much longer than in humans and aging in mice did not measurably increase the degree of co-localisation of DNA damage foci with telomeres [28]. This suggests that telomere shortening may only be a minor contributor to cell senescence in aging wild-type mice. Here, we measured telomere length by quantitative FISH (Q-FISH) in intestinal enterocytes and liver hepatocytes (Figure 2A, B). Following 3 months of DR, the average telomere length per crypt enterocyte nucleus was significantly higher than in AL fed mice (Figure 2A). The effect of DR on hepatocyte telomere length was smaller than in the intestine (Figure 2B), possibly because of the lower rate of proliferation. However, the difference between DR and AL was still significant in the centrilobular areas. Telomerase activity as measured by TRAP in whole liver and intestinal mucosa homogenates was not significantly changed by DR (Figure 2C). If anything, it tended to decrease under DR, possibly due to the anti-proliferative effect of DR, suggesting that other factors than telomerase must be responsible for the improved telomere maintenance under DR. The most probable of these is reduction of oxidative damage to telomeres [54].


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 improves telomere maintenance.(A) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of enterocyte telomere fluorescence intensity per nucleus (right panels, n≥2230 nuclei, 5 animals) in intestinal crypts. Mean nuclear telomere fluorescence intensity is indicated by blue vertical lines. p<0.001, Mann-Whitney rank sum test. (B) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of hepatocyte telomere fluorescence intensity in centrilobular (CV, top, n≥560 nuclei) and periportal (PV, bottom, n≥650 nuclei) in liver areas. Mean fluorescence intensities are indicated for AL (blue) and DR (pink). P-values for AL vs DR were calculated by Mann-Whitney rank sum test. (C) Telomerase catalytic activity (% of TRAP activity in 3T3 cells) in whole liver (left, n=4) and intestinal mucosa (right, n=5) homogenates. Data are mean±S.E.M. n.s.: not significant (T-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: DR improves telomere maintenance.(A) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of enterocyte telomere fluorescence intensity per nucleus (right panels, n≥2230 nuclei, 5 animals) in intestinal crypts. Mean nuclear telomere fluorescence intensity is indicated by blue vertical lines. p<0.001, Mann-Whitney rank sum test. (B) Representative Q-FISH images (left panels, red: telomeres, blue: nuclei) and distribution of hepatocyte telomere fluorescence intensity in centrilobular (CV, top, n≥560 nuclei) and periportal (PV, bottom, n≥650 nuclei) in liver areas. Mean fluorescence intensities are indicated for AL (blue) and DR (pink). P-values for AL vs DR were calculated by Mann-Whitney rank sum test. (C) Telomerase catalytic activity (% of TRAP activity in 3T3 cells) in whole liver (left, n=4) and intestinal mucosa (right, n=5) homogenates. Data are mean±S.E.M. n.s.: not significant (T-test).
Mentions: Despite the presence of active telomerase, telomeres shorten with age in various tissues of laboratory mice [28,53]. However, even in very old mice, telomeres are much longer than in humans and aging in mice did not measurably increase the degree of co-localisation of DNA damage foci with telomeres [28]. This suggests that telomere shortening may only be a minor contributor to cell senescence in aging wild-type mice. Here, we measured telomere length by quantitative FISH (Q-FISH) in intestinal enterocytes and liver hepatocytes (Figure 2A, B). Following 3 months of DR, the average telomere length per crypt enterocyte nucleus was significantly higher than in AL fed mice (Figure 2A). The effect of DR on hepatocyte telomere length was smaller than in the intestine (Figure 2B), possibly because of the lower rate of proliferation. However, the difference between DR and AL was still significant in the centrilobular areas. Telomerase activity as measured by TRAP in whole liver and intestinal mucosa homogenates was not significantly changed by DR (Figure 2C). If anything, it tended to decrease under DR, possibly due to the anti-proliferative effect of DR, suggesting that other factors than telomerase must be responsible for the improved telomere maintenance under DR. The most probable of these is reduction of oxidative damage to telomeres [54].

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