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Overexpression of Atg5 in mice activates autophagy and extends lifespan.

Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK - Nat Commun (2013)

Bottom Line: Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown.We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function.Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity.

View Article: PubMed Central - PubMed

Affiliation: Global Research Laboratory, School of Biological Sciences/Bio-MAX Institute, Seoul National University, Seoul 151-747, Korea.

ABSTRACT
Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Furthermore, mouse embryonic fibroblasts cultured from Atg5 transgenic mice are more tolerant to oxidative damage and cell death induced by oxidative stress, and this tolerance was reversible by treatment with an autophagy inhibitor. Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity.

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Related in: MedlinePlus

Metabolic characteristics of lean Atg5 Tg mice.(a) Representative physical pictures of 18-month-old WT and Atg5 Tg mice fed with a regular diet. (b) Body weight chart of ageing-induced obesity in WT and Atg5 Tg mice. The mice were fed with a regular diet for 24 months (n=180-–250) and their body weights were monitored monthly. The bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test. (c) Average daily oral food intake normalized to body weight, measured on regular diet. The food intake of mice (n=18–24) was measured for 2 weeks at 3-, 6-, 12- and 18-month-old age. (d) Quantification of gonadal fat pads from 18-month-old mice (n=11). ***P<0.0001 versus control; Student’s t-test. (e,f) Quantification of visceral (e) and subcutaneous (f) fat pads of 18-month-old mice (n=6). ***P<0.0001 versus control; Student’s t-test. (g) Enhanced glucose tolerance of Atg5 Tg mice. WT and Atg5 Tg mice were starved overnight and then given with an i.p injection of glucose (1 mg g−1 body weight). The results are the mean±s.d. of 12-week-old WT and Atg5 Tg mice (n=12). *P<0.01, **P<0.001, ***P<0.0001 versus control; Student’s t-test. (h) Enhanced insulin sensitivity of Atg5 Tg mice. WT and Atg5 Tg mice were starved for 6 h and then i.p injected with 0.75 IU soluble insulin. *P<0.01, **P<0.001 versus control; Student’s t-test. (i) Plasma levels of triglycerol (TG) in WT and Atg5 Tg mice. The mice were fasted for 3 h before measurement. Young mice (4-week old, n=8); old mice (18-month old, n=8). ***P<0.0001 versus control; Student’s t-test. (j) Plasma leptin levels in WT and Atg5 Tg mice (n=8–12). ***P<0.0001 versus control; Student’s t-test. (k) GSH/GSSG ratio in the liver (n=4 males, three times trial). **P<0.001, ***P<0.0001 versus control; Student’s t-test. (l) Respiration rates of mitochondria in WT and Atg5 Tg MEFs (n=2). (m) Wire-hang endurance test of Atg5 Tg and WT mice (n=10). All the bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test.
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f3: Metabolic characteristics of lean Atg5 Tg mice.(a) Representative physical pictures of 18-month-old WT and Atg5 Tg mice fed with a regular diet. (b) Body weight chart of ageing-induced obesity in WT and Atg5 Tg mice. The mice were fed with a regular diet for 24 months (n=180-–250) and their body weights were monitored monthly. The bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test. (c) Average daily oral food intake normalized to body weight, measured on regular diet. The food intake of mice (n=18–24) was measured for 2 weeks at 3-, 6-, 12- and 18-month-old age. (d) Quantification of gonadal fat pads from 18-month-old mice (n=11). ***P<0.0001 versus control; Student’s t-test. (e,f) Quantification of visceral (e) and subcutaneous (f) fat pads of 18-month-old mice (n=6). ***P<0.0001 versus control; Student’s t-test. (g) Enhanced glucose tolerance of Atg5 Tg mice. WT and Atg5 Tg mice were starved overnight and then given with an i.p injection of glucose (1 mg g−1 body weight). The results are the mean±s.d. of 12-week-old WT and Atg5 Tg mice (n=12). *P<0.01, **P<0.001, ***P<0.0001 versus control; Student’s t-test. (h) Enhanced insulin sensitivity of Atg5 Tg mice. WT and Atg5 Tg mice were starved for 6 h and then i.p injected with 0.75 IU soluble insulin. *P<0.01, **P<0.001 versus control; Student’s t-test. (i) Plasma levels of triglycerol (TG) in WT and Atg5 Tg mice. The mice were fasted for 3 h before measurement. Young mice (4-week old, n=8); old mice (18-month old, n=8). ***P<0.0001 versus control; Student’s t-test. (j) Plasma leptin levels in WT and Atg5 Tg mice (n=8–12). ***P<0.0001 versus control; Student’s t-test. (k) GSH/GSSG ratio in the liver (n=4 males, three times trial). **P<0.001, ***P<0.0001 versus control; Student’s t-test. (l) Respiration rates of mitochondria in WT and Atg5 Tg MEFs (n=2). (m) Wire-hang endurance test of Atg5 Tg and WT mice (n=10). All the bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test.

Mentions: In addition to enhanced longevity, the body weight of aged Atg5 Tg mice was apparently reduced. Compared with WT littermates, Atg5 Tg mice showed leanness on a regular diet (Fig. 3a). When we monitored body weight over 24 months on a regular diet, both Atg5 Tg mice and WT littermates gained weight at a similar rate at a young age. However, after 12 months, Atg5 Tg mice weighed on average 12% less than WT mice (Fig. 3b). We did not detect a significant difference in food intake between WT and Atg5 Tg mice (Fig. 3c). Along with their reduction in total body weight, the gonadal fat pads of Atg5 Tg mice weighed much less than those of WT mice and this difference was more prominent in aged mice (18 months) (Fig. 3d). Compared with WT mice, the weight of the visceral and subcutaneous fat pads was also reduced in Atg5 Tg mice (Fig. 3e,f). Thus, transgenic expression of Atg5 in mice results in leaner mice and confers resistance to age-associated obesity.


Overexpression of Atg5 in mice activates autophagy and extends lifespan.

Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK - Nat Commun (2013)

Metabolic characteristics of lean Atg5 Tg mice.(a) Representative physical pictures of 18-month-old WT and Atg5 Tg mice fed with a regular diet. (b) Body weight chart of ageing-induced obesity in WT and Atg5 Tg mice. The mice were fed with a regular diet for 24 months (n=180-–250) and their body weights were monitored monthly. The bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test. (c) Average daily oral food intake normalized to body weight, measured on regular diet. The food intake of mice (n=18–24) was measured for 2 weeks at 3-, 6-, 12- and 18-month-old age. (d) Quantification of gonadal fat pads from 18-month-old mice (n=11). ***P<0.0001 versus control; Student’s t-test. (e,f) Quantification of visceral (e) and subcutaneous (f) fat pads of 18-month-old mice (n=6). ***P<0.0001 versus control; Student’s t-test. (g) Enhanced glucose tolerance of Atg5 Tg mice. WT and Atg5 Tg mice were starved overnight and then given with an i.p injection of glucose (1 mg g−1 body weight). The results are the mean±s.d. of 12-week-old WT and Atg5 Tg mice (n=12). *P<0.01, **P<0.001, ***P<0.0001 versus control; Student’s t-test. (h) Enhanced insulin sensitivity of Atg5 Tg mice. WT and Atg5 Tg mice were starved for 6 h and then i.p injected with 0.75 IU soluble insulin. *P<0.01, **P<0.001 versus control; Student’s t-test. (i) Plasma levels of triglycerol (TG) in WT and Atg5 Tg mice. The mice were fasted for 3 h before measurement. Young mice (4-week old, n=8); old mice (18-month old, n=8). ***P<0.0001 versus control; Student’s t-test. (j) Plasma leptin levels in WT and Atg5 Tg mice (n=8–12). ***P<0.0001 versus control; Student’s t-test. (k) GSH/GSSG ratio in the liver (n=4 males, three times trial). **P<0.001, ***P<0.0001 versus control; Student’s t-test. (l) Respiration rates of mitochondria in WT and Atg5 Tg MEFs (n=2). (m) Wire-hang endurance test of Atg5 Tg and WT mice (n=10). All the bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test.
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f3: Metabolic characteristics of lean Atg5 Tg mice.(a) Representative physical pictures of 18-month-old WT and Atg5 Tg mice fed with a regular diet. (b) Body weight chart of ageing-induced obesity in WT and Atg5 Tg mice. The mice were fed with a regular diet for 24 months (n=180-–250) and their body weights were monitored monthly. The bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test. (c) Average daily oral food intake normalized to body weight, measured on regular diet. The food intake of mice (n=18–24) was measured for 2 weeks at 3-, 6-, 12- and 18-month-old age. (d) Quantification of gonadal fat pads from 18-month-old mice (n=11). ***P<0.0001 versus control; Student’s t-test. (e,f) Quantification of visceral (e) and subcutaneous (f) fat pads of 18-month-old mice (n=6). ***P<0.0001 versus control; Student’s t-test. (g) Enhanced glucose tolerance of Atg5 Tg mice. WT and Atg5 Tg mice were starved overnight and then given with an i.p injection of glucose (1 mg g−1 body weight). The results are the mean±s.d. of 12-week-old WT and Atg5 Tg mice (n=12). *P<0.01, **P<0.001, ***P<0.0001 versus control; Student’s t-test. (h) Enhanced insulin sensitivity of Atg5 Tg mice. WT and Atg5 Tg mice were starved for 6 h and then i.p injected with 0.75 IU soluble insulin. *P<0.01, **P<0.001 versus control; Student’s t-test. (i) Plasma levels of triglycerol (TG) in WT and Atg5 Tg mice. The mice were fasted for 3 h before measurement. Young mice (4-week old, n=8); old mice (18-month old, n=8). ***P<0.0001 versus control; Student’s t-test. (j) Plasma leptin levels in WT and Atg5 Tg mice (n=8–12). ***P<0.0001 versus control; Student’s t-test. (k) GSH/GSSG ratio in the liver (n=4 males, three times trial). **P<0.001, ***P<0.0001 versus control; Student’s t-test. (l) Respiration rates of mitochondria in WT and Atg5 Tg MEFs (n=2). (m) Wire-hang endurance test of Atg5 Tg and WT mice (n=10). All the bars represent the mean±s.d. ***P<0.0001 versus control; Student’s t-test.
Mentions: In addition to enhanced longevity, the body weight of aged Atg5 Tg mice was apparently reduced. Compared with WT littermates, Atg5 Tg mice showed leanness on a regular diet (Fig. 3a). When we monitored body weight over 24 months on a regular diet, both Atg5 Tg mice and WT littermates gained weight at a similar rate at a young age. However, after 12 months, Atg5 Tg mice weighed on average 12% less than WT mice (Fig. 3b). We did not detect a significant difference in food intake between WT and Atg5 Tg mice (Fig. 3c). Along with their reduction in total body weight, the gonadal fat pads of Atg5 Tg mice weighed much less than those of WT mice and this difference was more prominent in aged mice (18 months) (Fig. 3d). Compared with WT mice, the weight of the visceral and subcutaneous fat pads was also reduced in Atg5 Tg mice (Fig. 3e,f). Thus, transgenic expression of Atg5 in mice results in leaner mice and confers resistance to age-associated obesity.

Bottom Line: Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown.We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function.Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity.

View Article: PubMed Central - PubMed

Affiliation: Global Research Laboratory, School of Biological Sciences/Bio-MAX Institute, Seoul National University, Seoul 151-747, Korea.

ABSTRACT
Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Furthermore, mouse embryonic fibroblasts cultured from Atg5 transgenic mice are more tolerant to oxidative damage and cell death induced by oxidative stress, and this tolerance was reversible by treatment with an autophagy inhibitor. Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity.

Show MeSH
Related in: MedlinePlus