再回过头来看Cell文章(Cabreiro F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 2013, 153: 228-239),它通过二甲双胍使甲硫氨酸合成酶及S-腺苷甲硫氨酸合成酶双缺陷型线虫形成甲硫氨酸限制,结果也能延缓衰老进程。类似结果见于芳香族分支氨基酸营养限制引起的中年小鼠骨骼肌线粒体增殖(D'Antona G. et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metabo 2010, 12: 362-372)。
最后,还剩下一个二甲双胍抗炎的话题。Aging Cell的文章(Moiseeva O. et al. Metformin inhibits the scenescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 2013, 12: 489-498)强调二甲双胍通过抑制炎症信号转导通路中IKK/NF-κB的激活阻止促炎细胞因子合成。我们知道,促炎细胞因子可诱导iNOS合成大量病理性一氧化氮,而这个过程又通过精氨酸竞争抑制eNOS合成少量生理性一氧化氮。由于二甲双胍的抗炎作用,避免了一氧化氮爆发引起的细胞损伤、衰老和癌变,其最终结果与热量限制激活eNOS效果一样。另外,具有抗炎作用的免疫抑制剂雷帕霉素就表现延寿作用,进一步说明缓解炎症也是延长寿命的重要举措之一。
Anti-diabetic drug slows aging and lengthens lifespan, animal study suggests
Date:
June 2, 2014
Source:
KU Leuven
Summary:
Researchers have provided new evidence that metformin, the world’s most widely used anti-diabetic drug, slows aging and increases lifespan. Scientists teased out the mechanism behind metformin's age-slowing effects: the drug causes an increase in the number of toxic oxygen molecules released in the cell and this, surprisingly, increases cell robustness and longevity in the long term.
Roundworms treated with metformin show very limited size loss and no wrinkling.
A study by Belgian doctoral researcher Wouter De Haes (KU Leuven) and colleagues provides new evidence that metformin, the world's most widely used anti-diabetic drug, slows aging and increases lifespan.
In experiments reported in the journal Proceedings of the National Academy of Sciences, the researchers tease out the mechanism behind metformin's age-slowing effects: the drug causes an increase in the number of toxic oxygen molecules released in the cell and this, surprisingly, increases cell robustness and longevity in the long term.
Mitochondria -- the energy factories in cells -- generate tiny electric currents to provide the body's cells with energy. Highly reactive oxygen molecules are produced as a by-product of this process.
While these molecules are harmful because they can damage proteins and DNA and disrupt normal cell functioning, a small dose can actually do the cell good, say the researchers: "As long as the amount of harmful oxygen molecules released in the cell remains small, it has a positive long-term effect on the cell. Cells use the reactive oxygen particles to their advantage before they can do any damage," explains Wouter De Haes. "Metformin causes a slight increase in the number of harmful oxygen molecules. We found that this makes cells stronger and extends their healthy lifespan."
It was long thought that harmful reactive oxygen molecules were the very cause of aging. The food and cosmetics industries are quick to emphasize the 'anti-aging' qualities of products containing antioxidants, such as skin creams, fruit and vegetable juices, red wine and dark chocolate.
But while antioxidants do in fact neutralize harmful reactive oxygen molecules in the cell, they actually negate metformin's anti-aging effects because the drug relies entirely on these molecules to work.
The researchers studied metformin's mechanism in the tiny roundworm Caenorhabditis elegans, an ideal species for studying aging because it has a lifespan of only three weeks. "As they age, the worms get smaller, wrinkle up and become less mobile. But worms treated with metformin show very limited size loss and no wrinkling. They not only age slower, but they also stay healthier longer," says Wouter De Haes. "While we should be careful not to over-extrapolate our findings to humans, the study is promising as a foundation for future research."
Other studies in humans have shown that metformin suppresses some cancers and heart disease. Metformin could even be an effective drug for counteracting the general effects of aging, say the researchers.
The study was carried out by Wouter De Haes under the supervision of Liesbet Temmerman and Professor Liliane Schoofs (KU Leuven) and in close collaboration with Professor Bart Braeckman (Ghent University).
Story Source:
The above story is based on materials provided by KU Leuven. Note: Materials may be edited for content and length.
Journal Reference:
Wouter De Haes, Lotte Frooninckx, Roel Van Assche, Arne Smolders, Geert Depuydt, Johan Billen, Bart P. Braeckman, Liliane Schoofs, and Liesbet Temmerman. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. PNAS, 2014 DOI: 10.1073/pnas.1321776111