Short-term fasting of a single amino acid extends lifespan

作者：Tahlia L. Fulton, Mia R. Wansbrough, Christen K. Mirth, Matthew D. W. Piper

GeroScience：2024/02/02

Diet and health are strongly linked, though the strict changes in diet required to improve health outcomes are usually difficult to sustain. We sought to understand whether short-term bouts of amino acid–specific modifications to the diet of Drosophila melanogaster could mimic the lifespan and stress resistance benefits of dietary restriction, without the requirement for drastic reductions in food intake. We found that flies that were transiently fed diets lacking the essential amino acid isoleucine, but otherwise nutritionally complete, exhibited enhanced nicotine tolerance, indicating elevated detoxification capacity. The protection from isoleucine deprivation increased with the duration of exposure, up to a maximum at 7-day isoleucine deprivation for flies 2, 3, or 4 weeks of age, and a 5-day deprivation when flies were 5 weeks of age. Because of these beneficial effects on toxin resistance, we intermittently deprived flies of isoleucine during the first 6 weeks of adulthood and monitored the effect on lifespan. Lifespan was significantly extended when flies experienced short-term isoleucine deprivation at 3 and 5 weeks of age, regardless of whether they were also deprived at 1 week. These results indicate that short-term bouts of isoleucine deprivation can extend lifespan and highlight its cumulative and time-dependent benefits. Interestingly, we found that isoleucine-deprived flies lost their protection against nicotine within 3 days of returning to fully fed conditions. Therefore, the mechanisms underlying lifespan extension may involve transient damage clearance during the bouts of isoleucine deprivation rather than sustained enhanced detoxification capacity. These data highlight a new time-restricted, nutritionally precise method to extend life in Drosophila melanogaster and point to a more manageable dietary method to combat ageing.

飲食和健康有著密切的聯(lián)系，盡管改善健康結(jié)果所需的嚴(yán)格飲食變化通常很難維持。我們試圖了解是否對飲食進(jìn)行了短期的氨基酸特異性改變；黑腹果蠅；可以模仿飲食限制對壽命和抗壓能力的好處，而不需要大幅減少食物攝入。我們發(fā)現(xiàn)，短暫喂食缺乏必需氨基酸異亮氨酸的食物，但在其他方面營養(yǎng)完整的蒼蠅，表現(xiàn)出更強(qiáng)的尼古丁耐受性，表明解毒能力提高。對異亮氨酸剝奪的保護(hù)作用隨著暴露時間的延長而增加，2、3或4周齡的蒼蠅在7天的異亮氨酸剝奪時達(dá)到最大值，5周齡的果蠅在5天的剝奪時達(dá)到最高值。由于這些對毒素抵抗的有益影響，我們在成年后的前6周間歇性地剝奪蒼蠅的異亮氨酸，并監(jiān)測其對壽命的影響。當(dāng)蒼蠅在3周和5周大時經(jīng)歷短期異亮氨酸剝奪時，無論它們在1周時是否也被剝奪，它們的壽命都會顯著延長。這些結(jié)果表明，短期缺乏異亮氨酸可以延長壽命，并突出其累積和時間相關(guān)的益處。有趣的是，我們發(fā)現(xiàn)缺乏異亮氨酸的蒼蠅在恢復(fù)到完全進(jìn)食狀態(tài)的3天內(nèi)就失去了對尼古丁的保護(hù)。因此，延長壽命的潛在機(jī)制可能涉及在異亮氨酸缺乏期間的短暫損傷清除，而不是持續(xù)增強(qiáng)的解毒能力。這些數(shù)據(jù)強(qiáng)調(diào)了一種新的限時、營養(yǎng)精確的方法，可以延長患者的壽命；黑腹果蠅；并指出了一種更易于管理的對抗衰老的飲食方法。

不少動物研究告訴我們，適當(dāng)減少熱量攝入，或者是一些間歇性禁食策略有助于延長壽命、促進(jìn)健康衰老。但要真正做到這一點，卻是談何容易。因此，如果能理解不同營養(yǎng)元素影響健康、長壽的具體機(jī)制，將為我們帶來更可行的飲食建議。