As one of the classic targets in the scientific research of aging, mTOR is undoubtedly the focus of the spotlight, and rapamycin, which has been confirmed by a large number of experiments and can effectively regulate the mTOR signal, is naturally also crowned with luxurious titles such as "life extension drug" and "life-sustaining drug".
However, for a long time, with the purpose of "safe and effective intervention in aging", the academic community has been trying to explore a better way to use rapamycin. Recently, a recent study in the pre-print phase seems to provide us with a whole new way of thinking.
On the 21st of this month, professor Linda Partridge, the director of the Max Planck Institute of Aging in Germany and a top scientist in the field of aging, made a breakthrough discovery that only the brief administration of rapamycin in the early life of the model organism Drosophila and mice can effectively increase autophagy and harvest the same life-prolonging effect as long-term use of drugs [1].
For the new report of rapamycin, Time Pai is also extremely honored to invite Dr. Lu Jiongming, one of the authors, to comment, and the sharing content is detailed at the end of the article.
Note: This groundbreaking finding is currently being made public in preprint
rapamycin:
A mysterious visitor to Easter Island
In the vast south Pacific ocean, there is such a mysterious island: the island is lined with many huge stone statues, scattered with a large number of wooden planks carved with strange patterns, but where these objects came from and what they represent is still an unsolved mystery.
Attracted by this seductive unknown for a long time, many explorers have traveled to Easter Island, including some scholars. Perhaps it may have been some kind of mysterious force that created the island's unique environment, and from the soil samples brought back from Easter Island, scientists isolated an antifungal compound and gave it a fairly appropriate name "Rapamycin" after the island's alias "Repa Island".
In subsequent studies, rapamycin was accidentally found to have immunosuppressive function, and in 1999, it was officially approved for marketing by the FDA (United States Drug Administration) as an anti-rejection drug after organ transplantation. In 2009, rapamycin was acquired by pharmaceutical giant Pfizer under the trade name sirolimus.
It is such an anti-rejection drug, with the emergence of more mechanism-level scientific research, scholars have found that rapamycin can significantly prolong the lifespan of a series of model organisms such as fruit flies, nematodes, mice and so on by regulating the metabolism of substances in the organism and the important pathway related to cell growth - mTOR[2], and even in the old age of the organism has been "powerless to return to heaven", the effect is still quite good [3-6].
Note: Rapamycin feeding from mice about 20 months later can also significantly extend the mid-term lifespan. Image source[6]
However, no matter how loud the experimental data is, the background color of rapamycin immunosuppressants has never changed. Long-term or high-dose use of rapamycin, thrombocytopenia, and decreased wound healing capacity, insulin sensitivity, and glucose tolerance are common and unattainable side effects [7].
With such an "anti-aging elixir" in hand, we naturally want to find ways to minimize its side effects. The researchers first targeted the drug dose, and in two currently completed human clinical results related to aging, the safety of low-dose rapamycin use has been confirmed [8, 9]. The next step, exploring the timing of administration in the method of drug use, may be another important breakthrough.
It is better to use it more than to use it skillfully!
Short-lived use early in life,
The life-prolonging effect benefits for life
In the German Max Planck Institute for Aging, one of the strongest institutes in continental Europe, Professor Linda Partridge and her team also paid attention to the problems in the actual use of rapamycin, and tried to explore intermittent drug administration in order to come up with a safer and more effective "cost-effective" rapamycin application strategy.
After considering multiple factors, the researchers tried to use rapamycin on fruit flies as soon as they become adults. They were pleasantly surprised to find that using rapamycin (200 μM) in just 15 days could achieve a life extension effect that was almost completely different from long-term medication.
Moreover, follow-up trials have also shown that the short use of rapamycin in the early stage of life can reduce intestinal cell damage, slow down the renewal cycle of epithelial cells, prevent aging-related intestinal stem cell depletion, dysplasia and loss of barrier function, produce lasting protection for the intestine, and the effect is not lost for long-term administration, and the body seems to form a "memory" of rapamycin.
Note: Brief rapamycin therapy in early adulthood in Drosophila prolongs life and maintains intestinal function without difference from long-term treatment
And this ability to form a "long-term memory" of rapamycin is not unique to the Fruit Flies, and when the subjects are replaced by mammalian mice, the myth continues. From the 3-month-old mice (at this time, the mice were just adults) and treated with 3 months of brief rapamycin (14 ppm), compared with the long-term treatment group, no difference in the improvement effect between the two groups was also found: the changes in intestinal permeability associated with aging were reversed, and the regenerative capacity of intestinal epithelial cells was maintained.
Note: Short-term rapamycin therapy can maintain intestinal barrier function and regenerative capacity, and the efficacy is the same as long-term treatment in mice
Unlock the "Rapamycin Memory" password:
Enhance autophagy and enhance specific enzyme expression
The discovery that can be used briefly in early adulthood for life can be said to provide a new avenue for the practical anti-aging application of rapamycin. So, why can the short-term use of rapamycin form a long-term effect, and what are the key regulators?
Using specific Drosophila models, the researchers first ruled out the direct target ribosome protein S6K downstream of the mTOR pathway[10] and found that even overexpression of the S6K protein did not activate mTORC1 (one of the mTOR complexes characterized by the inclusion of protein Raptor rather than Riccitor), affecting the long-term efficacy of rapamycin after transient use.
Next, the scholars turned their attention to another key factor in the mTOR pathway, autophagy, and this time they found that even 10 days after stopping the drug (rapamycin was used for 15 days), the flies maintained a high autophagy flux in the intestines, and the use of rapamycin for short periods continued to activate the autophagy process.
Note: Short-term rapamycin therapy induces persistent autophagic activation
Moreover, when the autophagy process of intestinal cells is artificially blocked, regardless of short-term use or chronic administration, the aging improvement effects such as rapamycin that once extended life and strengthened the intestinal barrier no longer exist, and at the same time, the "rapamycin memory" was completely eliminated.
Note: Drosophila whose autophagy process was eliminated were not able to benefit from the use of rapamycin compared to the control group
Further proteomic analysis eventually revealed another key factor in "rapamycin memory". The transient use of rapamycin in early adulthood has led to long-term significant changes in the proteome of Drosophila's intestine, in which proteins involved in carbohydrate and hexobolic metabolism are highly enriched, especially α-mannitosidase V (LManV) in lysosomals.
Note: Rapamycin induces significant changes in the proteome in the intestine of Drosophila
This key enzyme, present in lysosomals that regulates the sugar degradation pathway [11], synergizes autophagy and together promotes the secretion of lysozymes [12, 13], improving the characteristics of intestinal aging.
Note: A sustained increase in LManV induces elevated autophagy and lasting improvement in intestinal health after brief rapamycin therapy
At this point, the mystery of "rapamycin memory" was finally solved: the body's brief use of rapamycin in early adulthood can activate the autophagy of intestinal cells in the body for a long time, and increase the expression of α-mannosease V in lysosomes for a long time, which ultimately improves the structure and function of the aging intestine, and plays the same life-prolonging effect as long-term use of drugs.
Time Pie reviews
"Short-term use, long-term efficacy", this discovery alone is enough to make people excited, and compared with long-term use, the two indiscriminate improvement of efficacy, but also eye-catching, if you contact rapamycin such as long-term use of drugs that may have certain health risks, the discovery of this study is more precious. Whether the scientific laws obtained in these model organisms can ultimately guide human medication may be known to us in human clinical trials in the near future.
The study was led by Professor Linda Partridge of the Max Planck Institute for The Biology of Aging and the Institute of Healthy Ageing in the Department of Genetics, Evolution and Environment at University College London, with Paula Juricic as the first author and Chinese scholar Lu Jiongming, the author of the first issue of Nature Aging, also on the list of authors.
Author comments
Lu Jiongming
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He is currently working as a postdoctoral fellow at the Max Planck Institute for Aging in Germany, under the tutelage of Professor Linda Partridge, director of the institute and vice president of the Royal Society, focusing on nutrition and aging.
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The study greatly expanded the understanding of the role of rapamycin as a "life extender" at different ages. It has a more sustained effect on healthy longevity in both old age and early adulthood than dietary restrictions. At the same time, we should point out that the theoretical guiding significance of the study is far greater than its specific practical significance. Because the use of healthy aging interventions in early adulthood (such as rapamycin) is not encouraged in the field of aging research. However, this study tells us very clearly that anti-aging should be done sooner rather than later, the sooner the better, and that you may get unexpected long-term health results.
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