Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, function in cell-to-cell communication through delivery of proteins, lipids and microRNAs to target cells via endocytosis and membrane fusion. These vesicles are enriched in ceramide, a sphingolipid associated with the promotion of cell senescence and apoptosis. We investigated the ceramide profile of serum exosomes from young (24–40 yrs.) and older (75–90 yrs.) women and young (6–10 yrs.) and older (25–30 yrs.) rhesus macaques to define the role of circulating ceramides in the aging process. EVs were isolated using size-exclusion chromatography. Proteomic analysis was used to validate known exosome markers from Exocarta and nanoparticle tracking analysis used to characterize particle size and concentration. 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.
Highlights
The public health burden of age-related diseases is increasing rapidly as the aging population grows globally
Extracellular vesicles (EVs) are highly enriched in the sphingolipid ceramide [8,9], which is known to promote cell senescence and apoptosis [10,11,12,13]
[8,9], which can itself promote cell senescence and apoptosis. These findings are clinically important since elevated key roles in a number of pathologies in vivo such as cancer metastasis [14,15] and neurodegenerative promote cell senescence and apoptosis
Summary
The public health burden of age-related diseases is increasing rapidly as the aging population grows globally. The care provided to those with Alzheimer’s disease (AD) in 2016 reached an estimated economic value of $221.3 billion, and the healthcare cost of osteoporotic fractures in the US was estimated at $14 billion. Reductions in lean mass and bone loss have both been observed to precede the age-related. 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 [3,4]
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