Once upon a time, the life process of all things was seen as a procedural feast, aging was the last gift before its end, and everything that had been choreographed before the opening was almost impossible to intervene.
However, with the strong intervention of cutting-edge medical technology, we realized that perhaps organisms can be rewritten, overwritten, and exported in the same way that computer code runs, and the trajectory of life can be changed to some extent.
Thanks to the painstaking exploration of scholars in the field, epigenetic reprogramming, and senescent cell removal, these stories that were once thought to be fantastic are gradually coming true. On 22 January, researchers from Yale-Nugget University College announced that transient cell reprogramming or senescent cell clearance extended the lifespan of fruit flies, and that the combination of the two was more effective, up to 31.6% longer [1].
Note: The study is currently being published in preprint on the bioRxiv platform
May the silver be broken to resist decay,
Bezos is optimistic about reprogramming and senescent cell scavenging techniques
To ask what topics in the field of aging research in the first half of 2022 are the hottest, in Jiang Cha's view, epigenetic reprogramming must occupy a place.
I don't know if it is related to the "banknote ability", since the world's richest man Bezos founded the "strongest anti-aging company in history" Altos Lab, with a huge amount of $3 billion into the game, and announced that epigenetic reprogramming as the current direction, the small partners of the time school content department every time collect the latest research results in the field, reprogramming related reports can be described as common and new, endless, more to ... We really can't write it...
Table Note: Incomplete statistics for 2022 epigenetic reprogramming studies
(As of writing)
Not only does the scope of targeting organs gradually expand (including the heart, liver, skin, etc.), the reprogramming technology has gradually evolved from the initial simple introduction of "mountain factors" (four transcription factors, OKSM: Oct4, Sox2, Klf4, and cMyc) to achieve the reversal of mature somatic cells into pluripotent stem cells [13, 14], and has evolved to control transcription factor expression.
As a super-rich man with a special love for anti-aging business, in fact, as early as 2016, Bezos invested in an anti-aging company called Unity Biotechnology, mainly engaged in the research and development of Senolytics (senescent cell scavengers). Unfortunately, even if it is not bad money, Unity still suffered "Waterloo" last year, the star product UBX0101 Phase II clinical failure, drug development was forced to terminate.
In a short period of time, it seems that Bezos has spent some unjust money, but in fact, his layout is really not bad at all. As a leader in the industry, Senolytics therapy has recently made new breakthroughs, whether it is reincarnated with immune cells [18] or taking natural substances such as PCC1 (proanthocyanidin C1) [19], as long as the accumulated senescent cells in the body are removed, the myth of longevity will come true, and when the effect is good, it can even extend life by 64.2% [19].
On December 7, 2021, the authoritative academic journal Nature Metabolism published a breakthrough study by mainland scholars
In Bezos's "immortality" territory, epigenetic reprogramming "symptomatic" stem cells depleted, Senolytics therapy "bites" cell aging, for the classic nine major aging logos [20], he has easily occupied the two, let's make a bold guess, relying on this "return to youth" magic, Bezos to ascend to the world's richest throne is not known.
Maintain intestinal stem cells, alter gene expression,
Reprogramming in conjunction with Senolytics is starting to see great results
If the two major youth magic weapons reprogramming and Senolytics, if they are two-pronged, can they collide with a more brilliant spark? Scientists think so, and so do.
Using Drosophila as a test subject, the researchers successfully reprogrammed intestinal cells by introducing "Mountain Factor" (OKSM). However, in order to remove senescent cells, they did not choose common substances such as dasatinib and quercetin, but used FOXO4-DRI, a polypeptide that specifically regulates the FOXO-p53 axis [21]. This polypeptide competes with p53 for the FOXO4 protein binding site, interferes with the formation of the FOXO4-p53 complex, promotes the transfer of the p53 protein to senescent cells, and induces mitochondrial-dependent apoptosis [22, 23].
After some time, scholars found that although reprogramming alone or Senolytics treatment could improve the differentiation potential of intestinal cells, it also greatly accelerated the renewal cycle of intestinal epithelial cells, bringing about possible stem cell depletion problems, and the combination of the two improved this problem to some extent.
Note: Reprogramming and senescent cell clearance at different points in time have led to an increase in intestinal stem cell proliferation
Subsequently, further gene expression analysis showed significant changes in genes associated with amino acid metabolism, cell cycle regulation, and specific developmental signaling pathways (e.g., WNT pathways associated with cell senescence and aging diseases) compared with wild-type drosophila, which underwent reprogramming or senescent cell clearance[24].
Unexpectedly, however, the combination therapy of reprogramming and Senolytics has not been found to have a unique gene expression pattern, and scholars speculate that perhaps the gain effect of the two is obtained through the superposition of effects of their respective pathways.
Note: Changes in gene expression in the intestines of Drosophila under different interventions
Extend life by 31.6%! The two-pronged approach works wonders
Although these measures have improved the aging of cells in Drosophila, continuous expression of OKSM factor is not a good choice (greatly increasing the risk of cell carcinogenesis [17]), and Professor James Kirkland, known as the father of Senolytics, has stated: "The formation of senescent cells takes 10 days to 6 weeks, and it is enough to administer it every half a month or month [25]. ”
So the researchers optimized the protocol, performed "multiple transient reprogramming or/and Senolytics," and documented differences in fruit fly lifespans over different interventions. Compared with continuous cell reprogramming and removal of senescent cells, the multiple cycle strategy clearly has a much better outcome: fruit flies have significantly reduced mortality and a significant increase in the length of lifespan, with the best effect of circulating for 12 hours twice a week.
In the 12-hour cyclic expression test group, the data also showed that the combination of reprogramming and Senolytics significantly extended the median lifespan (to reflect the average lifespan of the population) and the maximum lifespan of Drosophila: compared with the control group, the combined intervention had an unexpectedly good effect of 31.6% life extension!
Note: Multiple transient reprogramming or removal of senescent cells can extend the lifespan of drosophila, but the combination of the two works best
For this surprise finding, scholars speculate that the combination of the two interventions can further reduce the risk of fruit fly death early in life and help them live longer.
Note: Instantaneous reprogramming in conjunction with Senolytics is best for reducing death early in life and maintaining survival
Time Pie reviews
With the advancement of research in the field of aging, more and more potential targets are explored, and many related interventions are derived, and there are more choices, and we will naturally have such a problem: between different interventions, is it less is more (less is more), or 1+1>2? In the author's opinion, the answer to this question will be different from time to time, like today's study, although instantaneous reprogramming combined with senescent cell clearance to achieve additional gain effects, but if you change another measure, it may not be able to harvest the positive results of doubling the efficacy, or rely on practice to test.
Speaking of the study shared today, although the combination of reprogramming technology and senescent cell clearance has achieved initial results, it also provides a new intervention idea in the future, but as far as the research itself is concerned, ginger tea I still have to raise some doubts.
For example, the experiment chose to selectively remove aging cells by interfering with FOXO4-p53 binding, but as an important regulatory axis in vivo, will direct intervention affect the expression of other associated signaling pathways and introduce interference factors to the experiment itself? For example, the activated p53 protein significantly affects the development of stem cells in vivo [26], so will the reprogramming of somatic cells in this study be affected by this, resulting in some results bias? Perhaps, we need to do some more exploration to finalize that instantaneous reprogramming and Senolytics are really "good couples".
The study was led by Professor Nicholas S. Tolwinski of the Yale-Nunus University College of Science, with Prameet Kaur as the first author. The research was supported by the Ministry of Education of Singapore, the National University of Singapore, and yale-NUS College.
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