Anti-aging：抗老化不是夢？
我半年前曾經有一篇文章提到相關議題，規律飲食、運動、遠離菸酒不良習慣等金科玉律固然重要，但有夢最美，既然科技如此發達，為什麼人類不能發明萬靈丹，光吃藥就能延年益壽，防止歲月在我們身上留下的痕跡？
總部位於麻州劍橋，共同創辦人為哈佛教授的Sirtris藥廠似乎在這場抗老化戰爭中取得領先，他們與Harvard、UC San Diego合作研發出一種新藥，在老鼠實驗中對於與老化高度相關的第二型糖尿病有很不錯的療效，這個成果發表在最新一期的Nature雜誌。
科學家很早就發現，卡路里的攝取和壽命有顯著相關性：基因相同的老鼠，減少每日熱量攝取，將延長其壽命。熱量攝取愈少，壽命延長更明顯。科學家也試著找出其原因，後來發現，在限制卡路里攝取的狀態下，體內一種酵素SIRT1的活性（與其相關的sirt1基因)會提高，這個SIRT1會藉由增進胰島素在周邊受器的敏感度(insulin sensitivity)來調控血糖的平衡，SIRT1也會抑制脂肪的儲存，促進脂肪分解；此外，SIRT1與清除體內不好的膽固醇也有關係，可以說是人類對付老化導致的許多問題的好朋友。
酵母菌等較低等的生物也有個類似的基因sir2（產生SIR2酵素)，在周遭環境比較不好，養分比較匱乏的時候這個gene也會被啟動，具有延長其壽命的功能。
紅酒裡頭有一種成分Resveratrol，會增強SIRT1(與SIR2）的活性，同時有抗氧化、抗發炎的特性，因此被認為對人體有益。在酵母菌的實驗上resveratrol的功效無庸置疑。在老鼠上則必須用到很高劑量，如果在人身上，要從紅酒攝取足夠量的resveratrol以期得到抗老功效，需要太龐大而不切實際的量（1000瓶紅酒）。針對這個問題，Sirtris合成了一種物質，但其強度是resveratrol 1000倍，更強效地增加SIRT1的活性。而在老鼠的實驗對付第二型糖尿病相當成功，發表在Nature。
隨著人口老化、西化飲食、工作壓力，代謝性徵候群(metabolic syndrome，包括高血壓、糖尿病、肥胖、高血脂等，本來認為各自獨立，但愈來愈多的證據顯示背後似乎有共同的原因)的發生率節節高昇，造成中老年生活品質下降，健康花費負擔增加，這個promising的結果似乎相當值得期待。
呼應我的理念：「20年後的醫學，和現在，會很不一樣！」=======
Sirtris在NASDAQ的股價單日大飆7%，貼上一則Yahoo Finance新聞：
Sirtris and Harvard Unveil Promising, Novel SIRT1 Activators for Treating Diseases of Aging; Therapeutic Type 2 Diabetes Data Published in the Journal Nature
Wednesday November 28, 1:00 pm ET
In November 2006, Sirtris scientists and Sirtris co-founder, Prof. David Sinclair from Harvard Medical School, published consecutive papers in the journals Cell and Nature showing that resveratrol, a SIRT1 activator found in red wine, could reduce the impact of a high fat diet, increase stamina two fold and significantly extend lifespan of mice. Unfortunately, it was estimated that a person would need to drink 1000 bottles of red wine to obtain an equivalent dose of resveratrol. Now, scientists at Sirtris have developed SIRT1 activating molecules that are chemically distinct from resveratrol and are 1000 times more potent.
"The new drug candidates represent a significant milestone because they are the first molecules that have been designed to act on genes that control the aging process. For this reason, we feel they have considerable potential to treat diseases of aging such as Type 2 Diabetes," said Christoph Westphal, M.D., Ph.D., Chief Executive Officer and Vice Chair of Sirtris Pharmaceuticals. "The breakthrough in potency we have achieved with the novel chemical entities (NCEs) means that we can obtain the health benefits of resveratrol in a more specific manner."
The Nature paper from Sirtris shows that in diet-induced obese and genetically obese mice, Sirtris’ small molecule NCEs improve insulin sensitivity, lower plasma glucose levels and increase the function of mitochondria (the powerhouses of all cells). In another well-established preclinical model of Type 2 Diabetes and insulin resistance (Zucker fa/fa rats), these SIRT1 activators improved whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. These rodent models of diabetes are considered highly predictive of efficacy in humans.
The World Health Organization (WHO) indicates that Type 2 Diabetes (formerly called adult-onset diabetes) results from the body’s ineffective use of insulin. Type 2 Diabetes accounts for 90% of diabetes around the world, and is largely the result of excess body weight and physical inactivity. WHO estimates that more than 180 million people worldwide have diabetes and this number is likely to more than double by 2030. Furthermore, WHO projects that deaths due to diabetes will increase by more than 50% in the next 10 years. Activating SIRT 1 appears to mimic the beneficial effects of calorie restriction on mitochondrial and metabolic function in mammals in vivo and holds promise for treating diseases of aging, such as Type 2 Diabetes.
"We are very excited about these findings, which expand on the breakthrough data published in 2006 in the journals Nature and Cell, which demonstrated that SIRT1 activators mimic calorie restriction and extend lifespan. For the first time, the article published today shows that the novel drug candidates we have identified are the most potent SIRT1 activators ever to be published -- 1,000 times more potent than resveratrol -- and can potentially unlock a whole new approach to treating Type 2 Diabetes," stated Jill C. Milne, Ph.D., lead author of the Nature study and Senior Director of Biology at Sirtris.
Westphal added, “These NCEs represent the first molecules to be designed to activate SIRT1. Now we have an even more potent and specific way of eliciting the beneficial effects observed in earlier research with resveratrol. The NCEs characterized in this study are significantly more potent than and structurally unrelated to resveratrol. These findings highlight the tremendous potential of our NCE program to treat diseases of aging, and we look forward to advancing one of these promising new compounds into human clinical studies in the first half of 2008.”
Sirtuins are a recently-discovered family of enzymes that promote the body's natural defense against disease. There are seven human sirtuins (SIRT1-7). Sirtuins are attractive drug targets because some have a specialized function in mitochondrial activity which may be therapeutically beneficial for metabolic and other diseases of aging. Sirtuin therapeutics offer the potential for a novel class of drugs that can treat diseases of aging in a new way.
Online copies of the article “Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes” by Jill C. Milne, et al., Nature; November 29, 2007 can be obtained at: http://www.nature.com and a PDF of the paper can be obtained on www.sirtrispharma.com.
