Ceramides in Extracellular Vesicles Increase with Age and Induce Cellular Senescence

Much of the signaling that passes between cells travels via varieties of extracellular vesicle, tiny membrane-bound packages that contain a wide variety of presently poorly cataloged molecules. The varieties of vesicle are also poorly catalogued, and are at present given a loose taxonomy based on size. No doubt there are many subtypes within any given size category, depending on circumstance and mechanism, with the contents varying characteristically by subtype. Nothing is simple in cellular biology.

Vesicles are currently a subject of growing interest in many fields of medical research. In regenerative medicine, for example, it is hoped that harvesting vesicles from stem cells in culture and delivering them to patients can replicate much of the beneficial effects of stem cell therapies, but at a lower cost and with fewer complicating factors. Vesicles should not provoke immune reactions, for example, and thus do not require patient-matched or otherwise carefully chosen and engineered cells. In most cell therapies used to date, the transplanted cells die out quite rapidly. Beneficial outcomes result from the signals that they secrete, inducing changes in the native cell behavior. Thus why not just stop using the cells for this class of treatment?

Another area of interest is the way in which senescent cells manage to wreak havoc in tissues even when they are present in small numbers. They generate a potent mix of signals that creates chronic inflammation, destructively remodels the surrounding extracellular matrix, and alters the behavior of other cells for the worse, directly or indirectly. Moreover, senescent cells encourage other cells to become senescent. Therefore we should expect to see intracellular signals in the aged environment that can induce senescence. Those are starting to be discovered: versican is one example, to go along with the very long chain ceramides noted in today's paper.

The vesicles containing these molecules may be secreted by senescent cells. Or they may be generated in other ways, implying that the state of senescence is more readily achieved in older, damaged tissues independently of existing senescent cells. Or both. Knowing more about these mechanisms will inform the appropriate use of senolytic drugs to remove senescent cells in the years to come: if senescence occurs more often in old tissues, then senolytic drugs should be used more often rather than less often by older people. If, on the other hand, new senescence is largely driven by existing senescence, then much more infrequent use is all that is needed.

Very Long-Chain C24:1 Ceramide Is Increased in Serum Extracellular Vesicles with Aging and Can Induce Senescence in Bone-Derived Mesenchymal Stem Cells

Emerging patterns of disease progression suggest that degenerative changes in one organ or system are likely to contribute to degenerative changes in other organs and systems. For example, reductions in lean mass and bone loss have both been observed to precede the age-related development of cognitive impairment and Alzheimer's disease. Thus, cross-talk among various cells, tissues and organs may underlie non-autonomous aging in different cell and tissue populations. This concept is supported by studies in which young cells exposed to aged serum exhibited changes characteristic of older cells.

A barrier to progress in correcting the problem of age-related tissue dysfunction is the poor understanding of the molecular and cellular mechanisms underlying these non-autonomous cellular communication pathways. Exosomes are small (40-150 nm) and microvesicles are larger (more than 100 nm) membrane-derived structures that are released into the extracellular space by a variety of cell types. These membrane-bound extracellular vesicles (EVs) can transport proteins, lipids, and mRNAs between cells, delivering these molecules to target cells. EVs are highly enriched in the sphingolipid ceramide, which is known to promote cell senescence and apoptosis. In addition, EVs play a key role in a number of pathologies in vivo such as cancer metastasis and neurodegenerative disease. Thus, EV-derived ceramide is one potential aging factor that may promote degeneration in multiple organs and tissues.

We investigated the ceramide profile of serum exosomes from young (24-40 years) and older (75-90 years) women and young (6-10 years) and older (25-30 years) rhesus macaques to define the role of circulating ceramides in the aging process. EVs were isolated using size-exclusion chromatography and specific ceramide species were identified with lipidomic analysis. Results show a significant increase in the average amount of C24:1 ceramide in EVs from older women (15.4 pmol/sample) compared to those from younger women (3.8 pmol/sample). Results were similar in non-human primate serum samples with increased amounts of C24:1 ceramide (9.3 pmol/sample) in older monkeys compared to the younger monkeys (1.8 pmol/sample).

In vitro studies showed that primary bone-derived mesenchymal stem cells (BMSCs) readily endocytose serum EVs, and serum EVs loaded with C24:1 ceramide can induce BMSC senescence. Elevated ceramide levels have been associated with poor cardiovascular health and memory impairment in older adults. Our data suggest that circulating EVs carrying C24:1 ceramide may contribute directly to cell non-autonomous aging.


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