Fight Aging!

Exosomes, or extracellular vesicles, are one of the modes by which cells communicate. They are tiny membrane-wrapped packages of signal molecules, constantly secreted and ingested by any population of cells - though note that exosomes are, confusingly, not the same as the larger microvesicles, also membrane-wrapped particles that can carry molecules between cells. Nothing to do with cells is simple or straightforward. In recent years, the falling cost of core biotechnologies has enabled an increasing number of researchers to investigate the contents of exosomes and relate them to specific changes in cellular behavior.

To pick a few examples, exosome signaling is important in the way in which excess fat tissue produces inflammation and metabolic disruption. Researchers are also digging through exosome contents in search of the signals that allow stem cell transplants to produce beneficial effects - it will probably be much more efficient just to deliver the signals themselves. Some groups are adopting an intermediary approach of harvesting and delivering exosomes rather than cells. The specific contents of exosomes definitely change with age, though the details differ for every cell population and process of interest. Senescent cells are one of the root causes of aging, and they produce harmful effects in surrounding cells and tissue structures through inflammatory and other signaling processes - the senescence-associated secretory phenotype. Their exosomes are quite different from those of normal cells, which we might expect to be the case.

The two open access papers I'll point out today touch on the contents of exosomes in a different context, that of neurodegenerative conditions and the age-related decline in cognitive function. These progressive failure modes are all very complex in their biochemistry, largely because the brain is very complex. Simple root causes give rise to end results that are as complex as the surrounding system. Most neurodegenerative conditions have numerous contributing causes and later consequences, tangled up into an unclear mix of layers of only partially understood cause and effect. Changes in cell signaling are certain in there somewhere, along with inflammation, failure of cell maintenance processes, immune system disarray, and growing deposits of uncleared metabolic waste.

Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal

Exosome discovery has exhibited enormous growth over the past three decades. Once known primarily for their role in eliminating excessive cellular proteins and undesirable molecules, exosomes are now known to be required for many physiological processes, such as, the maintenance of normal physiological functions and cell-to-cell communication, and to play important roles in the progression of diseases, such as, cancer and neurodegenerative diseases. Their involvement in neurodegenerative disease progression are attributed to their abilities to transfer biomolecules and pathogenic entities across biological barriers. Furthermore, their abilities to transport proteins and nucleic acids (siRNA, miRNA) have been exploited for the delivery of drugs and other encapsidated biomolecules.

Exosome secretion has been reported for a number of cells in the nervous system. Exosomes have a great effect on cell-to-cell communication, due to: (1) interactions between topical proteins and receptors on target cells; and (2) proteolysis of their cargoes and internalizations of their contents via endocytosis. Furthermore, they allow intercellular communications, via the transport of protein and nucleic acid entities under both normal and diseased states, which suggests exosomes participate in development, cellular function and associated pathologies.

Aggregation of proteins is a hallmark of neurodegenerative diseases, and their accumulations in the central nervous system hinder mitochondrial and proteosomal functions, axonal transport and synaptic transmission and enhance endoplasmic reticulum stress. The ability of exosomes to carry misfolded or aggregated proteins enhances the progression of neurodegenerative diseases. In line with the prion-like spreading hypothesis, their implications in the transmission of infectious particles - prions, amyloid precursor protein, α-synuclein, and superoxide dismutase 1 - between cells in the nervous system are currently being explored.

miRNA in Circulating Microvesicles as Biomarkers for Age-Related Cognitive Decline

Neuroimaging, genetics, and circulating biomarkers are being developed to differentiate normal aging from diseases that affect cognition. While genetic markers may suggest susceptibility to disease, these gene markers are not diagnostic. Similarly, more accurate techniques for identifying pathology, such as positron emission computed tomography, are expensive and may miss early diagnosis, which is critical for treatment. Due to the relative ease of collecting blood, blood based biomarkers could provide a simple and relatively inexpensive means for tracking the progression of cognitive decline and effectiveness of treatments, as well as providing information on mechanism for cognitive impairment. Recent research suggests that non-coding RNAs found in the circulation can act as biomarkers for diseases of aging including cancer, cardiovascular and neurodegenerative disease.

Within the circulation, microRNAs (miRNAs) can be found attached to proteins or in extracellular vesicles, small (50 nm to 1 μm) vesicles of endocytic origin that are released from cells into the extracellular environment. Some (e.g., exosomes) are able to cross membranes (e.g., blood-brain barrier) and can be detected in bodily fluids including serum, urine, and saliva. In this way, microvesicles can provide intercellular and inter-organ communication by delivery of miRNAs to influence transcription and altering genetic processes. Indeed, studies suggest that circulating levels of miRNAs in plasma or in exosomes may be able to identify Alzheimer's disease.

In the current study, we describe miRNAs associated with extracellular microvesicles from plasma as possible biomarkers of cognitive decline during aging. Community dwelling older individuals from the North Florida region were examined for health status and a comprehensive neuropsychological battery, including the Montreal Cognitive Assessment (MoCA), was performed on each participant. A subpopulation (58 females and 39 males) met the criteria for age (60-89) and no evidence of mild cognitive impairment. Despite the stringent criteria for participation, MoCA scores were negatively correlated within the limited age range.

A decrease in MoCA score was associated with increased expression of several miRNAs. The rise in expression of brain selective miRNA could signify conditions in the brain, such as aberrant neural activity, damage, or disease, that result in increased synthesis or release from the brain and a decline in function. In addition, it is possible that highly expressed miRNA are delivered to the brain from the circulation, to influence brain function. The miRNA biomarkers from plasma microvesicle exhibited an expression profile, which was different from that previously described for Alzheimer's disease, suggesting that these biomarkers may be specific to cognitive decline in normal aging.