A Mitochondrial Signal of Sarcopenia and Frailty Found in Small Extracellular Vesicles

Much of the signaling that passes between cells is carried in extracellular vesicles, small membrane-wrapped packages of molecules. There are numerous classes of such vesicle, varying in size, such as microvesicles and exosomes. The study of vesicles has expanded considerably in recent years, as they are much easier to work with than cells, and their use is applicable to many therapeutic goals.

For example, most cell therapies presently in use produce their benefits via the signaling that is generated by transplanted cells in the short period of time before they die. Cells can largely be replaced with extracellular vesicles in this scenario, leading to a much simpler logistic chain for the therapy. Further, extracellular vesicles can be engineered to carry specific molecules into cells, a form of vector that is easier to manufacture and manage than many of the other present options.

Diagnostics and metrics may also benefit considerably from a closer look at extracellular vesicles. Vesicles are present in blood samples, and their contents and composition is, in principle, a reflection of the state of health and aging. Senescent cells, for example, produce quite a different mix of vesicles and vesicle contents in comparison to normal cells. In the same way that biomarkers are constructed from DNA methylation and protein levels, extracellular vesicle analysis may present another path to assays that can quantitatively assess the progression of aging and disease.

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

Advancing age is associated with declining muscle mass, function, and strength, a condition referred to as sarcopenia which increases the risk of incurring negative health-related outcomes. No effective pharmacological treatments are currently available to prevent, delay, or treat sarcopenia, which is mostly due to the incomplete knowledge of the underlying pathophysiology. To further complicate the matter, at the clinical level, sarcopenia shows remarkable overlap with frailty, a "multidimensional syndrome characterized by a decrease in physiological reserve and reduced resistance to stressors", often envisioned as a pre-disability condition. Hence, the two conditions have been merged into a new entity, referred to as physical frailty and sarcopenia (PF&S).

Mitochondrial dysfunction and sterile inflammation are invoked among the pathogenic factors of PF&S. Derangements at different levels of the mitochondrial quality control machinery have been reported in older adults with PF&S. However, whether and how cell-based alterations may spread at the systemic level and impact muscle homeostasis is presently unknown. One of the mechanisms by which cells communicate with each other involves a conserved delivery system based on the generation and release of extracellular vesicles (EVs). This shuttle system also contributes to degradative pathways responsible for eliminating oxidized cell components, including mitochondria, by establishing inter-organelle contact sites. As such, the generation and release of mitochondrial-derived vesicles (MDVs) may represent a complement to mitochondrial quality control systems.

Cell-free mitochondrial DNA (mtDNA) has been identified among the molecules released within exosomes that may act as damage-associated molecular patterns (DAMPs). However, whether and how this mechanism is in place in the setting of PF&S is unexplored. In the present study, we purified small extracellular vesicles (sEVs) from older adults with and without PF&S, quantified their amount, and characterized their content for the presence of mitochondrial components. Our results show a greater amount of sEVs in serum of PF&S participants compared with non-PF&S controls. A lower protein expression of CD9 and CD63 was found in the exosome fraction purified from participants with PF&S. These observations are in keeping with the heterogenous composition of exosomes themselves, likely reflecting a different vesicle trafficking regulation.

Lower levels of the mitochondrial components ATP5A (complex V), NDUFS3 (complex I), and SDHB (complex II) were found in participants with PF&S. With the intent of preserving mitochondrial homeostasis, mitochondrial hyper-fission segregates severely damaged or unnecessary organelles that are subsequently disposed via mitophagy. However, mitochondrial-lysosomal crosstalk may dispose mildly oxidized mitochondria via MDV release. Such a mechanism may therefore restore mitochondrial homeostasis before whole-sale organelle degradation is triggered. Though, in the case of defective mitophagy or disruption of the mitochondrial-lysosomal axis, accrual of damaged mitochondria, misfolded proteins, and lipofuscin may occur as a result of inefficient cellular quality control. Therefore, the increased sEV secretion in participants with PF&S might reflect the cell's attempt to extrude dysfunctional mitochondria. However, the reduced secretion of MDV in the same participant group may indicate that mitochondrial quality control is impaired or that the damage to mitochondria is too severe to be disposed via MDVs.


So does this mean we could have an effective treatment for sarcopenia within 10 years? That'd be great as I would be 70 years old then and really, that would suck trying to minimize muscle loss while fighting the aging process:(

Posted by: Robert at May 7th, 2020 5:29 PM

I'm confused, is having exosomes injected as a general anti aging therapy a good thing or a bad thing? This article seems to imply frail people have MORE extracellular vesicles ( exosomes) floating around than healthy people do.

Posted by: August33 at May 7th, 2020 9:07 PM

As I understand it,
The article says that old people have different exosomes. And they might be useful diagnostic markers.

From other studies we know that some of the exosomes have signaling functions, and in case of extracellular mitochondria probably can deliver functioning organelles to enhance the existing cells.

It is assumed (not by the article itself) also that some of the said signaling is pro-inflammatiry or otherwise harmful in older organisms. There are many unknowns and the science or extracellular vesicles is pretty young (since mid oughs) but there are very promising studies. Of course, it might take a decade before we have level ii and III clinical studies.

Posted by: Cuberat at May 7th, 2020 10:43 PM

It appears really to depend on the cargo carried by the exosome, which itself appears to change with age. Empty liponanovesicles are themselves mildly antiinflammatory hence used in some sports gels. Once loaded, and the vesicle can be loaded with any number of molecules either endogenously generated or put in artificially for use therapeutically, exosomes can become very useful diagnostically or in treatment. This is very much an expanding area.

The idea of using exosomes as a biomarker for ageing is very interesting. Certainly would be a shortcut

Posted by: JLH at May 8th, 2020 4:54 AM
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