June 14th, 2024 | 6:49

Bizkaia

Rejuvenation the next incredible advance

Jesus Carames

May 22, 2024 | 8:30 a.m.

Exosomes and their potential for rejuvenation

In the first half of the 21st century, the extracellular vesicles (EVs) have captured the attention of the scientific community. Think of them as natural lipid nanoparticles or endogenous viruses. These vesicles transmit information throughout the body and are small enough to be exhaled and carry out interindividual and interspecies communications. Encapsulated in fats that facilitate their entry into cells, EVs contain proteins, RNA, DNA and lipids, all of which carry information. EVs represent a universal biological language, a barely explored means of communication.

Recent research and its implications

An extraordinary paper was published last week demonstrating the rejuvenating potential of EVs from very young animals injected into old animals. The authors come from the Smidt Heart Institute in Los Angeles and their primary field is cardiology, not gerontology, so they focus on heart-derived EVs and their heart-rejuvenating benefits. However, the observed benefits go beyond the heart and include life extension in rodents and rejuvenation of human cells from rat-derived EVs.

This research must be understood in light of the parabiosis experiments carried out by the Conboys, Rando and others, and in particular in relation to Harold Katcher's rejuvenation technology. Katcher's blood-derived rejuvenation serum is called E5, and Akshay Sanghavi, Harold's partner, informed me about this publication. According to Akshay, E5 includes EVs in addition to a wide range of proteins. The current article suggests the possibility that it is solely EVs that are responsible for the E5's benefits. In fact, the authors repeated their experiments with (1) whole blood plasma, (2) plasma without EVs, and (3) only EVs. They found rejuvenating effects associated with whole plasma and with EVs alone, but not with plasma without EVs. If this is confirmed, it is the most important finding of the study. Akshay mentioned that EVs are easier and cheaper to isolate than the molecular constituents of E5 (proteins).

Potential and applications of exosomes

For everyone involved in parabiosis and plasma exchange research, I suggest that it be an immediate priority to replicate Smidt's findings that all the rejuvenating power of young blood is found in EVs. The Conboys might be interested in investigating whether the pro-aging effect of old-to-young plasma infusions is also an effect of EVs.

The most advanced EV separation technique for large volumes is called acoustic nanofilter. Ultrasonic pressure can be adjusted to separate a particle of a particular size in a specially designed medium. If I were advising Yuvan, I would suggest that they develop expertise in acoustic nanofiltration as soon as possible as a next-generation replacement for their plasma fractionation technology.

Exosomes are the most common type of EVs and probably the most relevant for applications in aging. They appear to be a general vehicle for intercellular and interindividual communication. The study of exosomes is in its infancy, but it is already known that exosomes are labeled in a way that recipient cells can distinguish and choose which exosomes to pick up and "read the message."

One area of ​​exosome activity that has been studied is the communication of antigens to the immune system. A particular type of exosome includes foreign proteins that are potential invaders and are shared not only within the body but also through the air. When you think about herd immunity, consider not only the spread of diseases by people, but also the information about what diseases are in the air that are transmitted in social interactions.

During COVID-19 lockdowns, one consequence was preventing uninfected people from learning and mounting an immune response to the virus through the exchange of exosomes.

Recent research and results

The rejuvenating effects of young extracellular vesicles in aged rats and in cellular models of human senescence were studied by Grigorian-Shamagian et al. in Nature Scientific Reports, with Eduardo Marbán as lead author.

The authors extracted EVs from neonatal rat hearts and applied them to cell cultures and injected them into old rats (22 months). They used complete plasma and plasma without EVs as controls, establishing that it is the EVs that carry the benefits. They extracted corresponding EVs from neonatal human cardiac cells and applied them to human cell cultures.

They found electrocardiogram evidence showing that the hearts worked better in the treated animals. Insulin resistance and blood sugar were reduced. Exercise resistance increased in treated animals, while it progressively decreased in controls. They found that tissue flexibility was restored to youthful levels. Hearts, lungs, muscles and kidneys improved function in the treated rats. The tissue samples (muscle and heart) looked better in ways I don't pretend to understand.

Old rats were treated with four monthly infusions, then maintained for a further 16 weeks before all animals were sacrificed. During those 16 weeks, 6 of 14 control rats and only 3 of 36 treated rats died. My calculation (Fisher's exact test) indicates a life extension at the 99% confidence level.

Tests were performed on two human cell cultures: fibroblasts from middle-aged donors treated with human EVs and cardiac cells treated with rat EVs. Fibroblasts increased their reproductive capacity, decreased apoptosis and showed a more youthful transcriptome. Similarly, cardiac cells exhibited better self-assembly and a more youthful transcriptome.

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